Document 3Qw8VLb2nD5o6jpbgmZEkbpLx

/1 s5 11 5 8j DOW OOVV 669857 HERBICIDE FQR THE CONTROL OF TREES, BRUSH AND BROADLEAF WEEDS Low-Volatile Brush and Weed Herbicide for Industrial Vegetation Control, Fencerows, and Rangeland ACTIVE INGREDIENT 2 -1 $ 'Tnc Mo ro phe noi yac eiic A o d Propylene Glycol Butyl Ether E l l e ' * .............................................. . . .. 63 3s# INERT I N G R E D I E N T S ...................................................................... 2 4 S Tr<c^lorophnoiYacet>c Acid Equivalent -- 4S 0s 4 Pounds per Gallon - 30 8 * E R A R e g i it 'i J io n No 464-705 E P A 'cs l <64 Ml-' P RE C A U C IO N AL USUARIO Si usted no lee mgies no use esie producto hasta qu la etiqueta I t haya uda eipncaaa ampliamente T R A N S L A T I O N |TO THE USER II you cannoi read English cyj nn| use lh>s produrt until the lapel has Peen luiiy espiamcd to you ) ' 18.93 L / 5 gal '<>-1064 PRINTED IN U .S .A . IN JANUARY, 1980. PLACES SPECIMEN LABEL 86-1064 PRINTED IN SEPTEMBER, 1979. -- uLSCARD PREVIOUS SPECIMEN LABELS. r - m I r r -V I nr>rtr>r\n aaA n jV Insert 1 Insert 2 <> ESTERON 245 HERBICIDE Contains Propylene Glycol Butyl Ether Esters of 2,4,6*T * Acid Equivalent: 4 Pounds per Gallon DIRECTIONS FOR USE CSICRON M ( b u * * le c amwin ded loa u ta w w ril w jiw u n ce n ita l, I N h n b 4 cndete htilMCMvi and oo4y pitAh mdw*#ig toen J.4-D I M KMC4i m al. btocfc gutn. b iiw tto l, gtourtelmrry. hewlhwn, Nhmam ata. ma^a. mtoqwta, ota. eaayaoranga. primerie. ferian y. ftterilypaa caela. udboy. itaionria**y. >*a>gum. M toeckbatty. wdd aaa, and t < a h pacte 4 Rdma. D a M i nip ly CSTCHON M arfiara eptay M i m ay aa U cl naatby I.4 .IT auto epteto tia y i m aS a l l il t i l l plaal* My i ia in a la a S ala Ia im M fw IrHfaUaw 1 doma de wrpaaaa R aed t M m N Uaa Procoutatom taran an tato tabal m atta Mia I l/2g*enao<C S K R O N 246m 100M ona 0 il ftru a h o l maga danari to 4 lo 6 M ai agh ma u ria up lo 180 patena M apra m u tu i pai aca. S lum p Treatm ent W hwe gre m iti te me* d u n 6 w P te n ta , c u i ri ctoaa 10 dm fo u n d and NMiy dm lin N y c u i aiumpa r i nuda u n iti ) patena ed CSICHON 246 in 100 patena i l p m i* 4 g rito n a l e fo ri. tm iadihotougM y io m o ri laam iarri pacma. uaa 4 patena I C SIIH O N 246 m 100 patena I l puri m 3 adonti o l ed. W am wouphtveeeeoeeodbeifc aem adaecuiaielecea rtm irm anaaptuyuipw n ld un down et tu o ff lo tea ground te a anowcaatoa O tri e> rough bark ipw a dwa aptav etera dmn ounp e* am eetfi ba*k. Appi a l an lane, mctodmg wmaar m onde, eacapl a te i ma. anew e* maw* piovani aptaymp io dm ptound b*m. Seat raatea a ebtaumd on Itaardy c u i e tte te tw o melma ctoaa o* lu p a i. M aprilacovaiapano*m aaqw uaal*om S d U p a te n a p ri aera dapatenp PREPARINO THE SPRAY Uaa a**ty 4 d a d . M a. I M o. > te e !o d o * U araai wtea*e a te raaom OH <pt T * Add CSTtRON 346 te dm rtpuod amemd a l e ri m dm apra te te or riarnp la te end mia dmtaupW . Trite m u ta r* can te moda M any tana dolere ac tu a l uaa and no taparatem H o u o . Oo no te i any woaa*. e* o4 mata* m uiura prava pa* te a dm ESTIRON MB a* im p dm fcnm ted maM a . aa h ma le n a P* H a w S pray*- f i dm aptav te te about te d lu i rid i ctean mate, add dm amead am ouri of tS U II N 346 and compte! feteny dm la te Mm dwreupM and commua ayKauon udvte aptaym p Cauden: Boa N O T I ta perasaapl* d*t O d W ater M ie tu ta S p ra y*. O N W tu r M ie tu ta S pray: W lm n rigotoua a*UW on te uaad. I g r ite e t CSIEHON 346 m d n tu M y up le 10 paiono e< ed m 100 p a te n t od cp**V < *m iw i. fa , pramte dm IS T IH O N 346and d r i l aapaiala cem ainat De not atom u iy mate* o* n u a lu * coniam m p m atai te pa l m io dm IS T IH O N 34$ 01 dm p o n w . f d dm apra la te te o u l had M vrih m atet. dmn dowdy add ite ptatw a m riti con- bnuoua ayriauon and com piala fitenp dm te te mdh mate*. H dm piam te p u l m dm la te m idm ul any m alt, dm (te l m a lti addad moy form d a te "m va ri" tm a ttf in od muteion m tacri a d te tm id to btaak. A s an riam ata ptocadura, dm o4 may te added a llo t dm IS T IH O N 346 te m u d in dm m atet; b u l lupM y vipotoua wmchanicN ayiiauon ta q u rte and a pom om itan may ba lo tmud. Tim ptatm a m attm d a ptdatad. N O T !: C S IIH O N 346in m atet a t od mate* prava torm a an nmtetan. n o i a to ta won. and ta patauoti moy ia k * piaco wriaee ap*ay* a*o ap im iad confanouriy Moclmtwcal priaiion a tac emanandad - -, H IG H V O L U M I S P R A Y S S aaai H ath Trooam ont: fttu a h and atnaH waaa can bo conwoPad by aptaymp dm bacai patta o f M ira ti eterna and ara* P utea lo a height o l 13 lo 16 merma bom dm proundUrm O to a a e ta h e n o f 3 g rita rm o lfS U R O N 2 4 B in 1DDg rita r* I I pm *m 4 pedonai 0 ed. W rih emtam ramalam apacma. 4 pedona a l C S IIH O N 246 m 00 padana I I pm l m ] pedonai a l od. te e ffa c tta . Aa only dm bead potW on* o l dm tauab a* uaaiad on a apoi batte, dm loud amomw aptaiod pet act w ould not ba aapaclad w aacaod lOO pedona. Knapaack o pomar yjipanani may ba waod. ta rt cnm pten m oibnp oI dm indicated atoa te itecaaaaty. p a tiicu te tiy a t dm ground fena Trim tamaa aptaymp u n ii tun-dam n a t ru n -o ff M dm pround Una te o n r if dria DM o r tough b o ri roquriea M i aptdy Pmn young 01 em qpO A pf*. Lorn ptaaautaa at daaaabte dpp a may ta rn . tactadtap Sm mintat ta y d R . - a p i wtm n m m . me a t mate* piovani apteying to dm p ttu nd tem. O ften Id te y ld n apenaa and lid mp can bo t e n n i . D otm anl S m uri. Traal any rim a afa b ru te te dam rnnl and amai a l dm labapa Ima dropped Spray h o te l ba concanwaiad a l lh a bata oI atewm and m edditwn, dm uppar pana o l dm tema ahould.bo M o id ta a l prayed anougri le m ol dmm. ( M u raeiauctarm y apucma tu te aa sumac, gwannm on. aaaateaa te d M ila , ala apray dm ground atoa io con e l amad to o l tu ck ara hai may n o n p a y te f " F fiT Truaim arm . fa t b ig aaa. maria a amptehac* g a tfa 01 "ri4 T o I ovarlappinp * c u lt Mnptetety m ound dm baa aa ctoao lo Urn ground aa teaariria. Sptay dm h d iharowpto wamp a m uring e l > pteene o l C S IIH O N 346 m 100 padarm it/3 pm l in 1 peional d od S pot Fadepa Tram m u n i Oaa 1/4 pM e f CSTEHON 246 m 3 pedone e l m atet and apt*v to mot ad tedtepa- ahootc. ten and bark m rihoui tunoN LOW VO LUM E SPRAYS Apply tew veriwm aptaya cem auwig C S IIH O N 246 when to t apt m mad davalopadand piama a*a k u P ptom np. For bate ta a u rii on m oody apacma. aed tnomiwta hated bo uHictenl to ptom oia loriar grom lri Spraytnp d u rn g ptotong ad h o t. d*y n u id m t or a lte t iaavua have le a l dmu n a m d groan cotet and vapor may no pm* M tofactory conuol A pply lorn voritm a lp ta y l by ter or ground quiptnani otdy when apray d rill i not ba a problem - now uee ptacauriona. I m M liw w n a i U atag P ow m ad Hrm paach S p ta ya t - riba \ 1 /3 to 2 padotm o f C S IIH O N 246 w ith fu e l od or barooatm to maria 20 padotm e l tola aptay aorii ben A pply w rih a potlabte knapaack nwiM om at to a d a*datoltem t b ru te ttom c Irp u d rp dm re e l cedar. Good covetape o l dm tom cedar a oatenfad to i boat ruateu Hun mmtelotm M 1/4 to 1/3 Irito ld a to t b a il aptay tM inoiy and covQtapa For maaanum d rd i conuet uae a baaal m w tte a iia ch fim n i and do not n rate n u d a above dm hotuoni poem on A IH A m .C A TIO N FON B R U S H C O N H O L I Cotm ri ha Aptrctehrtalupanm anl Biafaon. you ta tu i lu iu im . . .. 9 0 Hanpa paomriaaa to beai im m H> w a tt and mad to t a waalman m uut a*aa ^ Oo n e l uaa barn aayboot lo ite aiapam lm ia prato toadptoducw onb datoad. M aopw ito; U4 I puri IS T IAON 246 prim /2 to padon o l od m enough mata* le marie 4 ptetene a i to ta l aptay pat acre Apply 40 u SO dayt afta t S tai teavae Send S h ta tto ty O te Uaa 1/2 to I pum i o IS T IH O N 346 prim 1 p o te i a od m neugh matar to maria 4 gritan <d lo tr i pt*v P act fe to a rri Ptaf bjef b Otee. Uaa 2 o u a iia o l IS tC H O N 346 prim I peden o f edm nouph mutar to a te a 4 to 6 gritona to tota aptay pa i era USE PRECAUTIONS N o ia : Oo net p ia i dauy atmwab on baatad aiaa mfan 6 a d Hot ppdcd- e lN fc& 9 n* 9 U * <n* * 1 a** mdun 2 m u ta i e t taughtat. urir---------- ^ AVD4 CONTACT W lT #2.H .6bS U S C IH l6M C N O fS AN O OTHCH * C X tllV lL t ll> O U H II^ n A N ) ^ - lS ltH N l. o a o p td i) ria ptanM. T hatatoam te n o i apply teP cdy lo a admambo p a tite .S.oAm*gaf.m, _nt_aa_m_me_ont.ioa.r.bi..l_o* _cUda.m.ri*.aTdcai.wtraalbo.bn,p.lani >uSecbaap.ctae..ote, rl.oite2..4i.te..6m.T,.vD_oog'aAtatob.tuoo-*. A }# H ^ r apraardmuaa * * * * * * te O T A f f i Y W THS T R M H V OF COTTON. SHAPES. TOBACCO. T S M A IO IS OR OTHER D C S |R A R ll L l f t J IA C IP T R U CROPS OR > fS 3 iy iM lU ttA H T ................. OO NOT IP IU V W H IN W H O 1 S U M fM O lO W M O I ftU ftC C P ttftU MinCROPS OH O R N A M IN TA1 PLANTS A V O ID SPRAY 'A p fW c tuona botata te mada erri wlm n dim a no h a iw d h o m apra * d i emcavar em aleu#nirim aelapa w Ach me n e i te mi Me. m aavuelv yuta auacaptato crepa durm p bote pom m y and domam penoda Uaa coarta apta lo mmunu a te d i am, under ari*a*M wearimt conte bona. U*m apra te ptela ma te d i a mate a* m m it e apra dw kenm p apana, N A IC O lllO i1. ma te weed w n ti tem produci b a d a tariu e n p apio te d i. d `N A L C O M O l Trademark a l N A iC Q O m nw rd C QHOUMO la u m n c N i - w m g u m * by km pm p dm apray boom aa low a potatola; by m te te p IS pteena or mm gI ap*ay pot a ct*, by uamp no m ot dmn IP pound p r i i u g ptaaama mari terga to optai ptoduem p n o tda hpa; by aptaymp teen wand roteedy aP te a pat how a te a * Do no apply math M a e cone lypa amacio ida to od M noirte a dm p duce a tom d*optai apta A C H lA L A m tC A T tO N -W d h auctah. (rid i can ba teaianad by apptymg a coatto apt*v ; by uamp no m ora dmn ID g o u tte apra p a ta a l dm m u ta ; by uamp M a g ii Waam n o iita duoctod rio p ri* Sacri, tey uamp a apt*v boom m tonga* dmn 1*4 ha mmg ip a n e t dm artexte. and by pymg etay udmn mmd vatocriy a tata dmn S mph OO NOT A m r HV AJHCHAFY W H IN A N A H I TKridPiH ATU AC H W (H SfO N CXISTS. Such contbwon b chaiactom ad by Mda e t no mmd and wMh m tom paiaiut tom ai m m dm ground dmn a l hghor b vab The u m e t a corrim ueua m oria coritm n a i e t n a ti aria o l appfacauon m auggaeiad le t r i t i l i totee M n and vatocriy o l ad m ovam arri, and lo mtocata a tem pataM a Mmmn by iayutm p et dm tm aria A i ivph totnpotalut labov* t6 wF l vapo>a Itom dim produci tney mpua wacapii Ma piani ytom m p nearby D o m lu M n a r rma* a p itd u w u ( u iu r m a m o u trii 0 d io ha*b>c*da m dm a o i nmv w n Do n o i uaa a toutid dm hom o, lacraawon m uto 01 a u ite t in Thm produci m e w lH K aapouioM taaa. twaam a. and p o rte Do mi con tananai m aiat by ctaatvnp e t u q u **neni e t dripuaa e t maata* Do n o i <ottanvnm n ya iio n d rich a t o t m alar u m 4 Iu npafaon ot dum *-n< pur p u tto llv a produci can ba toradm anutom alud budrtaip b u i d p o trtl lo tu b ira u im p lam pa*M ulto. MmuM ba mannad 10 e t b e a i 4CT'f and m u d dmuugdy b*ora uwnp Do n o i iota rmut b t r i/ t u . lauda, m aacictoaa 01 lu n p rite * Oo n o i rauca c o n ta tto t la voto y * 10 dawtabta p ta U . do Uri tota, te n d i et P friy edm a g iriu b u tri chatfvcab vtoi dm un m to n to m n tm eqMpfn* n* M ari m ilhfS IC H O N 2 4 6 a u tu aa apacriwd un riva trim l A m a to m m r i aeri contornate and dnpo*a r i m u by b u y n g n wn crop la tte amay from m atot auplrima C orriam ati thm rid ba dapouud by punchmp mtaa r ii dm*n and butym g adh m alta 01 fedom e tf*.ri ta c ri aionutm wdtim na M conlarim t dupoari lo c a i cotteirona nay a lia c i dm uaa a l hattactoaa C onate yout Stata A p n cto M ri l ip aanatri Stabon e t (iw m m Sar wca maod apac r ir il lo Anca r i iria c lm g aaim ania hom d to te tte io beai ri beta co tta te n e # > dm* uaa o ld M pro d u ci condorma 0 appricabta laputeim na Appfy m produci atri aa t e t t i t i < *> *" N O TICI S ate umr dm ria a it a i u ta u a i t e r i a n n o i 1 nd m------n-a-ater-m'-acaanted-pa-mt-ri ept^uaMa-M-b-aud-ian-uo-o-mriiter r i* i an--ka-t-Uu-| tm4u*--a-ramca--.maa.dr.aa.trmia.iau-ntetoaatlt-keM--mH- C H AM IASH ITV ON I I I M 6 S I O H A P A H llC lA A A P UHPOM . t o 't o t a......... .. u tonda aa * m e e t em ptaduci canuary la tea mefawchana. m mtam anamte u r il al any auefauaa. mua THE i)OW CHVIICAL COMPANY ASD SUIIlDlAkiyfa idiDLANO. MICHIGAN 41 ft 0 USA HOflQEN. SWITZERLAND H0NQ MONO CORAL 0ABLE8, FLORIDA 1 11 )4 . USA SARNIA. ONTARIO. CANA0A b T r i d a m i r i ol t H | 0 0W CMjMlCAL COMPANY CO co o o o 1> DOW 669859 ESTERON 245 Herbicide Proposed Label Amendments June 2i I960 Insert 1 DIRECTIONS FOR USE It is a violation of Federal law to use this product in a manner incon sistent with its labeling. ESTERON 245 herbicide is recommended for use to control vegetation growing on industrial sites, fencerows, and rangeland. Do not use in forest lands, rights-of-way, or pastures. ESTERON 245 controls numerous herbaceous and woody plants, including 2,4-D resistant species, such as-- ash, black gum, brambles, groundcherry, hawthorn, horsenettle, maple, mesquite, oak, osageorange, palmetto, poison ivy, pricklypear cactus, redbay, salmonberry, sweetgum, wild blackberry, wild rose, and certain species of Ri bes. Insert 2 Foliage Treatment; For control of woody vegetation up to 8 feet tall, apply when foliage is well developed and plants are actively growing. Spraying during prolonged hot, dry weather or after leaves have lost their normal green color and vigor may not give satisfactory control. Use 3 to 4 quarts of ESTERON 245 in 100 gallons of water and apply as a full-coverage spray. Usually 100 to 200 gallons per acre will be required, although dense stands of brush may require up to 400 gallons per acre. Completely wet all plant parts including leaves, stems and bark. Poison ivy, some brambles and many broadleaf weeds may be con trolled using 2 quarts of ESTERON 245 in 100 gallons of water. Insert 3 AIR APPLICATION FOR RANGELAND BRUSH CONTROL J ?9P?u ltyour* State Agricultural Experiment Station or local Extension *.Service weed or range specialists for best time to treat and need for .rerreatment in your area. 0 0 3 4 i7 / 7 fc n (*> DOW049918 Original Articles The Mortality Experience Journal of Occupational Madicino January 1980 VoL 22 Na 1 of Workers Exposed to Tetrachlorodibenzodioxin in a Trichlorophenol Process Accident Judith A. Zack, and Raymond R. Suskind, M D. A standardized m o rta lity analysis was conducted on workers exposed to tetrachlorodibenzodioxin in a tric h lo ro p h e n o l process acciden t a t the M onsanto Com pany ' p la n t in Nitro, W est Virginia. One hundred and tw entyone workers who developed ddoracne resulting horn this acci dent o n M arch 8,1949, were selected fo r study. Follow -up o f th is group was 100% com plete. The standardized mor ta lity ra tio fo r a ll causes o f death was show n to be 0.69, w ith 32 deaths observed and 46.41 expected. For the. categories o f m alignant neoplasms and circu la to ry diseases, the standardized m o rta lity ratios were 1.00 and 0.68, respectivelY. Because o f the sm all size o f th e cohort and th e relatively sm all num ber o f deaths observed, the results o f this study cannot be considered conclusive. However, it is im portant th a t no apparent excess in to ta l m o rta lity o r in deaths from m alignant neoplasms o r diseases o f the circu la to ry system was observed in a group o f workers w ith a high peak exposure to tetrachlorodiben zo d io xin who were fo llo w e d over a p e rio d o f nearly 30 years. The results o f this study w ill be incorporated w ith those o f a larger study w hich w ill include pla n t workers ex posed in the course o f 2 4 ^trich io ro p h e n o xya ce tic a d d p ro d uction during the period 1948 to 1969. A wide variety of acute and sub-acute health effects has been reported in workers involved in the manufacture of 2.4,5-trichlorophenoxyacetic acid (2.4,5-T) from 2.4.5-trichlorophenol (TCP). The most consistent clinical finding is chloracne. a skin disease characterized by com- Fram ttw Dcpanmant o i M t&cm t and E iiiiu an an u l Haahh. M on u n o Company. XI N U nam gh B h d . S t U n it MO U U t <M Z dt tpwtfmwiutuil. m d ri Imwuw of E m m m i i u l Mh Mi Laboratory, th* Un m ntty of CmcxnJD Madita l Cai'Oar. Cinem a n . OH <SJ67 (Or. Stakmd. O n e tort edones, cysts, pustules, and abscesses. Hepatic dysfunc tion, peripheral neuritis, disorders of fat metabolism, and porphyria cutanea tarda are other frequently reported findings in these workers.' Chloracne has been shown to be essentially due to 2J7.8-tetrachlorodibenzodioxin (TCDDI1 a byproduct in the synthesis of 2,4.5-T. The sub ject of this paper is the chronic health effects of exposure to TCOO, as reflected in the mortality experience of a * cohort of Monsanto Company workers who developed symptoms of chloracne following a trichlorophenol pro cess accident at the Nitro, West Virginia, plant in 1949. Production of trichlorophenol began in the fall of 1948at the Nitro plant. In this process, the reactants 1,2,4.5-tetrachlorobenzene. sodium hydroxide, and methanol were all added to the autoclave. Heat was ap plied and, when the pressure reached the desired point the autoclave was vented. On March 8.1949, about six months after production start-up, a violent reaction and decom position occurred when temperature and pressure within the autoclave became excessive The relief valve opened and the fumes and tarry residues from the decomposed contents of the autoclave were discharged into the at mosphere and into the interior of the building. Employees who worked in the area of TCP production or were involved in the dean-up began to develop symp toms immediately following exposure to the material which was discharged from the autoclave. Symptoms in cluded eye and respiratory tract irritation, headache, diz ziness and nausea, and a severe irritant reaction of the ex posed skin. After these initial symptoms subsided, the chloracne and other symptoms became evident Ashe and Suskind*"4 examined a total of 12 more severely affected workers on three occasions during the period of 1949. to 1953. Another 26 persons with chloracne. apparently not related to the accident, were also examined in 1953. The Journal ofOccupational Medldne/Vol. 22. No. 1/January 1980 ' 11 000081 DOW 049920 Tabi* 1. -- Observed and Exported Deaths Among 121 Males Exposed to Tetracitlorodtoenzodioxta In a Trichloraphand Process Accident Cause All causes a1death AD malignant neoplasms Buccal cavity and pharynx Digestive organs and peritoneum Stomach Liver All other digestive organs Respiratory system Lung AH other respiratory organs Skin Genitourinary organs Lymphatic and hemsupeiodc tissue Other sites Diseases or the nervo system end-same organs Diseases of the circulatory system Arteriosclerotic heap disease, including coronary hMR flts m i U other disease ot the circulatoty system .. Diseases ol the respiratory system Diseases of the digestive system Ad other diseases External causes of death . . ICO Ha. (Bgfeth RevtsiM) 140-209 140-149 150-159 151 155-156 -- 160-163 162.163 -- 172.173 185-189 200-209 -- 320-389 390-458 410-413 -- 460-519 520-577 -- 800-998 Observed 32 9 0 0 0 0 0 5 5 0. 1 0 3 0 0 17 13 4 1 0 2 3 46.41 9.04 0.30 2.59 0.50 0.18 1.91 3.02 2.85 0.17 0.15 1.18 0J8 0.94 0.36 25.01 17.74 .. 7.27 2.78 2.26 3.18 3.78 SUR .69* 1.00 t t t t 't 1.66 1.75 t t t t t t 0.68 0.73 t t ,t t t p < 0 .0 5 t in s than 5 served d o n a tained. The underlying cause of death was coded to the 8th Revision of the International Classification of Diseases, Adapted11 by an experienced nosologist Results All of the 121 members of the study cohort were traced. Eighty-nine were verified living and 32 were verified deceased by death certificate. The Tesults of the standardized mortality analysis of the 121-member study cohort are shown in Table 1. The standardized mortality ratio for all deaths is shown to be 0.69, with 32 observed deaths and 46.41 e xpected. This is the only statistically significant difference shown in this ta b le There were nine deaths from malignant neoplasms with 9.04 expected. There were no deaths from stomach or liver cancer. There were five lung cancer deaths versus 3.02 expected and one skin cancer death with 0.15 ex pected. The malignant tumor was a fibrous histiocytoma presumably of dermal origin, which is rare. There were three deaths from neoplasms of lymphatic and hematopoietic tissue with 0.88 expected. There were 17 observed deaths from circulatory diseases with 25.01 expected. The standardized mortality ratio for circulatory diseases was low a t 0.68. Case summaries for the cancer deaths are given in Table 2. . Discussion Because the study cohort was small and only 32 deaths were observed, the results cannot be considered con clusive. Nevertheless, the analysis of the mortality ex perience of these workers indicated no apparent excess of total mortality or of deaths due to malignant neoplasms or circulatory diseases. The TCDD-exposed workers in the present study repre sent the largest group ever investigated after long-term follow-up The criteria for inclusion (presence of the workers at the 1949 accident and the subsequent o ccu r rence of chloracne) limit the group to those with a signifi cant exposure at that time. The latency period of 29 yean TaMa 2 . -- Cancer Deaths Among a Cohort of 121 Males Exposed to Tetrachiorodibeiuadioxie in a TricMorophenol P ro e m Accident. T is rs f Birth 1909 1910 1911 1922 1915 1920 1919 1907 1910 Yeerst Hh* 1943 1927 1939 1945 1939 1946 1943 1943 1939 Tem ei D oth 1962 1970 1964 1973 1970 1978 1973 1971 1976 Detta Certificate SUteeuet t f Coese ef Detto Lung eaneer (162.1) Puknonary carcinomi (162.1) Bronchwgenic carcinoma (162.1) Bronchiogenic carcinomi (162.1) Lung cancer (162.1) Malignai tibrous Mstioeytoma of sott Itssue origm (173.9) Hoogkm's distasi (201.0) Lymphauc leukema (204.9) Acute myetogthous hukema (205.0) Smoking history m s ootnnod by nW vm rs nth tormor co-workers s i th t dscaoems JournalofOccupational Medidne/Vol. 22. No. 1/January 1980 S ittin g H ista rr Cigarettes Cigarettes Cigarettes Monsmoker Cigarettes Cigarettes Cigarettes Pipe Cigarettes A u > &300S.5 is longer than that of any previous study, and the follow up is complete. Therefore although the cohort is small, it repre se nts the best opportunity so far to study the long term effects of TCDD on mortality. By augmenting these 4. Sw kind R it CMoracna and aisociatad heafth preblAm m tha m anufactura o f Z4.5-T. Report to the lo in t Conf ia n c e Nabonal In-ttftu te o f Em rironm cnul Health Sdances. Interna tional apancy fe r Research on Cancer, Lyon. France, lanuaty 11,1971 7. Young AL Catcagni IA. Thalken CE. et ai: The toncolopY. eo data with the results of comparable mortality studies, the yirenmantal fata. and human rk assodatad rith harbidda oranga long-term effects of TCDD may be more definitely evaluated. and bs auodaud dirawi US Air Farce Occupabenal and En- venmental Health Laboratoty. Report OEHL TR-78-9Z Brodu Air Force Basa. Taxai. 1971 I InramabenalAcancy for Resaaichen Cancat: Long-Htm hasards Th* mhIi i mb IB a * M i lo u t Taut, Mr. I m d r F taM t and M n of potycNorinaud dibanaodiedns and pelychiohnatad dhw PtarMa Kan* far A W auaciaca A Aa d m co b a a w . zofuram. IARC Imarnai Technical Rtpan N a 78001. Lyon. 1971 9 .1basait L KaJamky I. and Kubac K: Acna cMerina and porphvifa cutanaa tarda during tha manufactura of hartuodm Cash Osrmaaof References 4*304-317.1971 1. in ta n u b o n a l A gancr for R n c aich a n C m c a c IAJIC Monoprapri 10. Hrawb L Kaiandcy I. Kubec K. at a t Acna cMerina. porshyria o n cha E v iiu ro o n of thvC aronogentc Rok of Q w m c a ii tp M a a . VoL cutanaa tarda, and her manifastatiom of ganaral poborang durit* 1 1 S e n ta Fumjpaiws. th a Harbidda* Z 4-D and Z4.5-T, CN or a i m d tha manufactura o f hasbiddas. IL Cas* O arm acoi 49:145-157.1974. P ram o d o n re an d M eattanaouf Indunrial Q w m c a ii. ly arc 1ARC. 1977. Tl. Paadtcwa I. lufcas E. Namcma h t at at Oaunie pouomng by chiprinarad hydretarbons formad bi tha preduaian of sodium Z KJmmic | an d S ch u h Kt* O eeueadenal a m (to-caad 14,3-uicMoiophmpsyacetata. Pue U k 31332-339.1974. cM om cnt) d u a to tha d d o r im a d arem adc cyefic u n . O m * 1Z Koaba RL Kayet DC. Bayer IE. at at Rasults of a hao yaar u m o h m a 113340-546. 1957. chranie tosadtyand onropanierty itudy of Z 3 7 > tmracMespdfcawt 1 A shaW F andS uriundR R : Rdpom on c M o r a o ia .c w . Mon j i giP p dtarin m rats. Tedcof Appf Wwnwacef 41279-3011971 C ham icai Company. Nipp. W a n Virginia. R apens of th a Kattanng I I Van Miller JF, LaUch IL and Allan JR: Inoaaud mddmea of Labormtory. O aeam bar 1949 and April 1950. 4. S iokind Mt: A dinical and wae n m tn tal Mtvay, M n ran n e p-dfodn. Cbamesphara 1537-544,1977. C hem ical Company. Nitro. W art VfapMa. R apen of tha Kacurtng 14. Mornon RJL Analysisof raUthra survtvai and proponional mon labora w ry. luly 1951 tahty. Comput B o rn a i Ras 712S-33Z1974. 1 Susfcmd RR: Chloracna and a n e d a c a d prabW r a . R apen io tha 11 Eifth Ravisiow. International Classification e<OisaaiM.Adap(Bd Ca nfaia n c a of th a National Im tn u tt of Entironm anril Haahti fer Usa in tha United Stes. U l. Oepaitmam of Health. Educaben S o a n c a s e n C M erinand P ih an ro d o o m an d P lb a n r o fw n a April 1 and Wattare Publie Health Service. PHS Publication No 1691 1971 WashmgMC U l. Covammam Printsra Office 1977. O O O CD CD N> Future Risk In the industrial countries we have grown rich during the age of hierarchical business corporations, in which each executive arranges what the man below him will do with his hands, all the wav down to the man turning a screw on the assembly line. Now, two rather fundamental things have happened. First we have begun to realize that workers in rich countries don't tike working in such places. Secondly, the rich countries are moving out of the postmanufacturing age. but they still have great hierarchical c o p porations in which executives sit behind their desks trying to arrange what the man below will do with his imagina tion. This no longer works. New forms of business organization wilt have to be found, probably changing big corporations into confedera tions of entrepreneurs. The firms and countries that will go bust in these circumstances are those that try to replace hierarchical corporations by even more ossified, forms of hierarchy -- say. by deciding that you mustn't have a boss trying to arrange what free men do with their imaginations, but can have a trade union committee .doing so in stead. -- F ra ifi U -- d S u m C m K0 Cu b b i -- And le n d -- p tt W M m * by Mdnm n Mbctbb. SnWnoniBn.hAr1976. 00 00 816H Mortality ExperienceofWorkersExposedtoTetradikmlibenzodioodn/ZackandSuskind Lui O ', Ll / mtiuoy 799 ODZGH^Oa * Literature Reviews * of Four Selected Herbicides: - 2,4-D, DicHobenil, ^ Diquat & ' Endothall Public Heaith Effects by Dr. Ruth Shearer Effects on the Aquatic Environment by Mark Halter ( -A ' v C ^ ;w / , -V January, 19SO CGK165 Municipality of Metropolitan Seattle ZSZML MO PREFACE This report is the product of a comprehensive search of the world-wide literature relating to possible effects on the public health of using the herbicides 2,4-D, dichlobenil, endothall, and diquat in the human environment. Sources included the followings Computer searches: Medline, Cancerline, Toxline Northwest Regional Health Sciences Library University of Washington libraries: Fisheries, Biochemistry, Science Reading Room, and Government Documents at Suzzallo Library National Library of Medicine Municipality of Metropolitan Seattle Library Friends of the Earth Pennwalt Corporation Thompson-Hayward Chemical Company Chevron Chemical Company Inter-library Loan Service of Health Sciences Library Since most readers are not toxicologists, this report begins with a brief explanation of the vocabulary and usual testing procedures of environmental toxicology. Following this introductory chapter, there are four chapters devoted to a review and analysis of research to cate on each herbicide in question. A final chapter offers general conclu sions about the relative risks to human health from these substances. A brief summary and chart are included at the beginning of the report. Studies reporting animal assays for the detection of developmen tal toxicity, interference with reproduction and fertility, and car cinogenesis are described in detail in a Technical Appendix to allow the more knowledgeable reader the opportunity to evaluate their valid ity. This author's evaluation is presented after each experiment, followed by the conclusions this author considers justified, based on the results reported and the adequacy of the methods used. Studies funded by chemical manufacturer who profit from sale of the chemicals are so identified to allow the reader to determine the possibility of bias. Studies reported here do not involve mixtures of chemicals unless this is specifically stated and the controls used are defined. 0004167 - 1- sotj SUMMARY OF FINDINGS The findings and conclusions of this report are briefly sum marized in answer to the questions listed below. The chart on the following page graphically illustrates the results of research to date on the four herbicides being considered for use in Lake Washington. 1. What are the potential risks to human health from aauati'c use of these herbicides? Potential risks include both acute and long-term toxic effects. Acute effects are those likely to be experienced by people applying the chemical without adequate precautions, for example by inhaling it or spilling it on skin or eyes. Long-term effects, which are the main subject of this report, may result from repeated exposure to small amounts of the substances, for example by swimming in treated water, ingesting contaminated food or water, or walking in sprayed areas. These include developmental effects on fetuses and growing children (malformations, malfunctions, growth retardation or death); reproduc tive effects on the rate of pregnancy and the number of embryos; gene tic effects (mutations, damage to DNA molecules or the process of cell division); and carcinogenic effects. It is important to note that in the United States, people are widely exposed to a variety of untested, potentially cancer-causing substances along with a lesser number of proven carcinogens, which lead to an accumulation of pre-cancerous cells in the body. Americans now face a 25% chance of developing cancer at some time during their lives. Under such conditions, the presence in the environment of additional chemicals which can stimulate these pre-cancerous cells to grow into tumors must be considered a significant hazard. 2. Which of these risks is associated with each of the herbicides unde r"~considerat ion? The risks for each herbicide are displayed in Columns 5 and 6 of the accompanying chart, and summarized below: For 2 >4-D, laboratory tests have shown developmental toxicity of all four varieties listed above, and have been positive for genetic and carcinogenic effects; there is no indication of effect on repro duction. Acute effects of 2,4-D observed in humans include headaches, dizziness, impaired senses of taste and smell, nausea, sore throat, muscular spasms and nerve damage. Toxicological testing of dichlobenil has been extremely limited. Carcinogenic tests have been inadequate and there has been no .testing of developmental or genetic effects in animals. One study indicates that dichlobenil inhibits the growth of young rats and decreases fer tility. Seme of its breakdown products are known to be highly toxic GCO^iSB' - 2- O n ^ O T . a*oft range from the. nearly meaningless.dichlobenil cancer tests .to the nearly adequate diquat cancer tests, -Where conflicting Tesults were obtained in .two or more technically adequate studies, additional tests should be conducted by another laboratory to clarify the conclusions reached. It should be noted that all the tests for developmental toxicity, reproduction/fertility and carcinogenesis reviewed in this paper were done with mammals. Mutagenic tests reported here include those done with cultured cells or lower organisms as well as with mammals. 6. Based on existing information, what conclusions can be drawn about the possible toxic effects on humans of the aquatic use of these herbicides-, their chemical impurities and breakdown products? Column 7 of the chart indicates the relative risk to human health of both acute and chronic exposure to the four aquatic herbicides. Toxic effects are summarized briefly below, in order of increasing risk to human health: Endothall is poorly absorbed through the skin, lungs or gastrointestinal tract, unless the membrane is first damaged. It is not meta bolized in the body, and is excreted without chemical change. At low doses, little of the chemical is absorbed into the body and the only acute effects are local irritation to skin, lungs and eyes. Research to date has given negative indications of developmental toxicity, effects on reproduction and fertility, and mutagenic effects in rats. One impartial test indicates a mutagenic effect in fruit flies. One test for carcinogenic effect has been negative, but another is still incomplete; results of this study are essential before a conclusion can be made about this product. Dicuat is also poorly absorbed into the body unless the membrane is first damaged. It is metabolized by intestinal bacteria to unknown products of unknown toxicity which are partially absorbed. The sub stance does not accumulate in the body; however, it can alter metabo lism in many organs. A number of acute effects have been observed in humans. Inadequate tests in mammals suggest possible developmental toxicity; one study in amphibians shows developmental toxicity at concentrations lower than*proposed for Lake Washington. At low doses, chronic exposure to diquat has caused cataracts in rats and dogs. Cancer experiments on diquat have been less than adequate, but one screening test for possible carcinogens with cell cultures was posi tive. 2 ,4-D is rapidly absorbed through the skin, lungs and gastroin testinal tract and rapidly distributed to all tissues. It is not metabolized in the body, but is excreted more slowly than endothall and diquat. This herbicide causes a number of acute effects in humans.* It has been found to cause all four types of developmental toxicity in a number of tests in several animal species. Tests of 2,4-D for carcinogenicity have been inadequate but have still demon- 0004171 . -4 r TABLE OF CONTENTS SUBJECT Preface Summary of Findings Table of Contents Chapter 1: Introduction to Basic Terminology and Methods of Environmental Toxicology A. Introduction B. Absorption and Metabolism C. Impurities and BreakdownProducts D. Acute and Subacute Toxicity E. Developmental Toxicity F. Reproduction and Fertility G. Mutagenic Effects and Other Short Term Tests for Cancer ' H. Carcinogenic Effects Bibliography Chapter 2; Health Effects of 2,4-D and Its Derivatives A. Introduction B. Metabolism of 2,4-D C. Impurities and 3reakcowr. Products D. Acute and Subacute Toxic Effects - 6- o PAGE <y 1% 2 6 9 9 9 9 10 10 12 12 13 15 rw 16 16 o Q 16 17 19 oow 749270 G. Tests for Mutagenic Effects and Other Short Term Tests for Cancer H. Tests for Carcinogenic Effects I. Conclusions about Health Effects of Endothall Bibliography Chapter 5; Health Effects of Piqut A. Introduction 'B. Metabolism of Diguat C. Impurities and Breakdown Products D. Acute and Subacute Effects E. Tests for Developmental Toxicity F. Tests for Effects on Reproduction and Fertility G. Tests for Mutagenic Effects and Other Short Term Tests for Cancer H. Tests for Carcinogenic Effects and Chronic Toxicity I. Conclusions about Health Effects of Diguat Bibliography Chapter 6: Comparison of the Health Effects of Aquatic Herbicides Bibliography Technical Appendix 43 44 44 46 47 47 47 49 49 50 51 52 52 53 55 58 62 63 0G04173 " 80 b - 8- T/ t CHAPTER 2: HEALTH EFFECTS OF 2,4-D (2,4-dichlorophenoxyacetic acid) AND ITS DERIVATIVES Oo A. Introduction The herbicide 2,4-D was prepared in 1941 by the interaction of 2.4- dichlorophenol, monochloroacetic acid and sodium hydroxide, and a similar process is used in its commercial production. 2,4-D is a systemic herbicide widely used for site preparation and conifer release in forestry, for control of broadleaf weeds in cereal crops and sugar cane, and on turf, pastures and non-cropland. It is also used to control the ripening of bananas and citrus fruits, to delay preharvest dropping of some fruits, and in some countries as a fungi cide for the control of Alternaria rots when lemons are to be held for storage. As a component oil kAgent Orange," 2,4-D was used to defol iate jungle areas in South Vietnam (IARC, 1977). The EPA has approved the use of 2,4-D, marketed as "Aqua-Kleen" by Amchem Products, Inc., for control of several aquatic plants including water milfoil. Label requirements include a "caution" against accessibility of the product to children; applying to water used for irrigation, sprays, dairy ani mals or domestic use; or contact with skin, eyes, and clothing. B. Metabolism of 2,4-D A total of nine human male "volunteers" in two different studies have been fed a single dose of 5 mg/kg of 2,4-D (Kohli et al., 1974; Sauerhoff et al, 1977) to determine its metabolism. Essentially all of the 2,4-D was absorbed from the gastrointestinal tract. It was distributed widely through the body and excreted in the urine unchanged. No metabolites were detected. No symptoms of illness or abnormal blood chemistry were detected. 95% of the dose was recovered from urine in six days. The metabolism of isotope-labeled 2,4-D in rats has been deter mined and is in agreement with the human studies above (Khanna and Fang, 1966). Radioactivity was found in all organs and tissues exam ined, with 9% to 32% in the nuclear fraction. All was unchanged 2.4- D, suggesting that the chemical in the cytosol was not peptidebound as found in plant tissues. _ 2,4-D is lipid-soluble and therefore rapidly absorbed from the lung (Burton et al., 1974), when assayed in rats. 2,4-D amine salt administered orally was readily absorbed by rats, pigs, calves, and chickens, but 2,4-D butyl ester was much more slowly absorbed and the circulating chemical was all in acid form, indicating that the ester was hydrolyzed during absorption (Erne, 1965). Absorbed 2,4-D was distributed rapidly through the body with - 16- 17 L ^ pg- pg, 18 first para., line 3; 4,6'-tetrachloro-; line 4 : diphenoxymethane diagram should be: OCHzCOH 2,4-D rCl corrected diagram below: a / fi Va* <1 CD chloromalaylacatic acid (7, ^ 2-chloro-4-icetoadipie acid / chlorosuccinic acid / succinic acid Mlaylacatic acid V (7) 3-katoadipie acid \ succinic acid Fig. 1. Pathways of Microbial degradation of butyl astar of 2,4-0. Nunbars ara rafarancast (1) M y and Faust 19 (2) Tiadja and Alaxandar 1969, (3) Staanson and Walker 1957, (4) Ball 1957, (5) Bollag at al. 1968, (6) Loos at al. 1967, (7) Duxbury at al. 1970, (6) Tiadja at al. 1969, (9) Audus 1960, (10) Fernley and Evans 1959, and (11) Evans and Smith 1954. SOURCE: Doris F. Paris and David I>. Lewis, "Chemical and Microbial Degradation of Ten Selected Pesticides in Aquatic Systems," Residue Reviews, Volume 45, 1973, p.107 8q 0004173 in initiated controls). After a longer period of application -to the skin, it was able to induce tumors without prior application of the initiator (75% with papillomas and 6% with carcinomas after 24 weeks). After 39 weeks of treatment with 2,4-dichlorophenol, 62% of the mice had carcinomas. The test substance was dissolved in benzene in these experiments, and control animals were treated with benzene alone <* (Boutwell and Bosch, 1959). This indicates that 2,4-dichlorophenol is a skin carcinogen in mice, or at least a cocarcinogen with benzne which is not carcinogenic by itself in this system. butyl ester of2,4*0 butanol hyck-oxy glyoxylarte -- rralonie alanine serriaidehyds 2,4-D 3,&dchlorocatechol . <hiorcm jconic add 2,5-dfchlarocatBchol 2,4<fichIorophenoi ds,d$*2r4*dichiorontJCon>c add cl / 2-chtoro 4 catox/n'ethylene but-2-endide ( -chiaro -carbaxymethyiene -butanolide) / K chloromaleylacetjc add (7) / 2-chJoro-4-ketoatfpic add / chlorcsucdntc add t sucanic add 4*chlorocatBchai \ ds^3*chloranuoonic add \ 4-carboxyiTBthylenebut-2-enoiide (-carboxyinahylene-butanolide) maleylaceticadd \ (7) 3-ketoadpicadd \ sucdnicadd Fig. 1 Pathways of microbial degradation of butyl ester of 2,4-D. Numbers are references: ( 1) A ly and Faust 1964; (2) Tdedje and Alexander 1969; (ZJ S tee n so n and Walker 1957; (4) B e ll 1957; (5) B o lla c e t a l . , 1963; (6) Loos e t a l . , 1967; (?) Duxbury e t a l . , 1970; (8) T ie d fe e t a l . , 1969; (9) Audus 1960; (10) F em ley and Evans 1959; and (11) Evans and Smith. 1954. SOURCE: Doris F. Paris and David L. Lewis, "Chemical and Microbial Degradation of Ten Selected Pesticides in Aquatic Systems," Residue Reviews, Volume 45, 1973, p. 107. -2,4-dichlorophenol, like other polychlorinated phenols, can form c'nlorodibenzo-dioxins when heated (Epstein, 1970), but not the infa mous -TCDD (2,3,7,8-tetrac'nlorodibenzo-p-dioxin) found in 2,4,5-T (Gribble, 1974). The most likely dioxin produced by heating- 2,4-dicnlorophenol would be 2 ,7-dic'nlorocibenzo-p-dioxin, which* is reported to be minimally toxic (Schwetz et al, 1973, Dow Chemical Co.). No eaths occurred in four male mice given 2000 mg/kg or in two female rats given 1000 mg/kg. No signs of toxicity were observed in these 0G04173 n i n r . AA O n throat, irritation of the Tiasal mucosa, substernal pain, and loss of consciousness. Recovery took four to nine days. Workers engaged in the spraying of 2,4-D and its derivatives from aircraft for three to five years and longer complained of rapid fatigue which usually cleared overnight. They periodically had headaches, pain in the liver and epigastric regions, and poor appe tite. They had impaired taste sensitivity to salty, sour, bitter, and sweet test solutions. There was a deterioration in sensitivity to odors also. No changes in blood chemistry were found (Fetisov, 1966). In addition to the symptoms above, peripheral neuropathy has been reported in humans hours or days after exposure to 2,4-0 on the skin and probably simultaneously by inhalation (Goldstein et al., 1959; Berkley and Magee, 1963). The symptoms progressed through several weeks until pain, paresthesias, and paralysis were severe. Disability was protracted, and recovery was incomplete even after the lapse of years. Numbness and aching had extended proximally from the fingers and toes, and the patients became unable to walk because of pain and weakness. They also suffered moderately severe sensory deficits on tests of touch, pain, and temperature. Autopsy of a human fatality due to ingestion of 2,4-D revealedwidespread plagues of acute demyelination in all parts of the brain, with central petechiae (Dudley and Thapar, 1972). Multiple petechiae were seen throughout the white matter of the brain, and the kidneys were hyperemic. The nervous system of rats, cats, and dogs was studied after 2.4- D administration parenterally (Desi et al., 1962). A reversible inhibition of cerebral electrical activity was observed in the acute experiments, and in chronic experiments the same was present to a gra dually increasing degree. According to conditioned-reflex experi ments, the higher nervous activity suffered severe damage. The point of attack seemed to be the reticular formation. Lesions in this region paralyze the function of the cerebral cortex. Pretreatment of rats with 250 mg/kg 2,4-D three hours prior to administration of 9 mg/kg ^4C-2,2-D greatly increased the level of ^4C in rat brain and spinal fluid as compared to plasma level (Elo and Ylitalo, 1977). The increase was much more striking in the brain (11-fold) and spinal fluid (39-fold) than in the liver (4.5-fold). The likeliest explanation of this is that 2,4-D impaired function of the blood-brain barrier by causing capillary injuries. Cattle and sheep which died after 5 to 34 daily oral doses of 2.4- D alkanolamine salt were necropsied (Palmer and Raaeleff, 1964). Lesions included liver and kidney degeneration, the heart -usually con tained hemorrhages, and there was usually an excessive quantity of pericaridal fluid. 0G04I51 -2 0 - 74927b hemorrhaging into.the abdominal cavity at the higher dose and vascular distention -at both doses. The other experiment tested single doses of 1/2 LD50 given intraperitoneally on various days of gestation, and found increased resorption of fetuses with reduced litter size, growth reduction with increased size of brain ventricles, and hemorrhaging into the abdominal cavity. ^ A test for developmental toxicity in hamsters was done by Collins and Williams of the O.S. Food and Drug Administration. They used oral doses of 20 to 100 mg/kg/day during organogenesis and found a dose- Q dependent increase in fused ribs at 60 mg/kg/day and above which w a s Q significant only if repeats were pooled. ^ . Two studies of the teratogenicity of 2,4-D in mice have been done. A large series of tests using different strains of mice, dif ferent doses, and different esters of 2,4-D was completed in 1968 by Bionetics Research Laboratories, and has now been published. Oral administration of 100 mg/kg/day of 2,4-D acid during organogenesis caused a significant increase in fetal mortality and percent of abnormal fetuses, with most of these being eye and jaw malformations. 2,4-D acid produced a significant increase in fetal abnormalities in four of six adequately-sized groups of three strains, when given subcutaneously at 100 mg/kg/day. Subcutaneous administration resulted in a significant increase in abnormal fetuses in one strain after 48, 9 4 , 100, or 130 mg/kg/day of the isooctyl, isopropyl, butyl, and isooctyl esters respectively. This was a repeat of a previously nega tive study. The anomalies were mainly of the eye and jaw. All of these subcutaneous administrations were dissolved in dimethylsulfoxide, which is a teratogen for the nervous system of the hamster (Ferm, 1966). However, the DMSO controls in this mouse study showed no significant increase in developmental toxicity over untreated controls. The other mouse study was done by Courtney of the U.S. Environmental Protection Agency. She used oral doses of 150 or 250 mg/kg/day of 2,4-D and four of its esters during organogenesis and found growth retardation at both doses and cleft palate at the higher dose. Other malformations were not assayed. Two developmental studies on pigs have been done by Bjorklund and Erne of the Swedish Royal Veterinary College and National Veterinary Institute. A pig was fed 500 ppm of 2,4-D amine while pregnant plus six weeks after. The fifteen piglets born were underdeveloped, apathetic, and did not want to suck, and ten died the first day. No malformations were observed. In the second study, eight-week-old pics were fed 500 ppm of 2,4-D amine for 12 months. After one month, 2 out o f '5 in the experimental group developed malformations -in-..the hooves on the forelegs, making walking difficult. 0004182 -2 2 - F. Tests for Effects on Reproduction and Fertility 1. Summary of Research A study by Schwetz et al., of Dow Chemical Company, claims to show that 2,4-D has no effect on fertility, but it actually contains no^ such experiment. The only study of the effect of 2,4-D on reproduction and fer tility was done by Hansen et al., of the U.S. Food and Drug Administration. They used rats for a three-generation study and found no effect on fertility. 2. Conclusions On the basis of a single study in a single species, there is no indication that 2,4-D might interfere with reproduction and fertility in mammals. G. Tests for Mutagenic Effects and Other Short-Term Tests for Cancer 1. Summary of Research Assays of 2,4-D for both forward and reverse mutation in bacteria and bacterial virus are consistently negative (Fahrig, 1974; Shirasu et al., 1976; Simmon et al., 1977: Andersen et al., 1972). These included tests run in the presence of an activation system prepared from'the livers of rats or mice. This is to be expected since 2,4-D is a chlorinated hydrocarbon and these as a class are negative in the Ames test. 2,4-D caused a significant increase in recessive lethal mutations in Drosophila melanogaster when it was fed to male flies at 1000 ppm for two weeks (Magnusson et al., 1977), but was negative when the flies were treated with a 9mM solution for 3 days (Vogel and Chandler, 1974) and after unspecified treatment (Fahrig, 1974). 0.001 mM to 1.0 mM 2,4-D with or without rat liver activation induced unscheduled DNA synthesis in SV-40 transformed human fibro blast cells' in culture (Ahmed at al., 1977a). 0.01 mM 2,4-D in the medium of primary human fibroblast cultures caused DNA damage leading to increased removal and reinsertion of bases. Th type of repair was that seen following ionizing radiation (Hart et al., 1977). 0.01 mM 2,4-D in the culture medium caused a significant increase in forward mutation to ouabain resistance in the Chinese hamster V79 aneuploid lung cell line (Ahmed et al., 1977b). -- 0.01 mM or 0.1 mM 2,4-D in the culture medium of bovine fetal muscle cells caused the mitotic cells to exhibit unipolar and trioolar - 24- OGG4H35 A mouse carcinogenesis study was sponsored by the National Cancer Institute/ also in the 1960's, and the data published years later. It consisted of both oral .feeding studies and single dose subcutaneous injection studies. Two strains and both sexes were studied, but only 18 mice were included in each group and all were killed by 18 months. In the original study, strains and sexes were pooled to give a large enough sample size for statistical analysis by the chi-square method, and a significant increase in total tumors and in reticulum cell sar coma was found after subcutaneous administration of 2,4-0 isooctyl ester. No other tests were postitive using this approach, which hides strain and sex differences in sensitivity. Analysis of the data by strain and sex, using the chi-square method, indicates a carcinogenic effect of feeding the isooctyl and butyl esters of 2,4-0 to females of one strain, with the reservation that the method is not totally reliable with such small samples. Analysis of the data by strain, sex, and organ system using more elegant statistical methods indicated that the induction of reticulum cell sarcoma by 'injection of the isooctyl ester is most significant, in females of the other strain. However, the importance of this observation to human health is limited by the injection route of administration and the knowledge that 2,4-D esters taken orally are probably split into the acid form before absorption (Erne, 1966} so that circulation of the ester might not happen after contamination of humans. This study is described, ana lyzed, and discussed in Bionetics, 1968, Innes et al., 1969, Reuber, 1979, Mrak report, 1969, and Jurek, 1974. Its primary defect is its short duration, but the small group size and less-than-optimal oral dose given the adult animals could also contribute to false negative results. This study also had a rather high background level of tumors in the control animals. ^ C A study at the Institute of Nutrition of the USSR Academy of Medical Sciences included three experiments. The first experiment used adequate numbers of rats and duration of feeding 2,4-D amine, but the dose was not over 1/2 MTD. The background was very low and the tumor increase insignificant. However, the publication (Arkhipov and KoXlova, 1974) does not state whether the rats were autopsied and whether histopathology was done, so small tumors might not have been found. A similar experiment with mice (100/group) was also negative, with no tumors in either the control or treated animals. The third experiment involved application of the herbicide to the skin of mice (100/group) , with or without prior application of a low dose of an initiator of skin carcinogenesis. Animals treated with either the herbicide alone or the initiator alone did not develop any tumors, but 17.7% of those given the sequential treatment developed skin papillo mas, the premalignant lesion of skin carcinomas, indicating strong tumor-promoting activity of 2,4-D. Again, there is no report of histopathology, so it would be impossible to distinguish conclusively between papillomas and carcinomas. 00041S7 - 26- The conditions of the American experiments approximate the con ditions of American -people: wide exposure to a variety of cancer ini tiators and a 25% spontaneous cancer rate in lifetime studies. Over such a background/ the presence of additional nonphysiologic chemicals which can stimulate the rate of development of cancers from premalignant cells must be considered a significant hazard. I . Conclusions About Health Effects of 2,4-D 2/4-0 is lipid soluble and is rapidly and completely absorbed through all normal routes of exposure. Its butyl ester, and therefore probably all of its estersf is hydrolyzed before absorption from the gastrointestinal tract. It is not metabolized in animals, but rapidly penetrates the placenta. 2/4-0 as normally manufactured does not contain chlorodibenzodioxins because the reaction is not heated sufficiently to form them. However, 2,7-DCDD (also known as 3,8-DCDD) could be formed if the reaction mix was overheated or if partially degraded 2,4-D were heated during storage or disposal. This dioxin is far less toxic than the TCDD found in 2,4,5-T, but has been shown to be fetotoxic to the heart muscle in rats. Many cases have been reported of human poisoning by inhalation or absorption through the skin. Damage is primarily to the nervous system, and some such symptoms are not readily repaired. Gastrointes tinal symptoms and irritation of mucous membranes are also seen. Laboratory tests have shown development/^toxici ty of 2,4-0 in four species of animals. These include all four classes of developmental toxicity (malformation, malfunction, growth retardation, and lethal ity) but not all four in any one experiment. They include tests of the esters and amine of 2,4-0 as well as the parent compound, and both pre- and postnatal adverse effects. A synergistic toxicity of 2,4-0 and its primary microbial breakdown product, 2,4-dichlorophenol, on the fetal circulatory system was demonstrated in rats. The abstract of a Russian study, which is not available in the United States, reports a survey of workers in the P*oductionof herbicides of the 2,4-D family and finds that "substantiaT^mens^r3iSl?and child-bearing functions arise manifested as higher rate of miscarriages, premature births, toxicosis of second half of pregnancy, and the menace of miscarriages during the whole pregnancy period" (Elina, 1974). An adequately designed study indicated that 2,4-D does not inter fere, with fertility in rats, although other studies have shown that it causes point mutations in animal cells, damages DNA in a manner simi lar to ionizing radiation, and stimulates cell division. Carcinogenicity testing of 2,4-D has been limited to three studies, none of which meets today's minimum standards. In spite of :he inadequate experimental design or assay, two of these studies - 28-, BIBLIOGRAPHY o O 3 749280 Abo-Khatwa, Nabil and Hollingsworth, Robert M. (1974) Pesticidal Chemicals Affecting Some Energy Linked Functions of Rat Liver Mitochondira n Vitro. Environ. Contam. & Toxicology 12, 446-4S4. Ahmed, Farid E., Hart, Ronald W . , and Lewis, Neil J. (1977a) Sesticide Induced DNA Damage and its Repair in Cultured Human Cells. Mutation Research 2, 161-174. Ahmed, Farid E., Lewis, Neil J., and Hart, Ronald W. (1977b) Pesticide Induced Ouabain Resistant Mutants in Chinese Hamster V79 Cells. Chem. Biol. Interactions 19, 369-374. Aleksashina, Z. A., Buslovich, S. Y., and Kolosovskaya, V. M. (1973) Embryotoxic Action of the Diethylamine Salt of 2,4-D. Gigiena I Sanitariya 2, 100-101. Andersen, Kenneth J., Leighty, Edith G., and Takahashi, Mark T. (1972) Evaluation of Herbicides for Possible Mutagenic Properties. . J. Agr. Food Chem. 0, 649-656. Antonenko, T. A. (1977) Experimental Data from a Study of the Permeability of the Placental Barrier for the Herbicide 2,4-D (Acid Form) and its Passage with the Mother's Milk During Feeding. Gog. Aspekty Okhr. Zdorov'ya Naseleniya 1977, 177-178. Arkhipov, G. N. and Kozlova, I. N. (1974) Study of the Carcinogenic Prooerties of the Herbicide Amine Salt of 2,4-D. Voprosy Pitaniya 5, 83-84. Ashton; F. H. and Crafts, A. S. (1973) Mode of Action of Herbicides. Wiley & Sons, p. 274. Basrur, S. V., Fletcher, R. A., and Basrur, P. K. (1976) In Vitro Effects of 2,4-Dichlorophenoxy Acetic Acid (2,4-D) on Bovine Cells. Canadian J. of Comparative Medicine 0, 410-415. Berkley, Mary C. and Magee, Kenneth R. (1963) Neuropathy Following Exposure to a Diroethylamine Salt of 2,4-D. Arch of Int. Med. Ill, 351-352. Bionetics Research Labs, Inc. (1968) Evaluation of Carcinogenic, Teratogenic, and Mutagenic Activities of Selected Pesticides and -Industrial Chemicals. Vol. I, Carcinogenic Study. Vol. II, Teratogenic Study. National Technical Information Service, U.S. Dept, of Commerce. 3jorklund, Nils-Erik and Erne, Kurt (1966) Toxicological Studies of Phenoxvacetic Herbicides in Animals. Acta Vet. Scand. 7, 364-390. 0004131 - 30- 749288 Elo, Heikki and Yli.talo,. Pauli .<1977) Substantial Increase in the Levels of Chlorophenoxyacetic -Acids in -the CNS of Hats as a Result o Severe Intoxication. Acta Pharmacol, et Toxicol. 1, 281-284. 3 Epstein, Samual S. (1970) A Family Likeness. Environment 12, 16-25. Erne, Kurt (1966) Distribution and Elimination of Chlorinated Phenoxyacetic Acids in Animals. Acta Vet. Scand. 7, 240-256. ' Fahrig, R. (1974) Comparative Mutagenicity Studies with Pesticides. IARC Sci Publ. 10, 161-176. Fedorova, L. M. and Belova, R. S. (1974) 2,4-D Detected in the Reproductive Organs and Fetuses of Treated Pregnant Rats; Ways and Dynamics of i-ts Removal. Gig. I Sanit. 39, 105-107. Ferm, Vergil H. (1966) Congenital Malformations Induced by Dimethyl Sulphoxide in the Golden Hamster. J. Embryol. Exp. Morph. 1, 49-54. Fetisov, M. D. (1966) Occupational Hygiene in the Application of Herbicides of the 2,4-D Group. Hygiene and Sanitation 31, 383-386. Goldstein, Norman P., Jones, Peter H., and Brown, Joe R. (1959) Peripheral Neuropathy After Exposure to an Ester of Dichlorophenoxyacetic Acid. J. Amer. Med. Assoc. 171, 1306-1309. Gribble, Gordon W. (1974) TCDD, A Deadly Molecule. Chemistry 47, 15-18. Hansen, W. H . , Quaife, M. L., Habermann, R. T . , and Fitzhugh, 0. G. (1971) Chronic Toxicity of 2,4-Dichlorophenoxyacetic Acid in Rats and Dogs. Toxicology and Applied Pharmacology 0, 122-129. Hart, R. W . , Hayes, S., Brash, D., Daniel, F. B., Davis, M. T., and Lewis, N. J. (1977) In Vitro Assessment and Mechanism of Action of Environmental Pollutants. Annals New York Academy of Sciences 298, 141-158. Heene, Rainer (1975) Experimental Myopathies and Muscular Dystrophy. Schriftenr. Neurol. 16, 1-97. Huston, Beverley L. (1972) Identification of Three Neutral Contaminants in Production Grade 2,4-D. J. Agr. Food Chem. 20, 724-727. I ARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. (1977) 15, 111-138. 0004133 - 32- DOW Radionov, A. D . , Chumachenko, A. N,, and Kirilenko, I- U. <1967) The Toxic Properties of the 'Herbicide -2,4-D- Hygiene and "Sanitation 12, 1IS -1 1 8 . Reuber, Melvin D. (1979) Carcinogenicity of 2,4-Dichlorophenoxyacetic Acid. Manuscript, personal communication. ^ Sauerhoff, M. -W., Braun, W. H., Blau, G. E., and Gehring, P. J- (1977) The Fate of 2,4-Dichlorophenoxyacetic Acid (2,4-D) Following Oral Administration to Man. Toxicology , 3-11. Schwetz, B. A., Sparschu, G. L., and Gehring, P. J. (1971) The Effect of 2,4-Dichlorophenoxyacetic Acid (2,4-D) and Esters of 2,4-D on Rat Embryonal, Foetal and Neonatal Growth and Development. Food & Cosmet. Toxicol. 801-817. Schwetz, B. A., Norris, J. M . , Sparschu, G. L., Rowe, V. K., Gehring, P. J., Emerson, J. L., and Gerbig, C. G. (1973) Toxicology of Chlorinated Dibenzo-p-dioxins. Environmental Health Perspectives, September, 87-99. Shirasu, ?., Moriya, M . , Kato, Y., Fiiruhashi, A., and Kada, T. (1976) Mutagenicity Screening of Pesticides in the Microbial System. Mutation Research 0, 19-30. Simmon, Vincent F., Kauhanen, Kristine, and Tardiff, Robert G. (1977) Mutagenic Activity of Chemicals Identified in Drinking Water. Progress in Genetic Toxicology. Ed. by D. Scott, B. A. Bridges, and F. H. Sobels, 249-258. Syrowatka, Tadeusz, and Jurek, Andrzej (1974) Carcinogenicity of Pesticides. Roczniki Panstw. Zakl. Hig. 25, 563-576. Van Duuren, B. L. and Goldschmidt, B. M. (1976) Cocarcinogenic and Tumor-Promoting Agents in Tobacco Carcinogenesis. Journal of the National Cancer Institute 56, 1237-1242. Cf%tth<L l e n Vogel, E. (1974) Mutagenicity Testing of Cyclamate and Some Pesticides in Drosophila melanogaster. Experientia 3j0, 621-623. Woolson, Edwin A. (1972) Survey of Polychlorodibenzo-p-dioxin Content in Selected Pesticides. J. Agr. Food Chem. 20., 351-354. Zielinski, Walter L. Jr., and Fishbein, Lawrence (1967) Gas Chromatographic Measurement of Disappearance Rates of 2,4-D and 2,4,-5-T Acids and 2,4-D Esters in Mice. J. Agr. Food Chem. 15, 841-844. 0G04135 - 34- A7 $ ni January 3, 1980 TO: ALL DOW 2,4,5-T AND SILVEX DISTRIBUTORS RE: ESTERON* BRUSH KILLER, ESTERON* 2,4,5 AND KURON* The E.P.A. emergency suspension of 2,4,5-T and Silvex has caused problems in disposing of stocks of the above items. There is confusion in people's minds as to what are the non-suspended uses of these products. This confusion is compounded by the fact that both E.P.A. and state officials have changed their minds on this point. The attached sheet is the latest E.P.A. official policy on the legal and non-legal uses of 2,4,5-T and Silvex. There are still plenty of areas and uses for which these products are legally valid. Confusion continues as to what is rangeland and what is pasture. The official E.P.A. definition of these two words follows: "Rangeland is defined as land producing forage for animal consumptionj harvested by grazing, which is not cultivated, seeded, fertilized, irrigated or treated with pesticides or other such similar practices on an annual basis. Fence rows enclosing such areas are included as part of the range." "Pasture is defined as land producing forage for animal con sumption, harvested by grazing, which has annual or more frequent cultivation, seeding, fertilization, irrigation, pesticide application and other similar practices applied to it. Fence rows enclosing pastures are included as part of the pasture." Two points in these definitions are particularly important. irst - the long list of things needed to be done that can make grasslands a pasture (i.e. cultivated, seeded, fertilized, ir rigated, etc.) This may be interpreted as meaning that all of these practices need to be done or it is rangeland. Another interpretation would be that if any one of these practices (i.e. DOW230202 January 3, 1980 Page 2 irrigation, seeding, etc.) are followed it would make the grassland a pasture. Regardless of which interpretation is used, the use of the word annual is important. Thus, if these things (seeding, fertilization, irrigation, etc.) are not done on an annual basis, it is not a pasture. This definition would mean there is practically no pasture in this country. It is all rangeland. Nevertheless, publicity should be avoided even though the uses are legally correct. You should understand that these products are safe to humans, wildlife and the environment when used according to labeled instructions. Two outside groups of scientists have confirmed Dow's stand on this safety question. The best of luck and good selling. There is a real opportunity for you and your customers. Yours very truly, W. J. McCoy District Sales Manager Agricultural Department enc. jmz * Trademark of The Dow Chemical Company C0 0 1 2 ! 0 -9q z^ sonh- `i i o e z M O a # it feeds and then is transferred through pupa to adult (//). Similarly, senecio alkaloids are incorporated by moths from food plants of the genus Senecio (12), and cardenolides are accumulated in grasshoppers and butterflies from milkweed plants (13). In Romalea, se questration may account for more than just the 2,5-dichlorophenol in the froth. The other components all occur as such Dow Chemical Co,, personal communication). 11. J. von Euw, T. Reichstein, M. Rothschild, Israel J. Chem. 6. 659 (1969). 12. R. T. Aplin. M. H. Benn, M. Rothschild, Nature 219, 747 (1968). 13. L. P. Brower, J. van Zandt Brower. J. M. Conrino, Proc. Not. Acad. Sei. (/S'. 57, 893 (1967) ; T. Reichstein, Naturwtss, Rundschau 20. 499 (1967); ---------, J. von Euw, J. A. Parsons, M. Rothschild, Science 161, 861 (1968) . 14. W. Karrer, Konstitution und Vorkommen der organischen Pflanzenstoe (exclusive Alka loide) (Birkhuser, Basel, 1958). 15. Supported by NIH grams Al-02908 and RR00355. We thank Dr. J. Hribar for his help with the chromatographic and spectroscopic studies. Dr. R. D. Liske for reading the manuscript, and Mr. R. Archbold, Director. Archbold Biological Station, for help and hospitality during our stay at the Station. . Report No. 30 of our series 'Defense Mechanisms of Arthropods.** Present address: Department of Chemistry Pennsylvania State University, University Pari 16802. 12 February 1971 or in similar form in many species of plants (14), and the grasshopper may simply incorporate them with slight or Aplysia califomica: Analysis of Nuclear DNA in no change from the diet. But 2,5-di chlorophenol would still be unique be Individual Nuclei of Giant Neurons cause of its apparent ultimate deriva tion from an exogenous source recently Abstract The nuclei o f the giant neurons o f the marine mollusk Aplysia cali unleashed upon the ecosystem by man fomica can contain more than 0 2 microgram o f D N A. This is more than 200,00C - a himself. times as much D N A as the haploid amount found in Aplysia sperm. On the basis T homas Eisner o f nuclear D N A content, the giant neurons R-2, P-1, and L-6 o f adult animals Division of Biological Sciences, Cornell can each be divided into at least two populations. The mean D N A content of these University, Ithaca, New York 14850 two populations (0.067 and 0.131 microgram o f D N A) are approximately related L. B. H endry* by a factor o f 2. This suggests that much and perhaps all o f the genome replicates Department o f Chemistry, Cornell University, Ithaca repeatedly (up to 16 times) during the growth and development of these neurons and that each replication is synchronous. The enormous amount o f D NA in these D. B. P ea k a ll cells opens up the possibility o f characterising the D N A and other constituents of Division o f Biological Sciences, chromatin from individual but phenotypically different neurons. Cornell University J. M e in w a l d The giant neurons of Aplysia repre Aplysia nervous system; L-6 is some Department o f Chemistry, Cornell University sent one of the largest somatic cell what smaller. types in the anim al kingdom. These The giant cells are surrounded by References ami Noies 1. Pieces of fresh Integument <25 mm*) of Romalea, treated with droplets <1 to 2 pi) of froth, were ignored by ants (Paratrechbta iongicomis) when placed in their foraging trail. Untreated controls were carried away. Tethered Romalea exposed on soil to foraging ants (Pogonomyrmex badius) discharged froth (and regurgitated crop fluid) when attacked, thereby repelling their assailants. After deple tion of froth (and crop fluid) the grasshop pers were vulnerable. 2. J. Meinwald, K. Erickson, M. Hartshorn, Y. C. Meinwald, T. Eisner, Tetrahedron Lett. 1968. 2959 (1968); -------- , L. Hendry, ibid. 1969. 1657 (1969). 3. Over 30 additional components of the froth remain unidentified. 4. T. Eisner and J. Meinwald. Science 153, 1341 (1966); , in Chemical Ecology, E. Soad- heimer and J. B. Simeone, Eds. (Academic Press, New York. 1970), pp. 137-217. 5. J. Weatherston and J. E. Percy, in Chemicals Controlling insect Behavior, M. Beroxa, Ed. (Academic Press, New York, 1970), pp. 95- 144. 6. J. Roche, M. Fontaine, J. Lepoup, in Corns- parative Biochemistry, M. Florkin and H. S, Mason, Eds. (Academic Press, New York, 1963), vol. 5, pp. 493-547. Alkaloids with chlorinated aliphatic side have beeo reported from some higher plants but are suspected of being artifacts rather than natural products (J. W. Hylin, R. E. Spenger, F. A. Gunther, Residue Rev. 26, 127 (1969)]. , D. Townsend and R. Burgess (comity *f--i*^ Collier and Hendry counties, Florida), p e r^ \P -^n|amy-^ntinn The rearrangement of chlorine from a 2.4 to a 2J5 substitution pattern presupposed by this assumption seems plausible in view of the demonstrated occurrence of such rearrange* meni in the degradation of 2.4-D by fungi and higher plants. (J. K. Faulkner and D. Woodcock. Nature 203. 865 (1964); E. W. Thomas, B. C. Loughmaa, R. G. Powell. , ibid. 204, 765 Q9641L > loiogical station. Lake Fladd, Highland County, Florida. 10. Lethal range: QS to 2.8 g/kg (V. K. Rowe, neurons, which range in size up to 1 mm in diameter, each contain a single nucleus which comprises approximately 30 percent of the volume of the cell body. The large size of the nucleus and the staining characteristics of the nu cleoplasm with the Feulgen stain led Coggeshall (1) to suggest that the giant cell nuclei contain considerably more DNA than the diploid amount for Aplysia. This possibility was supported by an unpublished observation of Strumwasser (2) that the largest neurons contain 50,000 times as much DNA as mammalian cells. We have quanti fied the nuclear DNA from individual giant neurons and have found that the amount of DNA in Aplysia giant neu rons is many thousands of times greater than the haploid value for these ani mals. One of the remarkable features of the Aplysia nervous system is that indi vidual neurons can be easily recognized in the abdominal ganglion; over 30 of these cells have been characterized electrophysiologically and morphologically (5). We chose to study cells R-2 and L^6 of the abdominal ganglion [nomen clature of Frazier et aL (5)] and the single giant cell of the left pleural gan glion, which we have .abbreviated P-1. Cells R-2 and P-1 have been called the colossal cells and are the largest in the thousands of glial satellite cells and con tain a large complement of mitochon dria. Therefore, in order to quantify the nuclear DNA of the giant neurons, it seemed necessary at the outset of these experiments to isolate the nuclei from the giant cells and rule out any contamination from glial or mitochon drial DNA. This precaution was justi fied in light of the finding that the glial cells and neuronal cytoplasm contrib ute 33 percent of the DNA to the intact giant cell (4). An abbreviated description of the procedure for removing the giant cell nucleus from the cell body follows. A more complete description will be pub lished separately (4). The abdominal and left pleural ganglia were removed from the animal and immersed in Millipore-filtered seawater (pH 7.4). The ganglia were incised under observation with the dissecting microscope, and selected cells were removed by sever ing the single axonal process. The neu rons were transferred to a depression slide containing Mfllipore-filtered sea water. A small hole was made in the giant cell membrane, and the nucleus was extruded from the hole by gentle squeezing of the cell. The nuclei of the largest neurons are polymorphic and take on many odd shapes. However, when the nuclei are extruded into sea- 278 SCIENCE. VOL. m cooieii C2CTC2on SUSPENDED USES 2,4,5-T1 ) SILVEX [ 2 ,4,5-trichlorophenoxy acetic acid, esters, amine salts] [2-(2,4,5-tri chlorophenoxy] propionic acid, esters, amine salts] Firetrails and lanes Forest lands, management areas, plantations, and stumplands-. Rights-of-way: highways, pipelines, powerlines, utilities, roadsides, roadways, etc. Pasture Farm buildings Forestlands and management areas Golf courses Home use, lawns, grass, ornamental turf, patios, sidewalks, driveways, farmyards Ditchbanks, drainage ditchbanks, ponds, pond margins, standing water Lake, lake margins Rights-of-way, all; roadsides, road ways, etc. Pasture Ditches - water Parks, athletic fields Marshlands, canals, aquatic sites NON-SUSPENDED OSES' 2,4,5-T SILVEX Rice Rangeland Airports "ences, hedgerows (not otherwise included in suspended uses, e.g., rights-of-way, pasture) Lumberyards Refineries Nonfood crops Storage areas Noncrop areas Wastelands (not otherwise included in suspended uses, e.g., forestry) Vacant lots Industrial sites and areas (not other wise included in suspended uses, e.g rights-of-way) Rice Rangeland Sugarcane Preharvest fruit drop of apples, prunes and pears Fence rows, hedgerows, fences (not otherwise included in suspended uses, e.g., rights-of-way, pasture, home and garden) Nonfood crop areas Noncrop areas Storage areas Waste areas Vacant lots, parking areas, etc. Industrial sites or buildings (not otherwise included in suspended uses, e.g., rights-of-way, commercial/ornamental turf) Certain uses of 2,4,5-T were suspended and cancelled in 1970. P. R. Notice 70-11, April 20, 1970, suspended the registrations for products containing 2,4,5-T and bearing directions for all uses in lakes, ponds and ditchbanks, and liquid formulations for use around the home, recreation areas, and similar sites. P. R. Notice 70-13, May 1, 1970, cancelled the registrations of 2,4,5-T products including all granular formulations for use around the home, recreation areas and similar sites, and all uses on food crops intended for human consumption, except for products whose labeling could be modified by deleting such claims. coois;5 8O92 3 CONFIDENTIAL - SUBJECT TO IN JU N C TIO N D.C., E.D. M l. 4- 4-78; D O W /E P A AGREEMENT 9 -7 9 8 1n N> 2 M A T E R I A L SAFETY DATA SHEET PAGE: ? DOW C H E M I C A L U . S . A . M I D L A N D M I C H I G A N 4 8 6 4 0 EM ER G EN C Y P H O N E : 5 1 7 - 6 3 6 - 4 4 0 0 EFFEC TIVE DATE: 08 JAN 80 PRODUCT CODE: 28749 PRODUCT NAME: ESTERON CR) 2 4 5 BRUSH AND WEED K IL L E R MSD: 0303 INGREDIENTS (TYPICAL VALUES-NOT SPECIFICATIO NS) :* ; 2*4*5-TRICHL0R0PHEN0XYACETIC ACID* PROPYLENE GLYCOL BUTYL ETHER ESTERS EM ULSIFIERS PLUS PETROLEUM SOLVENT :: : 69.2 I : 30.8 : SECTION 1 PHYSICAL DATA BO ILING POINT: IBP > 300F ( 1 5 0 0 : SOL. IN WATER: EMULSIFIABLE VAP P R E S S : < 6 MMHG a 2 0 C : SP. GRAVITY: 1 .0 6 5 (6 8 /6 8 F ) VAP D E N S ITY ( A IR = 1 > : NOT A P P L IC . : X VO LATILE BY VO L: N IL UNDER APPEARANCE AND ODOR: AMBER L I Q U I D . 150C SECTION 2 F IR E AND EXPLO SIO N HAZARD DATA FLASH POINT: (1 ) 180F (2) 154F : FLAMMABLE L IM IT S (STP IN A IR ) METHOD USED: ( 1 ) TOC (2 ) TCC : L F L : NOT D E T E R . U F L : NOT D ETER. E X T IN G U IS H IN G M E D IA : WATER FOG* FOAM* ALCOHOL FOAM* C 0 2 * DRY CH EM IC A L. S P E C IA L F IR E F IG H T IN G E Q U IP M E N T AND HAZARDS: USE S E L F -C O N T A IN E D A IR S U P P L Y . NOXIOUS FUMES UNDER F IR E C O N D IT IO N S . C O N T A IN WATER FROM F IR E F I G H T I N G TO PREVENT ENTRY TO WATER S U P P L IE S . SECTION 3 R E A C T IV IT Y DATA S T A B I L I T Y ? A V O I D T E M P E R A T U R E S N E A R OR A B O V E F L A S H P O I N T . in c o m p a t ib il it y : a c id * BASE* OXIDIZING m a t e r ia l , consult MANUFACTURER FOR S P E C IF IC CA SES. HAZARDOUS DECO M PO SITION PRODUCTS: NOXIOUS FUMES UNDER F IR E C O N D ITIO N S - HYD CHLORIDE AND OTHERS. HAZARDOUS PO LYM ER IZA TIO N : W ILL NOT OCCUR. SECTION 4 S P I L L * LE A K * AND DISPO SA L PROCEDURES A C TIO N TO TAKE FOR S P IL L S (USE WITH INERT DRY MATERIAL SUCH I N CASE OF LARGE S P I L L S . DO D IS P O S A L METHOD: BURY WASTE IN APPROPRIATE SAFETY E Q U IP M E N T ): ABSORB S P IL L S AS S A N D OR S A W D U S T . D I K E A R E A I N NOT USE WATER FOR CLEANUPNON-CROP AREA AWAY FROM WATER S U P P L IE S . (C O N T IN U E D ON PAGE 2 ) ( R ) I N D I C A T E S A TR A D E M A R K OF THE DOW C H E M I C A L C O M P A N Y . % MATERIAL SAFETY DATA SHEET PAGE: 2 DOU C H E M IC A L U . S . A . M ID L A N D M IC H IG A N 4 8 6 4 0 EMERGENCY PHONE: 5 1 7 - 6 3 6 - 4 4 0 0 EFFECTIVE DATE: 08 JAN 80 PRODUCT CODE: 28749 PRODUCT C C O N T ' D ) : ESTERON CR) 2 4 5 BRUSH AND WEED K IL L E R MSD: 0303X SECTION 5 HEALTH HAZARD DATA ?u IN G E S T IO N : MODERATE SINGLE DOSE ORAL T O X IC IT Y . RANGE OF 7 0 0 TO 1 0 0 0 M G /K G . EYE C O N TA C T: MAY BE A M IL D I R R I T A N T BUT SHOULD SLIGHT TRANSIENT CORNEAL EFFECTS. LD50 CAUSE CRAT) IN THE NO MORE THAN C tn fo 2 tri S K I N C O N T A C T : MAY C AUS E M I L D TO MO DERATE I R R I T A T I O N ON R E P E A T E D C O N T A C T . S K IN ABSORPTION: NOT ABSORBED IN TO XIC AMOUNTS. I N H A L A T I O N : NO G U ID E FOR CONTROL OF M IX T U R E E S T A B L I S H E D . DOU IH G 10 MG/M3 KEROSENE. EFFECTS OF OVEREXPOSURE: NAUSEA I F SWALLOWED. SECTION 6 F IR S T A ID -- NOTE TO P H Y S IC IA N FIRST AID PROCEDURES: e y e s : IR R IG A T E WITH FLOWING WATER IM M E D IA T E L Y AND CONTINUOUSLY FOR F IF T E E N M IN U TES . REFER TO MEDICAL PERSONNEL. S K I N : CONTACT W IL L PROBABLY CAUSE NO MORE THAN I R R I T A T I O N . WASH OFF I N F L O W I N G WATER OR S H O W E R . WASH C L O T H I N G B E F O R E R E U S E . IN H A L A T IO N : REMOVE TO FRESH A IR I F EFFECTS OCCUR. CONSULT M EDICAL PERSON I N G E S T I O N : DO NOT IN D U C E V O M I T I N G . CALL A P H Y S I C I A N AND /O R TRANSPORT TO EMERGENCY F A C I L I T Y . NOTE TO P H Y S I C I A N : EYES - MAY CAUSE M IL D I R R I T A T I O N . MAY CAUSE CORNEAL IN J OR B U R N . S T A I N FOR E V I D E N C E OF C O R N E A L I N J U R Y . I F C O R N E A I S BURNED* IN S T IL L A N T IB IO T IC STERIOD PREPARATION FREQUENTLY. CONSULT OPTHALMOLOGIST. S K IN - MAY CAUSE MILD I R R I T A T I O N . I N H A L A T I O N - NO TOX D A T A . NO E F F E C T E X P E C T E D . I N G E S T I O N - MAY C AUS E R E A C T I O N S I M I L A R TO P E T R O L E U M OR P E T R O L E U M - L I K E S O L V E N T . MAY CAUSE C H E M IC A L P N E U M O N IA I F A S P IR A T E D IN T O L U N G S . NOT L I K E L Y TO BE ABSORBED I N ACUTELY T O X IC AM O UNTS. I F LAVAGE IS PERFORMED SUGGEST ENDOTRACHEAL AND/OR ESOPHAGOSCOPIC CONTROL. S Y S T E M I C - A N E S T H E T I C OR N A R C O T I C E F F E C T MAY O C C U R . HAY C AUS E L I V E R DAM AG E. MAY CAUSE K ID N E Y DA M A G E . NO S P E C I F I C A N T I D O T E . TREATMENT B A S E D ON SOUND J U D G M E N T OF P H Y S I C I A N AND TH E I N D I V I D U A L R E A C T I O N S OF TH E P A T I E N T . BASED ON M I N I M A L D A T A . HUMAN E F F E C T S NOT ESTABLISHED. SECTION 7 SPECIAL HANDLING INFORMATION V E N T IL A T IO N : RECOMMEND CONTROL OF KEROSENE VAPORS TO SUGGESTED G U ID E . R E S P IR A T O R Y P R O T E C T IO N : NONE L IK E L Y TO BE NEEDED IN A N T IC IP A T E D OPERATIONS. PROTECTIVE CLOTHING: CLEAN BODY-COVERING CLOTHING. EYE PROTECTION: SAFETY GLASSES WITHOUT SIDE S H IE L D S . (C O N T IN U E D ON PAGE 3 ) ( R ) I N D I C A T E S A TRADEMARK OF THE DOW C H E M I C A L C O M P A N Y . 0003204 ow zyovvoa MATERIAL SAFETY DATA SHEET PAGE: 3 DOW C H E M I C A L U . S . A . M I D L A N D M I C H I G A N 4 8 6 4 0 E M E R G E N C Y P H O N E : 5 1 7 - 6 3 6 - 4 4 0 0 EFFEC TIV E DATE: 08 JAN 80 PRODUCT CODE: 28749 PRODUCT ( C O N T * D > : ESTERCN ( R ) 2 4 5 BRUSH AND WEED K I L L E R MSD: 0303 S E C T IO N 8 S P E C IA L PRECA UTIO NS AND A D D IT IO N A L IN FO R M A TIO N P R E C A U T IO N S TO BE TAKEN I N H A N D L IN G AND STORAGE: SEE L A B E L . KEEP OUT OF REACH OF C H IL D R E N . A V O ID CONTACT WITH S K IN AND E Y E S . P R O V ID E W A S H IN G F A C I L I T I E S NEAR WORK A R E A . DO NOT STORE NEAR F E R T I L I Z E R , S E E D S , I N S E C T I C I D E S , AND F U N G I C I D E S . KEEP AWAY FROM OPEN F L A M E . ADDITIONAL INFORMATION: REVISIONS 1 /8 /8 0 -- SECTIONS 5 , 7 . LAST PAGE ( R ) I N D I C A T E S A TRADEMARK OF THE DOW C H E M I C A L C O M P A N Y . THE I N F O R M A T I O N H E R E I N I S G I V E N I N GOOD F A I T H , BUT NO W A R R A N T Y , E X P R E S S E D OR I M P L I E D , I S M A D E . 18O I 8 UUW M A T E R I A L SAFETY DATA SHEET PAGE: 1 DOW CHEMICAL U.S.A. MIDLAND MICHIGAN 48640 EMERGENCY PHONE: 517-636-4400 E FFEC TIVE DATE: 08 JAN 80 PRODUCT CODE: 2 8 7 5 0 PRODUCT NAME: ESTERON ( R ) 2 4 5 BRUSH AND WEED K IL L E R .(PL i BULK) MSEC 0 3 0 3 IN G R ED IEN TS (T Y P IC A L VALUES-NOT S P E C IF IC A T IO N S ) 2 4 5-TR IC H L0R 0P H E N 0X Y A C E TIC ACID PROPYLENE GLYCOL BUTYL ETHER ESTERS E M U L S IF IE R S PLUS PETROLEUM SOLVENT SECTION 1 PHYSICAL DATA XZ \ J %69.2 : 3 0 .8 : t : o* ^ vji O' B O IL IN G P O IN T: IB P > 3 0 0 F ( 1 5 0 0 JSOL. IN WATER: EM U LSIFIA B LE V A P P R E S S : < 6 MMHG B 2 0 C : S P . GRAVITY: 1 .0 6 5 ( 6 8 /6 8 F ) VA P D E N S IT Y ( A I R = 1 ) J NOT A P P L IC . : Z V O L A T IL E BY VO L: N IL UNDER APPEARANCE AND ODOR: AMBER L I Q U I D . 150C SECTION 2 F IR E AND EXPLO SIO N HAZARD DATA F L A S H P O I N T J* ( 1 ) 1 8 0 F ( 2 ) 1 5 4 F : FLAMMABLE L IM IT S (STP IN A IR ) m ethod u s e d : (i> toc (2 ) tcc : l f l : not d e te r , u f l : not d e t e r . E X T IN G U IS H IN G M E D IA : WATER FOG FOAM ALCOHOL FOAM C02 DRY C H E M IC A L . S P E C IA L F I R E F IG H T IN G E Q U IP M E N T AND HAZARDS.* USE S E L F -C O N T A IN E D A IR S U P P L Y . NOXIOUS FUMES UNDER F IR E C O N D IT IO N S . C O N T A IN WATER FROM F I R E F IG H T IN G TO PREVENT ENTRY TO WATER S U P P L IE S . SECTION 3 R E A C T IV IT Y DATA S T A B I L I T Y : A V O ID T E M P E R A T U R E S NEAR OR ABOVE FLA SH P O I N T . i n c o m p a t i b i l i t y : a c i d b a s e o x i d i z i n g M A TE R IA L. CONSULT MANUFACTURER FOR S P E C IF IC CASES. HAZARDOUS DECOM POSITION PRODUCTS: NOXIOUS FUMES UNDER F IR E C O N D ITIO N S - HYDROGEN CHLO RIDE AND OTHERS. HAZARDOUS P O L Y M E R IZ A T IO N : W IL L NOT OCCUR. * . CGG575I SECTION 4 S P IL L LEAK AND D IS P O S A L PROCEDURES ,/ A C T IO N TO TAKE FOR S P IL L S (U S E APPRO PRIATE SAFETY E Q U IP M E N T ): ABSORB S P IL L S W I T H I N E R T DRY M A T E R I A L SU C H AS SAND OR S A W D U S T . D I K E AREA I N I N CASE OF LARGE S P I L L S . DO NOT USE WATER FOR C L E A N U P .- D I S P O S A L M E T H O D : BURY WASTE I N N O N -C R O P AREA AWAY FROM WATER S U P P L I E S . ( C O N T IN U E D ON PAGE 2 ) ( R ) I N D I C A T E S A R E G I S T E R E D OR TRADEMARK NAME OF T H E DOW C H E M IC A L COMPANY 1 M A T E R I A L SAFETY DATA SHEET PAGE: 3 D O W C H E M I C A L U . S . A . M I D L A N D M I C H I G A N 4 8 6 4 0 E M E R G E N C Y PHONE,* 5 1 7 - 6 3 6 - 4 4 0 0 E F F E C T IV E DATE: 08 JAN 80 PRODUCT PR O D U C T ( C O N T ' D ) . * ESTER O N ( R ) 2 4 5 BRUSH AND WEED K IL L E R (P L BULK) PR O TEC TIVE C LO TH IN G : CLEAN BODY-COVERING C LO THING EYE PR O TEC TIO N : SAFETY GLASSES WITHOUT S ID E S H IE L D S . CODE: 2 8 7 5 0 2 MSD: 0 3 0 3 SECTION 8 S P E C IA L PR EC AUTIO NS AND A D D IT IO N A L INFO RM ATIO N P R E C A U T IO N S TO BE TAKEN I N H A N D L IN G AND STORAGE: SEE L A B E L . KEEP OUT OF REACH OF C H IL D R E N . A V O ID CONTACT W ITH S K IN AND E Y E S . PRO VIDE W A S H IN G F A C I L I T I E S NEAR WORK A R E A . DO NOT S T O R E NEAR F E R T I L I Z E R S E E D S I N S E C T I C I D E S AND F U N G I C I D E S . KEEP AWAY FROM OPEN F L A M E . A D D IT IO N A L IN FO R M A TIO N : R E V IS IO N S 1 / 8 / 8 0 ~ SECTIONS 5 7 . Last page <R> I N D I C A T E S A R E G I S T E R E D OR TRADEM ARK NAME OF T H E DOW C H E M IC A L COMPANY T H E IN F O R M A T IO N H E R E IN I S G IV E N I N GOOD F A IT H BUT NO WARRANTY E X P R E S S E D OR I M P L I E D I S MADE. n r? c cr ( ( ,/ "'JirUJJ#"^iAjti->;' !$:* 'C'1'-" 9-'^:>'* '".''v-'V-- ':.-i-.V^.. .> Vi'-i?.v ''%*" ' tw t^ ftn.nr.1 Bru*l\ K ille r ":.yV:S :...'.' fv /. ' **'*l*i<'ft* of botv 'atyron uni BruAy. ill r w#rt* nf*Tifcr*d''b? Ad4dKi - V l ` lc 3*-W h :t n **>-;.* -,'> :rV cc-i f w 1 -bon.t^r.* W v a W / T ^ ^ i l *"****,? r,> *?-'3t"t4M -fo"r* -* ' V rmt.>tnunt*fttn*.r gf vo*r5N*jAfcuolauirdd^.*&^j;s. rew*.r%v;.^v4r. -.A hl M ^ T7 ' `ni: \*r? .ruii * sAftj .Jy'y.-y J L c ^ .1 IZI Vw- 1 DOW 48 C'J '".5 O CD 252061 i' i -, i i1 .*. t V ESTERON 245 HERBICIDE FOR THE C O N T R O L OF TREES, B R U S H A N D B R O A D L E A F W E E D S Low Volatile Brush and Weed Herbicide for Industrial Vegetation Control, Fencerows, and Rangeland ACTIVE INCiflED'ENT ? 4 5 T r' Cr>'oopt'<,' ' o i y . i t che A c r l P r o p y ' o n p G tycn'RulylEinpfEiHrs INEPT iNGREDiFNTS 2 4 i T f C r' l O' ppH' o o i y , i c r l : i . A c d E qi .nt .i l on! - 45 O- ' J P ui tr ul s po> G.i Hnn E P A nnr3Mp.1 t.on No te 4 ?05 69?". JO - E P A Esl 46 Wl I P R E C A U C I O N AL U U A P lO S ..il oO nn lop mq lo s no uso r-str* pro du cto h ,i s1.1 p uf ' I. ( 1 q u l ` t.1 N` K l y .1 sidO i ' i pl 'C rld.l i m p l . i i m o n l o Tf l A N S L A T I O N ( T O T h E U S F n I y o u c n n n p t r r , i d t ^ <1 ps ' ' rln n ol 11 ^ r- Ihi. prOcJuM i . r t i l M' r M h o t h ns h ^ c n u l1 y p i p l . v n r c t | q yo u | k e e p O u t o f t h e r a c h o *' c h i l d r e n CAUTION HARMFUL IF SWALLOWED MAY CAUSE IRRITATION Avoid Contact with Eyes. Skin end Clothing Do Nol Cut or Weld Container H r i l l o! in *m*rg*n* f frc U n ju nq i fr or p io ptrty in3l*mq ih<i p.oduci t a il r o i'p n 517-636-4400 AGRICULTURAL CHEMICAL C 't S i i S ^ o e 'S 'T i r t . i h f o o - l rili P iuq i tv C ioih-',q 18.93 L /5 gal 86-1064 PRINTED IN U.S.A. IN JANUARY, 1980. REPLACES SPECIMEN LABEL 86-1064 PRINTED IN SEPTEMBER, 1979. DISCARD PREVIOUS SPECIMEN LABELS. REVISIONS INCLUDE: USES ON INDUSTRIAL SITES AND FENCEROWS REINSTATED BY EPA. W' i.-^; V.V: iJoi Mt-u '.* .-i - >'.Vi'^1 i to ' 'B r: ' 1 m *v. V ** Insert I 1f M-o W 1 V ' it' . t'/: Ufvi> NJ N< 'Atl..- i.V S r *:!r- 4 t ro !<*>' tj*j 'I n a r t 2 ' `v h' > I& - I* ESTERON 245 HERBICIDE C o n tain s P ropy len e Glycol B utyl E ther Enters of 2.4.S-T A cid E quivalent: 4 P o u n d s p er G allon amean o wa r ow uae M se. m w . lU U in h . I iw m iiH ' 1 1 - 1 in i rth * - - M f e w D * ft* ESTIRON M w t w e f y M tt May i w M tl w iifc|i S.4.DT ewempURto T i p i at o d o r m i r a t ptonee at mey rewtomtoete PREPARINO THI SPRAY Uce erdy dtoeM eS. N e. I e t N e. S M eS er b rn m ea A ere eS N w OS epreye: ASS TIRON M le tepuHeS m io i S A ta te re y M r mtatog M R enS Ne oieepW y, T ito etoboe cm He mede e t oy tto e Helara ecM A use enS ee o p e ra to e t eeeo. Oe s e i N i cny te r, er eS eeM toim e eprey* p A Use S o ESTIRON M er H ite W * Antahel m m . m R msy lerm e AreS emewM s i ESTIRON MS end esmpN N RRnp S o H A , MA Sm ronglto end n n iS m i epReHen M e p r H p . Ceudee: See N O T I H paragraph re OR W ater Mtotaure Spreye. NAto. U ta 1 l / l r * -~ i A ISTERON M U A b ro I e l. M i I m oepe w W | iw i lw l high am i Ao m to M> | * w A M W < * ta ii pm act*. M p w r U iliim N ta lM iM M , eu H A b m ta So M M p i ar retoe M i S p S m <4 IS T IRON M U tOOgea'om i l ita M p H u lM MtoS a to lA to For mere reetoem pectoe, Me 4 petot A TIRON MS U MO p o m I I pint in 1 A onel I c l p*~` [ i* i[i n rn tY ------ -------- --- *------ O m e tre rprv*"0et A n m d cvm a tun A l to d o ground Ine H nebceeHNOW a rm a ta berta reetdtM m ere eprey otarme (to n young e r rm e e th berta, A p p ly e l en y m e. to ctuton g adoquoie n r Trepe nermeto *epwHM Hem 10 te MO ebete per eoe H eentfnp en denehy at m ry e ar rtA e . "PH" T reatm ent: Fer tope treee. M e e etogRdeAi M e er " W al e Nppnp n r ente em wNtely erauwd S e see a Aar Spray H o Ir ti Staeuptoy uAnp e nSrhrre at 1 p N n t at ESTIRON M A MO pelero M /l pto tai 1 Ir r o i a t a O pel PeAepe Treeim eM ; Um 1/4 pee A CST lRON M A I Mane at ont end apr*v te oe A l M ope. A eete. eNme end berta M ou nmeM LOW V O LU M I SARAVS Apply lew ye lm o epreye M n to to g IST1R 0N M o rto leM pe N A e M ould He eufltdenl te prem eo loSer p ip o . SmPytog durAp piApnp es le i. P y eeSor et A ter lemee im e teA P o i mmA green caler mtd per n o y n e l p io w d re ta ry aero A Apply N o vetarme *re *e Hy A r or prermd ISTERON SM A rwmNSy up te M p A ire A c l taMO peAene A eprey M ta n . PHet prenM S o ESTIRON MS end e s in e erp a ile ce n tM w . Oc net A teo eny w etaerM rrm m ecenotaU nsvoM r I I gA A ie S o CSTCRON > a S o premo. i. M S o premie H pw Ht (eea bt eR emAAen wNch yrO He to rd te Week. Ae en At o m pS mpy be eSSed A te r S o ISTERON MS H rA m d H S o A TIRON MO MS> tarA eS a fc rie rm t te Potae IS p Sen. A pA r taM e pateM e hropeec* mieN4cor le A ASM A tew o HruAi eterne IrtAuAnp S o root ester. OesS carempP A D a reel eeWr I reeAO ` 1/4 w i / l r - * TtO pm N O T I: ESTIRON MSH H K IH V O L U M I SSR ATS HceA pero A HnMt etaane end eee mmtae M HelpN A I t o IS tavJoe Hem So r o rrA N o Um s eAuHPn A l A e ro A ESTIRON M Hi MO pM cne I t pHn A 4 pA enA A A W tdi ecroH iiilr t ii epeAee. 4 A e ro A ESTIRON MS A MO pA e ro 11 pH Hr | peianel A A . la A e cSre, As erdy P o HceA $erbaio A So cenp N o oefSnp A S o HAreM d ee H n oe m ay. pprScAedy m So round in e . TtaO nom o m i * * A rurvPpwn a m a tt le S o round Ero H rodeeeWH. OW a rewpH betta n rH n mere eprey S on y * n | a emoorh berta. Leo p e iiii ee a e deAmWe. Apply at am Sme. IAeAnp So enor m ondo. eept on a te o . Ne a m m preen aprcydn m So ro u n d One O ften dAeyed P iu m a Sim R: TreA eny me A m knA to dprwen A d m m A S o NAepe to e dropped Sprey A ouA He edneeneeted A S o Hem A atome A d H. edAlton. S o vppa pero A s o oM m A o A d He H rrrP rt el rprpyed o w S * ta A Som . U ndo rooM ataerNp e p ig1-- aneti ee em roc, paelmm 3 1-RwM De no M Hem early Heel M A etepe Aere r a n eeed predwcSen H deeded M eepA te: Uee I pM (TIR O N SA p io 1 /1 M I ^ a A A In aow ph m w meta 4 peSero A M A eprey por eoe. A #A r A te M deye attm RrA Na.ee eppea- Send SM nnery O A : UM 1/1 le I p u a i A ISTERON MS ptare I pA en A A H enough veto m ohe 4 A e ro A te A M **v per earn. S eat end Bteeta jc A Oetac. Um I o r ti A ESTIRON M ptam I pA cn A A N enough m a le mdke 4 te 0 p N o A w A eprey p a eue- USE PRECAUTIONS N ote: Oe ne prete deUy enHAH en heeod ercee APA 0 > iiA e A m p A co len. Oe ne r u e mee ermAS a H eetA ereee oM dn 1 eetae A SSuphM, AVOID CONTACT WTTM L4.0-T B U S C tm S U CROPS AND O TH IR O ISIRASLS SROAOUAF PLANTS-ESTCRON M MaitaW di N UpAoue te e A m ktaro e n o w O eenteci oelten, p p . toHecde. H A t po m . epeteHNa. S o o n , CrromenteN a Sm dASetoto |S w to H to S M to 1.4.ST O e n H u m Hi at na a pmenheuM OO NOT APP1V IN TMS V ia M TV OP COTTON. RAPSS. TOtoACCO, TOMATOES OR O TH IR M S JR A R U M A T SURCEPTISU CROPS OR ORNAMENTAL PLANTS. DO NOT SPRAY W H IN W IND IS S L O W S TOWA M M SU toC BPnSU C H O FI OS O AN AM C N TAl R IAN TS. AVO ID S F fU V O A V T -A pplcedam A e N Se m N er#y c N n D e * N ee A e m w * N lM N lN ie l n v .e N A M r ie tN N 1M Mone. In e M *to R upNte m m dtS e rn ie cr mere H e a m i StoAnto p egent. NALCO T R O t', n e r He u tN u b i N i produci le Ad ta ' ------- *-- " ueed teOm e w M m HAICD 1 R 0 L - liodcm otta al NAiC O Cliq tto A Cemper^ OROUND lO U tP M E N T--WIS gfm d re tH e o e . M # y M R cen He NeeeneS Hy ta p in g P o prey Haem m le ** ee peeeRto. Hy ip lM m 9 (A e re er mere e l eprey per cera; Hy wAng ne mere Pier 1S pe mde epH itog pramme *R tope p ie re i producing n o ita Rp; Hy M 'cytnp Am i M H id ty R S e N i pee Hew er leee. De n e l epply M hA too cene-type keocHeMo er edM rocrtoc M pro- A lR IA i APSU C A TIO N -W W i M a A l. drS l c o i He NMHM ceerae a m i. Hy M*np ne mere d on 10pownSe rp re i Neeewe i ueAp eeApN reeem noiA M Areered etrApM HecA. Hy eeAp eprey Heem m lonpa Son 3/4 So Hip tapen A S o oU apIt: end Hy M fr*S erVy wben And eNAly N leee S on S mpn. DO NOT A S S IT SV A lACRAPT SINON AN A IR T1MSSRATURS M V tR - SION EXISTS SvA eendMen N chaecoraed Hy MSe a ne NnoAPtane A o a npa S o fO rrnd Son M ta ilo r ImeN. Thetoe A e o rt a neer AO A eppSceMn O cuppeeted le AAHeee Me H FI pern Hem Sr We pieno fre w in p neerHy i m l tree A a mam a preatReo em euno A AN HaWASe H S o A may om pererly HSMR eeeSp De n e i toe ere o A S o Ho THN product H MAc M AAi- ReapOut A H pceer TNe product en A to i AH A uAoetod HA A n p H A io heednp om paeM M . rheAS ka mamm ta at NeA 40*F end mh bAere uelng De nec emre ro a M SOere. le e . IraecSeMM HmptASm. Oe ne reuM ta io ia e Te veld kp a y te SeeHrAe pN no, de A Am e. to n d e a HAta dih ISTERON hetoe HSom a A Hmytos *Sd mete e* Atoa eRtoW R Ic c A u nd Som n oy Atoe S o oe A hetM AdM CeneAl yem Shoe At N A m A Eepenmem Siedan er U b a i Sentae reeS tpeeMhH to r adrfoe to edHcSnp HM im eno Hem Sto NHA o HeA to toeA eenddero. Sc ama Sm mamml Sto r duct cenlerm c to A wANeM e rcputoSero. Apply R O T IC I: S cM m e ta S e i S o em bua M to w r o He ehm to teeeenrHiv to M d o popeee o e o d a S o M M A on m A o eeea un do na m A epndtoeM A ta d . to d M d m S N tn n M N M r a ir A CHANTAIUlTV OS F IT M If FOR A PARTICULAR PURPOSE, a onde to the M A H to p re to e t e a o a y to ta *A toabw eboo. a e Hto M M . endHuya THE DOW CHEMICAL COMPANY AND SU USIUl A lili S M lD LA N O , M IC H IG A N 4 1 1 4 0 . U SA H 0R G E N . SW ITZE R LA N D HONG KONG CORAL G ABLES FLO RIDA J 1 3 4 . USA S M IM A . O N TA R IO . C A N AD A 4 > 1 > i.'i*n > rik n i r MI 0 0 W I MI I A i. C'J 'A P t N > co O':i\ t/-; o .1^ oo .'4 O' f'D O ..'J/AV i ; 1 *'. ;ti th tX ';li''i' / ! 8X DOW1081805 \ DOW CHEMICAL U.S.A. February- 4, 1980 MIDLAND. -MICHIGAN 48640 To: R. R. Cook > M.D. Re: A CRITICAL REVIEW OF: "CASE-CONTROL STUDY OF MALIGNANT MESENCHYMAL SOFT-TISSUE TUMORS AND EXPOSURE TO CHEMICAL SUBSTANCES." SUMMARY This report presents a critique of the study by Hardell and Axelson which according to the authors "Indicates that exposure to phenoxy a d d s must constitute a risk factor with regard to the origin of malignant mesenchymal soft-tissue tumors, and that the risk relates not only to those phenoxy acids that like certain chlorophenols, may contain polychlorinated dibenzo-dioxins and dibenzofurans but also to other phenoxy acids." - It is not clear whether the cases selected for study are repre sentative of all cases in the area. The individual diagnoses of soft-tissue sarcoma include a rather diverse listing of tumor types. Several subtle sources of bias may have been introduced in the selec tion of the controls, which may have influenced the percentage re porting employment in the occupations of interest, agriculture and forestry. Information concerning exposure was obtained via telephone interview and a mailed questionnaire; there was no documented evi dence of exposure presented. Media attention to previous studies by Hardell may have sensitized the cases to recalling exposures better than controls. Questionnaire information was, in some cases, supple mented by a telephone interview and this further increased the possi bility for the introduction of bias. The individual relative risks for exposure to a number of specific chemical pesticides were signifi cantly greater than one. It can be argued that the study did not test the risk of exposure to specific chemical agents but instead assessed the risk associated with employment in agriculture and forestry. In view of the lack of reliable exposure information, in con sideration of the several sources of bias introduced by the methodology employed, and despite the consistency of the findings between this and another identical study done by Hardell in the north of Sweden, one must regard the suggested association as suspect. CG0GGS7 A N OPERATING UNIT OF THE DOW CHEMICAL COM PANY 908T801 MOO R. R. Cook, M.D. Tebruary 4, 1980 Page 2 INTRODUCTION In a recent case-control epidemiologic study an association between soft-tissue sarcomas and prior occupational exposure to phenoxyacetic acids or chlorophenols was suggested. One hundred and ten (110) male patients, aged 25-75 years, with malignant mesen chymal soft-tissue tumors verified at histopathological review, were individually matched with two controls each on the basis of sex, age, place of residence, vital status, and year of death for those deceased. Living patients and controls were contacted by telephone and mailed a questionnaire concerning past occupations, types of occupational exposure (especially chemical), smoking habits, etc. The next of kin of deceased patients and controls was contacted and mailed a similar questionnaire. The answers were studied for possible exposure to phenoxyacetic acids or chlorophenols and it was noted that exposure had occurred to 22.72 of the patients and to 5.92 of the controls, thus generating a relative risk of 5.1. This study is remarkably similar in design to an earlier study done by Hardell et al , which demonstrated a very similar relative risk (5.7) for soft-tissue sarcoma associated with exposure to phenoxy acetic acids or chlorophenols in a geographically distinct area from the area surveyed in the present study. These two studies by Hardell are, to the best of my knowledge, the only ones to suggest an associa tion between soft-tissue sarcoma^and exposure to phenoxyacetic acids or chlorophenols. Other reportsJ suggesting an association with cancer have been confined to case-reports and geographically limited studies; the lack of a sentinel tumor has somewhat weakened the putative association. Available data concerning human exposure to the phenoxy herbicides, 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methyl-phenoxy-acetic acid (MCPA), which do not contain the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin, indicate no associative relationship with the development of neoplasia. Car cinogenic or tumorigenic responses have not been produced in mice fed 46.6-100mg/kg, 2,4-D of diet nor in rats fed 1,250 mg/kg, 2,4-D of diet for 18 to 24 months. Single subcutaneous injections of 21.5215 mg/kg, 2,4-D did not produce carcinogenic or tumorigenic re sponses in mice. . CC06G83 8109 DOW J081807 R. R. Cook, H.D. February 4, 1980 Page 3 CRITIQUE .- Background The authors present background information on the tonnage of phenoxy acid used in Sweden in 1977. Figures regarding phenoxy acid use 10 years ago and before would have more relevance to the cancer cases diagnosed from 1974 to 1978. It is mentioned that as a result of prohibiting the use of 2,4,5-T in 1977, the phenoxy acids, MCPA and 2,4-D, have seen increased use. The following paragraph suggests that this study will offer the possibility of specifically analyzing the potential effects of MCPA and 2,4-D. It is not clear how much use MCPA and 2,4-D had 10 years ago and before, when exposures relevant to the cancer cases in this study may have occurred. Selection of Cases Cases of malignant mesenchymal soft-tissue tumors were selected for study from all male cases which were diagnosed and reported to the National Social Welfare Boards' Cancer Register in the years 1974-1978. The authors do not indicate what percentage of all can cers are reported to the Register, nor do they discuss possible se lection bias which could influence the reporting of cases. Thus, it is difficult to evaluate the representativeness of the sample. In any case-control study, it is imperative that the cases chosen for study are representative of all such cases or there is no unknown bias influencing their selection. From Table VI, Histopathological Diagnosis in the Reviewed Material, the rather lengthy and diverse list of diagnoses included for study can be noted. Certainly, a sufficient number of cases of Leiomyosarcoma existed so that the study could have been restricted to individuals with such a diagnosis, and a more meaningful study may have resulted. Selection of Controls Controls must be selected from the same general population which gave rise to the cases. Any known bias which influenced the selection CG0GGS3 DOW 1081808 R. R. Cook, M.D. .February 4, 1980 Page 4 of cases must be applied equally to the selection of the controls. The matching design employed in this study proved to be quite waste ful, the authors eventually discarded over 700 originally selected controls. It is unclear why 8 controls were initially matched for each living case and 10 controls were matched for each deceased case. For cases dying in 1978, controls who were deceased in 1977 were matched for ethical reasons. This may have created a systematic bias, since next of kin for controls may have had more difficulty recalling exposures due to the increased time since death. The matching design was compromised as 12 controls were selected from municipalities which were separate and distinct from those which gave rise to the cases. If such areas are underrepresented by workers in the occupations of interest (farming, forestry work) then there is bias introduced. Another source of possible systematic bias was introduced when controls were selected conditional upon gainful employment until five years before the subject's retirement or death. This condition was not stipulated for selection of the cases, and may have eliminated controls who worked in the occupations of interest. It is quite possible that the nature of occupation is related to the age at retirement. Assessment of Exposure In any case-control study, it is critical that information concerning possible exposures be gathered in a comparable manner for both cases and controls. Since the analysis is dependent upon a comparison of responses by the cases and controls, it is especially sensitive to the influence of bias in the reporting of exposure. There is a tendency for cases to recollect prior exposures better than controls, thus leading to a relatively higher reporting rate by cases. Answers to questionnaires were studied and supplemented over the telephone. This can lead to a problem with the lack of compara bility in the accuracy and completeness of responses by the cases and controls. If a greater proportion of cases than controls were con tacted for supplementary information, there is the possibility that bias entered into the reporting and perhaps inflated the exposures CCG6G30 (,' 8111 DOW f081809 R. R. Cook, M.D. February 4, 1980 Tage 5 reported by cases. Unfortunately, the authors do not indicate vhat proportion of the study subjects were contacted for supplementary information, nor do they Indicate the nature of the questions asked. It is mentioned that employers, boards of agriculture, machine pools, neighbors and others were interviewed in order to elucidate possible exposures. The authors did not indicate how this information was used in the analysis, nor do they indicate whether it corroborated or contradicted information obtained from study subjects or next of kin. The specific nature of the questionnaire mailed to study subjects is not provided. The authors feel the questionnaire masked its true intent, but it is unlikely that respondents knew or remembered which chemicals they were exposed to without some prodding on the part of the investigators. It is more probable, given the media attention to phenoxy herbicides and dioxin, that respondents were particularly alerted to questions about exposure to these chemicals. Apart from whether or. not the responses from cases and controls were obtained in an equally valid manner, is the rather vague nature of the exposure information. It is apparent that what this study is testing is not the risk associated with working with chlorophenols and phenoxy acids, but the risk associated with working in forestry and agriculture. These occupations are associated with exposure to a variety of physical, chemical and biological agents. It is impos sible to single out one or even several of these agents as the cause of soft-tissue sarcoma based on the environmental data presented. The authors do not discuss the intensity or duration of exposure in curred by study participants nor do they discuss latency. Both of these factors made the conclusions drawn by Hardell in his earlier study incompatible with the relevant scientific literature on exposure to phenoxy acids and chlorophenols. Statistical Methods The statistical analysis employed is generally appropriate; however, the authors decided to dissolve the matching when it is generally recognized that more correct estimates of both risk and statistical significance are obtained when the analysis maintains the matching. The only motivation for dissolving the matching is the relatively simplified calculations which result. GGQ6031 l 8112 DOW 108181Q i R. R. Cook, M.D. February 4, 1980 ?age 6 Results One control was excluded In the analysis stage and no justifi cation for his exclusion was given. One could argue that the matched case and other control should have been dropped as well. The authors note the loss in efficiency resulting from dispersal of the matching (relative risk for matching retained 5 . 1 versus relative risk for .dissolved matching 4.7), yet they drop the matching to simplify the analysis. Table II presents exposure to phenoxy acids in cases and controls after exclusion of chlorophenols and dissolution of matching. The relative risk of 6.8 was statistically significant at a 95% confidence interval. The authors imply a dose-response relationship appeared in the division of the material, but to infer such a relationship is ludicrous. The difference between the exposure strata was one less control in the strata reporting exposure greater than 30 days. Statistical significance was established for the risk associated with exposure to all of thp herbicides analyzed. Although the rela tive risk associated with exposure to each of the agents was statis tically greater than 1.0, this would tend to argue that the risk is associated with the occupations and not with any specific agent which could be singled out for analysis. The authors fail to see this logic and contend that exposure to all the agents examined resulted in an increased risk. Table V provides evidence that the cases reported exposure to everything more often than did controls. This argues two points; one, the number of potentially harmful agents associated with working in forestry or agriculture precludes singling one or several agents out as the causative agent, and two, the cases were much more sensitive to questions concerning exposure and were more likely to report ex posure to chemical agents than controls. Discussion It is apparent that either the living controls used were not checked against the National Cancer Register and excluded if they appeared, or that the Register is not a complete listing of cancer patients. The authors admit that a living control in fact had cancer, v/v>Uou^w DOW 1081811 R. R. C ook, M . D. February 4, 1980 Page 7 and view their error as one of conservatism. If the Register is not a complete listing of cancer cases, one must question which factors influence the reporting of cases to the Register and how the distribu tion of this factor may differ amongst the cases and controls. The authors state that, "No calculation of the risk for individual chemical controls other than phenoxy acids was considered meaningful since there were too few exposed cases and controls." One could argue that the paucity of subjects and controls exposed to other chemical pesticides is a direct result of an incomplete and incomparable effort to obtain information concerning exposure to other pesticides and other chemical agents. The authors admit that it is conceivable that the cases attach more importance to questions concerning exposures than do the controls. They attempt to demonstrate that there was no distortion of the es-' tablishment of exposure to phenoxy acids with some questionable sta tistics in Table VII. The authors argue that if misreporting of exposure by cases were to "occur, that this misreporting would occur independent of the persons' occupation. What is really at issue is whether or not cases within an occupational group recall specific exposures better than controls within the same occupational group. This requires a validity check on responses which is not provided in this study. Thus, the authors cannot assume that misreporting did not occur on the basis of the analysis they perform Conclusion Consistent findings across epidemiologic studies generally lend support to the findings; however, in this instance, since both studies were done by the same authors and therefore, probably repli cated both the results and the errors in design, collection of data or analysis, little significance can be attributed to the consistency of the findings. Given there are several potential sources of bias in these studies and the validity of the exposure information is suspect, the association between soft-tissue sarcomas and prior occupational exposure to phenoxyacetic acids or chlorophenols suggested by this and the earlier study must be regarded suspiciously. Further studies of this association should address the plethora of exposure agents asso ciated with the occupations (forestry and agriculture) which have been identified as being at an increased risk for soft-tissue sarcoma. C006033 V. DOWf 081812 R. R. Cook, M.D. February 4, 1980 ia&e Perhaps a study design which is not case-control retrospective in nature, could be employed to obtain a better estimate of the risk associated with agricultural and forestry work. In any event, further studies must direct attention towards obtaining more complete and valid exposure data. Gregory G. Bond, M.P.H. Epidemiologist U.S. Area Medical, H&ES GGB/mp CG06031 DOW1081813 References 1. T. Hardell, M. Eriksson, N. Berg, T. Moller and 0. Axelson, 1979. Case-Control Study of Malignant Mesenchymal Soft-Tissue Tumors and Exposure to Chemical Substances. Submitted for publication. 2. T. Hardell, A. Sandstrom, 1979. Case Control Study: SoftTissue Sarcomas and Exposure to Phenoxyacetic Acids or Chlorophenols. British J. Cancer. 39:711-717. 3. Young, A.L., J.A. Calcagni, C.E. Thalken, J.W. Tremblay, 1978. The Toxicology, Environmental Fate, and Human Risk of Herbicide Orange and its Associated Dioxin. USAF OEHL Report TR-78-92. 000603^ 8ii e IS3 I83 'CO 8 FEB 60 A QUALITY ASSURANCE SYSTEM SELECTED LISTIN G PAGE 8 M . S . D . S . DOCUMENTS L I S T IN K . S . D . S . NUMBER SEQUENCE USDS * LEVEL 70 COOE PRODUCT NAME 0303 0303 "S T E R C N ( R ) 2 * 5 BRUSH AND WEED K IL L E F ESTERON (R> 2 * 5 BRUSH AND WEED K IL L E R lP L l BU LK } o O' O' VJ1 VJ1 O' DOW999223 YtVa-PS - 0 \O J -^ 'i (p O\0opv"7S' C>\ t>< 0003733 18 4- \ 8119 mz/OM health and environm ental SCIENCES J L . ~ d x & ^ f/' i V/} Co /) /7, /A > ~ T -L je J t / / */1 ' *W%** < / f . 6 A /r * * * , to. /f. (^. A /^U4/ //.A <2*** ^^Zu h . ^ Uu*+x/+< C .Z> . U Z+ nC *, 0 * 0 JL. A1'. U / +*++ 2 T S re /e sA / 2^ $^ e s r e /z o # / ^ tfit/e tA J /+ * * y t^ ir ^ jA , / n ^t(r>y <o/Lc<y . ^-t ^ u r in `+~*+L yC4> &+** ^<**5i Xt S7U **r s/ aJsoU , . nM m a r g u e r ite l. LENG 9008 B u ildin g Phone(517) 636 -372 0 ,0 ; ,, - -i,<'0 0008420 ISS' 18 r I 21 > IT ^I U/JSS8 J\ ^ WO** UNITED STATES ENVIRO NM ENTAL PROTECTION AGENCY W A S H IN G T O N . O .C . 2 0 4 6 0 DOW 212891 as r- Marguerite L. leng, Ph.D. Dow Chemical Company P.O. Box 1706 Midland, MI 48640 Dear Dr. Xeng: Subject: Revised 2,4,5-T and Silvex Interim Amended Registration for KURON IOW-VOLATIEE BRUSH AMD WEED HERBICIDE EPA Registration Ho. 464-162 ESTERON BRUSH 1CELIER EPA Registration Ho. 464-204 ESTERON 245 HERBICIDE EPA Registration Ho. 464-205 Tour letters of January 3, 1980, and January 21, 1980 The labeling referred to above, submitted in connection with registration under the Federal Insecticide, Fungicide and Rodenticide Act, as amended, is acceptable. A stamped copy is enclosed for your records. Sincerely, Willa T. G a m e r , Ph.D. Product Manager (23) Fungicide-Herbicide Branch Registration Division (TS-767) Enclosure: Stamped label RECEIVED F E B 1 5 1980 REGISTRATION 0001778 DOW212892 LOW-VOLATILE BRUSH AND - Contains;Propylene Glycol Butyl E ^Acid: Equivalent: 4 pound fo r t h e : CONTROL OF MANY WOODY ANNUAL AND PERENNL ACTIVE INGREDIENT: Silvex, [2-(2,4.5-Trichlorophenoxy) propionic Acidl Propylene Glycol (CjHtO to C9HisOj) Butyl Ether E sters'.....................69.2% INERTTINGREDIENTS:.....................................................................................30.8% Silvex|2-(2,4,5-Trich!orophenoxy) propionic Acid| Equivalent;45.B%-- 4 pounds per gallon E.P.A. Registration N o .464-162 E.P.A. Esl. 464-MI-1 PRECAUCION. AL. USUARIO: Si usted no lee-ingls, no-use este producto ;hastaque la etiqueta le haya sido explicada ampliamente. -TRANSLATIO N: (TO.THE USER: If you cannot read English, do not use this product until the label has been fully explained to you.) * .' HAM _ U cruoll propertyi| *> 18.93 L/.5,d %- h 86-1092 PRINTED IN U.S.A. IN JANUARY, 1980. --- REPUCES SPECIMEN U B E L 86-1092 PRINTED IN SEPTEMBER, 1979 D I S U R D PREVIOUS SPECIMEN LABELS. REVISIONS INCLUDE: USES ON INDUSTRIAL SITES AND FENCEROWS REINSTATED BY EPA ctuctut. 8123 0 0 0 1 7 , '; 9 r ACCJEP2 D 13 FEB ISSO Ur.r-Tv.- C 3 L. . Ac .- _ -Jr Lm p i j u i i i j . ii" . DO W 212893 BRUSH ( Low-Volatile Brush am For: the-.Control of M o st Kinds of Unwanted Trees- and Brush, as] on Rangelands. Fencerows. and Industrial Sites I ACTIVE INGREDIENTS: : 2,4-DlchIorophenoxyacetlc Acid, Propylene Glycol Butyl Ether Esters 36.0% 2,4,5`Trichlorophenoxyacetic Acid, Propylene Glycol Butyl Ether E s te r s ......................................................3 4 /1 % IN E R T IN G R E D IE N T S :...................................................................................... :.*2V.S& 2,4-D A d d Equivalent 22.2% -- 2 pounds per gallon 2,4,5-T Acid Equivalent 22.2% -- 2 pounds per gallon .. E.P.A. Registration No.464-204 EPTA/EsL McflU-3 P R E C A U C IO N -A L USUARIO: Si usted no lee ingl6s. no use este pro3ucto hasta que la etlqueta le hayasldo expllcada ampllamente. % % %T R A N S L A T IO N : (TO THE-USER: If you cannot read English, do not us%e lh ls product until the label has been fully explained to you.) Inc) %% 18.93 L / 5 ( 86-1066 PRINTED IN U.S.A. IN JANUARY, 1980. RE PU CE S SPECIMEN LABEL 86-1066 PRINTED IN SEPTEMBER, 1979. DISCARD PREVIOUS SPECIMEN UBELS. REVISIONS INCLUDE: USES ON INDUSTRIAL SITES AND FENCEROWS REINSTATED BY EPA. 0001780 DOW212S94 ESTER HERB! FOR THE CONTROL OF TREES, B Low-Volatiler Brush' and Weed Herbicide for Industri ACTIVE INGREDIENT: 2.4;5-Trichlorophenoxyacetic Acid." Propylene ; Glycol Butyl Ether E s te rs ..............i'.................................... .................. ..69.2% .IN E R T IN G R E D IE N T S : .................................. ........................... ......... 2.4.5>Trichlorophenoxyacetic Acid Equivalent -- 45.0% . - -4 Pounds perGallon / * ! E:P.A`.:Registration No''464-205' E.P.A.Est. 464-M M - 'PREC AUC IO W AUU SUAR IO rST usted:no-lee ingls. no.useVestt ^ ro d u c ** '^ hasta que la etiqueta le.haya sidoexplicadaam pliam ente. ' ***** T R A N S L A T IO N f(T O THE USER: II you cannot read English.,do notmse this product until the label has been fully explained to you.) %*>% % % . 's T3.93 L/ 86-1064 PRINTED IN U.S.A. IN JANUARY, 1980. REPLACES SPECIMEN LABEL 86-1064 PRINTED IN SEPTEMBER, 1979 DISCARD PREVIOUS SPECIMEN LABELS. REVISIONS INCLUDE: USES ON INDUSTRIAL SITES AND FENCEROWS REINSTATED BY EPA. OOdftBl \8^ O Page 62 Topic M aterials News. February 20. 1980 DOW208572 NTP ASSIGNS MANAGERS FOR CHEMICALS IN TESTING SCHEDULE Individuals, dubbed managers, are being designated by the National Toxicology Program to be responsible .for individual chemicals Dr. ichsrd jGrelsemer cold'two -subgroups of the Clearinghouse on Environmental Carcinogens last week. The managers have met with Interested personnel in other agencies to agree on objectives, clarify what needs to be done and design experiments. Some chemical selection is already in progress, Greisemer added. Various selection processes span eight Federal agencies, he said, making it difficult to project progress for next year, since all the agencies have different needs. NTP will not test chemicals which it believes industry ought to test, he ~ added. However, the agency will retest substances already tested by industry to re view data or if the substance is high volume. NTP's Board of Scientific Counselors met for the first time in January and formed three subcommittees: (1) to review chemical selection projects and evaluate ongoing activities; (2) to review data processing and management needs for test data management plans for automated data systems; and (3) a peer review of reports for release of data. In other organizational work, an office has been created to deal with industry and trade groups; it is headed by Dr. Thomas Cameron. The government has sufficient lab facilities, Greisemer noted, since they were built in anticipation of the Toxic Substances Control Act and industry could build to meet its needs within a year; shortages do exist for toxicologists and industrial hygienists, however. *** CALIFORNIA LAWSUITS CHALLENGE STATE PESTICIDE RULES California's new pesticide rules are being challenged in court by both environ mentalists and industry, one .group charging that the state rules are not stringent enough and the latter group claiming that the standards conflict with Federal rules'. The suit filed by environmentalists, farm workers and labor officials claims that state laws based on Environmental Protection Agency standards underestimate the amount of hazardous substances present in foods in the state. Since Federal residue estimates are inaccurate, according to the suit, the state should enact more strin gent rules to take the place of EPA laws. Meanwhile, two trade groups and 13 agricultural chemical firms challenged the state's authority to register pesticides with the state since they already must be registered with EPA. The suit also attempts to prohibit the state from labeling pesticides, issuing permits, establishing lower tolerances than EPA and releasing trade secret data. Central to the industry lawsuit is whether individual states should be allowed to adopt differing pesticide regulatory programs preempted by the Federal EPA plan. *** MONTANA WOMEN BLAME HERBICIDE 2,4-D FOR MISCARRIAGES Out of 10 pregnant women in rural Condon, Montana, only one gave birth success fully in a 12-month period and residents are blaming the herbicide 2,4-D, which is used in the area to control weeds along roads. Nine women had miscarriages and the only successful birth was by a woman who had not lived in the area for most of her pregnancy. County officials, however, claim that they have not used 2,4-D in the area where the 10 women live, although farmers in the area may be using the pesticide. The substance is used as an alternative to 2,4,5-T which was linked to miscarriages 'by Oregon women. In Interviews conducted by a county health nurse, it was noted that the victims and their families ate vegetables from their own gardens, drank milk from cows which grazed along roadsides and purchased their meat and dairy products from local pro ducers . Environmental Protection Agency recently approved the use of 2,4,-D for forest control in Oregon (TMN, Feb. 13, 1980, p. 55) claiming no significant impacts of its use. f r 5 0001777 I8*i uil Text E N V IR O N M E N T A L P R O TE C TIO N A G E N C Y R EVIEW A N D C O N C L U S IO N S C O N C E R N IN G PO TEN TIA L HEA LTH EFFECTS OF THE H E R B IC ID E 2.4-D April 1980 2,4-D is one of the m ost widely used herbicides in the United S tates. T here a re approxim ately 1,500 products con taining 2.4-D registered w ith EPA , and m ore than 70 million pounds of the active ingredient are distributed annually. The te rm " 2,4-D " re fe rs to the phenoxy herbicide 2,4dichlorophenoxy acetic acid and its 35 derivative s a lt and es te r form s. 2,4-D is used to control broadleaf weeds in a variety of places including home lawns, cereal and grain crops, com m ercial areas, com m ercial turf, rights-of-way, and forests. Public concern about the potential adverse health effects of 2,4-D has intensified since the em ergency suspension of 2.4.5- T and Silvex in M arch 1979. This concern stem s prim arily from (1) the chem ical sim ilarity of 2,4-D and 2.4.5- T a s phenoxy herbicides, and (2) the question of 2,4-D dioxin-contam ination, especially contamination with tetrachloro-dioxin, a m anufacturing contaminant in 2,4,5-T, which causes cancer and m iscarriages. Due to the chemical sim ilarity of 2,4-D and 2,4,5-T, the public has expressed con cern about the potential for cancer and miscarriages from the use of 2,4-D. There is also concern because the controversial m ilitary defoliant Agent Orange, used in Viet Nam, was composed of 2.4.5- T and 2,4-D. Agent Orange was never registered by 'PA for civilian use in the United States. Its use in Viet Nam oy the U.S. m ilitary has resulted in claim s of adverse health effects to Am erican m ilitary personnel. The Veterans Ad m inistration is studying these claims. P rom pted by these concerns and E PA 's need to resolve the questions surrounding the use of 2,4-D, the Agency in itiated a review of the available information on the potential health effects of 2,4-D. This review was conducted in p a rt to determ ine if the herbicide should be reviewed under the R PA R p ro c e s s (R e b u tta b le Presumption Against Registration) or if another regulatory action was ap propriate. II. A g e n c y R e v ie w a n d C onclusions Based on the results of this review, EPA has concluded th at (a) th e p resently availab le inform ation on the potential adverse health effects of 2,4-D does not support a regulatory action to rem ove 2,4-D products from the m arket; (b) infor mation from scientifically valid studies does not indicate th at the continued use of 2,4-D poses an im m inent hazard or unreasonable adverse effect when used according to label precautions and direction for use; and c) the Agency should act quickly and vigorously to obtain better toxicological in form ation on 2,4-D. These conclusions a re based on these following con siderations: 1. T h ere is no evidence available at this tim e th at in dicates 2.4-D contains any form of dioxin. This includes the tetrachloro-dioxin (TCDD), which is a manufacturing con`"minant of 2,4,5-T and causes cancer and m iscarriages. rCDD is not th eoretically expected to be found in 2,4-D. ih e manufacturing processes and starting chemicals from which 2,4-D and 2,4,5-T a re m ade a re not the sam e. Although other much less toxic dioxins a re theoretically possible in ^ 2,4,-D, they have not been found despite thorough chemical analyses. 2. Because products containing 2,4-D have been registered ^ for use since the 1940's, m ost of the scientific data submitted ^ to support the product registrations now on the m arket were vjl developed many years ago. While some of these studies are O scientifically valid, m any others do not m eet today's stan- dards for scientific testing. As a result, there are significant inform ation gaps in several are a s including cancer-poten tial, reproductive effects, neurotoxicity, and m etabolism in anim als. 3. The studies most pertinent to the question of tumor- causing potential (oncogenicity) of 2,4-D w ere considered in adequate and inconclusive. No valid conclusions could be drawn one way or another from the data. 4. Almost all animal tests conducted on the potential reprdductive effects of 2,4,-D show that, unlike 2,4,5-T with its contaminant TCDD, there is a no-effect level for injury to the fetus (fetotoxicity) from 2,4,-D. A no-effect level in anim al studies is the dose level below the low est. dosage that produces observable adverse effects. At comparable dose levels, 2,4-D induces less serious fetotoxic effects than 2,4,5-T contaminated with TCDD. In tests with rats, 2,4,5-T with its TCDD contamination caused resorptions of the fetus (dissolution of the unborn anim al) at very low levels. This effect was virtually non-ex istent in ra ts fed 2,4-D a t the sam e dose levels. Because of the significance of fetotoxic effects and because several of the reproductive tests on 2,4-D w ere found to be scientific- ly deficient, new tests will be needed before sound conclu sions can be made. 5. The scientific evidence available a t this tim e does not indicate the potential human exposure is sufficient to result in human health effects. 6. The m ost vigorous authority available to E P A under the pesticide law to fill information needs is a new section of FIFRA (Federal Insecticide Fungicide Rodenticide Act) passed in 1978. This provision, known as 3 (c)(2 )(B ), allows EPA to request any additional data from pesticide registrants that is considered necessary to m aintain the registration of existing products. The Agency can immediately require the m anufacturer to develop the data where gaps exist. The registrants have 90 days to show th at they a r e complying. Their product registrations m ay be sum m arily suspended if they fail to m eet the Agency's conditions. No o th e r action could obtain this information any faster. EPA is putting the data requirem ents into final form and they will be issued to the registrants after review by our Scientific Advisory Panel. These scientific experts will review and comment on the data requirem ents to assure that they will provide the information EPA needs to more definitively answer the questions on potential health effects of 2,4-D. 7. Based on a review of the toxicology data (see section IV below), and a review of the risks of other pesticide chemicals now undergoing regulatory action, the Agency believes that the risks of several other pesticides a re higher 5-2-80 O. TM E BUREAU O * NATIONAL AFfAlRS INC WASHINGTON D C 20037 0003950 < u s f ' I \ CURRENT REPORT 135 and b e tte r docum ented than those associated with 2,4-D. To put the review of these other higher priority chemicals aside in order to devote EPA resources to taking action against -2,4-D would not, in th e Agency's opinion, b e st serv e ih e public interest. III. Additional A ctions In addition to requiring several im portant studies of the m anufacturers on 2,4-D, EPA will also: 1. Conduct several tests on reproductive effects (through o u r Office of Research and Development) of several deriv ativ es of 2,4-D in o rd er to quickly get new information and have a good basis for comparison with the companyproduced data. 2. Continue its ongoing review of forest pest control prac tices. This review will evaluate all chemical and non chem ical controls to identify the m ost environmentally protective ways to control forest pests. The Agency believes th a t a piecemeal approach to forest chem ical regulation only leads to confusion, both to the industry and to the public. Unless we review the whole range of possible controls, ex am ining one chemical a t a tim e only gives rise to questions ab o u t the chem icals which would be used to replace those ex am ined and prohibited from use. 3. Review all new data as it comes in to determ ine if a change in our regulatory posture is warranted. This includes evaluating the results of new anim al tests as well as looking into reported incidents involving human exposure to the chem ical. 4. Continue to support Held tests to m easu re exposure to 2,4-D during the present growing season. 5. EPA is informing the Inter-Agency Work Group, es tablished by the White House to study the possible long-term effects of Agent Orange, of the actions being taken. EPA will also share its scientific findings with this committee. IV. Toxicology B ackground The potential hazard of a chemical is usually m easured in laboratory animal tests. Animals are given doses of a chem ical over a specific time period. Scientists attem pt to derive from m ost of these tests a " no observable effect level" (NOEL) -- the dose level below the dosage where effects are first observed. From the animal tests and NOEL's, the potential effects on humans and other animals can be estim ated. A set of brief definitions is provided below to perm it better understanding of the subsequent discussion of toxicological findings. A. G en era l te r m s 1. A c u te o ra l to x ic ity (LD50) -- this te st determ ines the dose level which produces death in half the test animals after a single oral dose (short-term test). Used to predict the near-term toxicity of the chem ical im m ediately upon contact with people or other non-target animals. 2. C hronic fe e d in g te sts -- anim als a re fed for most th e ir life span (usually g re a te r than 18 m onths in rodents) in o rd er to determ ine the dose level which shows no toxic effect in test animals. This is the test from which the NOEL is (usually) derived. 3. O n co g en icity te stin g -- anim als fed relatively large doses of the te st chem ical for th eir life span (usually 18 m onths to 2 years in rodents) to try to induce tumors. These tests are used to predict whether the chemical may pose a cancer hazard. 4. R e p ro d u c tiv e te stin g -- these tests evaluate the effects of the chemical on the fertility of both the m ale and fem ale parents by exposing the animals for a period of time before breeding. The tests also m easure the possible effects of the chemical on the pregnant fem ale and the fetuses through several generations. (The test with rodents through 3 generations runs approxim ately 14 m onths.) 5. T e ra to lo g y te s tin g -- these tests evaluate the effects of ihe chemical on Ietuses by exposing pregnant fem ales dur ing the short period of tim e that the fetus is most susceptible to congenital malformation. Teratogenic effects include cleft palate, central nervous system deformities, eye and limb deformities, and internal organ malfunction. These are considered to be life-threatening effects that put the animal a t a disadvantage for surviving in its environm ent. 6. F e to to x ic ity -- fetotoxic effects can be seen in either the reproduction o r teratology tests. Toxicity m ay be seen in the extreme form as fetal death or as less severe problems, such as delayed formation of bones, reduced body weights at birth, or edema (abnorm al fluid accumulation in the tissue). Most fetotoxic effects appear to be reversible once exposure to the test chemical is curtailed. Therefore most fetotoxic effects are considered to be less serious than teratogenic effects, with the exception of fetal death. B. S u m m a ry o f T o x ic o lo g y R e v ie w Most of the data in EPA files on the potential health effects of 2,4-D a re centered on the acid form , even though there are many derivatives, such as salts and esters. This is because the many form s of 2,4-D m etabolize to the acid form in the environment and in the body. The discussion of animal data below, therefore, concerns the acid form of 2,4-D unless otherwise noted. 1. A c u te t o x ic ity -- low to m oderate. The potential for im m ediate poisonings from contact with the chem ical is un likely. 2. N e u ro to x ic ity -- There is little definitive information on the possible neurological effects of 2,4-D. In several reported cases of im paired nerve function, it was not known if the individuals w ere peculiarly sensitive to that type of effect or were exposed to other toxic m aterials. 3. R e p ro d u c tiv e e ffe c ts (effects on th e unborn) -- T ests have been conducted on rats, m ice and ham sters to evaluate the possible reproductive effects of 2,4-D. In alm ost all tests, no observable effect level has been established. 2,4-D causes some of the less serious fetotoxic effects, such as edema (swelling of tissues) a t the lower dose levels tested, and causes life-threatening birth defects (skeletal malfor m ations) and cleft palates only a t the very high levels tested. Based on the no observable effect levels in the animal studies, EPA estim ates th at the level of exposure in a " worst case" situation (e.g., a person standing directly un d e r a spray plane) would be 500 to 1000 tim es less than the dose level that might cause an effect. Much of the data available to judge these effects was generated by old study protocols, has deficiencies in the test methods, and needs clarification by fu rth er study. EPA also reviewed sum m aries of tests conducted in the Soviet Union which sta te th at som e derivatives of 2,4-D produced adverse effects on unborn anim al fetuses a t much lower levels than indicated by the data in E P A 's files. These sum m aries could not be used in the Agency's review because the identity of the test m aterial, and its im purities, was un clear, and because th ere w ere no num erical data to back up the sum m ary conclusions. In some cases tests need to be done on specific derivatives of 2,4-D. 4. O n c o g e n ic ity (potential for causing tum ors) -- Several rodent studies have been conducted to date. The tests were conducted a decade ago and are considered to be inadequate and inconclusive by today's scientific standards. New studies on rodents a re needed. 5. M u tu g e n ic ity (inheritable effects) -- th e v ast m ajority of the m utagenicity studies conducted on 2,4,-D are negative. However, there are three positive studies. Taken 5-2-80 PuMisnt.fi by THE BUREAU OF NATIONAL AFFAIRS. IN C . WASHINGTON O C 20037 r ^ n if ?o0 0 0 3 9 5 1 rv n n X, I t 1 M f i n I *136 fi CHEMICAL REGULATION REPORTER ' as a group, the results of the studies can be described as in consistent and inconclusive. A new series of tests being con ducted by the D epartm ent of Health. Education, an d Welfare will be reviewed by EPA-when they are completed. 6. E p id e m io lo g y -- No epidemiological studies of human nealth effects from 2,4-D exposure have been completed. However, EPA is currently investigating reports about alleged ad v erse effects from potential chem ical exposure in several p a rts of the country. EPA will be looking a t the results of those studies and will decide in the near future about additional field work. V. E x p o s u re to 2 .4 -D There are at least three ways that the average citizen might come into contact with 2,4-D -- through the diet, dur ing home use, and drift of the herbicide from nearby use. (a) D iet The EPA has set tolerances for residues of 2,44) in various food crops. The Food and Drug Administration (FDA) routinely sam ples a variety of foods (the Market Basket Survey) which FDA considers to be representative of the average American diet. Samples are analyzed for pesticide residues. During the period of 1974 to 1977, no 2,4-D residues w ere found in any of the products surveyed. However, during the 1965 to 1977 period, a variety of other food products w ere analyzed, of w hich.about 1.1% w ere positive for 2,4-D in very minute quantities that w ere well below E P A 's tolerance (allowable residue) levels. (b) H om e use There are currently a number of registered home-use products which contain 2,4-D in a variety of formulations. Exposure to the herbicide in home-use situations will depend to som e extent on the specific form ulation used. If c are is ex ercised by the homeowner in adhering to the directions for ~e and precautionary statem en t on the label, exposure to i-D should be low. (c) D rift " D rift," the airborne transport of pesticide m aterials to a non-target area, is a common source o f exposure. Som etim es, a pesticide will d rift during application, depen ding on clim atic conditions (tem perature, wind speed), type of formulation used, terrain (forests, mountains), type of application method used (aerial, ground spray). Several States have imposed restrictions on 2,4-D use in order to cut down on drift potential. Once on the ground or targ et crop, the herbicide may become airborne again by the process of vaporization. This particular type of drift has been the subject of intensive research by the producers of 2,4-D. Since the introduction of less volatile forms of the herbicide over the last few years, this kind of drift has become much less extensive. , VI. E n v ir o n m e n ta l P e rs is te n c e 2,4-D is not a persistent pesticide. Breakdown of the her bicide begins almost immediately after application a t a rate dependent on several environm ental factors such as tem perature, humidity and medium (air, soil, crop, w ater). The rate of loss (commonly referred to as the half-lie) is a m easure of the time required for half of the substapce to be degraded or lost. On s p ra y e d v e g e ta b le s , th e half-life v aries from 1-3 weeks depending on geographic location, clim atic con ditions, vegetation type, application technique and form ula tion used. In soil, the half-life varies from several days to 2 weeks, depending on acidity, soil type and am ount of rain. In w a te r, the half-life varies from a few days to several months depending on factors such as oxygen concentration, acidity, light intensity, w ater tem perature and formulation used. <3 or o CO Journal CONGRESS (For the Period April 23-30) Senate Bills Introduced April 24 RCRA -- to amend the Solid Waste Disposal Act (the R esource Conservation and Recovery A ct), S 2609, (Heinz) to Environment and Public Works. House Committee Action Interstate and Foreign C om m erce, approved HR 7020, the Hazardous W aste Containm ent A ct of 1980, April 30. MEETINGS SCHEDULED Government Institutes, Inc., environmental laws and regulation course. M ay 15-16, Washington, D.C. (Govern m ent Institutes, Inc., P.O. Box 5918, Washington, D.C. 20014, (301) 656-1090) McGraw-Hill, conference on coping with industry en- m m ental costs, May 15-16, Arlington, Va. (McGraw-Hill a feren ce and Exposition Center, 1331 Ave. of the A m ericas, Room 3677, New York, N.Y., 10020. .. Vanderbilt University, hazardous m aterials training course, May 19-23, Nashville, Tenn.; June 16-20, S eattle, July 28-August 1, N iagara F alls, N.Y. (D r. R .D . Harbison, Vanderbilt Medical Center, Nashville, Tenn. 37232, (615) 322-4754). Center for Energy and Environmental Management course on strategic planning for disposal of solid wastes, May 20-21. Chicago; June 2-3, Washington. D.C.; Ju n e 24-25, Pittsburgh; July 14-15, Denver (CEEM , P.O. Box 536, F a ir fax, Va. 22030, (703) 250-5900). CEEM , course on E P A 's regulation of new chem ical sub stances. May 22. Chicago; June 4, Washington, D.C.; June 26, Pittsburgh; July 16, D enver (CEEM , P.O. Box 536, F a ir fax. Va. 22030. (703) 250-5900) Cosmetic, Toiletry and Fragrance Association, Inc., sem inars on regulatory and legislative issues relating to cosm etic m anufacturers. M ay 22, Los Angeles; Ju n e 5, Deerfield Beach, F la.; June 12, Rye. N.Y. (M argaret Smith o r D ebbie A lexander, CTFA, 1133 15th S t., N.W ., Washington. D.C. 20005, (202) 331-1770) The Institute for Applied Pharm aceutical Sciences course on good clinical practices. May 22-23. E a s t Brunswick, N .J. (Edith Webb, R egistrar, P.O. Box 964, E . Brunsw ick. N .J. 08816. (201) 248-1400) 5-2-80 Chemical Regulation Reporter OI8-7973-a(VSOO.SO Sl3l 0039S 2 89 N 9 \ 2 , 4 - D FACT SHEET '* .V s- I % Backq round 2 ,4 -D is one o f th e most w id e ly used h e r b ic id e s in the United S ta te s . There are approxim ately 1,530 products c o n t a in in g 2 ,4 - D r e g i s t e r e d w ith EPA, and more than 70 m illio n pounds o f the a c t iv e in g re d ie n t are d is t r ib u t e d a n n u a lly . The term " 2 ,4 -D " r e f e r s to the phenoxy h e r b i c id e 2 ,4 - d ic h lo r o p h e n o x y a c e t i c a c id and i t s 35 d e r i v a t i v e s a l t and e s t e r fo rm s . 2 , 4 - D i s used to c o n t r o l b r o a d le a f weeds i n a v a r i e t y o f p l a c e s i n c l u d i n g home l a w n s , c e r e a l and g r a in c ro p s , com m ercial are-as, com m ercial t u r f , r i g h t s o f-w a y , and f o r e s t s . Public concern about the p o te n tia l adverse h e a lth e ffe c ts o f 2 ,4 -D has in t e n s if ie d sin ce the emergency suspension o f 2 . 4 . 5 - T and S ilv e x in March 1 9 7 9 . 'T h is concern stems ~ p r i m a r i l y from 1) the c h e m ic a l s i m i l a r i t y o f 2 ,4 - D and . 2 . 4 . 5 - T a s p h e n o x y h e r b i c i d e s , a n d 2) t h e q u e s t i o n o f 2 , 4 - D d io xin -co n tam in atio n , e s p e c ia lly contam ination w ith te tra c h lo ro - d io x in , a m an u factu rin g contam inant in 2 , 4 ,5 - T , which causes c a n c e r and m i s c a r r i a g e s . Due to th e c h e m ic a l s i m i l a r i t y o f 2 . 4 - D and 2 , 4 , 5 - T , th e p u b l i c has expressed c o n cern a b o u t the p o te n t ia l fo r can cer-an d m is c a rria g e s from the use o f 2 . 4 - D. There is also concern because the c o n tro v e rs ia l m i l i t a r y d e f o l i a n t A gent O ra n g e , used in V i e t Nam, was composed o f 2 , 4 , 5 - T and 2 , 4 - D . A gent Orange was n e v e r r e g is te r e d by-EPA fo r c i v i l i a n use in the U n ite d S ta te s . I t s u s e i n V i e t Nam b y t h e U . S . " . m i l i t a r y h a s r e s u l t e d i n c l a i m s o f adverse h ealth e ffe c ts to'A m erican m ilit a r y personnel. The V eteran s A d m in is tra tio n is stu d yin g these c la im s . r l Prompted by th e s e co n cern s and EPA's need to r e s o lv e th e *... .questions su rrounding the use o f 2 ,4 - D , the Agency i n i t i a t e d a re v ie w o f . t h e a v a i l a b l e - i n f o r m a t i o n on th e p o t e n t i a l h e a lt h e f f e c t s , o f 2 , 4 - D . .This, r e v ie w was conducted in p a r t to * d e t e r m i n e I f t h e h e r b i c i d e s h o u l d -be r e v i e w e d u n d e r t h e RPAR process (R eb u ttab le Presum ption A gainst R e g is tra tio n ) or i f " .a n o th e r r e g u la t o r y a c t io n was a p p r o p r ia t e . . - DOW 357486 I I . Agency R eview and C o n c lu s io n s .* Based on t h e r e s u l t s o f t h i s r e v i e w , EPA h a s c o n c lu d e d t h a t a) th e p r e s e n t l y a y a i l a b l e in f o r m a t io n on th e p o t e n t i a l adverse h ealth e ffe c ts of 2,4-D does not support a re g u la to ry a c tio n to remove 2 ,4 -D p ro d u c ts from the m a rk e t; b) in fo rm a tio n from s c i e n t i f i c a l l y v a lid s tu d ie s does not in d ic a te th a t t^e c o n tin u e d use o f 2 , 4 - D poses an im m in e n t h a z a rd o r u n re a s o n a b le a d v e rs e e f f e c t when used a c c o rd in g to la b e l p r e c a u tio n s and d i r e c t i o n f o r use; and c) the Agency sh o u ld a c t q u i c k l y and v i g o r o u s l y to o b t a in b e t t e r t o x i c o l o g i c a l in f o r m a t io n on 2,4-D . .' * / 813.3 These c o n c l u s i o n s a r e based on th e s e f o l l o w i n g c o n s id e ra tio n s : v 1 . T h e r e i s no e v i d e n c e a v a i l a b l e a t t h i s tim e t h a t in d ic a te s 2 ,4 -D c o n ta in s any form o f d io x in . Th is in c lu d e s the t e t r a c h lo r o - d io x in (TCDD), which is a m an u factu rin g c o n ta m in a n t o f 2 , 4 , 5 - T and causes c a n c e r and m is c a r r ia g e s . O 'H357487 TCDD i s n o t t h e o r e t i c a l l y e x p e c t e d to be fo u n d i n 2 , 4 - D . The. m a n u f a c t u r i n g p r o c e s s e s and s t a r t i n g c h e m ic a ls from O which 2 , 4 - D and 2 , 4 , 5 - T a r e made a r e n o t th e same. A lth o u g h o t h e r much l e s s t o x i c d i o x i n s a r e t h e o r e t i c a l l y p o ssib le in 2 ,4 -D , they have not been found d e s p ite thorough chem ical analyses. .. 2. Because products c o n ta in in g 2 ,4 -D have been re g is te re d fo r use since the 1 9 4 0 's , most o f the s c i e n t i f i c d a t a s u b m it t e d t o s u p p o r t th e p r o d u c t r e g i s t r a t i o n s now ' on t h e m a r k e t w e r e d e v e l o p e d m a n y y e a r s a g o . W h i l e some ^ ,o f th e s e s t u d ie s a re s c i e n t i f i c a l l y v a l i d , many o th e r s do "not m e e t t o d a y ' s s t a n d a r d s f o r s c i e n t i f i c t e s t i n g . As a r e s u lt, th ere are s ig n if ic a n t in fo rm a tio n gaps in several iO areas in c lu d in g c a n c e r - p o t e n t ia l, re p ro d u c tiv e e f f e c t s , n e u r o t o x ic it y , and m etabolism in - a n im a ls . ' 3. The s tu d ie s most "p e rtin e n t to th e q u e s tio n o f -- tum or-causing p o te n tia l (o n c o g e n ic ity ) o f 2 ,4 -D were c o n s i d e r e d i n a d e q u a t e and i n c o n c l u s i v e . No v a l i d c o n c lu s io n s c o u ld be drawn one way o r a n o th e r from th e d a ta . 4 . A lm ost a l l a n im a l t e s t s conducted on the p o t e n t i a l r e p r o d u c tiv e e f f e c t s o f 2 ,4 - D show t h a t , u n lik e 2 , 4 , 5 - T with* ftis. c o n ta m in a n t TCDD, t h e r e is a n o - e f f e c t l e v e l f o r i n j u r y , t o t h e fet-us* ( f e t o - t o x i c i y ) f^orn 2 , 4 - D . A n o - e f f e c t l e v e l i n a n i m a l s t u d i e s i s t h e d'o s * l e v e l b e l o w t h e } owes.t` 'dosage t h a t .produces o b s e r v a b le -adverse e f f e c t s . At c o m p a r a b l e d o s e l e v e l s , 2 , 4 - D i n d u c e s l e s s s e r i o u s fe to to x i.c e f f e c t s t h a n - 2 , 4 , 5 - T c o n ta m in a te d w ith TCDD. 8 1o In- t e s t s w i t h r a t s , 2 , 4 , 5 - T w i t h i t s TCDD c o n t a m i n a t i o n caused r e s o r p tio n s o f trie fe tu s ( d is s o lu t io n o f the u n b o rn , a n im a l) a t v e ry low l e v e l s . T h is e f f e c t was v i r t u a l l y n o n - e x i s t e n t in r a t s fed 2 , 4 - D a t th e same dose l e v e l s . Because o f th e s i g n i f i c a n c e o f f e t o t o x i c e f f e c t s and because s e v e r a l o f th e r e p r o d u c t iv e t e s t s on 2 , 4 - D w e re found to be s c i e n t i f i c a l l y d e f i c i e n t , new t e s t s w i l l be needed b e f o r e sound conclusion can be made. < h 5. The s c i e n t i f i c evid en ce a v a ila b le a t t h is tim e does n o t i n d i c a t e th e p o t e n t i a l human e x p o s u re is s u f f i c i e n t ------ t o r e s u l t i n h u m a n h e a l t h e f f e c t s . v .jifV \ <. T h e m o s t v i g o r o u s a u t h o r i t y a v a i l a b l e t o EPA u n d e r ,, th e p e s t i c i d e la w to f i l l i n f o r m a t i o n needs i s a new s e c t i o n o f F I FRA ( F e d e r a l I n s e c t i c i d e F u n g i c i d e R o d e n t i c i d e A c t ) passed in 197B. T h is p r o v i s i o n , known as 3 ( c ) ( 2 ) ( 3 ) , a l l o w s EPA t o r e q u e s t a n y a d d i t i o n a l d a t a fro m p e s t i c i d e r e g i s t r a n t s th a t is considered necessary to m ain tain the r e g is tr a tio n o f e x is t in g p ro d u c ts . The Agency can im m ed iately re q u ire the m a n u fa c tu re rs to d e v e lo p the d a ta where gaps e x i s t . The r e g i s t r a n t s have 90 days to show t h a t th e y a r e c o m p ly in g . T h e i r p r o d u c t r e g i s t r a t i o n s may be s u m m a rily suspended i f t h e y f a i l t o m e e t t h e A g e n c y ' s c o n d i t i o n s . No o t h e r a c t i o n c o u l d o b t a i n t h i s i n f o r m a t i o n a n y f a s t e r . EPA i s p u t t i n g t h e d a t a r e q u ir e m e n ts i n t o f i n a l form and th e y w i l l be issu ed to the r e g is t r a n t s a f t e r re v ie w by our S c i e n t i f i c A d v is o ry P an el. These s c i e n t i f i c e x p e r ts w i l l re v ie w and comment on the d a ta requirem ents to assure th a t they w i l l pro vid e the in fo rm a tio n EPA n e e d s t o more d e f i n i t i v e l y a n s w e r t h e q u e s t i o n s on p o t e n t i a l health e ffe c ts of 2 ,4 -D . . * . 7 . Based on a' re v ie w o f the t o x ic o lo g y d a ta (see s e c t io n IV b e lo w ) , and a re v ie w o f the r is k s o f o th e r p e s t ic id e ch e m ic a ls now u n d e rg o in g r e g u l a t o r y a c t i o n , th e Agency b e l i e v e s t h a t th e j > r is k s o f s e v e r a l o th e r p e s tic id e s a re h ig h e r and b e t t e r d o c u m e n t^ th a n th o s e a s s o c i a t e d w i t h 2 , 4 - D . To p u t th e r e v i e w o f t h e s e ^ o t h e r h i g h e r p r i o r i t y c h e m i c a l s a s i d e i n o r d e r t o d e v o t e EPA r e s o u r c e s t o t a k i n g a c t i o n ,_aga i n s t 2 , 4 - D w o u l d n o t , i n t h e Agency's o p in io n , best serve- the p u b lic in t e r e s t . I I I . A d d itio n a l A ctions In a d d itio n to re q u irin g s e v e ra l Im portant s tu d ie s of t h e m a n u f a c t u r e r s on , 4 - D , EPA w i l l . a l s o : ... * 1. Conduct s e v e ra l te s ts o n -re p ro d u c tiv e e ffe c ts ;- {-through our. O f f i c e o f Res'earch and- Developmen-t) o f s e v e ra l -der iu a J tiv ts o f 2 , 4 - D i n o r d e r t o q u i c k l y g e t a e w - i n f o r m a t i o n ."nd h a v e a good b a s is fo r com parison with, th e c o m p a n y -p ro d u c e d 'd a ta . 2 . C o n t i n u e i t s o n g o i n g r e v i e w o f f o r e s t * p e s t c o n t r o l ' p r a c t i c e s . T h is re v ie w w i l l e v a lu a te a l l ch e m ic a l and non- chem ical c o n tro ls to id e n t if y the most e n v iro n m e n ta lly p ro te c tiv e - ways to c o n tr o l f o r e s t p e s ts . The Agency b e lie v e s th a t a piecem eal approach-to fo re s t chem ical re g u la tio n o n ly leads to c o n fu s io n , b o th to the in d u s tr y and to the p u b l i c . U nless we r e v i e w t h e w h o le r a n q e o f p o s s i b l e c o n t r o l s , e x a m i n i n g one chem ical a t a tim e o n ly g iv e s r is e to q u e s tio n s about * th e c h e m ic a ls w h ich w.ould be used to r e p l a c e th o s e exam ined and p ro h ib ite d from use. 8135 3 . 'R e v i e w a l l n e w d a t a a s i t c o m e s I n t o d e t e r m i n e I f a change in our re g u la to ry posture is w a rra n te d . This Includes e v a l u a t i n g th e r e s u l t s o f new a n im a l t e s t s as w e ll as lo o k in g i n t o r e p o r t e d i n c i d e n t s in v o lv in g human e x p o s u re to th g c h e m ic a l. 3 ^v 4. C ontinue to support f i e l d te s ts to measure exposure to 2 ,4 -D during the present growing season. v 5 . EPA i s i n f o r m i n g t h e I n t e r - A g e n c y Work G r o u p , e s ta b lis h e d by the W hite House to stu d y the p o s s ib le lo n g -te rm e f f e c t s o f A g e n t O r a n g e , o f t h e a c t i o n s b e i n g t a k e n . EPA w i l l also share its s c ie n t if ic fin d in g s w ith th is com m ittee. oOV*357489 IV . T o x ic o lo g y Background The p o t e n t i a l hazard o f a ch em ical is u s u a lly measured in la b o ra to ry anim al te s ts . Animals are given doses o f a chem ical over a s p e c ific tim e p e rio d . S c ie n tis ts attem pt to d e r iv e from most o f these te s ts a "no observab le e f f e c t l e v e l " (NOEL) -- th e dose l e v e l below th e dosage where e f f e c t s a r e f i r s t o b s e rv e d . From th e a n im a l t e s t s and N O E L 's , th e p o t e n t i a l e f f e c t s on humans and o th e r a n im a ls can he e s tim a te d . A s e t o f b r i e f d e f i n i t i o n s is p ro v id e d below to p e rm it b e tte r understanding o f the subsequent discussion of to x ic o lo g ic a l fin d in g s . A. G en eral terms 1 . A c u te o r a l t o x i c i t y (LOSS) - t h i s t e s t d e te r m in e s the dose le v e l which produces death in h a lf the te s t.a n im a ls a f t e r a s in g le o ra l dose ( s h o r t - t e r m t e s t ) . _Used to p r e d i c t th e n e a r - te rm t o x i c i t y o f the. c h e m ic a l im m e d ia te ly upon co n tact w ith people or o th e r n o n -ta rg e t anim als. i-- 2. Chronic feeding te s ts - anim als are fed fo r X m o s t t h e i r l i f e s p a n ( u s u a l l y g r e a t e r t h a n 18 months in rodents) in o rd e r to d eterm ine the d o se l e v e l w h ic h shows no t o x i c e f f e c t in t e s t ^ a n i m a l s . Thi.s i s th e t e s t fro m w h ic h t h e NOEL - . i s (usually) d e riv e d . * 3 . O n co g en icity te s tin g - anim als fed r e l a t i v e l y " v- ' l a r g e d o ses o f t h e t e s t p h e m ic a l f o r t h . e i r l i f e .. . s p a n ( u s u a l l y 1 8 - m o n t h s t o 2 y e a r s i n r o d e n t s ) to t r y to induce tu m o rs. These t e s t s are. used. ' ' to p r e d i c t w h e t h e r t h e c h e m i c a l may pose a cancer hazard. 4 R eproductive te s tin g - these te s ts ev a lu a te the e f f e c t s o f the c h e m ic a l on th e f e r t i l i t y o f bothth e m ale and fe m a le p a r e n ts by exp o sin g th e anim als for a period of tim e before breed in g . T h e t e s t s a l s o m e a s u r e t h e p o s s i b l e e f f e c t s o.f th e ch e m ic a l on th e p re g n a n t fem ale and the '-fetuses through s e v e ra l g e n e ra tio n s . (The te s t w ith rodents through 3 g e n e ra tio n s runs a p p r o x im a t e ly 14 m o n th s .) . .. -.8136 I:., -5. T e r a t o l o n y t a s t in g - these tests e v a l u a t e xthe ef fe ct s ot t he chemi cal on fetuses by ex posing pregnant fe ma le s during the short period of time that the fetus is most su sc ep ti bl e to congenital malformation. Teratogenic effects include cleft palate, central nervous system deformities, eye and limb deformities, and internal organ malfunction. These are c o n s id er ed to be l i f e - t h r e a t e n i n g ef fect s that put the animal at a d i s a d v an t a ge for s u r v i v i n g In its en vironment. 6. F e t o t o x i c i t y - fe to to xl c effects can be seen in either the reproduction or teratology tests. T o x i c i t y may be seen in the ex tr em e form as fetal death or as less severe problems, such as d e l a ye d f o r m a t i o n of bones, re du ce d body I'C w e ig ht s at birth, or edema (abnormal fluid a c c u m u l a t i o n in the tissue). Most fetoto xl c effects ap pear to be reve rsible once ex po su re ~ to the test chemical is curtailed. Th er ef ore most fetotoxlc effects are considered to be less serious than terato ge ni c ef fe cts, with the exception of fetal death. DOW357490 B. S u mm ar y of T o x i c o l o g y R e vi ew Most of the data in EPA files on the potential health effects of 2,4-D are centered_on the acid form, even though there are many d e r i v a t i v e s , such as salts and esters. This is be ca us e the ma ny forms of 2;4-D m e t a b o l i z e to the acid form in the e n v i r o nm en t and in the body. The di s c u s s i o n of 'animal data below, t h e r ef or e, co nc er ns the acid form of 2,4-0.unless otherwise noted. 1. Ac u t e t o x i c i t y - low to mo de ra te . The potential 7- -for immedi ate po isonings from contact wi th the - - `chemical is uni ikely .* -r - ? 2. N e u r o t o x i c i t y - T h e r e is little definitive- * 7 -in/ormation.on the possible neurological effects * of 2,4-0. In.several reported cases of Impaired nerv e function, it was not known if the in div idu als were peculiarly sensitive to that type of effect or we re ex pose d to other toxic ma te ri al s. r 3. R e p r o d u c t 1 ve ef fe ct s (e ff ec ts on the unborn) Tests have been conducted on rats, mice and hamsters to evaluate the possible reproductive e f f e c t s of 2,4-0. In almost all test s, a NOEL * * has been established. 2,4-0 causes some of.the less serious fe to to xi c ef fe ct s, such as edema (swelling of tissues) at the lower dose levels tested, and causes 11 f e - t h r e a t e n i n g birth defects (skeletal m a 1fo rm at io ns) and cleft p a l a te s only at the very high levels tested. ( Based on the NOEls 1n the anlnul studies, EPA estima te s that the level of exposure in a "worst case" situation (eg. a person standing directly under a spray plane) would be 500 to 1000 times less than the dose level that might cause an effect. Much of the data avai la bl e to judge these effects was generated by old study protocols, has de fi ci e n c i e s 1n the test methods, and needs clarification by further study. EPA also reviewed summaries of tests c o n d u c t e d ' in Russia which state that some deriva ti ve s of 2,4-D produced adverse effects on unborn animal fe tuses at much lower levels than indicated by the data In EPA's files. These summaries could not be used in the Ag en c y ' s review b e c a us e the identity of the test material, and its impurities, was unclear, and because there were no numerical data to back up the summary conclusi on s. In some ca se s tests need to be done on .s peci fi c de ri vati ve s of 2,4-D. re f-is e ^ 0 0 3. O n c o g e n i c i t y -(potential for causing tumors) - Several rodent studies have been conducted to date, but none of these studies produced data that showed 2,4-D was oncoge ni c in test :l: l" animals. The tests were conducted a decade ago and are cons id er ed to be Inadeq ut e by today's scientific standards. New studies on rodents are needed. 4. M u t a g e n i c i t y (i nh er it ab le effects) - Th e vast ma jo rity of the m u t a g e n i c i t y studies cond uc te d on 2,4-D_are negative. However, there are three . positive* studies. Taken as a group, the r e s u l t s / of the.-studies can-best- be descri be d as in co ns is te nt and .inconclusive. A new series'of tests being . co nd uc te d by the De pa rt me nt of Health, Education, " and "Welfare will be reviewed by EPA when they ` are -completed'. 5. E p i d e m i o l o g y - No ep id em io l o g i c a l studies of human health effects from 2,4-D exposure have been completed. However, EPA is cu rr e n l t y investigating reports about alleged adverse effects from potential chemical exposure in several parts of the country. EPA will be looking at the results of th os e studies and will decide 1n*the near future about additional field wp rk. ^ :81 -000-2177 A* V. Exposure to 2 ,4 -D ' There are at least three ways that the average citizens might come into contact with 2,4-D - through the diet, during home use, and drift of the herbicide from nearby use. a) Diet The EPA has set tolerances for residues of 2,4-D In various food crops. The Food and Drug Administration (FDA) routinely samples a variety of foods (the Market Basket Survey) which FDA considers to be representative of the average American diet. Samples are analyzed for pesticide residues. During the period of 1974 to 1977, no 2,4-D residues were found in any of the products surveyed. However, during the 1965 to 1977 period, a variety of other food products were analyzed, of which about 1.1% were positive for 2,4-D in very minute quantities that were well below EPA's tolerance (allowable residue) levels. b) Home use i - There are currently a number of registered home-use products which contain 2,4-D in a variety of formulations. Exposure to the herbicide in home-use situations will depend to some extent on the specific formulation used. Zf care is exercised by the. homeowner in adhering to the directions for use.and precautionary statement on the label, exposure to 2,4-D should be low. D O CO cn c) Drift "Drift", the airborne transport of pesticide materials' to a non-target area,.is a common source of exposure. Sometimes, a pesticide will drift during application, depending on climatic'conditions, (temperature, wind spaed), type of formulation used, terrain (forests, mountai-cs)^ _ *. and type of .application method used Jaeria.l, ground apr-ayj. Several States have Imposed restrictions on 2,4rD use-'in." order to cut down on drift -potential. - CD ro Once on the ground or target crop, the herbicide may . * become airborne again by the process of vaporization. This particular type of -drift has been the subject- of intensive research by the producers of 2,4-D. Since the introduction of less volatile forms of the herbicide over the last few years, this kind of drift has become much less extensive. 8139 0002178 * VI. Environm en ta l Pe rsistence 2,4-0 1s not a pe rs is te nt pesticide. Breakdown of the *' ' . h e r b i c i d e begins almost immedi at el y after ap pl ic at io n at a rate d e pe nd en t on several en vi ro nm en ta l factors such as temperature, humidity and medium (air, soil, crop, wat er ). The rate of loss (c om mo nl y refe rr ed to as the ^ h a l f -l if e) is a m e a s ur e of the time re quired for half of the q s u b s t a n c e to be de gr a d e d or lost. On sprayed vegetables, the half-life varies from 1-3 weeks depending on geographic location, climatic conditions, <1 vegetat ion type, a p p l i c a t i o n te ch n i q u e and f o r m u l a t i o n used. CO in s o i l , the ha lf -l if e varies from several days to 2 ^ weeks, d e pe nd in g on acidity, soil type and amount of rain. ' In w a t e r , the ha lf -l if e varies from a few days to several month s de pe n d i n g on factors such as oxyg en c o n c e n t r a t i o n , acidity, light intesity, water temperature and formulation used. April 22, 1980 C b- t *600021 101 2.4.Q FACT SHEET oaiy 1085277 I. Background 2,'4-0 is one of the most wiaely used herbicides in the United States. There are aoproximately 1,500 products containing 2,4-0 registered with EPA, and more than 70 million pounds of the active ingredient are distributed annually. The term "2,4-0" refers to the p-henoxy herb i cide 2 ,4-dichiorophenoxy acetic acid and its 35 derivative salt and ester forms. 2,4-D is used to control broadleaf weeds in a variety of places including home lawns, cereal and grain crops, commercial areas, commercial turf, rightsof-way, and forests. 9ublic concern about the potential adverse health effects of 2,4-0 has intensified since the emergency suspension of 2 . 4. 5- T and Silvex in March 1979. This concern stems primarily from 1) the chemical similarity of 2,4-0 and 2 . 4 . 5 - T as phenoxy herbicides, and 2) the question of 2,4-0 dioxin-contamination, especially contamination with tetrachlorodioxin, a manufacturing contaminant in 2,4,5-T, which causes cancer and mi scarriages. Due to the chemical similarity of 2.4- 0 and 2,4,5-T, the public has expressed concern about the potential for cancer and miscarriages from the use of 2.4- D. There is also concern because the controversial military defoliant Agent Orange, used in Viet Nam, was composed of 2,4,5-T and 2,4-0. Agent Orange was never registered by EPA for civilian use in the United States. Its use in Viet Nam by the U.S. mi litary has resulted in claims of adverse health effects to American mi 1 itary p e rs on ne l. The Veterans Administration is studying these claims. rompted by these concerns and EPA's need to resolve the questions surrounding the use of 2,4-0, the Agency initiated a review of the available information on the potential health e j e c t s of 2,4-0. This review was conducted in part to determine if the herbicide should be reviewed under the RPAR process (Rebuttable Presumption Against Registration) or if another regulatory action was appropriate. II. Anencv Review and Conclusions Based on the results of this review, EPA has concluded that a) the presently available information on the potential adverse health effects of 2,4-0 does not support a regulatory action to remove 2,4-0 products from the market; b) information *rom scientifically valid studies does not indicate that the continued use of 2,4-0 poses an imminent hazard or unreasonable adverse effect when used according to laoel precautions ana direction for use; and c) the Agency should act quickly and vigorously to obtain better toxicological information on 2,4-0. * ..... . 8142 0006137 D 0 \{/J 08527S These conclu si on s are based on these following cons iderat io n s : 1. There is no ev idence availa bl e at this time- that indicates 2,4-0 contains any form of dioxin. This includes the t e t r a c h l o r o - d i o x i n (TCOD), which is a ma nu fa ct ur in g contaminant of 2,4,5-T and causes cancer and miscarriages. TCOD is not th eo re t i c a l l y expected to be found in 2,4-0. The manufacturing processes and starting chemicals from which 2,4-0 and 2,4,5-T are made are not the same. Although other much less toxic dioxins are theoretically po ss ib l e 1n 2,4-0, they have not been found despite thorough chemical analyses. 2. Se cause products cont ai ni ng 2,4-0 have been registered for use since the 1940's, most of the scientific data submitted to support the product registrations now on the market were developed many years ago. While some of these studies are scientifically valid, many others do not meet today's standards for scientific testing. As a result, there are si gnificant Information gaps in several areas including cancer-potential, reproductive effects, ne uro to xi ci ty , and m e t a b o l i s m 1n animals. 3. The studies most pertinent to the question of tumor-causing potential (oncogenicity) of 2,4-0 were considered inadequate and inconclusive. No valid conclusions could be drawn one way or another from the data. 4. Animal tests conducted on the potential reproductive effects of 2,4-0 show that, unlike 2,4,5-T with its contaminant TCOD, severe 1ife-threatening effects were generally absent from 2,4-0 tr ea tm en ts at mo de ra te or high doses. However, new tests will need to be conducted at lower doses to cle arl y establish no-effects levels. In comparison, TCOD, which is present in 2, 4,5-T and not in 2,4-0, produces serious 1 if e- th re at en in g effects on the fetus at minute doses including the lowest dose tested in many studies. 5. The s c i e nt if ic evidence available at this time does not indicate the potential human ex posure 1s sufficient to result in human health effects. 6. The most vigorous authority availa bl e to EPA under the pe st ic id e law to fill information needs is a new section of FIFRA (Federal Insecticide Fungicide Rodenticide Act) passed in 1978. This provision, kjiown as 3(c)(2 )( B) , allows EPA to request any additional data from pesticide registrants that is co ns id er ed ne ce ss ar y to maintain the registra ti on of existing products. The Agency can immediately require the 8143 GGGGi23 DOW1085273 *,a nu f act urer s to develop the data where gaps exist. The registrants have 30 days to show that th<ey are complying,, " hei-r product read strati on s may he summarily suspended if they fail to meet the Agency's conditions. No other action could obtain this information any faster. EPA is putting the data requirements into final form and they will be issued t o t h e registrants after review by our Scientific Advisory Panel. These scientific experts will review and comment on the data requirements to assure that they will provide the information EPA needs to more definitively answer the questions on potential health effects of 2,4-0. 7. Based on a review of the toxicology data (see section IV below), and a review of the risks of other pesticide chemicals now undergoing regulatory action, the Agency believes that the risks of several other pesticides are higher and better documented than those associated with 2,4-0. To put the review of these other higher priority chemicals aside in order to devote EPA resources to taking action against 2,4-0 would not, in the Agency's opinion, best serve the public interest. III. Additional Actions In addition to requiring several important studies of the manufacturers on 2,4-0, EPA will also: 1. Conduct several tests on reproductive effects (through our Office of Research and Development) of several derivatives of 2,4-0 in order to quickly get new information and have a good basis for comparison with the company-produced data. 2. Continue its ongoing review of forest pest control practices. This review will evaluate all chemical and non-chemical controls to identify the most environmenta 1ly protective ways to control forest pests. The Agency believes that a piecemeal approach to forest chemical regulation only leads to confusion, both to the industry and to the public. Unless we review the whole range of possible controls, examining one chemical at a time only gives rise to questions about the chemicals which would be used- to replace those examined and prohibited from use. 3. Review all new data as it comes in to determine if a change in our regulatory posture is warranted. This includes evaluating the results of new animal tests as well as looking into reported incidents involving human exposure to the chemical. s cooGisa DOW 1 085200 a . C o n t i n u e to support field tests to measure exposure to 2,4-0 during the present growing season. 5. zPA is informing the nt.a r-Agency i/flrk Srouo, e s t a b l i s h e d by the White House to study the possible long-term effects of Agent Orange, of the actions being taken. E?A will also share its scientific findings with this committee. IV.. Toxicology Background The potential hazard of a chemical is usually meas ur ed in la bo ra to ry animal tests.. Animals are given doses of a chemical over a specific time period. Scientists attempt to derive fr om most of these tests a "no observable effect level" (NOEL) -- the dose level below the dosage where effects are first observed. From the animal tests and N O E L 's, the potential effects on humans and other animals can be estimated. A set of brief definitions is provided below to permit better understand!'ng of the subsequent discussion of toxicological findings. A . General terms 1. Ac ut e oral toxicity (L05Q) - this test determines the dose level wnicft produces death In-half the test animals after a single oral dose (short-term test). Used to predict the nearterm toxicity of the chemical immediately upon contact with people or other non-target animals. 2. Ch ronic feeding tests - animals are fed for most their life span (usually greater than 13 months in rodents) in order to determine the dose level which shows no toxic effect in test animals. This is the test from which the NOEL is ( usual 1y ) deri ved. 2. O n co ge ni ci ty te st ing - animals fed relatively large doses'of tne test chemical for their life span (usually 13 months to 2 years in rodents) to try to induce tumors. These tests are used to predict whether the chemical may pose a cancer hazard. A. R e p r od uc ti ve testing - these tests evaluate the effects of the cnemical on the fertility of both the male and female parents by exposing the animals for a period of time before breeding. The tests also measure the possible effects of the chemical on the pregnant female and the fetuses through several generations. (The test with rodents through 2 generations runs ap pr ox im at el y 14 months.) 8145 C O O G iSO 5. T eratology testing - these tests evaluate the effects or tne chemical on fetuses by exposing pregnant females during the short period of. time that th-e fetus is most susceptiole to congenital m a 1formation. Teratogenic effects include cleft palate, central nervous system deformities, eye and limb deformities, and internal organ malfunction. These are considered to be 1ife-threatening effects that put the animal at a disadvantage for surviving in its environment. 6. Fetotoxicity - fetotoxic effects can be seen in either the reproduction or teratology tests. Toxicity may be seen in the extreme form as fetal death or as less severe problems, such as delayed formation of bones, reduced body weights at birth, or edema (abnormal fluid accumulation in the tissue). Most fetotoxic effects appear to be reversible once exposure to the test chemical is curtailed. Therefore most fetotoxic effects are considered to be less serious than teratogenic effects, with the exception of fetal death. 3. Summary of Toxicology Review Most of the data in EPA files on the potential health effects of 2,4-0 are centered on the acid form, even though there are many derivatives, such as salts and esters. This 1s because the many forms of 2,4-0 metabolize to the acid form in the environment and in the body. The discussion of animal data below, therefore, concerns the acid form of 2,4-0 unless otherwise noted. 1. Acute toxicity - low to moderate. The potential for immediate poisonings from contact with the chemical is unlikely. 2. Neurotoxicity - There is little definitive information on the possible neurological effects of 2,4-0. In several reported cases of impaired nerve function, it was not known if the individuals were peculiarly sensitive to that type of effect or were exposed to other toxic materials. 3. Reproductive effects (effects on the unborn) Tests have been conducted on rats, mice and hamsters to evaluate the possible reproductive effects of 2,4-0. 2,4-0 causes some of the less serious fetotoxic effects, such as edema (swelling of tissues) at the lower dose levels tested, and causes life-threatening birth defects (skeletal malformations) and cleft palates only at the very high levels te sted... CGOoioi DOIVJ 085282 in Basad on available animal studies, SPA estimates that the level of 3 x 0 0 sure in a. "worst, case" situation (eg. a person standing directly under a spray plane) would be 500 to 1000 times less than the dose -level that might cause an effect. Much of the data available to judge these effects was genera te d by old study protocols, has de fi ci en ci es in the test methods, and needs clarification by further study. EPA also reviewed summaries of tests conducted in Russia which state that some deriva ti ve s of 2,4-0 produced adverse effects on unborn animal fetuses at much lower levels than indicated by the data in EPA's files. These summaries could not be used in the Agency's review because the identity of the test material, and its impurities, was unclear, and because there were no numerical data to back up the summary conclusions. In some cases tests need to be done on specific derivatives of 2,4-0. 4. On co ge ni ci ty (potential for causing tumors) Several rodent studies have been conducted to date. The tests were conducted a decade ago and are cons id er ed to be inadequte and inconclusive by today's scientific standards. New studies on rodents are needed. . Mutagenicity (inheritable effects) - The vast majority of the mu ta ge nicity studies conducted on 2,4-0 are negative. However, there are three positive studies. Taken as a group, the results of the studies can best be described as inconsistent and inconclusive. A new series of tests being conducted by the De part ment of Health, Education, and Welfare will be reviewed by EPA when they are completed. 6. Ep id em io lo oy - No epidemiological studies of human health effects from 2,4-0 exposure have been completed. However, EPA is cu rr en lt y investigating reports about alleged adverse effects from potential chemical exposure in several parts of the country. EPA w i M be looking at the results of those studies and will decide in the near future about additional field work. D0W.1 085283 I. Exposure to 2.4-0 There are at least three ways that the average citizens might come into contact with 2,4-0 - through the diet, during home use, and drift of the herbicide from nearby use. a) Diet The EPA has set tolerances for residues of 2,4-0 in various food crops. The Food and Drug Administration (FDA) routinely samples a variety of foods (the Market Basket Survey) which FDA considers to be representative of the average American diet. Samples are analyzed for pesticide residues. During the period of 1974 to 1977 ,' no 2,4-0 residues were found in any of the products in the Market 3asket Survey. However, during the 1965 to 1977 period, a variety of other food products were analyzed under other surveys in which about 1.1% were positive for 2,4-0 in very minute quantities that were well below EPA's tolerance (allowable residue) levels. b) Home use There are currently a number of registered home-use products which contain 2,4-0 in a variety of formulations. Exposure to the herbicide in home-use situations will depend to some extent on the specific formulation used. If care is exercised by the homeowner in adhering to the directions for use and precautionary statement on the label, exposure to 2,4-0 should be low. c) Drift "Drift", the airborne transport of pesticide materials to a non-target area, is a common source of exposure. Sometimes, a pesticide will drift during application, depending on climatic conditions (temperature, wind speed), type of formulation used, terrain (forests, mountains), and type of application method used (aerial, ground spray). Several States have imposed restrictions on 2,4-0 use in order to cut down on drift potential. Once on the ground or target crop, the herbicide may become airborne again by the process of vaporization. This particular type of drift has been the subject of intensive research by the producers of 2,4-0. Since the introduction of less volatile forms of the herbicide over the last few years, this kind of drift has become much less extensive. CSOGiou 8148 J 7 1 . z n v i-ronmental Pers'* stance 2,*-0 is not a persistent pesticide. 3reakdown of the h e r b i c i d e begins almost immediately after application at a rate dependent on several environmental factors such as temperature, humidity and medium (air, soil, crop, water). The rate of loss (commonly referred to as the half-life) is a measure of the time required for half of the su bst ance to be degraded or lost. On sprayed v e g e t a b l e s , the half-life varies from 1-3 weeks de pe nd in g on geographic location, climatic conditions, vegetation type, application technique and formulation used. In s o i l , the half-life varies from several days to 2 weeks, ae oe nd in g on acidity, soil type and amount of rain. In w a t e r , the half-life varies from a few days to several mo nt hs depend in g on factors such as oxygen c o n c e n t r t i o n , acidity, light intesity, water temperature and formulation used. April 22, 1980 DOW.] 085284 Ob V OSTS 0b\ IONS & ROUTING: Any world area may originate (specify). Unless critical leave effective date blank Systems by QA Office. This will be don' One person may sign for both Mark' organizational structure. Originator tends signed form to Product Quaii.. 1. This information b added by the QA Office to aid the Cor|. 2. To be completed by the Corporate Product Department. QA Office v area business & marketing concerns are properly represented by the Cr. the discontinuation thru Code Systems upon receipt, unless otherwise instruct Record any objections to discontinuation. Self-explanatory. X Names to be provided and notifications accomplished by Originator in the originating area. , - > lam >be provided ond notifications accomplished by QA Office, ssponsibility of notification of discontinuation on receipt of completed form; *4 wTi ` V*> \ x /9 Z 8029 -DOW CONFIDENTIAL INFORMATION R & D REPORT D O W CHEM ICAL U.S.A. R&D REPORTS SHOULD REMAIN ON THE PREMISES OF THE DOW CHEMICAL COMPANY CPARTM(NT TnYTrni ncv prsFAPfn i ARnPAmpy CRI N U M |(R - K-66681-(40) La IORATORY K?ORT coos HET K-66681-(40) )atc idsuco May 30, 1980 ft I 1III' 2,3,7,8-TETRACHLQROOIBENZO-p-QIOXIN: ACUTE ORAL TOXICITY IN HAMSTERS cUaJs 2 A l* T h O A vSJ 3 Z J. W. Henck, M. A. New and R. J. Kociba a UGNA TUPE 131 u / J f . ^ k . ft/* * 2L PAGES IN F U L L REPORT S3 Ci* O E J C R IP T I V E SUMMARY WITH CONCLUSIONS: C O The acute oral toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 00 was evaluated in hamsters. Male hamsters (Engle Laboratory Animals, Inc., Farmersburg, Indiana) weighing 70-120g received 0 (corn oil only), 300, 600, 1000, 3000 or 6000 ug TCDD/kg body weight by single-dose oral gavage. To facilitate dosage, TCDO was fed as a 0.062 or a 0.162 suspension in a acetone/com oil (1:9). All hamsters were maintained for observation at least o 55 days following dosage. ac The 55-day single-dose oral LD5Q was calculated by the moving average method of analysis to be 5051 ug .(3876-18,487 ug/kg, 952 confidence interval). Initially, no hamsters exhibited adverse effects related to dosage with TCDO. However, 4-5 weeks following dosage, hamsters of the 1000, 3000 and 6000 ug/kg dose groups began to develop unkempt hair coats. A doserelated depression of mean body weight when compared to control weights was observed in hamsters of the 1000, 3000 and 6000 ug/kg dose groups by 3 weeks post-treatment. ro 03 CO At the termination of the study, all surviving hamsters were subjected to a gross pathologic examination. The following lesions were observed in hamsters dosed initially with 0, 300, 600, 1000 or 3000 ug/kg: a slight decrease in abdominal adipose tissue (300, 600 and 3000 ug/ka dose groups), a slight decrease 1n thymus size (600-3000 ug/kg dose groups), and sporadic instances of U v e r lesions (600 and 3000 ug/kg dose groups). Hamsters were dosed at a later date with 0, 1000,3000 or 6000 ug/kg. One hamster of the 1000 ug/kg dose group exhibited pale, coalescing areas in the liver, all other lesions observed in the hamsters of this second group were felt to be spontaneous 1n nature and unrelated to treatment with TC00. The hamsters dosed Initially were subjected to a gross necropsy 16 days after the hamsters; of the second group. It 1s possible that this 16-day time BEC J E E P DISTR IB U TIO N : JULB 1980 DEPARTMENT FILES R 4 0 ADMINISTRATION C E N T R A L REPORT INDEX - 1* COPIES { S66 Bid*. - Midland) Distribution list is continuad an ^ fto c h a d ^ io flo jJ ^ jQ FORM C-OOO FRMTCO F-J-00 . MIDLAND BI i a s-. r 0 0 H 2 11 1 6 9 8 interval was sufficient for lesions to begin to develop; this may explain why no lesions were observed in hamsters of the 6000 ug/kg dose groups. 8155 DOW CONFIDENTIAL INFORMATION l**3 c 8156 q \|^ 2 5 2 0 5 9 r MN061593 June 2 , 1980 THE DOW CHEMICAL C O M PA N Y POST OFFICE BOX 1706 MIOLANO. ' MICHIGAN 48640 Mr. James M. Stone Product Manager 23 Registration Division (TS-767) U.S. Environmental Protection Agency 401 M Street, S.W. Washington, DC 20460 bec: D. M. Frederick M. L. Leng A. J. Watson Action Pile: ESTER0N 245 Dear Mr. Stone: Subject: ESTERON* 245 EPA Registration No. 464-205 Application for Amended Registration The accompanying application concerning the subject product is largely self-explanatory. Basically, we propose reinstatement of the foliage treatment inadvertently deleted from the label at the time of our initial compliance with the March 22, 1979 suspension order. In addition, some minor text changes are proposed to improve flow and/or clarity of the existing wording. We believe that this application complies with the compensation exemptions cited under 40 CFR 162.9-1(b)(7), (b)(9), and (b)(17); consequently, an Offer-to-Pay and Certification Statment have not been included. Your earliest possible consideration and approval of this application will be appreciated. Sincerely, Robert W. Morgan Registration Supervisor Product Registrations Regulatory and Legislative Issues Health and Environmental Sciences er Attachment *Trademark of The Dow Chemical Company m m * * * * DOW C O N F I D E N T I A L * * * * 28750 THE DOW CHEMICAL COMPANY QUALITY ASSURANCE OFFICE QACACI SPECIFICATION CONFIRMATION COPY OATE PRINTED: 5 JUN 80 PAGE: 1 PRODUCT: 28750 QACI 290 REVIEWED: 2 JUN 80 REPLACES: 28750 19 FEB 80 { NAME: OBSOLETE * ESTERON CR) 245 BRUSH AND UEEO KILLER CPL 8 BULK) DESC: AMBER* OILY* EMULSIFIABLE LIQUID. PRODUCT NO LONGER PROOUCED ANO DECLARED OBSOLETE 2 JUN 8 0 . msd: 303 :S PROD*N PTS u.s. : mh DEPT:31 oates : latest: PRIOR : PROD*N : : 4 jun 7* : 9 JAN 76 l DATA TERM*L RAW MAT' L sales: TEST METHOD : iv: Ct PROD*N NOTE PRODUCT DECLAREO OBSOLETE 2 JUN 80 RAW MAT*L NOTE i PRODUCT OECLAREQ. OBSOLETE 2. JUN 88 SALES NOTE ''.y. PROOUCT DECLARED" OBSOLETE 2 JUN 80 TERMINAL NOTE ' PROOUCT DECLARED. OBSOLETE 2 JUN 80 APPROVERS: U.L GOLD J.M FRASER" 'APPROVAL OF CHANGES INDICATED ABOVE! OGGOGGOGGGGtGGPGGGGGtGGGGGG APPROVERS OF INOIVIOUAL SPECS! prodn: . SALES! < raw m: v TERML! "8 approvals ^snxv-D E Pr : datE - : approvals r DIV-DEPT : DATE. ' \ A CR) INDICATES A REGISTERED OR TRADEMARK NAME OF THE DOW CHEMICAL CO. * * * D O W C O N F I D E N T I A L * * * LAST PAGE 0007481 I T 5* DOW089067 ::wiM.-v. SYNONYMS c : . : . - - c s ;t ;c n . MEDICAL b r u s h .a n h kii.u -.r 1,(1 ; sr.i- back ^ __________________ ' _____ INFORMATION '/-TSR.AL NO r'w SOLlUTY -H.U1 ifiable PHYSICAL STATE. TOXICOLOGY -- ANTICIPATED H U M A N R E S P O N S E - BASED ON: E'-ES Slight ro nodorate pain, slight transien conjunct irai infl ammat ion and iritis. i an.'.al o a t *. ... ; Prolonged contact, intact skin, unconfined: slight erythema. Repeated skin contact slight to moderate erythema and edema. Skin absorption capacity not evaluated (Based on minimal tox study). ORAL: Moderate to low acute oral lethality (1.1)50 rats approx. 1 g/kg body weight. (Based on minimal tox study). RES?. One hour exposure of 20. rats to an aerosol, of M-53l>( resulted in no adverseeffects. 5r __ Pat Keeler tOATE flcFEnSNCE .1 ' 6-24-jW :*Rcyised 1 SUGGESTED -- TREATMENT AND HUMAN EXPERIENCE pyCC- Stain for evidence of corneal abrasion or injury. NOTICL POW COPY M TO rkp. DEFIGIEHT ORIGINAL May cause reaction similar to AL. petrolouni or petroleum-1ike solvent. Product moderately toxic. Danger of chemical pneumonia must be weighed against toxicity. If lavage is performed suggest endotracheal and/or esophngoscopic control. SYSTef...;. Human effects not established. Probably could cause serious illness with spontaneous recovery. Based on minimal data. J.M..Lanham TiA T c . 10-30-73 p lF E R tN C E - ,, l.-CEET EI' -iR T AID P R O C E D U R E S EYES Irrigate with flowing water immediately and centinuousiy for fiftc. a minutes. Refer to medical personnel. SKIN Wash off in flowing water. Decontaminate clothing and accessories before reuse. Good personal hygiene. Remove to fresh air if effects occur. Gansu 1 ".edica personne 1. no not induce vomiting. Call a physicin nc i1ity . I 8161 000C9i3 DOW 089068 COMPOSITION 9.2 2,4,5-trichlorophenoxyacct ic acid PGBL Pstcrs 0 . 9 'o polyglycol 59-15 2.6 v Eir.col C 51-2 T.5 Bay refining PF Solvent r 8i6 3 0000914 write this, then it had to be the EPA sending this to Dow outside the normal public channels telling them why they were cancelling their 2,4,5-T. In any event, it is a very damaging document to Dow. S ' L90. 5/5/80 Document entitled: "Product Discontinuation - For the Product Esteron 2.4.5 Herbicide". Comment: Dow Chemical stops the use of Esteron 2,4,5 in the United States in PL and bulk sizes". 191. 5/16/80 Dow R&D Report: "Picloram: Results of a 32-Day Toxicity Tolerance in Feed in Mice", with attached report. 192. 5/30/80 J .W . Henck. et al., Dow R&D Report on 2,3,7,8-Tetrachlorodibenzo-P-DioxinAcute Oral Toxicity in Hamsters". This is a report summary. ^ 193. 6/2/80 Letter to Stone of the EPA from Morgan of Dow re: Esteron 2,4,5 Application for Amended Registration. L"" 194. 6/5/80 Dow Quality Assurance printout on Esteron 2.4.5 Brush and Weed Killer. Comment: Esteron 2,4,5 has been declared obsolete on 6/2/80. x"95. 6/24/80 Dow form of medial information from Esteron 2,4,5m^t2.0 a H A ^ jr j <jO<~^Q /u c Comment: See exhibit 195a below. 195a. 6/24/80 * The back page of the document in exhibit 195 which is entitled: "Composition Listing Chemical Ingredients". Comment: This states that Esteron 2,4,5 can cause serious illness (from a Dow medical sheet). If gives all chemicals I j in this product and they contain no ^>, aner-t e I (In other words, nothing is hidden here in what Dow is actually / putting in their product. They usually ,, hide the deadly ingredients under e neg-ts and then list some percentage like 35% . * ' " ' enerts. In this case we are getting to see for the first time everything that Dow puts in their Agent Orange product.) ATTACHMENT TO MEMORANDUM DTD 11/13/91 - 29 ( 111 191 8l65 DOW 1078054 APPENDIX E ALL REGISTRANTS WITH MANUFACTURING-USE PRODUCTS FOR THE FOLLOW!NG: 2 ,4-Dich Ip r o ph eno xy ace ti c acid 148 264 359 464 524 677 2217 6305 7173 7969 8997 39335 39511 Thompson-Hayward Chem. Co., Kansas City, KS 66106 Union Carbide Agrie. Prod. Co., Ambler, PA 19002 R h o n e - P o u Ienc Chem. Co., Monmouth Junction, NJ 08852 DOW Chemical USA, Midland, Ml 48640 Monsanto Co., Wash., D.C. 20036 Diamond Shamrock Agrie. Chem., Cleveland, OH 44114 PBI-Gordon Corp. , Kansas City, KS 66118 Robeco Chem. Inc., New York, NY 10016 Chempar Chem. Co. Inc., New York, NY 10016 BASF Wyandotte Corp., Parsippany, NJ 07054 Shepard Chem. Indust. Inc., New York, NY 10022 Fa I Iek-Lankro Corp., Tuscaloosa, AL 35404 Vertac Chem. Inc., Memphis,TN 38137 Butoxyorooyl ester of 2,4-Q 464 DOW Chemical USA, Midland, Ml 48640 Isooropyl ester of 2,4-0 524 677 5481 m Monsanto Co., Wash., D.C. 20036 Diamond Shamrock Agrie. Chem., Cleveland, OH Amvac Chem. Corp., Los Angeles, CA 90023 44114 Isooctyl (ethylhexyl) ester of 2,4-D 148 V 228 359 464 524 677 2217 .39511 40831 Thompson-Hayward Chem. Co., Kansas City, KS 66106 Ri ve rda le Chem. Co., Ch ic ag o Heights, 111 60411 R h o n e - P o u Ie n c Chem. Co., Monmouth Junction, NJ 08852 DOW Chemical USA, Midland, Ml 48640 Monsanto Co., Wash., O.C. 20036 Diamond Shamrock Agrie. Chem., Cleveland, OH 44114 PBI-Gordon C o r p . , Kansas City, KS 66118 Vertac Chem. Inc., Memph is, TN 38 137 * Falls Chem. Inc., Great Falls, MT 594Q3 CGQ6GS $16$ ns ns % m 1 085236 V Arr;!.. X LIST OF YOUR COMPANY'S PRODUCTS CONTAINING SOME FORM OF 2,4-D V- r11IIt-li./j III / I t/ll.i PRIIIMH'T S l ^ > ^ . ISIINIl PRODUCI I.ARfl I I LE 01 ( 0 3 0 0 ) 2. 4 I) PARE I |l 63 RII.IMPANI' onoll.1 NAMI ANI) AlUllT SS IHIW CHI MIRAI IJ 5 A Al.RICIJI MIRAI PRONOMS I1 IV PII I1IIX |7(li MINI ANO MI 46640 5176361000 ( Il II II 1 1 IHIW 1ORMI II A 40 lil'l 40 I I I R f m . l D f 1NRM: 15 SOI lll'.IE CONCE MIRAI E APDATE 0729G3 PM* 23 DATE 0376 TOXICIY- 3 INORIOIIMIS n i n i ) IO 5 9 . 7 0 0 0 A l k a n o l * il mino 2 . 4 - d I r. l il or o pl ie n ox ya c a 1 a 1e ( s a i l s o f Die e Diano 1 a n d IMI 111 1 1 IlOW IIMA 6 WELO K i l l FR I v l ' l 40 III UI'.ICIOE IOPM: 15 SOI 11(11 E CONCE NI RAIF 072767 PM* 23 DATE* 0375 TOXICITY* 2 1NlRFII 1 FNI S o:iOOI`l 61) 50IKI II in o 1hy 1ani I n e 2 . 4 -d Irli 1o r o p l i e n n x y a c e 1il 1o IMI 1*1*1 I M I RON 00 t i l l : 40 1IFRO ICI DF IIIRM 12 TMill SIT 1ARI F COMCFMIRA 1F IEC OR E) 02 1 154 PM* 23 DATE 0173 TOXICITY 3 llli.Rf I lIf NIS0 10072 4 1 OOOO Pi i >|iy l o n e g l y c o l b u t y l o i l i e r 2 . 4 - d I c h 1o r o p h e n o x y a c e t a t e 1 (MI IM I 1 now m i r tri. 2 0 5 ' IVPF. 40 1ITRP. 1i. 1OF IIIRM: 17 1 MOI SITI ARIE CONCFNIRAIE IEC OR E 1 0 2 2 I5G PM* 23 DATE 1274 TOXICITY* 3 Co CO iNiiRrnirrns LEZS80rm I IH PRODIirI SM <1/M/>!H I uniirmi il(.i m i .'ami O'Hiif.i prodi iri o n inn now mirri ?s inorerifni v 0300'>6 i ! ) . fi(K)i) R u l y l 2 . 4 -d IcIiloi'ofilKifiuxyiico l a l e n o 184 PRODUCI NAME ......................... .. DOW P.IIIYL 4 00 1 rPF : 40 1vl'l : 41 lYPF; 77 l'IJRM: 12 III HOICIDE HERBICIDE 1ERRE SIR 1AL ONCI ASSI FIFO t Mill S 1F 1ABI E C0MCEII1 RA 1E ( EC OR FI IMI.REDI ENI S m u u ' i f i 5 5 . 4 0 0 0 R u l y l 2 . 4 0 1 r ii 1or oplionoxy.Ktp 1il 1o ISI IN( I PARE 84 APDATE 061270 0 *PM* 23 DATE* 0779 TOXICltY 3 1 M>III / i 1 SII RUN lOIIR 1IIW VOI Al ILE WEED KILLER 1/PF. : 4 0 IIERII 1C IDI FORM 1? FMill ' ill 1ARI E COOCENIRAIE CFC OR CI INORI DIE HI 0 3 00 5 5 7? . HOOO UiilOKypropy 1 2 . 4 -ri 1c h i o r o p h e n o x y a c e t a t e uom o DMA 4 III RII IC IDI IYPF 40 III' RR IOIDE IORM: IO SOI IIP.I E CONCEHI RAI E iriGREDIENIS* o n o r i l o 4 9 . 3 0 0 0 II iinetliy Ini Ine 2 , 4 (I I c h I o r o p h e n o x y a c e l a l e 042471 23 0275 1 APDAI E 070572 PM* 23 OAIE * 0475 IOXICITT 2 882880 I ^ g g 05 K COOoiiS O 11 mimici si .1311NO .i.. I H . 1 1 / V! I 1 (,HNI IIII If III I'll 3 1RANI OOil'Ili'l i -in ii mm. i o o : > o i DMA a i l i n n i c i u t I hK'O 1 1 I M I RUN '.I'l Cfllll.l M11?A11 hi'i 40 hi no it: m e IIII.M IQ SOI Mill I COIIClNIMAir APOA1E oa25r>7 INGKCIIIINIS* o UH)/; /.'Udito I ' ro p y loin) i i l y c o l b u t y l e l l i e r 2 ,4 -d 1 cl i l o r o p h e n o x y a c e l a t o I'M* 23 I'Aiit ( 85 DACE < 0875 lOXfCIIV 3 4hi:>o 4 1 MCRflN I'.RIISII K i l l 1K ll>f 4 0 Ilf II 1C i n t 1 1 IRM: 1 2 1 MOI S i r 1 AHI I CONCFNIRAIE (EC OR E I 020758 23 1075 0'|(io/2 0020/2 1MORC II 11 N 1S * 30 0 0 0 0 I't rtpy l e n e g l y c o l b u t y l e t t i n r 2 . 4 -d I c t i l o r o p l i e n o x y a c o t a t o 34 loot) Ilo t o x y e 1by 1 2 . 4 . 5 t r 1e h 1o i o p l t e n o x y a c n t a t e Use coiie mi. 082053 3 m y ; r.i 1 11*0011 2 2 iin 40 i il mi I c l of ihum lb SOI lim i CONCIMI HAI E 042561 iNr.ncnitNis* 0 1 0 0 / 2 Hi n o n o l*inpvloiw? g l y c o l b u t y l o I liur 2 . 4 - il Inli Ior opboi l o y a c e t n 1e 0H'20V> 34 4(K>0 Hu I ox y p i o p y I 2 . 4 , 5 t r I c h I t>i o p h e n o x y a c e t a t e 23 0567 3 CS3S80 I }MM 0C0uiI3 n I I I I I ' ! I u r n m i n m h i m i ' a n i i m o .i g .i 2i r o i h k : i 0 0 2 1 9 i i i t o n ? mu iiici r.ru? i si me. PAGE 1)6 ....................... ............ I*1MilJlli | IIAMf ......................................... *>.>. / I llllW IMFRIIN 76 HE WffD K I I I F R I V1*1 40 IlfRI*. 1C 11)1 IlIRM: 12 [Mill S11 I Ani F CtINCEMIRA TF (EC OR E I AI . . E * 00026/ ..1 DA 1( l O l i f l l Y * 23 0275 6 in c r f o if n is * 070* 1 (1 6 7*1.2000 l l ' i l y l 2 . 4 -d i e h 1o r n p h n r i o x y a c e l a Io ...................................... I'ROOIICI flAME .................... .. M<i2l(*l VI I'Mill CT WIFI) ANI) RRIISII K I I I FK IVPE : 4 0 IIERIIICIDE IORM: 12 I Mill 5 1 1 I AEil E CONCfNI RATE I EC OR El APOAIE* 030669 PM* 23 *OAI f . 0369 TOXICITY* 3 I NliREI) I EMI S * 0 3 0 0 / 2 3 6 . 0 0 0 0 I'ropylen p l y c o l b u t y l e t h e r 2 . 4 -d i c h I o r np l t ei i nx y a c e t a t e 0 1 1 2 0 6 5 3 4 . 1 0 0 0 On I o x y p r o p y I 2 . 4 , 5 1r Ie h Io r opl lenoxy a e a I a I o o< no(> . I'linmiCI NAME I . . . . . . . . . . . . . . . IIIROON IOI MIX HIRE WFFI) ANT) IIRII5II KILLER 1VPF 40 HEROIC IDF. i vi*r 99 RISIRICTED 1ORM 15 HOl.lim.C CUNCFNIRA 1F APOAIE* 06 1463 PM 23 DA IE * 1070 TOXICITY INGPFDIFNIS* 0 05 102 1 0. 2 0 0 0 I r I I s o p r o p a n o I am llie p l c l o r a i n ( 4 - am ( n o - 3 , 5 . 6 - I r I c l i l o r o p I co I In Ic a c i d I 0 3 0 0 3 6 .7*1.6000 I r I i s o p r o p a n o I am I ne 2 , 4 - d I c l i l o r o p h a n o x y a c e Ia I e Of?$Q0\ iidOO Oii>OujUi iI t i l t 14 / l'.l i * Mulinici si .i m ini; i l i m I (l<ll III li I MI TAMI I H H i i r .4 Midi Min 0 0 14/ I ORI MIN IO I MlrllJRF Wl fi) AMI) BRUSII K l l . l t R (M1.I4 / 1 i m i rom r.F i i FRi nci oi : I l i o 4 0 IIERIUI IDE IORM. 13 EMill. S 1r 1AHI E CONCENIRAIE (EC O R E ) i 1NORTH 1FIJTS o:!OOI>:< 94 41 Kl 1:ir 1y II 2 >thylhexyl) 2 . 4 - d 1c h 1o r o p h e n o x y n c e t a t e PAC.F. 87 ARDA I E 112965 RM 23 DATE 0375 l O x r I EY* 3 OO 140 Wl 1l KIM TR 411 11-1 40 HERBICIDE IORM 13 1MOI S i l i AHI E CONCI NI RAH (EC OR E> INORI DII NI5 (.'loOCi l /O .fMHMi 1none 1y 1( 3 e lliy lliexy 1 1 2 .4 - d i ch 1o ro p h en o x y n ce 1a 1e 122865 23 1274 3 oo'is: Crii,Il KII 1 I R 3 2 1V1*1 : 40 HERBICIDE fliRM: 12 I MI I I SI II Ani E CONCEMIRA TE ICC OR El INORI II UN IS O RKifi l 34 . /(jOO 1,ooc 1y 112 - e I hy 1he* y 1 1 2 . 4 - d I c h 1o r o p h e n o x y n c e 1a Ie OH.iiii'l 3.1. lOMO 2 E lliy llie * y l 2 . 4 . 5 1r Ich 1o ro p h e n o x y a o o l n I e OI25G6 23 0475 3 I llliw lOROIIN 2 1 2 MI ' I I IRl HERBICIDE. IYPE. 4 0 NERBI CIO lYl'l 90 RISIRICIED I OHM. IO SOI OBI F COMCENIRAIE INORI OIENIS* 0 8 1 IG7 25 0468 3 ntuwi n m o CGOi.ilOf , 1 1 / ' M/Hi) t t * munir. ; M n<; * * * '.s i n n i Him i.-i g i m p a m i i h k i u . i 1 -1.-1 1 1 1 1 1 1 . 1 n o : i i . Dow i oouon ? 1 2 m h i i w f 1 1 1 p i i i c i d e IMl.PI III I NI S ipiOIo ? ni Kim) 11 i I sop np.iiin I /iinino p i c l o r a m I 4 -nini n o '.1.5.8 t r I c h Im o p Ino I In Ir: Miriti ) iilooi-.i J / . / n o o li i 1 s n p i n p . u i n l run 1 1 1 0 ? . <1 <J 1 d i 1 0 1 o p l i e n o x y a c o Ia Ie page as ...................................... I'PUOIICI NAME . i p i IEO' I AWN WIFI) K l l l f P <I VIT 4 0 IIIRKIC.IDE -11)1.-11 I? I Mill M l I AHI C CONCI NI RA I F. 11C OR El APOAIE *PM< 11087 1 23 -OATE0275 -TOXICITY3 <INOPE I) I FMIS " l i - i i i i ' i^ ' . *1-1 Ol i l i C i i t o x y p i n p y I 2 . 4 - ri I c:l I o i r i p l i e n o x y n c G a l e iiM:-!i-.i!> IOOOIMI Hu l o x yp i opy I s II vex ( 2 - 12 . 4 . 5 - 11 I d i Ioi upliRnoxy I p r o p i o n l<: a c l i l I ...................................... PRODUCI NAME ............. .. IM).1:>-| PI PION :>l) I /PI 40 Mi PP.I CIO -IOPM 12 EMOI S I f I AHI E CONCENIRAIE (EC OR E I APOATE OS2 3 7 2 -PM23 -DATE0375 -TOXlCItY- 6 IMl.RE El I FNl 5 0 1 1 1 0 / 2 PI f.ooO pi opy I on y l y c o l h i l l y I e t l i o r 2 . 4 -<11cl 1 1oi-opliono <y n c e t n I e i h)*i1 1 : I'. l 1) ACID FOP MANDI ACIIIPINO PURPOSES ONLY IVI'E- 40 IIERCiriOE -IOI.-M OI lElllNIf.At r.l If M1CAL APOAIE* 012673 'PM' 23 -DATE 0375 TOP 1C11 V 3 INOPI DII NI S ' OIOOOI n-l.(PURI 2 . 4 II Ioli l or npht t nnxyc i ce I Ic a c i d CGOujLIG /--I ztzssol MQ rI' i'll ii//M/m PROIHJCI < I -iI |NO i < 1 1 1 1 1 I him i,'i i i i m d a n i onni r.A p r o i i i i c i i hiasa :*.i n A t m i o p m a n i j i a c h i r i n g p u r p o s e s u n i y i i i i I ' mI NAM* ...................................... 1 II AC III. OAMI* TOR MANUTAC HIRING PURPOSES ONI Y I /PI AG III Hl'.|(. I i n HRRFSIRIAI. Ilf** 77 UNCI ASS If I r II I IIRM: (II IFCIINICAL CIITMICAL INGRCDII NIS* ii.Kl/Xil 97.(WKXi 2 , 4 (11c h i o r d p l w n o x y a c e t Ic a c i d ( KM' .I. :*.a i i . r.ui/i i s i i r s I y1*1 40 IILRP. ICIOF I (HIM III I f Cl INI CAL CHEMICAL INCRFIlIFNIS* O.IOOGG 9 8 . 8 0 0 0 P.ulyl 2 , 4 - d Iclil o r o p l i n n o x y a c e I a t e Of MS / * 1*11001IC I NAME HOW 2 . 4 11 llUlnxY PROPYL ESTERS TOR MANUFACTURING USES ONI V 1 V1 *1 46 III Rill Cl Of ITRRISIRIAL 1 /PI 77 UNCI ASSI F 1FI) TIIRM Ol IFCIIMICAI CHEMICAL INGUri'l TNI ri 0 3 00 6 6 99.001X1 P . ol ox yp ro py I 2 . 4 - d Ic h Io r o p l i e n o x y a c e I a I e (MHsn . i PRDOUCI NAME HOW 2 . 4 0 IS00C1YI ESTFRS FOR MANUEAC HIRING USE ONLY IYPI 40 UIRP.ICIliF f IIRM Ol 1FCl INI CA|. CHEMICAL INGREIUTNIS' tZS80 PAGE 89 APDA1E * 012373 PM* 23 OAIE 0275 TOXICITY* 3 APIIAIF 010673 PM* 23 OAIE 0475 1OX I C11Y 3 APDATE 022673 1 PM* 23 DATE 0476 ` TOXICITY* 3 APDATE* 022673 "PM* 23 ` DATE* 0475 TOXICITY* C O O iiil? r1'i'i-r. / ' I I/Ml I produci sf>^ 1.1 STING i < m u imiii hi i n r. i r a n i ( hi n i i . i I ` K i l l IK. I I M U S H IIIIW .>.-1 I t I S O O C I Y I r S I E R S f OH MAN1 IF AC I UR I N G USE ONLY IM G R IhlfN IS * o l o n i r i ! l / . o o o o I jin: I y 113 o I liy IIn*, y I I J . 1 (I ie h Ioi' 0 |/hoiox ya c e I a 1 o PAGE 90 non. < 1 M l RON AA IMPROVED I .PI -ill Ilf HIIICILiE I OHM \ J IMIII S l f IAUI.E CONIfNIRAlE (EC OR FI APOATE 070! 73 PM* 23 DATE 0175 TOXICITY 6 IN<.RE01 EIIIS* l :ioul.lt >I oOOO O nl y I 2.-1 tlicliloro|iMRHr>y.ii:el.>te OOAI./ PRODUCI NAMI HOW IIMA fi IINSI OHIM fREI) IVPI AO III HP 1C IDE 1YPE : 7 / Hill.I ASSIF ICO 1(IRM 03 1ORMlil A11ON INTERMEDIATE APOAIF* 011073 'PM* 33 *DA I E* 0779 IOXICITY 5 iN (.Rtoirm s> OKU) 1*1 (i(, (i(XK) I) .me t liy I an. .<>< 2 . >1il loll Io r o p l . e i . o n y a c e I fl ( e !*><>/ AMINI fOIIR HEROIC lilt I I'F AO IIIROICIhF IORM Ift SOI IHi I I CONCFIJIRATF APOATE 1 1 IR7A PM* 23 DATE I 17 A TOXICITY J INGRfhllNIS* OilOolO i i / . IOOO AIFaiii. I* Anal or 2 . A -rt I c h In r o p l . a n n x y a c e I a I e ( s a i l s o f (lie e l l i a n o l a.Ml I s p r o p a i t o l s e r i e s ) PHOHOCI NAME .................... (X)`l III HOW lORIION IOIR E0RFS1RY IIFRniClOE 1 .PI AO III RP.ICIIlf 1YPI : AG IIIROICIhf IfRRESIRIAl ' , 1IIRM hi SOI III ION PFAOY IO USE APUAT E 022575 *PM> 25 DATE * 1 179 TOXlCltY* 2 Ifll.Rf D II NI S Q) **2S80 fcv O G jL lQ 1 t a i1*-1m7(1i1nHnICci1 Ss rF*' ` -. 1I S II NOf < i n : / i i / * i t m m m r i >.i M t'Aiii IKMI1 I.-1 i-ri mi li i I H I M I I DOW lOIIIIIIN toil.* 1 ORI H R Y 1IC171t 1C 1 OC 1Nllll I MI III 5 ( 105 1 0 2 5 Anno 1 r 1 I ' -.npiop.mo 1am lim p i e I m am 1 4 -aia I no 3 . 5 . 6 - 1r ( e h l o r o p I co I l o l e a c i d 1 Il imi 15 2 0 `limo l i l i s o p r o p n i i n 1 am i n a 2 . 4 - 0 n:li l o r o p l i o i i o x y a c n l n I a .............................- ...................... l-linoill. 1 NAMf ...................................... il I :i llllW 2 . 4 II. DIF IIIANUI AMINF SAI I 5 i )ri -io i i f h d k i d e I lllfM 15 SOLimi r CONCrMIRAlF APOAIE* 0522/5 PM 23 l-AOF : i 31 *UAIE0575 TOXICIIV* 3 INOUIOIFNISI1UII6 Gil 30IKI 0 in 1llano 1am ino 2 . 4 d i e h 1o i o p h e n o x y a c o I a t e 005 M Pl.-nnilCI NAMF .............................. DOW 2. <1 I). IDI f IIIANOI AMINE SAI. 1-4 I V1*1 : -IO III RDIC IDE 15 s o l i m i F CONCEMI WA1 F. lurjn h im is o . i o n m <4 momo li i<>Il ioni) 1nm i no 2 . 4 ci *eli 1ornpMoi ok yar:e t n i o APDA1E 052275 *PM* 23 DAI E 0575 ` TOXICITY* 3 iilil.l-. l'POOIIl 1 MAME ...................................... IHIW P.IIIOXV l'WIII-Vl F S I I R MIX NO . I TYPI : 40 1 II URICI DE 1OHM 15 soi imi f c o r i r t N i n A i F APDA TE 052275 *PM* 23 DATE 0575 lOXICITY 3 4 1NOWr01 ENI 5 0 . 10055 fifi . (irmio p.u i iiy v p i o p v I ? , A il I c h I o i o p l t n n o x y a c o I n I e 0112555 7 1 . 1 0 0 0 Ku1 o ypi o p y 1 s i l v n x 1 2 - 1 2 . 4 . 5 r I d i 1 n r n p h e n o x y ( p r o p Ion le a c i d I T" 05 Av-4 V V -& Z S 8 0 0000113 ( I I I I I I . .1 r < JC1 SFAI" ` 'i mu min i>ii;imra)ji nnoii.4 iroiiih.i nr.Hr.t> imw brusii kii i er x iierpiciiie I S I INO t pare o: ......................... .. PRODUCI MAM) ..................................... OI.Hf.ii I IH.'MUI A -10 lit RUI CIO I vl*l : 40 IIIRHICIIH <f(IRM: 15 SOI uni E CONI'f NI RA I [ APOAIE IA OIOI76 PM 23 DAI E* 0176 lOXICtfY* *3 INOPEUlfNIS* R l i x u o i.<i. 7000 AlEarinl* ni.ifno 2 , 4 d Ioli Iorfiplienov y a c e I a i e . ( s a i l s of t h e e t h a n o l a n d i s p r o p a n o l s e r i n s ) 1 Hil'l 11IRMIII A 40 IILRBICIOE IV t*r : 40 III RBI CIO I OHM: 15 SOI HIM E CONTENI RAIE APDAIE III OIOI7G PM* 23 DA1E > 0176 MIX ICI TV* 3 <I MORI Dt I HIS* n o n i o 55.70IHI A l E a n n l . a m i n e 2 , 4 -d I c h I o r o p h e n o x y a c e t a l e ' ( s a l t s o f ( h e e t h a n o l a n d I s p r o p a n o l s e r i e s ) ni.H'i/ DMA 4 MIRRI CIUF I (I' t . i o III RMI(IOE IURM 15 SOI UHI I CONCINI RA IE APIlAfE III OIOI76 PM* 23 DA 1E * 0176 1 0 X1 CI | y 9 INORI 1)11 H I S ' OIOOI'J 4 `)J(/iK> 11 ime I hy I am i n e 2 . 4 - d I c h l o r o p h e n n x y a c e t a I o ...................................... I'KOI Jill; I NAME .............................. Ol,.rill IIMA 4 IIERII 10 1Of 'IYP 40 IIERRiriOF I ORM: 15 Mil Uhl E CIIIICfNI RA IE APDAIE CA OIOI76 'PM* 23 DATE 0176 FOXICrV. 9 IIKiRtll I ENI S GuOuJLHeQ 03 9fZ980rMO(i ( IIS11~.4 h / i -I/ m i plumin'i I u m INDI I'l UIMI/AMI OOM4I.4 i -ii hi< n n t , i H now r . i m i n p h iii' vi e s i c r m i , n o i s i im . . P AGF 9 Mn * t * t PRODUCI IIAMf IIIIW 2 . 4 II fll OAy E 1HANOI f. S 11 R . 1 vl'f : 4 0 IIFROICIIlF . 1 vl*E 46 Hf II ICI OF 1FRUE 5 1R1Al 1VIT 77 UNCI ASSIf IfO 1 URM Ol Il CIINICAI. CIIFMICAI APAE 071575 PM 23 DATE* 0779 I0X4CITV' 3 INI.filli NI 5* oliHifO `I!. GOOD Hul ovynl l i v' l 2 , 4 11eli I o r n p l i n n o x y a c e I a e (Ml1. I'I PRODUCI NAME HOW IDE MIE fio I i ypf 4h IIIRBICIDE IERRESTHIAI i ypf 77 UNCLASS I F IEO I l)M O? rURMUIAIION IMIFRMr.)| AIE APOAIE* 071575 PM 23 DATE 07/5 lOXlclIV 3 inr.Rrniiois* 0'l00(.:l fif.. OnOO I s i m r . l y 11 2 e t l i y lliexy I I 2 . 4 - d I c h l o r o p h e n o x y a c o I a Ic OI I 2! i f . 3 : I I . i x h n > I s < i < i c l y | l 2 e t l i y l l i . i x y I I s l l v u x ( 2 - ( 2 . 4 , 5 I r I t . l t I - l opl i Gi i uxy I p r o p i o n i c n e l cl | ...................................... PRODUCI KAMI . . . . . . . . . . . . . . . . IMI1. . ' / n o w DROMI K M I f I II MK 1CI Ilf . i Vir.. i n i il P. 1 1 . i de I IJRM : 12 I M i l l S i r I AHI F C ONCI N I RA I F ( I C OR I I APDA IE 101775 PM 21 *DAIE 1075 IOXICI(y J INGRfUIfNIS* 0 3 0 0 5 5 3 6 IXiOO R u l o v y p r n p v l 2 . 4 - d l c l i l o r o p l i o n o x y a c R l a l o lil!;>li,i!i 3 4 IIkhi r . u l c i x y f i . p y I 2 . 4 . 5 - t r I r l ) l o r o p h n i ' . o v y a c o l a l o fzmo i CGOGii I<i.|i n <i//il/ut produci s r / ' I si l mi; ' l u m i n i l i III I . IMPANI 000404 mumer nr>H<in iima a iierpiciiie inoredii Niso r i n o l o 4 0 . Unno Il Init; I hy l a m i n o 2 . 4 d Ic h Io r o p l i p n o x y a r e t n t n PAGE CA ...................................... PRODUCI NAMi: ...................................... o'iM'i'i iima i> w r m K i i i r n IYPE : 4 0 IIERRICIOE f UHM 15 SOI UHI E r()N(TNI RA1E AI'riAlE in o i o t /6 *p m ?3 o a i e * oi76 io x ic I ty* o INC.HLDIINIS- O'innlO O'J.SOflO Diinrtlhy l a m i n e 2 , 4 - d Ic h I orophenoxync t a I e O/OHI IIIRIION I R) 101 Ml XIURE WEED ANO CRUSH KII.IFR IYIM 40 IIERRICUiE I OHM 15 SOI UP.I E CONCEDIRAI E APOATE WA OIOI76 PM* 23 DA 1E 0176 OXICIlv< 9 INORI DII III S nuli 102 1 0 . 2 0 0 0 I r l i Sf>|>io|iniif> I>imi n e p i e l o r a m I 4 - ni Ino 3 . 5 , G- t r lei il o r o p l e u I in l e a c i d I 0100:15 3 9 . GODO li I i sn p i o p a n o l a m i n e 2 . 4 -d I ch l o r o p h t i n o x y a c e In t e ................................... PRODUCI NAMI ............. .............. .. O/ofll IIIRIION (RI MIXIIIRr Urli) ANI) HRIISII Kit 1ER I O'I 40 IIERII I CI DE IORM : 15 SOIIilil E CONCEN1RAIE AI'DAIF* OR 010176 *PM 23 *DAI E 0176 EOXICIIY 3 iNORruirNiS' 0 0 5 104 IO 2 0 0 0 P o t a s s i u m p i e l o r a m I 4 - am I n o - 3 . 5 . 6 - I r l e h l o r o p I c o l l n l e a c i d I 0.10035 3 0 . OOnO 11 i t s n p r n p a o o I am Ine 2 . 4 - d l c h l o r c p l i e n o x y a c e l a t e i i A-: 03 03 8PZSo r m s COOG22 rIHI; >// M/HO rnniiic:i s*.' ,i MSI lifts PAGE 05 h j i h m m ri o r . i r a n n o o n , 4 I'I'DDUCI 0/0115 I0H00N (HI MIXIIIRE WEED AND RRIISII KII.LFR OR ..................................... l>HI)l)ll':i NAME .......................* ............ (I/Oil1. IORDIIN ( R | MIX IIIRF WffO AND RRIISII K I I I F R I .11 . 40 III RIIII IDF. fORM; 15 SOI UBI F CONCENI HA IE APOATE 10 0 I 0 I 7 G 'PM* 23 DATE* 0176 TOXlCITr* 9 I NI.RF III f NI S nor. III? l o . ? o o n I r i i r.opi u p a n o Ion loo p le lor am I 4 - n m i n o - 3 . 5 . 6 - I r Icli loi op i c o I In i c a c i d I 0 3 0 0 3 5 3*1.6000 I r i I R n p i o p an o I am Ino 2 . 4 d I c h l o r a p l i e n o x y a c e t a t e ozono 101)1)011 (III IOI MIXTURE WFF.D AND RRIISII KIILER I VPF: 4 0 HERBICIDE I OHM: 15 SOIIIBI f CONCENIRATE *APOAIE CA OIOI76 PM* 23 DAIF 0176 lOXICIIV 9 I NGRF I) I f NI S 0 0 6 IOP 1 0 . 2 0 0 0 I r I I s o p r o p a n o l am I ne p l c l o r a m ( 4 - am Inn 3 . 5 . 6 - 1r I c l i l o r o p I co I In I c a c i d I 0 3 0 0 3 6 3 0 . 6 0 0 0 1r l I s o p r o p a i io Iam Inf) 2 . 4 -d I c h l or nplieiic. xynce l a I e ii ii ii NUMBER OF PRODUCTS LISTED: 43 i.ii il.li.iI.ii ii.il_li.il.iI li.Il.iI.il.II.II.lI ii..li.Ii_li iI.iI.Il.iI.Il.lI.Ii li Il . li. lI. ll. iI. ll. ll. lI. il. ll. li. il. ll. il. li. ll. ii. 8*2580 17i C&GG33 3 DOW 1085250 r r " u e t Ae i 2 1 r 3 1 i r u !: e r : ' . ? . - i s t r a : : `. ' s " nr.e: T " 7 r * ** * * ' * *"* J r .. ~ i r "A Ce c tio r. 3 (c ) C2 ) <l ) As -in auil'sr iced represent at ive of the registrant of the rrc.uict identified above, I h ere by certify that: iM CO O (-0 o (1) I have rend afid submission of date under active ingred ien t ir. the or. familiar with the terns of ____ conce rn ing o requirement FIF2A C ac ticn 3(c) !')C.") on 11 class of 2, '*-3 cor.pounds* / for (2) "y firm requests that F?A not suspend the r e g i s t r a tion of our product, despite our lack of intent to submit the data in question, cr. the round that the product is ar. end-use product and it will contain an active ingredient in the class cf 2,^-2 compounds solely as the result 0 : the in c o r p or a ti on into the product (during formulation or pacha-jin:;) of another product which contains that sai.:e active ir.yr ed i e n t , which is registered under FIFA A Zection 3, and which is purchased by us from, another producer. 1 (3) '-h accurate confidential formula statement for the a b o v e- i de nt i fi e d product, curre nt as of the date of this Ce rti f ic at i on , is on file uith FPA's Registration Ci vision or attached tc this certification. That formula statement indicates, by company name, registration number, 2 nd p r o du c t name, the source cf the spe cific 2, b-2 c cm pound in : y firm's product. Vy fir:, -..ill apply for ar. am.enc men t tc t:'* r eo i sir: tior. prior tc chr.nui nj the source cf that specific form of in cur product.- f\ -- ' * ** ^ . fl Sf i ds' t< t ^; * * t . t . --J if at any time any of * 4 p i + -- + s i i w 1 c t i m . '.*. vit: .**. nit *. w* t .. the statements in t..is ~ )c--r--.-r' iwy *.;i -: z .:e ?:r.r.e r1 2 .:in js r.su >1 v **ft - ,r* *l. -;:xi " U *- V ,.A `* U>` 1,' TT^ 1 r*M.* *i*~> . 1 ^ . . 7i ' T V T* > ' I w .1 J1 . . Cl) I a:: -July ai:t he rized to represent the :ell si;ir.j fir::(s) *.*i:r> ;sre subject to the requirer.eut cf an Croer rrt! "otice d a t e d ____________under Flri-'A Section 2(c) (2) (1), 7 " .7.7. Section 12 be (c ) (2 ) (7 ) , tc subr.it data concerning 2 , ichi crop he r.oxy a cet ic acid and related salt and estar Terrs: "ere of Fir:: :?A Cor.par.y "under (This fi rr. or ,-roup of firr.s is referred to be lev: a; "r,r fir::".) O GO M ro CST (7) :*y firr. is willing to svelop ? r.d subr.it the data r-s required by that Crd er id Notice, if n e c e s s a r y . "cv.'fiver , ry firr: w ould prefe * enter into an ajjree- er.t i:i th one c r r.ore other re strsnts tc develop jointly, cr tc -'vare ir. the cost of developing, the following required iterr rr lata: :c.-. an r e-rs n t , erec in writ in ' -r t itr h ti on de e ini cn ur.der FIT "A * - T - v o - v t on ri: terr.s sen Id rot be . *S f\ .7ec t ic r. J (s ) 2 ) (1) \ re ache- c _/ Q O O u a w 'J 8 /ss -- ov (>r , r:y .f i r :*s ' s .o f f e r w;nr-.s rr..cci r.cc-ep ted by ar.y at* ti.ooe firn( s ). (0 Y j f i r : , r e q u e s t s t h a t F. not suspend the rujistrij- o f r:y f i r r . ' s p r o d u c t ' s ) . f any cf the natieo rapi . ( 3 ) a b o v e hs v e a j r s to submit the .iota listed r p ( .*) ) a b o v e i n a c c o r d oe with the Order and 'ctisc . I u n d e r s t a n d !\FA J i l l p nptly inforr. ::e whether ;:y ir:: rust sub nit the data to avoid suspension of its rejistr. ior.s under "IFA Sectio n 2(c) (2) ("). T'nted : for : Fi rr. (s ) SC2Sso l fAOQ 0&0i^G / /) n% A 185 DEPARTMENTAL MANUAL J S % Page 1 o f 4 4* 'eaV' itr ... TRANSMITTAL SHEET past. 517 DM 1 SU9JCC7 ENVIRONMENTAL QUALITY SELSASE NUMSES 2295 FOR FUR7H IMFOSMATICK. C&W7ACX Office of. Environmental Project Review Pesticide Use Policy Ba t e SE? 2 3 BSC EXPLANATION OF MATERIAL TRANSMITTED: This release completely revises and updates the Department's policies on the use of pesticides to reflect current statutes, regulations* research, and experience*. . t It abolishes the Departmental P a s t i d d a s Committee (formerly the Departmental Pesticides Working Group and its Advisory Group) which was chaired by the Director of the Office of Environmental Project Xeviev and assigns functions t o that Office. m i x IKSIROCTIOSS: Removes 517 Xtf 1 (1 sheer) Appendix 1-2 (1 sheet) 517 DM 2 (1 sheer) Appendix 1 (1 sheer) rry Z. Meieroro^ etary o f the Interior Insert: 517 DM. 1 (2 sheets) Appendix l (1 sheet) TO: JCm DONALDS - 9008 BUILDING FRO: FRED MAC COWAN - WASHINGTON. D.C. 8 jr -t 0003313 'U-*?- *. J *-/ 't"*- .--: * Department of the Interior DEPARTMENTAL MANUAL Page 2 of 4 - atti.-A^ar .* y . "`r* : Environmental Quality___________ _; Part 517 Pesticides Chapter 1 Pesticide Use Policy yXL.DW .l al I* Purpose. This Chapter seta forth the Department' s `*X*2f; p o lic ie s an the vise of pesticides on. lands and waters admin - O istered, or under programs funded by the Department* and for complying with the Federal Insecticide, Fungicide, and O Rodenticide Act o f 1372, as amended (FIFRA). . . ,1 viCD 1*2 Policy. TI t is the policy of the Department: *. - . oo A. To use pesticides only after fu ll consideration of `"alternatives - based on competent analyses of environmental ;: ^:- V e ffe c ts , effectiveness, safety, specificity, and benefit/ cost - demonstrating that the use of the pesticide is the least hazardous among those available and meets essential -- management goals. The fu ll range of alternatives including 03 c " chemical, biologicalr and physical methods, and no action must, be considered. B. To u tilize pest management research, control, edu cation, and assistance programs' to develop, support, and adopt integrated pest management (IPM) strategies wherever practicable. C. To use only pesticides registered by the Environ mental Protection Agency (EPA) in fu ll accordance with FIFRA, as amended, and as provided in regulations, orders, or permits issued by ZPA. D. That the handling and use of restricted-use pesti cides be conducted with caution and only by personnel who are either certified or under the direct supervision of a c e rti fied applicator. K-- To insure that a ll pesticides and pesticide contain ers are transported, stored, and disposed of in a manner * that w ill safeguard human health, fish and w ild life , and prevent so il and water contamination. F*. To* give fu ll consideration at a ll times to safety to humans, fish and w ild life , and other non-target organisms. 6 To use'pesticides in habitats involving endangered and threatened animal or plant species only a fte r i t is determined that such use w ill not adversely effect the species or its c ritic a l habitat. This determination w ill be made through the Endangered Species Act consultation process 9/23/40 *2295 f Replaces 7/31/70 #1215 0003314 Department of the Interior . ^ ^ DEPARTMENTAL MANUAL - Page 3 of 4 Environmental Quality_____ * ' *. ... . `V .. .*. 1 Part S17 Pesticides Chapter 1 Pesticide Use Policy 517 DM 1.4A ji v (2) Is responsible for coordinating any program . V ' : differences or conflicts between Assistant Secretaries. V.. B. Program Assistant Secretaries. Are responsible fo r . - .irti .^compliance with xIxiEA, EPA's impiemarvcing regulations - . . ' 5 " " ( 4 0 CFR 162), and with this Part for bureaus and offices ^ under their jurisdiction. - yl, * .. Cw Heads of Bureaus and Offices. 1~ 1-- - --- , -r?*-.. . (1) W ill comply with FIERA, EPA's implementing regulations (40 CFP 162), and with this Part. - . . (2) W ill evaluate, control, and monitor a ll pesti cide programs and a c tivities so as to protect and enhance the quality of the environment and bring into conformance a ll pesticide use with the intent, purpose, and procedures of FXFSA, NEPA, and ESA. (3) W ill provide technical support for Department a l pesticide review a c tiv itie s , as appropriate and requested. B* Office of Environmental Project Review. (1) W ill exercise oversight review of pesticide programs, projects, procedures, and performance for the Assistant Secretary--Policy, Budget and Administration. (2) W ill review and recommend revision to pesti cide policies of the Department as changing technical, pro cedural, or other conditions warrant. - (3) W ill a le rt bureaus when new information or other environmental, considerations require significant controls, advice, or warning concerning the use of pesti cides that aay pose an environmental threat. (4) W ill %review and approve certain proposed Departmental pesticide use projects and activities. (5) W ill advise the Assistant Secretary--Polic Budget and Administration on the policy aspects o f pesticideuse in Departmental, programs. 9/23/65 #2295 places 7/31/75 #1235 00033| 398l690M00' Dcoartment of the Interior DEPARTMENTAL MANUAL Page 4 of 4 Mi USE OF PESTICIDES 1* Prohibited List A* A ll pesticides cancelled by EPA .. .. B. The following pesticides: 2, 4, - T . . - 2, 5 - T? . ... .v . . * . .<-.* ^ ' ..-*** # ... 2 Restricted List A* A ll pesticide use restricted by EPA B, The following pesticides: Endosulfan Lindane m* i J isrr Appendix 1 /li, #2295 2{daces 7/21/70 #2213 O vr _ ^8 $ 0003316 MN 0 5 5 3 3 *2 DOW A085222 Received from the Environmental Protection Agency Certified Mail # 188525 September 8, 1980 Copies to: R. L. Charlton J. H. Davidson L. Castillo L. N. Jordan R. L. Gantz C . H . Goodman R. C. Hunter R. J. Kociba, 1803 S. J. Gorzinski, 1803 M. L. Lei^g, 1803 A. H. Morgan, 1803 R. W. Morgan R. D. Moss M. G. Norris J. K. Priddy A. E. Schober, 1803 B. A. Schwetz, 1803 J. M. Theis S. R. Vranish C. S. Williams J. W. Weseloh from: J. W. Weseloh Product Registrations Health and Environmental Sciences 9008 636-4770 085223 ORDER AND NOTICE Dear Reg is t r a n t : EPA recently completed a review of the available scientific information on the potential health effects of 2,4-D. On April 29, 1980, based on the findings of the review, the Agency announced that significant gaps exist in the data base for 2,4-D and that additional scientific information will be required from the registrants under Section 3(c)(2)(B) of Federal Insecticide Fungicide Rodenticide Act (FIFRA), 7 U.S.C. 13 6 a (c )(2)(B ). This provision allows the Administrator of EPA to request any additional data from pesticide registrants that is considered necessary to maintain the registration of existing products. Enclosed is a copy of the Fact Sheet on 2.4- 0 which outlines the results of the Agency's review of the scientific information and the decision to require new studies under Section 3(c)(2)(B). Since this Fact Sheet was prepared for the general public, it may contain information which you already know. However, we feel that the Fact Sheet will provide you with material which will clarify E P A 's reasons for requesting additional data from you. Our records indicate that you are the registrant of a pesticide product(s) containing one or more of the following active ingredients which we will refer to collectively as 2.4- D: i 2 , 4-d ich Iorop henoxyacet ic acid > lithium salt of 2,4-D J potassium salt of 2,4-D [ sodium salt of 2,4-D j ammonium salt of 2,4-D f alkancl amine salt of 2,4-D OOVIf 1085224 V alkyl amine (Cl 2) salt of 2,4-0 alkyl amine (C14) salt of 2,4-0 alkyl amine (fatty acids of tall oils) salt of 2,4-0 diethanolamine salt of 2,4-0 diethylamine salt of 2,4-0 dimethyI amine salt of 2,4-0 dimethyIoIeyI amine of 2,4-0 ethanolamine salt of 2,4-0 heptylamine salt of 2,4-0 isopropanoI amine salt of 2,4-0 isopropylamine salt of 2,4-0 morpholine salt of 2,4-0 o Iey I propy Iened iam ine salt of 2,4-0 octyl amine salt of 2,4-0 triethanolamine salt of 2,4-0 tri ethy Iami ne salt of 2,4-0 triisopropanolamine salt of 2,4-0 diethyIethanoI amine salt of 2,4-0 dime thy IoIeyIo-Iino IeyI am Ine salt butoxyethoxypropyI ester of 2,4-0 butoxyethyi ester of 2,4-0 butoxypolyethoxypropyI ester of 2,4-0 butoxypropyl ester of 2,4-0 butyl ester of 2,4-0 iso butyl ester of 2,4-0 V isooctyl (ethyl hexyl) ester of 2,4-0 isooctyl (ethyl methyl pentyl) ester of 2,4-0 isooctyl (octyl) ester of 2,4-0 isopropyl ester of 2,4-0 propylene glycol butyl ether ester (PG8E) of 2,4-0 A list of your products that contain any of these materials is shown as Appendix A. Also refer to Appendix H for state registrations under Section 24(c)(1) for special local need which are also covered by this letter. I. REQUIREMENT FOR DATA SUBMISSION As we have explained in the Fact Sheet, under the authority of Section 3(c)(2)(B) of FIFRA, EPA has determined that additional data, more fully described in Section II of this letter, are required to maintain your registration(s ) in ef fect. This letter notifies you that if you wish your registrations to be maintained in effect, you are required to take steps to produce and submit data to EPA in accordance with the schedule set forth in Section III of this letter. GCQGockj 819 3 r V Sections IV and V of this letter indicate two limited circumstances in which EPA will not act to suspend the registration of your products if you do not submit the required data. Section VI of this letter describes the procedures by which you may ask EPA to reconsider the requirements imposed by this letter. In responding to the data requirements established by this letter, you must choose one of the following options. If you fail to exercise one of these options within the time period specified, EPA may take steps to suspend the registration of each product to which the required data are pertinent. CO S22S80 (A) You must notify EPA within 90 days of your receipt of this letter that you are willing to produce (if necessary) and submit the data yourself; (B) You must notify EPA within 90 days of your receipt of this letter that you have entered into an agreement, with one or more of the other registrants who are subject to this notice's requirements, to jointly produce (if necessary) and submit the data, or to share in the cost of this work; (C) You must provide to EPA, within 90 days of your receipt of this letter, the "Statement of Willingness to Enter Into an Agreement with Other Registrants for Development of Data", in accordance with Section V and Appendix C of this letter, which will allow EPA to exempt you from the consequences of not submitting some or all of these data under certain circumstances; (D) You must provide to EPA, within 30 days of your receipt of this letter, the Certification described in Section IV of this letter, which will allow EPA to exempt you from the consequences of not submitting some or all of these data because each of your products is an end-use product and otherwise qualifies under that Sect ion; (E) You must fi le with EPA, within 30 days of your receipt of this letter, a request for a waiver of some or all of the data requirements imposed by this Order and Notice; or, (F) You must file with EPA, within 90 days of your receipt of this letter, a request that the registration(s ) for your products containing any or all forms of 2,4-Q be voluntarily cancelled. _7 4 CC0GG33 I U WHAT DATA ARE NEEDED EPA has determined that significant gaps exist in the data base for pesticides containing 2,4-D compounds. In order to make further determinations concerning potential health effects of 2,4-0, the Agency has determined that data from the studies listed below are required to support the continued registration of all products containing the various forms of 2,4-0. The required studies must be con ducted in accordance with the referenced sections of E P A 's proposed pesticide registration guidelines,-- or other approved test standards such as those which are adopted by the Organization for Economic Cooperation and Development (OECD) except as modified or supplemented below.-- ' TOXICOLOGY DATA The following section describes the tests to be conducted and the specific forms of 2,4-0 to be tested. When performing studies to produce the required data, you should be very careful to follow every applicable test standard contained either in the section of the guidelines cited or other approved test standards, except as modified in the paragraphs below. N IV C COMPOUNDS TO BE TESTED Some of the data requirements relate to specific technical grade forms of 2,4-0, while other tests pertain to formulated products. Because the salt and ester forms of 2,4-D will degrade to the acid form and to the metabolite 2,4-dichIorophenol registrants of products containing any salt or ester form will be responsible for all the required studies on technical grade 2 ,4-dichIorophenoxyacetic acid and on 2,4-dichIorophenoI. (See Appendix G). The required studies on the other technical grade forms of 2,4-D are the responsibIity of those registrants whose products contain V The Agency published proposed human hazard guidelines on August 22, 1978, 43 FR 37336. The required studies on 2,4-D (with the exception of subacute dermal neurotoxicity, standard metabolism in pregnant dogs, and dermal absorption) are described in this section. Copies of the proposed guidelines are available on request. **/ Note: you may request EPA to review the use of a test method which may vary from the test standards listed above in order to produce the required data. The procedures for submitting such a request are described in Section VI o f this Ierter. - 4 - C00G200 lo t-icso concourus as active in jrsd in*s. Tne required studies on each for-nu Iata d product, regardless of m e specific forms of 2,4-j it contains, are tfie responsibility of m e registrant to whom that product is registered. .TA ~:=:u l.tE^'cNTC T. r nc e en ic itv studies - standard oral exposure study in rats and r.ice (proposed Section I53.o 3-2, 3 FP. 37379-o2). rW--~i* "aterial to be tested: - technical grade (or purer) of 2,4-d ic!i Icrop henoxy cet ic acid .'.'ota: AI I registrants are responsible for this c O 2. Reproduction stud-/ - (proposed Section 1 5 3 . 0 3 - 4 , 3 FR T 7 ; Vn */* . :-owj/ ^4 `aterial to be tested: - *ecnnical grade (or purer) of 2,4-dichloropnenoxyacetic acid iota: AI I registrants are responsible for this data-- / Teratogenicity studies - (proposed Section 163.Si-3, 3 FK . 27332-S4) modified as follows: test to be done in the rat. Materials to be tested: - technical grade (or purer) of 2,4 - c ?cnIorophenoxyacetic acid - technical grade (or purer) of butoxypropyl ester of 2, 4-g - technical grade (or purer) cf alkanolanine salt of 2 , 4-~ - technical grade (or purer) of isopropyl ester of 2,4-g - 2,4-j ich Ioropheno I (metabolite of 2,4-u) Mote: AI I registrants are responsible for the data on 2,4-u acid and the metabolite, 2 ,4-dich IorophenoI. Registrants with products containina the salt and ester forms listed above are a Iso# r;espons iL-Ie for the data on those forms of Meurotoxicity studies a) su'ochrcnic oral neurotoxicity - (proposed Section 1S3.U2-3, 43 FM. 37374-75) modified as follows: test to bo done in the doa , rat, and chicken. Materials to be tested: - technical grade (or purer) of 2,4-JicnIorophenoxyaceric :ci. - technical grace (or purer) of d if.:eth y Iai..iie salt or 2,--- j i 5 * r j.` 7s of end-use pruduers formulated from a registered ech.n ica I r-_*r is I should consul Section lV fur sx e.-.ip7 fun from is rB';u i r - e n t . CGOoiOi GW 1035228 A 11 registrants are responsible for ine data on 2., acid . Registrants with products contain ing the i imo thy lami ne salt #c?f 2,4-0 are responsible for th da ta on th is form.-- 5) subacute dermal neurotoxicity in the doc - This stjdy will be required for the two compounds described in (a) unless otherwise indicatec by tne results cf the subchronic neurotoxicity study and the results of dernaI absorption study on that compound. EPA will review the results of tnese tests when submitted and inform the registrants whether to proceed with (b). At that time, registrants will be notified of the protocol to be used in developina th is data. 5 . ::oT a bo I?sri studies a) standard metabolism study - (proposed Suction 103.35-1, <3 F.R 37394-96) modified as follows: test to te done in the dog and rcit. Materials to bo tested: - technical yrade (or purer) of 2 ,4-dichIerophenoxyacetic acid - technical grace (or purer) of isocctyl (ethyl hexyl) ester of 2,4--b -technical grade (or purer) of P6CE ester of 2,4-u V Mote: AI I registrants are responsible for this data on 2,4-G acid. Registrants with products containing one of the two ester forms listed above are aljo responsible for the data on those forms.-- b) standard metabolism study in the precnant -dog This study will be required for rhe three cempouncs described in (a) unless otherwise indicated by the results in (a). EPA will review the results cf this test when submitted and inform the re-y ijtrdnfs whether to proceed w ith (b ). -At tha t time," Ttey ST rcJHTS will be no t f ied of the protoco 1 to be us dJ in deve 1op ing tnis data. Acute oral toxicity studies - (propos ed Section Ic 2 .: 1- 1, 3 FH 37353-56). Materials te ce tested: - eacn manufacturing-use preduct anq each end-use product containing any cf the 2,4-G compounds (Pefur to Appendix A for the list cf yc-r products "" J : is rrants cf en c*n ic;: 1 ".a ter 1a 1 s i s - e z e ir ere n t . products formulate f rzr. o r u _ . i s r a r d-w c o n s w I t S a c r i or. I ; f c r ex a:.p T i d e * r d : . DOVILI 085 2 2 $ for which this data -must te submitted). A registrant may cite acceptable studies previously submitted to support the registration of his product(s). In lieu of providing his own studies, a registrant may cite acceptable studies already on file with the Agency or submit studies on a sub stantially similar product, and offer to compensate for such stud ie s . 7. Acute dermal toxicity studies - (proposed Section 163.81-2, 43 FR 3 7356-57). Materials to be tested: - each manufacturing-use product and each end-use product containing any of the 2,4-0 compounds (Refer to Appendix A). A registrant may cite acceptable studies previously submitted to support the registration of his product(s). In lieu of providing his own studies, a registrant may cite acceptable studies already on file with the Agency or submit studies on a substantially similar product, and offer to compensate for such studies. Note: The Agency generally requires a series of acute toxicity tests.to support the registration of manufacturing use and formulated products. Acute oral toxicity and acute dermal toxicity studies are required for each manufacturing use product and each formulated product. Acute inhalation toxicity, primary eye irritation, primary dermal irritation, and dermal sensitization studies may be required to support the registration of each manufacturing use product and each formulated product, as specified in the proposed pesticide registration guidelines. While the Agency is requiring only acute oral toxicity and acuta dermal toxicity studies at this time, the other acute studies may be required at a later date as appropriate. The data which are being required at this time are essential to provide the Agency with a more accurate and detailed picture of any potentially significant acute oral and/or chronic health effects of 2,4-0. The Agency feels that acute oral and dermal toxicity studies will make a substantial contri bution to our understanding of the acute hazard that may be associated with the chemical. 8. Dermal absorption studies - At this time the Agency does not feel an acceptable protocol has been developed for testing pesticides. Therefore, although this testing remains a requirement as outlined in this letter, you will be notified.at a later date of the protocol to be used in developing this data. c g g g ig :; ` ' . a t e r i a l s t o be t o s t o o : - each end-use product formulated in Iiqu iJ form or as an e'lusi fiafcle conconTrato that contains any of the 2,4-C compounds. (Ksfer to A p pon c ix j for the list of your products for wnicn this data must be submitted). n i . sc:iEruLE f o r s u e k i t t i c -g d a t a The required data must be submitted to tne Agency on the following schedule. If progress reports are required, tne schedule will specify tne date on which the first progress report is due, and the frequency of progress reports thereafter. If required, progress reports must be provided as soecified Lelow. Cote: You may request that E~A extend any of the following deadlines. Tne pro cedures fer submitting such a request are described in Section '/I of this latter. I. Cncc::sn ?c ity studies Q 00 CT( Final report due by 12/1/33 Progress report due on 6/13/22 CO 2 Reproduction studies Final report due by 3/1/82 Progress report due on 1/1/32 of the first generation) (for the two litters 3 . Teratogenicity studies Final report due by D/l/ol - c & u r o T o x icity studies a) subchronic oral ncurctoxic.it/ Final report due by 5/1/21 fc) subacute dermal neurotoxicity - Registrants will be notified of the due date wnon they are notifie whether to proceed with this testin^. 3 . .'etabe 1ism studies a ) standard me ta boi i5.-.1 Final report due by 5 / I 0 / S 1 w) sta nda r u me ta ac 1 ism in jrejnanr deg - Rv, is fr an ..ill be ne t if iec: of tne jue d a r 3 -nun t-ie y--ar-u not if iou whetner to proceed w ith T u is Tsstirij. *W O G O G i.^ ^/ ' "-.cuts oral toxicity studies Final report due by 5/1/El 7. Ac-jtn dermal toxicity studios Final report duo by 5/1/21 b . Zer-.al abserntien studies Registrants will be notified of trie due d a t e at the sane time they are notified to proceed with th is festinj according to p r o t o c c ! 14 4 R E 3 1 "TRACT E E S P C C S 121L iTY FOR GEE: IO': F=.OV SUSP: SANCT 'Ii'.C. JL*_ :JSnr `J ; : I w' ' TI oWr S I< Wr The data described in Section II cf this letter relates, in certain cases, to the safety of specific 2,4-0 active ingredients (technical grade). According to Section 3(c)(2)(E) of rlFP.A, an applicant for registration cf an ami-use product containing one or more of These forms of 2,4-Q is not required to subr.it or pay cor.ipens a t ion for those data as a condition of obtaining registration if that form of 2,4-0 is present in his product solely as the result of his incorporation into his product (as parT of the formulation or packaging processes) of another registered product, containing that form of 2,4-C, which he purchases fron another producer. O o L* o CO ro CO The object of this provision is to simplify data compensation by making compensation for data on active ingredient safety an element of the market cost of registered manu factur i us-e products, so that fcrr.ulators or other registrants who purchase such procucts need not separately offer to pay for data on the safety of the active ingredient. E 'A has concluded that these principles should also apply in the closely analogous situation presented by This Section 3(c)(2)(E) red u irenient. However, principles of fairness to those who incur expenses of ueTa production and suorissicn require that a registrant may be ox amp ted from data submission requirements only if Tne specific form of 2,4-3 in his product (listed on the active ingredient stato-.enT) is purchased from a firm which dues have a c u t , to submit (or to offer to share in trie cost of uutuinin,.) the ca*3 required by this latter. Clef or to nppunjix E for a list of : i r r . s - irh registered manu `uctjr in s-use p Ir W- 'U<,MW~ 1 ? t ...... * Ou Ou x Oj DOW 1085232 if s registrant who is subject to this Order and Notice fails to comply with the data subnission requircMenf, the Ad r. in is tr a tor nay suspend his rua istrat ion. However, this authority is di sc ret ionary, and the Administrator will not exercise it to suspend a registration if: ( I ) The registration is for an enc-use product (as opposed to a ma nufacturing-usa (Refer to Appendices F and C); AND (2) The specific form of 2,4--2 in the end-use product is present solely as the result of the incorporation into that product (during formulation or packaging) of another product which contains that form of 2,4-0 which is registered under FI FRA and which is purchased by the registrant; (3) The registrant completes and executes a "Certification of Entitlement to Exemption from Suspension Under FI FRA Section 3(c)(2)(C)", in the form of Appendix L to this letter, for each of his registered products -cc itsining some form of 2,4-C and submits it to EPA not later than September 30, I9S0; AND, (4) Cne or more registrants actually undertake to submit, and do submit, all the data requirec by this Order and Notice. It should be emphasized that while the above procedures provide certain categories of exemptions, those data requirements that specifically relate to end-use (formulated) products are the responsibility of the registrant ty whom r-.et product is registered. (See Appendices A and u). V 'cte: In The case of data req u iromonts for technical grade forms of 2,4-0 far whicn there .are no registered ranufacturing-use products, the registrants of the enduse products are responsible for the cate. **/ Nets: Appendix F I ists the company numbers for those registrants who have enu-use products containing forms of 2,4-r, for which there are no registered menufacturing-us produces. B erar to Appendix C to obtain company names and addresses from tne company numbers. % C G G G iO G e x e ::p ' f -c:-: cF F T-, \W< a i ' ^ S r F-JK HE-JI STP.A1-.TS T;:E l P E N S E 1! CTA I :I:.s L AT FlFPA S e c t i o n 3(c)(2)(E) a u t h o r i z e s j o i n T dove I opr*.* n t of d a t a by t wo o r Mo r e r e g i s t r a n t s , and p r o v i d e s a M e c h a n i s m by wn i c h p a r t i e s can o b t a i n an a r b i t r a t o r ' s d e c i s i o n i f t h e y a g r e e t o j o i n t l y d e v e l o p d a t a Cut f a i l t o a g r e e on a l I the t e r e s of t h e agr eem en t. The s t a t u t e aoes not compel any r e g i s t r a n t to a gr ee to develop data j o i n t l y . In EF-.'s opinion, joint data development by all registrants who are subject to the requirements in this letter, or cost-sharing agreement between all such registrants, is clearly in the public interest. Cuplicaticn of testing is not only wasteful in terns of money, but could tie up testing facilities unnecessarily. As noted earlier, EPA has discretion not to suspend tho registration of a product when a registrant fails to submit data required under F IF'AA Section 3(c)(2)(E). EPA has concluded that it is appropriate to exercise its discretion not to suspend in ways which will discourage duplicative testing. Accordingly, if: (I) a registrant has informed us of its intent to develop and submit data required by this Notice and Order; and (2) a second registrant informs EFA that it has made a bona fide offer to the first registrant to share in the expenses of the testing (on terms to be agreed upon or determined by arbitration under FIF.'A Section 3(c )( 2) ( ) ( iii ) ); and (3) the first registrant has without good cause dcline to agree to enter into a costsharing agreement, EPA will not suspend The second firm's reg istrat ion . '..'h iIo the first firm is net required to agree to jointly develop data, EPA is not required to force the second firm to engage in economically inefficient Juplicative testing in order to maintain its registration. Thy format for informing EPA of the bonafide offer to the first registrant is shown as Appendix C. ::.s1* PFCCESUSES FCP PECdEST INO WAIVERS. CHANGES */ p- ih. WWyI w' __Zi * I C j recogni res that you may disagree with our conclusions regarding the need for data, the appropriate ways to develop the requireo data, and how quickly the data must be submi t t e d . `..'e will give you the opportunity to stat e the basis for your d isag reumunt an u request that .-.-0 change our req u ir em.ent s . Ae note that if you see* to cr.a 11e nge our roqu irament 3 in court, a j o d y CGOGiO? D w .l 085334 dismiss your lawsuit unless you have first presented your arguments tg.EPA according to the procedures descrioed below.-- If you think that EPA does not need the daTa required by this letter to determine whether your product causes unre-asonao Ia adverse effects on the onv ironr.-.ent, you May request a waiver. The waiver request must be subuitted within 30 days cf your receipt of this letter. The waiver request rr.ust be submitted in writing to the person specified at the end of this letter. The waiver request should state the reasons why you conclude that each particular kind of data is not needed. EPA will promptly review your recuest(s) and inform you whether the waiver has soon ^ranted. If you want to use, or think that you should use, a test methodology which does not satisfy the test stanuards specified in Section ll of this letter, you may ask c P a to review and approve that methodology. The request Must ae submitted in writing to tne person specified at the end of tnis letter. In nost cases, EPA will not rant an extension of time to submit required data on the round that you have requested Agency approval to change the required test methodology. Accordingly, you should submit the request as soon as possible. If you want, or think that you will need, more time to produce the required data than is allowed by EPA's scneuulo, you must sucr.iT a request for an extension of time. The extension request must be submitted in writing to tne person specified at the end of this letter. The extension request shcu Id state the reasons why you conclude that an extension is appropriate. -:o extensions -ill be granted based on the fact that the Agency is considering your request for an extension. Accordingly, you must continue to work diligently to rest the dead lino for suomitting the required data while EPA considers your request. V T n i s l e t t e r c o n s t i t u t e s " f i n a l Agency a c t i o n " u n l e s s you submit a r e q u e s t f o r a w a i v e r , a r e q u e s t f o r a m o d i f i c a t i o n in the r e q u ire d t e s t methodology, or a r e q u e s t f o r e x r a n s i o n of t i n e . I f any suen r e q u e s t has been s u b m i t t e d , EPA's a c t i o n -with r e g a r d to t h e s u b j e c t r.a ttc -r of The r e q u e s t does n o t become f i n a l u n T i l trie 'jency has a c t e d on t h e r e q u e s t . Tne Agency t h i n k s t h a t a r e g i S T r a n t must use the pr oc edu res de s c r ib e d in t h i s s e c t i o n of t h e l e t t e r i r, o r u e r t o e x na uST i t s ami n i s t ' r a t i v B r o i as. I DOW 1085235" -4 V I I-. CONCLUSION All responses to this notice should be submitted to: Director, Special Pesticide Review Division Office of Pesticide Programs U.S. Environmental Protection Agency 401 M St., S.W. Washington, D.C. 20460 (TS-79-1) ATTN: 2,4-0 Project Manager If you have any questions regarding the requirements and procedures established by this letter, please contact: Kevin Keaney, Chief, Chemical Review Branch #2, (703) 557-7716. Enclosures Edw in L. Johnson Deputy Assistant Administrator for Pesticide Programs L- St< 50 <A t. THE CARCINOGEN ASSESSMENT GROUP'S RISK ASSESSMENT ON (2 ,4 ,5-TRICHL0R0PHEN0XY)ACETIC ACID (2,4,5-T) (2 ,4 ,5-TRICHL0R0PHEN0XY)PROPIONIC ACID(SILYEX) 2 ,3 ,7 ,8-TETRACHL0R0DIBENZO-P-OIOXIN (TCDD) \ ,,Chairman September 12, 1980 PARTICIPANTS Elizabeth L. Anderson, Ph.D. Larry D. Anderson, Ph.D. Steven Bayard, Ph.D. David B ay llss, M.S. John R. Fowle I I I , Ph.D. Bernard H. Haberman, D.V.M., M.S. CharaHngayya B. H1remath, Ph.D. Chang S. Lao, Ph.D. Robert McGaughy, Ph.D. Charles Poole, M.P.H. Oharm V. Singh, D.Y.M., Ph.D. Todd'W. Thorslund, Sc.D. P ete r Yoytek, Ph.D. 3 COI 'ENTS ^ ' SUMMARY AND CONCLUSIONS.................................................................. ............................... 1 Q ualitativ e Risk Assessment ................................................................................. 1 Q uantitative Risk Assessment of 2 ,4 ,5-T, sllv ex , TCDD . . ........................6 QUALITATIVE RISK ASSESSMENT I . Introduction.................................................................................................................8 I I . Metabolism ............................................... ................................................................. 10 Metabolism of (2,4,5-Tr1ch1oropheno*y)Acet1c Acid (2 ,4 ,5-T) . ................................................................................................. 10 Metabol1sm and Storage of 2,3,7,8-Tetrach1orod1benzo-P-D1ox1n(TCDD) .......................................... 11 Aryl Hydrocarbon Hydroxylase (AHH) Induction Studies With TCDD .................................................................. 13 Covalent Binding of TCDD with Macromolecules...........................................15 I I I . Mutagenicity . . ........................................................................................................17 Mutagenicity of 2 ,4 ,5-T ..................................................................... 17 Mutagenicity of TCDD. . . . ........................................................................ 21 Conclusion................................................................................................................23 V IV. T oxicity........................................................................................................................... 24 Animal T o x ic ity .............................................. 24 Toxicity of 2 ,4 ,5-T .................................................................................... 24 Toxicity o f TCDD .......................................................................................... 25 Toxicity of 2 ,4 ,5-T, 2,4,5-Trlchlorophenol, and TCDD 1n Humans ....................................................... 27 V. C a rc in o g e n ic ity ............................................................................................................. 29 Carcinogenicity of 2 ,4 ,5-T 1nMice.................................................................29 Muranyl-Kovacs e t a l. (Oral) MouseStudy ............................................. 29 Muranyl-Kovacs e t a l . (Subcutaneous)Mouse Study .............................. 31 Inns e t a l. (B1onet1cs Laboratories) (Oral) Mouse Study . . . . 33 Inns e t a l. (B1onet1cs Laboratories) (Subcutaneous) Mouse Study ............................................................... 35 Carcinogenicity o f 2 ,4 ,5-T 1nRats ........................................................... 36 Kodba e t a l. (Oral) Rat S tu d y ................................... ... . . . . . . 36 Leuschner e t a l . (Oral)Rat Study ......................................................... 44 i 820 7 i Carcinogenicity of (2,4,5-Tr1chlorophenoxy)Propion1c Acid (Sllvex) . 48 Innes e t a l . (Bionetics Laboratories) (Oral) House Study . . . . 48 Innes ;et *1- iBionetlcs-Laboratories) (Subcutaneous) House Study .............................................................. BO Dow Chemical Company (Oral) RatStudy............................. 51 Dow Chemical Company (Oral) Dog Study...................... 52 Carcinogenicity of TCDD 1n Rats andMice . . . - . . . . ....................... 53 Korfba e t a l. (Oral) Rat S tu d y .............................................. 53 National Cancer I n s titu te (Oral) Rat Study ....................................... 60 Yan M iller e t a l. (Oral) Rat Study ....................................................... 63 Toth e t a l . (Oral) Mouse Study . ....................................... ... 67 National Cancer I n s titu te (Oral) Mouse Study ................................... 70 Other Related S tudies..................................................................................73 P ito t e t a l. Promotion Study 1n Rats ........................................... 73 National Cancer I n s titu te Skin Painting Study In Mice................................................................................................ 75 Berry e t a l. Skin Painting Study In M ic e....................................77 Cohen e t a l . Skin PaintingStudy 1n M ic e ........................................78 Kourl e t a l. Mouse Study .................................................................. 78 Estim ation of TCDD Levels 1n2 ,4 ,5-T Studies .. .......................................... 84 Potency o f TCDD............................................................................................ 87 Summary of Laboratory Animal Studies on 2 ,4 ,5-T, S llvex, and TCDD. . 88 VI. Epidemiologic S t u d i e s ..................................................................... 90 QUANTITATIVE RISK ASSESSMENT I . In tro d u c tio n ............................................................................................................... 102 I I . Estim ation of the Dose-Response Model................................................................ 104 I I I . Risks fo r A pplicators ....................................................................................... 106 F o r e s tr y ................................... * ..................................................................... 107 Range and brush control ............................................................................... 107 R1ce-weed control .......................................................................................... 107 Rights-of-way brush and weedcontrol ......................................................... 108 IV. Risks Due to Dietary Exposure................................................................................ 108 Beef and M 1 l k .......................................................................................................108 Deer and E l k ..................................................................................................... 109 R i c e ................................................................................. .110 V. Summary........................................................................................................................... 110 REFERENCES............................................................................................................................ 137 APPENDICES................................................... ......................................................................... 145 -A. Dose-rel-ated Mortality Estimates in Kociba's TCDD Rat Study {Tables). B. Pathologic Evaluations of Selected Tissues from the Dow Chemical TCDD and 2 ,4 ,5-T Rat Studies by Robert A. Squire, A ssociates, Inc (Summary T ables)...................................................................................................... C. Leuschner Histopathologic T e stic u la r Tumors 1n Rat (H istorical Control D a ta ) .............................................................................................. . . . D. Leuschner Histopathologic Report on Tongue 1n 2 ,4 ,5-T Rat Study . . . E. Memo from Wade Richardson Concerning the Telephone Conversation with Leuschner .............................................................................. ....................... F. Memorandom and report from Dr. David Severn, Hazard Evaluation D ivision, Office of P esticid e Program Exposure. Assessment of 2 ,4 ,5-T, Sllvex and TCDD...................................................................................... 6. Methods fo r Determining the Unit Risk Estimates fo r A1r P o llu ta n ts. . \ 111 SUMMARY AND CONCLUSIONS ^ QUALITATIVE RISK ASSESSMENT (2.4,5-Trlchlorophenoxy)Acetlc Acid (2,4,5-T) (2,4,5-Tr1chlorophenoxy)acetic acid , widely known as 2,4,5-T 1s used as a vegetation growth reg u lato r and h erb icid e. "Agent Orange," a d e fo lia n t used extensively by the U.S. Army 1n Vietnam, 1s a mixture of equal amounts of 2,4,5-T and (2,4-dichlorophenoxy)acet1c acid . In 1970, amid growing concern about the terato g en ic e ffe c ts of 2,4,5-T , th e EPA cancelled the re g is tra tio n of th e compound f o r uses "around th e home, recreatio n areas, and sim ila r s ite s " and "in crops Intended fo r human consumption." Before some uses were suspended in 1979, 1t was used prim arily to c le a r vegetation along powerlines, highways, p ip e lin e s, and railro ad rights-of-w ay, and on range, pasture, and fo restlan d s. The commercial preparation of 2,4,5-T contains 2,3,7,8-tetrachlorodibenzo v -p-diox1n (TCDD) as an unavoidable impurity present a t a concentration of approximately 0.05 ppm. TCDO 1s considered extremely to x ic . 2,4,5-T i s read ily absorbed by several mammalian sp ecies, Including man, and 1s excreted unchanged - mostly in u rin e. The av ailab le inform ation about th e mutagenic a c tiv ity of 2,4,5-T is considered to be lim ited . 2,4,5-T is indicated to be a weak mutagen in Drosophila and, under acid ic conditions, showed mutagenic effects 1n Saccharomyces c e re v isia e . Tests fo r th e chronic carcinogenicity of 2,4,5-T were performed by several in v e stig a to rs. Two stu d ies were carried out with Sprague-Dawley r a t s , one by the'Dow Chemical Company (Kociba e t a l. 1979) and one by F. Leuschner (1979), Laboratorium fu r Pharmakologie und Toxikologie, Hamburg, Germany. The Dow.study ^ showed an increased Incidence of carcinoma of the tongue in male r a ts dosed with 82 lo l sp e c ia lly p u rified 2,4,5-T a t 30 mg/kg/day. This Incidence as reported by the authors of the study, 1s marginally s t a tis t ic a lly sig n ific a n t (P * 0.063) when compared to controls. In-addition, there as-a significant-dose-related lin e a r trend by th e Cochran-Arm1tage t e s t . When compared to h isto ric a l co n tro ls, the Incidence of th is tumor, as reported by the authors, I s s ta tis t ic a lly s ig n ific a n t (P < 0.001); however, when the tongue tis su e s from th is study were reexamined by Dr. Squire, he found one additional tongue carcinoma 1n male r a ts ' tre a te d a t the high dose with 2,4,5-T which Increased the s ta tis t ic a l sig n ifican ce to P * 0.025. In a recently completed study by F. Leuschner, an Increased Incidence of i n t e r s t i t i a l c e ll tumors o f the te s te s was observed when compared with matched c o n tro ls. However, th is increase 1s not s ta tis t ic a lly x s ig n ific a n t when compared to h isto ric a l co n tro ls. The re su lts o f the Koclba e t a l. study provide highly suggestive evidence of the carcinogenicity of essen tially pure 2,4,5-T. In mice, two stu d ies by Muranyl-Kovacs e t a l. (1976, 1977) and two studies by Innes e t a l . (1969) (Bionetlcs Laboratories 1968) have not provided p o sitiv e evidence of oncogenic e ffe c ts of 2,4,5-T . However, several d eficien cies 1n th ese stu d ies make them inadequate to assess the lack of oncogenicity of 2,4,5-T. In summary, the Dow study 1n ra ts provides highly suggestive evidence of the carcinogen icity of 2 ,4,5-T , while the Leuschner study showed only equivocal r e s u lts . The mouse stu d ies were too in se n sitiv e to be considered v alid negative studies. (2 ,4 t 5-Trlchlorophenoxy)Propion1c Acid (SHvex) SHvex, lik e 2,4 ,5 -T , contains the highly to x ic TCDD. Uses o f silvex are sim ila r to those of 2 ,4 ,5 -T . Chronic carcinogenicity studies have been performed on mice and r a ts and a 2-year study has been conducted on dogs. Innes e t a1. (1969) (Blonetics Laboratories 1968) conducted two studies t ;1ng mice, one oral and th e other subcutaneous. These stu d ies were found to be inadequate to assess the carcinogenicity of silvex. Dow Chemical Company performed two feeding stu d ie s, a 2-year feeding study on r a ts and a two year feeding study on dogs which were summarized by Mullison (1966) and Gehrlng and Betso (1978). These have been found to be Inadequate to rule out the carcinogenicity of silvex. 2 .3 .7 .8 - Tetrachlorod1benzo-P-Dioxin (TCDD) Probably one of the most toxic chemicals known to man 1s 2 .3 .7 .8 - tetrachlorod1benzo-p-d1oxin. :The major source of i t s environmental contamination 1s from th e p estlcid al uses of 2,4,5-T , 2 ,4 ,5 -trich lo ro p h enol, and silvex. In small amounts, TCDD 1s a potent Inducer of aryl hydrocarbon hydroxylase 1n mammals. This 1s a complex enzyme system th a t co n sists of epoxldase, epoxidehydratase, and glutathione tra n sfe ra se . The enzyme epoxidase 1s known to mediate the formation of epoxides, which are p o te n tia lly active carcinogenic m etabolites. TCDD can be metabolized 1n mammalian species via the epoxide to dihydodiol and f u rth e r conjugates with glu tath io n e. P ersisten t residues of TCDD were found 1n liv e r and f a t 1n a 2-year feeding study 1n r a ts . S ig n ifican t covalent binding of TCDD to protein has be'en demonstrated by two in v e stig a to rs. Covalent binding of TCDD with DNA is less sig n ific a n t 1n liv e r c e lls . Currently av ailab le studies on the mutagenicity of TCDD are Inconclusive. Two b a c te ria l systems, Escherichia coli and Salmonella typhimurium (without metabolic a c tiv a tio n ), exhibited p o sitiv e mutagenic a c tiv ity . However, 1n another study of Salmonella typhimurium (with and without metabolic a c tiv a tio n ), th e re su lts were negative. 3 1 There are several -cancer bioassay studies of TCDO: 1) a Dow Chemical Company (Kociba et a l. 1978) study 1n male and female Sprague-Dawley (Spartan substrain) r a t s ; 2) th e Van t i n i e r e t a l. (1977) study in male Sprague-Dawley r a ts ; 3) the Toth e t a l . (1979) study 1n Swiss mice; 4) the National Cancer I n s titu te (1980a, b) stu d ies 1n ra ts and mice; 5) th e P ito t e t a l. (1980) promotion study in r a t s ; and 6) the Kouri e t a l. (1978) cocarcinogen1c ity study in mice. The study by th e Dow Chemical Company of male and female Sprague-Dawley r a ts fed TCDD in doses of 22 p p t, 210 p p t, and 2200 ppt revealed a highly s ta tis tic a lly sig n ific a n t excess Incidence of hepatocellular carcinomas in female r a ts a t the highest dose level and h ep ato cellu lar carcinomas and hepatocellular hyperplastic nodules 1n female ra ts a t th e middle dose le v e l, as compared to the co n tro ls. In addition, th e re was a sig n ific an t increase in carcinomas of the hard palate/n asal tu rb in ates 1n both high dose males and fem ales, of the tongue 1n males, and of the lung in females. The Van M iller e t a l . study also showed some evidence of a carcinogenic response in the liv e r and lungs of male Sprague-Dawley ra ts a t dosages of 1000 and 5000 p p t, even though th e study used a re la tiv e ly small number of animals. The Toth e t a l. study provides suggestive evidence th a t TCDD induced an increased incidence of liv e r tumors in male mice (females were not te ste d ) receiving 0.7 ug/kg/week by gavage. In the National Cancer In s titu te r a t study (1980a), male and female Osborne-Mendel ra ts were administered TCDD by gavage a t three dose lev els 0.01, 0.05, and 0.5 ug/kg/week. TCDD induced s t a t i s t i c a l l y sig n ific a n t increases of hepato cellu lar carcinomas, subcutaneous fibrosarcomas, and adrenal c o rtic a l adenomas in high dose female r a ts . TCDD also induced sig n ific a n t increases in , thyroid tumors a t low, middle, and high doses in male r a ts . 4 In a companion mouse study by the National Cancer I n s titu te (1980a), male and female B6C3F1 mice were given TCDD by gavage a t dose lev els o f 0.01, 0.05, and 0.5 ug/kg/week fo r males.and 0.04, 0 .2 , and 2.0 ug/kg/week fo r females. TCDD Induced s t a t i s t i c a l l y sig n ific a n t Increased Incidences of h ep ato cellu lar carcinomas 1n the high dose males and fem ales, and thyroid tumors, subcutaneous fibrosarcom as, and h is tio c y tic lymphomas 1n females. In a study by P ito t e t a l. (1980), TCDD has been shown to be a potent liv e r cancer promoter. In a study by Kourl e t a l . (197-8), TCDD has been shown to be a cocarcinogen. Epidemiologic Studies Several epidemiologic studies have been conducted which are relevant to the assessment of th e carcinogenicity of 2,4 ,5 -T , sllv e x , and TCDD. Two Swedish epidemiological case-control studies (Hardell and Sandstrom 1979, Erlkson e t a l. 1979) reported a very strong asso ciatio n between s o ft tissu e sarcomas and occupational exposure to phenoxyacetlc acid herbicides and/or chlorophenols. These studies indicated approximately five to sevenfold in c re a se s'in the risk of developing s o ft tis s u e sarcomas among people exposed to phenoxyacetlc acids only 1n comparison to people not exposed to these chemicals. Another Swedish case-control study (Hardell e t a l. 1980) provides suggestive evidence of an increased risk of developing lymphomas resu ltin g from occupational exposure to phenoxyacetlc acids. Two cohort stu d ie s, one by Axelson e t a l. (1980) and the other by Thiess and Frentzel-Beyme (1977) provide suggestive evidence th a t phenoxyacetlc acids and/or TCDD increases the risk of stomach cancer in humans. Four other cohort stu d ies by Ott e t a l. (1980), Riih1mak1 e t a l . (1978), Zack and Suskind (1980), and Cook e t a l. (1980) did not in d icate an Increased 5 8214 ris k o f stomach cancer, but th ree of these studies were of re la tiv e ly low s t a t i s t i c a l power, and the fourth (R11h1maki e t a l . 1977) has ce rtain Inconsistencies requiring clarificatio n . In summary, carcinogenic responses have been Induced in mice and ra ts a t very low doses of TCOD. In ad d itio n , TCDD has been shown to be a potent cancer promoter. These r e s u lts , together with the strongly suggestive evidence 1n epidemiologic stu d ie s, c o n stitu te su b stan tial evidence th a t TCDO 1s lik e ly to be a human carcinogen. In ad d itio n , on the basis of the Dow stu ty on TCDD, I t appears th a t TCDD 1s a more potent carcinogen than aflato x ln Bi which Is one o f the most potent carcinogens known. The lev els of TCDD (contained as a contaminant of the 2,4,5-T) used 1n the 2,4,5-T stu d ies apparently were too small to produce an observable response 1n those experiments. The lack of a s t a t i s t i c a l l y s ig n ific a n t tumor Incidence 1n most of the stu d ies on the 2,4,5-T product may be a ttrib u te d both to the very low le v e ls of TCDD In the product r e la tiv e to the lev els a t which 1 t produces observable carcinogenic e ffe c ts 1n r a ts and mice, as well as to the d eficien cies of those stu d ies. However, since TCDD 1s a carcinogen, any product containing TCDD, Including 2,4,5-T and sllv e x , can be considered to pose a human carcinogenic hazard. In ad d itio n , a r a t study on sp e cia lly p u rified 2,4,5-T provides highly suggestive evidence th a t e s s e n tia lly pure 2,4,5-T may be a human carcinogen. QUANTITATIVE RISK ASSESSMENT OF 2,4,5-T , SILVEX AND TCDD A Q uantitative assessment has been calculated fo r the carcinogenic risk posed to humans by the use of the herbicides 2,4,5-T and sllv e x . While there 1s 'no evidence fo r carcinogenicity of sllv ex , the evidence for 2,4,5-T 1s highly suggestive, and th a t fo r the contaminant TCDD Is su b sta n tia l. . Furthermore, TCDD 1s highly carcinogenic to animals. The assessment of risk from TCDD exposure covers only the herbicide ap p licato rs and d ietary exposure to beef, milk, deer, and elk . For unprotected workers, the upper lim its of life tim e risk of induced cancers a re i n many x a s e s as high as or 1n the 10~3 range. For the general population exposed to beef contaminated with TCDD, the upper lim it of risk fo r the estimated exposure 1s 2 .4 x 1(H>. For local populations consuming only beef which Is contaminated with TCDO, the risk 1s much g re a te r, as high as 1.9 x 10~* fo r the estim ated exposure. For local populations consuming only milk and other dairy products which are contaminated with TCDD, the risk 1s 4.7 x 10"4 . For deer and elk meat contaminated with TCDD, risk s to the local population are no g reater than 10"4 fo r 12 meals a y e a r. The upper lim it of d ietary risk associated with estimated exposures to 2,4,5-T 1n contaminated ric e and milk were 1n the 10-7 range fo r a high consumer eating only contaminated ric e or an average consumer drinking only contaminated nrflk. n )mmim m ) m iiU t itili m t l tt ai 8218 D O W 696375 1 A I DOSE LEVELS OF 2,4-D IN FOREST WORKERS J. C. Ramsey> F. A. Smith/ T. L. Lavy, C. N. Park, and W. H. Braun x* ro ro ro 6* O TOXICOLOGY RESEARCH LABORATORY Health and Environmental Sciences 1803 Building Dow Chemical U.S.A. Midland/ MI 48640 14 October 1980 uepartment of Agronomy, University of Arkansas, Fayetteville. 8219 J 0G 04G 57 DOW 696376 DOSE LEVELS OF 2,4-D IN FOREST WORKERS J. C. Ramsey, F. A. Smith, T. L. Lavy^ C. N. Park, and W. H. Braun ABSTRACT The dose level of 2,4-D absorbed by forest workers during the helicopter application of 2,4-D sprays has been deter mined. Three crews, each comprised of 6 workers, were engaged in 2 applications of ESTERON* 99*C herbicide. During the first application the workers used normal clothing and work practices. During the second applica tion they were instructed to use more stringent protective measures to minimize exposure. Measurements of airborne 2.4- D during the spray applications revealed that the respiratory route contributes an insignificant proportion of the total potential for exposure. Total daily urine samples were collected from each worker on the spray application days and for 5 days thereafter. Analysis of total urinary 2.4- D provided reliable estimates of the total amount of 2.4- D absorbed. Fourteen of the 36 exposures did not reveal detectable quantities of'urinary 2,4-D. Of the 22 exposures with detectable quantities of urinary 2,4-D, the maximum dose level was only 0.0557 mg/kg and the lowest was 0.00038 Trademark of The Dow Chemical Company. CG04G53 DOW696377 t \ r\ J -i- mg/kg. Those workers remote from the operations (super visors and observers) received even lower dose levels than did those in closer contact with the sprays (pilots, mechanics, and batchmen). The low dose levels observed following spray operations using customary precautions (first application) were reduced following spray operations using more stringent precautions (second application). Computer simulation of predicted body burden of 2,4-0 upon repeated daily exposures demonstrated a maximum accumulation of only seven- tenths of the daily dose. In conclusion, the very low exposure potential demonstrated by this study, coupled with the low toxicity of 2,4-D, supports the continued registration and use of 2,-4-0 herbicides. 8221 0C 04053 > DOV/696378 INTRODUCTION A reliable assessment of the potential risk to workers during pesticide applications in the field is dependent on accurate knowledge of the quantity of the pesticide absorbed into the body. This report concerns measurements of the amount of 2,4-D absorbed by applicators of 2,4-D formulations in the forest. / EXPERIMENTAL In an experiment conducted by T. L. Lavy (1) eighteen different workers were each engaged in 2 separate forest applications of 2,4-D formulations (ESTERON 99C applied by helicopter at a rate of approximately 2 lb. acid equivalents per acre). In the first application (Tl) all personnel followed normal work practices, followed label directions, and operated in compliance with regulatory requirements. During the second application (T2), in addition to the foregoing procedures, the workers all wore protective clothing (disposable coveralls, chemically impervious gloves and boots, and clean hats), were instructed to wash before rest stops and meals, and were instructed in further good hygiene practices by research personnel in the field?1 ................................................... .............. " 8222 ^Deviations from prescribed o; __iting conditions are noted in the report by Lavy (1). GG04G30 DOW696379 The applicators consisted of 3 crews of 6 persons each. Each crew was comprised of 1 helicopter pilot, 1 mechanic, 1 batchman-loader, 1 supervisor, and 2 observers. The members of crew number 1 were employees of Weyerhauser Company, and crews number 2 and 3 were comprised of commercial applicators. Details of the applicator personnel and specific operating conditions are given in the report by T. L. Lavy (1). Three indicators of worker exposure to 2,4-D were monitored: analysis of ambient air concentration of 2,4-D esters; analysis of patch samples attached to the workers clothing for 2,4-D esters; and analysis of total voided urine samples for 2,4-D and 2,4-D conjugates. The analytical methods and their validation are fully discussed in the report by Lavy. RESULTS AND DISCUSSION Airborne 2,4-D. Only one of the 36 personnel air monitors showed a detectable level of 2,4-D esters, and since this airborne concentration could account for no more than 1% of the 2,4-D excreted in the urine of this worker (No. 33, Tl) it was concluded that the inhalation route of exposure was negligible under these conditions. None of the 10 air monitors placed 8223 CGG4Goi 089G9^oa near the batch tracks at the heliports revealed detectable i levels of 2,4-D esters. Only 2 of the 5 air monitors placed directly in the spray areas revealed detectable concentrations of 2,4-D esters (equivalent to 0.033 and 0.167 yg 2,4-D per liter of air). Further corroboration of the negligible exposure hazard to phenoxy herbicides via the airborne route is.given by similar results following both aerial and ground . application of 2,4f5-T sprays in the forest (8). Patch Sample 2f4-D. Widely varying quantities of 2,4-D were detected on the various patch samples. But the poor correla tion between the estimated quantity of 2,4-D absorbed based on these data, and the amount excreted in the urine (see following section) shows that this indirect method of estimating the absorbed dose has little validity. In a similar study with 2,4,5-T spray applications in the forest, patch samples were shown to be inadequate indicators of the amount of 2,4,5-T actually absorbed (8). Urinary 2,4-D. The analysis of total urinary 2,4-D (on a daily basis) on the application day and for 5 days thereafter showed detectable quantities of 2,4-D for 22 of the 36 exposures comprising the study. The total quantity of urinary 2,4-D excreted on the application day and for 5 days thereafter QG04G32 1 J -4- was divided by the individual worker's body weight to yield an estimate of the absorbed dose in mg 2,4-D per kg body weight (mg/kg). These data for each worker are shown in Table 1 which is a condensation of the same data presented by Lavy (1). The dose levels thus reported are believed to be reliable and realistic estimates of the total absorbed dose of 2,4-D for the following reasons: Pharmacokinetic studies with 2,4-D in rats (2) have shown that orally ingested or intravenously administered 2,4-D is excreted primarily in the urine by a first order process with a half-life of approximately 2 hours. Thus, the rapid and efficient urinary excretion of 2,4-D appears to be essentially independent of the route of administration. Further studies (3) have shown that the PGBE esters of 2,4-D applied to the skin of rats are absorbed through the skin at a first order rate with a half-life of about 20 hours, and are then rapidly excreted as 2,4-D acid in the urine. In human volunteers (4) given an oral dose of 5 mg 2,4-D per kg, virtually the entire dose (greater than 95%) was excreted 8225 CC0`1G5C DOV/696381 DOW696382 -5- in the urine as 2,4-D and 2,4-D conjugates by a first order process with an average half-life of approximately 11 hours\ The foregoing data demonstrate that urine is indeed the major excretory route for 2,4-0 in both rats and humans, and that urinary excretion is an efficient process that can be described by first order kinetics at non-saturating dose levels (i.e., below approximately 50 mg 2,4-0 per kg (2)). Therefore, the measurement of total urinary 2,4-0 and its conjugates during the spray application day and for 5 days thereafter (as reported in Table 1 and Reference 1) is considered to be a realistic approximation of the total quantity of 2,4-D absorbed. Further support for the reliability of urinary 2,4-D measure ments in estimating the absorbed dose is derived from compari son with another closely related phenoxyacetic acid herbicide, 2,4,5-T. This compound is also excreted almost exclusively in the urine of rats, dogs and humans (5,6,7) by a first order process that is apparently independent of the route of exposure. And the PGBE esters of 2,4,5-T (10), like the PGBE ^Sauerhoff et al. (4) calculated the half-life for urinary excre tion of unconjugated 2,4-D as 17.7 hours. However, the inclusion of urinary conjugates of 2,4-0 with these data (subjects no. 1, 2 and 3, reference 4) indicate an average half-life of approxi mately 11 hours for the excretion of both conjugated and uncon n jugated 2,4-D. C G Q & G o -l -6- DOW696383 esters of 2,4-D (3), are absorbed relatively slowly through the skin of rats and then efficiently excreted in the urine as the corresponding phenoxy acid. Urinary 2,4,5-T has been shown to be a reliable indicator of the quantity of 2,4,5-T absorbed by forestry workers during application of 2,4r5-T sprays (8,9). In that study, urinary concentrations of 2,4,5-T were measurable for several days following the spray application in some of the workers, which enabled determination of the pharmacokinetic model parameters for the dermal absorption and urinary excretion of 2,4,5-T (9). Thus, the half-life for dermal absorption of 2,4,5-T esters in humans was shown to be approximately 18 hours. In contrast to the 2,4,5-T study cited above, the levels of urinary 2,4-D in the present study could not be measured for a sufficient length of time (because the exposure levels were so low that the concentration of urinary 2,4-D was often below the analytical detection limit) to allow direct determination of the first order rate constant for the dermal absorption of 2,4-D esters in these workers. However, because of the close similarity between the pharmacokinetic profiles of 2,4-D and 2,4,5-T, the rate of dermal absorption of 2,4-D esters in humans may be similar to that for 2,4,5-T esters. This assumption is supported by the observation ) 8227 -7- i that the half-life values for the dermal absorption of the PGBE esters of 2,4-D and 2,4,5-T in rats cure similar, approxi mately 20 hours and 24 hours, respectively (3,10). DOW 696384 In order to calculate.the pharmacokinetic fate of dermally absorbed 2,4-0 in humans, numerical values for the rate constants of absorption and elimination are required. Based on the considerations above, the dermal absorption rate constant of 2,4-D esters in humans was assigned the same value as that for 2,4,5-T esters (half-life *= 18 hours) (9). The urinary excretion rate constant of 2,4-0 and conjugates was assigned the value previously determined in a human study (half-life = 11 hours) (4). These values then allowed the calculation of the amount of dermally absorbed 2,4-0 that is excreted in the urine at any time following exposure (9). This calculation reveals that approximately 99% of a dermally absorbed dose of 2,4-0 esters would be excreted in the urine as 2,4-D and conjugates during the exposure day and for 5 days thereafter. These values for the rate constants were also used to obtain a computer simulation of. the body concentration of 2,4-0 that would result from repeated daily dermal exposures to 2,4-0 esters. The results of this prediction are shown in Figure 1 in which the body burden of 2,4-D is given in units y CG04G6S p nC- 9cS DOW696385 -8- of the dose that has been absorbed thru the skin. This simulation shows that the maximum body burden attained would be approximately 0.7 times the daily dose. In other words, if a dose of 0.050 mg 2,4-0 per kg were absorbed through the skin each day the maximum concentration attained in the body after repeated daily exposures would be only 0.035 mg/kg. This bioaccumulation factor is less than might be expected (as calculated based on 1 dose per day) because the absorp tion rate constant in the pharmacokinetic model is less than the elimination rate constant (i.e., a flip-flop model). Furthermore, the simulation shows that over 90% of this maximum concentration would be reached after 4 daily exposures. The quantitative precision of this prediction is limited by the underlying assumptions. However it is apparent that, as long as 2,4-D is not absorbed at saturating dose levels (orally administered doses of 5 mg 2,4-D/kg in humans show no evidence of saturation (4)), even repeated exposures to 2,4-D will not result in continually increasing accumulation in the body. Exposure Comparisons. Based on the absorbed dose levels reported in Table 1, the following comparisons concern possible differences in exposure to applicators based on n 0C04G67 usual (Tl) versus more stringent (T2) application procedures, possible differences between application crews, and different job descriptions within all 3 crews. DOW696386 Even though the dose levels received by the workers operating under usual conditions (Tl) were very low, there was never theless a slight but statistically significant reduction (p<0.05, two-tailed Wilcoxon matched-pairs signed-rank test) in the dose levels received by these same workers when utilizing protective clothing (T2). Of the fifteen expo sures in which, urinary 2,4-D was detected in one. or the other treatment (i.e., either Tl or T2), 11 exhibited a decrease in dose level during the second exposure (T2) whereas 4 showed an increase in urinary 2,4-0. Among the 3 different crews, there was no statistically significant difference in dose levels when compared by a nonparametric analysis of variance. However a nonparametric t-test revealed that the workers of crew 1 received a significantly lower dose than did the workers of crew 3 (p<0.05) . As would be expected, those workers in closer contact with the sprays (pilots, mechanics, and batchmen) received a significantly greater dose level than did the workers more 0G04G63 823 0 DOW696387 -10- remote (supervisors and' observers) when compared by a nonparametric analysis of variance (p<0.05). A similar correla tion between close contact with the spray mixtures and absorbed dose level was observed with crews applying 2,4,5-T sprays in the forest (9). In conclusion, forest workers engaged in the aerial applica tion of 2,4-0 absorbed minimal quantities of 2,4-D based on total urinary excretion data. Of the 36 total exposures comprising this study, 14 did not result in detectable concen trations of urinary 2,4-D. Of the 22 exposures yielding detectable concentrations of urinary 2,4-D, the maximum dose level was only 0.0557 mg/kg, while the lowest was 0.00038 mg/kg. Repeated daily exposures to 2,4-D formulations are not expected to result in continually increasing accumulation in the body. The very low exposure potential demonstrated by this study, coupled with the low toxicity of 2,4-D, ( supports the continued registration and use of this herbicide. ,8 2 3 1 0G04G63 DOW 696388 -11- DOSE LEVELS t)F 2,4-D IN FOREST WORKERS J. C. Ramsey, F. A. Smith, T. L. Lavy, C. N. Park, and W. H. Braun HET K-002372-(27) Problem #: 179-0000708 Date: 14 October 1980 1803 Building 14 October 1980 0^# oT- L. L/>vy lih < fS r T. L. Lavy', Ph.D. Altheimer Laboratory Department of Agronomy University of Arkansas 4 fyr,'r*k f o h s 1 * 0 __________ F. A. Smith, M.S. Toxicology Research Laboratory 1803 Building 14 October 1980 </. ic/is/zt C. N. Park, Ph.D. Health & Environmental Sciences 1803 Building 14 October 1980 V h ) B 'n a u ^b SLr ) t o ) / r fs * _______ W. H. Braun / "' Group Leader Toxicology Research Laboratory Health & Environmental Sciences 1803 Building Dow Chemical U.S.A. Midland, MI 48640 14 October 1980 0G04G73 8232 DOWG3G3S9 -1 2 - REFERENCES (1) Lavy, T. L. Determination of 2,4-D Exposure Received by Forestry Applicators. Project Completion Report to National Forest Products Association. August 29, 1980. (2) Smith, F. A., Nolan, R. j., Hermann, E. A., and Ramsey, J. C. Pharmacokinetics of 2,4-Dichlorophenoxyacetic Acid in Fischer 344 Rats. Dow Chemical U.S.A. Report in preparation. (3) Smith, F. A., Ramsey, J. C., and Dryzga, M. D. Pharmaco kinetics of 2,4-D PGBE Ester Applied Dermally to Rats. Dow Chemical U.S.A. Report in preparation. (4) Sauerhoff, M. W., Braun, W. H., Blau, G. E., and Gehring, P. J. The Fate of 2,4-Dichlorophenoxyacetic Acid (2,4-D) Following Oral Administration to Man. Toxicology , 3-11, 1980. (5) Piper, W. N., Rose, J. Q., Leng, M. L., and Gehring, P. J. The Fate of 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T) Following Oral Administration to Rats and Dogs. Toxicol.' Appl. Pharmacol. 26, 339-351, 1973. (6) Sauerhoff, M. W., Braun, W. H., Blau, G. E., and Gehring, P. J. The Dose-Dependent Pharmacokinetic Profile of 2,4,5-Trichlorophenoxyacetic Acid Following Intravenous Administration in Rats. Toxicol. Appl. Pharmacol. 36, 491-501, 1976. (7) Gehring, P. J., Kramer, C. G., Schwetz, B. A., Rose, J. Q., and Rowe, V. K. The Fate of 2,4,5-Trichlorophenoxyacetic Acid (2,4,5-T) Following Oral Administration to Man. Toxicol. Appl. Pharmacol. 26, 352-361, 1973. (8) Lavy, T. L. Measurement of 2,4,5-T Exposure to Forest Workers. Project Completion Report to National Forest Products Association. November, 1978. (9) Ramsey, J. C., Lavy, T. L., and Braun, W. H. Exposure of Forest Workers to 2,4,5-T: Calculated Dose Levels. Dow Chemical U.S.A. Report, January 17, 1979. (10) Young, J. D., Ramsey, J. C., and Braun, W. H. Pharmaco kinetics of 2,4,5-T PGBE Ester Applied Dermally to Rats. Dow Chemical U.S.A. Report, May 29, 1979. 8233 0004071 DOW 696390 -1 3 - n TABLE 1 ABSORBED DOSE OF 2,4-D IN FOREST WORKERS ESTIMATED FROM URINARY EXCRETION OF 2,4-D* CREW 1 - Pilot Mechanic Batchman Supervisor Observer Observer mg 2,4-D/kg Body Weight** Ordinary Special Precautions Precautions 0.00179 0.00044 0.00215 nd nd 0.00055 nd nd 0.00053 0.00038 0.00056 nd CREW 2 - Pilot Mechanic Batchman Supervisor Observer Observer 0.0557 0.00232 0.0189 nd nd nd 0.0237 0.00516 0.0196 nd nd nd CREW 3 - Pilot Mechanic Batchman Supervisor Observer Observer 0.00206 0.0136 0.0377 0.00692 0.0011 0.0013 0.00192 0.00388 0.0219 nd nd nd From T. L. Lavy (1), Table 21, p. 48. nd = not detectable at a detection limit of 0.04 ppm 2,4-D in urine. 8234 CG04G/2 * u\ Body Burden <Do I >t^ 00040/o 1 2 3 4 5 6 7 8 9 10 XI 12 13 14 15 16 17 18 19 20 21 No. of Exposures *= No.- of Days FIGURE 1. | Simulated body burden of 2#4-D in humans after a single dermal exposure and after repeated (daily) dermal exposures. The body burden is expressed in units of the dose level applied to the skin (D0). Digital computer Simula-^tion based on assumptions described in the text. Go fO Co c/r T60969 MOO A 03- ox. 8236 Agriculture Canada Information S AGRICULTURE CANADA OTTAWA K1A OC7 995-8963 w w j Subject: 2,4-D TESTS For Immediate Release ' T " OTTAWA* October 23* 1980 -- Agriculture Minister Eugene Whelan today announced that tests conducted by Agriculture Canada have identified previously unrecognized contaminants in some samples of the herbicide 2*4-0. Scientists in Agriculture Canada's Food Production and Inspection Branch, using state-of-the-art technology* have found that some 2*4-D products contain dioxin contaminants. It has generally been believed that 2*4-D products are dioxin-free. The majority of world tests have focussed on what is recognized to be the most acutely toxic member of the dioxin family* the 2*3*7*8-TCDD isomer. This dioxin has never been identified in 2*4-D. The intensive Agriculture Canada tests just completed have again confirmed the absence of 2,3*7*8-TCDD in 2*4-D. Other dioxin contaminants were* however* identified in some 2*4-0 products* while no dioxin contamination was detected in other 2,4-D samples tested. "We are now assessing these results in concert with officials in Health and Welfare Canada who work in co-operation with us in pesticide regulation. "A decision on how our new findings will affect the permitted uses of 2*4-0 will be made before the 1981 growing season," Mr. Whelan said. The herbicide 2*4-D is used to control broad-leaf weeds in everything from lawns to cereal fields. About eight million pounds of 2*4-D is used in Canada each year. This represents about 25 per cent of total herbi~` 'e use. 8237 CC07S14 'Z - * ? / / W /r= - 2- E-63 "These findings clearly identify dioxin contaminants in some, but not all, 2,4-D samples examined. Work is continuing t o gain a broader and more detailed understanding of these new findings." "When some pesticide products were registered, today's highly-sophisticated testing equipment did not exist. The investment my department has made in high-priced laboratory equipment and in highly-trained scientists is paying off with results like these. "My main concern is about the safety of all pesticide products used in Canada. "I can guarantee the public that Agriculture Canada will continue to work hard in keeping agricultural chemicals under constant review and to provide answers to concerns that may arise as a result of the review process," Mr. Whelan said. - 30 - For more information, media may contact: Wayne Ormrod Associate Director Pesticides Section ,, Food Production & Inspection Branch Agriculture Canada Ottawa, K1A 0C6 Telephone: (613) 995-5880 0007315 f r. : 03 i.- 8239 03 MN05J305. C13C "Radio Noon" October 27, 1980 12 : 16 to 12:20 p . m . Pr of Steve Safe, U of Guelph, Re Dioxin levels in 2'1-D and 2M5-T (4 minutes) * ** P ro fe s s o r S te v e S a fe s a y s d io x in fo u n d b y A g r ic u lt u r e C a n a d a in 2 4 -D sam ples is re la tiv e ly n o n -to x ic . Late last w eek A . D . S t. C la ir , P resid en t o f the C anadian A g ric u ltu ra l Chem icals A s so ciatio n , said he was p leased th e F ed eral te s t o f 24-D showed none o f th e h ig h ly -to x ic d io x in fo und in th e banned h e rb ic id e 2 4 5 -T . D r. S afe exp lain s th e d iffe re n c e betw een th at leth al form o f d io xin and the ty p e o f d io x in f o u n d in 2*1--D . S5 . T h e re a re m ajor d iffe re n c e s . It tu rn s o u t w ith 2 H 5 -T , th e e x p e c te d b y -p ro d u c t tu rn s out to be th e most to x ic d io x in in th e w hole s e rie s . T h e re a re a n u m b er o f d iffe re n t d io x in s . W ith 2*l-D th e e x p e c te d b y p ro d u c ts w hich h ave been id e n tifie d a re re la tiv e ly n o n -to x ic and it tu rn s o u t it's because o f the s ta rtin g m aterial -- in one case it's 2H D ip lo ra fin o ; in th e o th e r case it's 245 T r ic h lo r o fin o . So we te n d to g e t low er c h lo rin a te d d io xin s because o f th e ir s tr u c tu r e . T h e y 're much less to x ic , a lth o u g h c e rta in ly m ore w o rk has to be done on th e m , and in a d d itio n th e y 're p ro b a b ly m uch less p e rs is te n t. Q W hen y o u say less to x ic , is th e r e some k in d o f an e x a m p le y o u c o u ld use to com pare them to th a t v e ry s e rio u s ly to x ic d io xin ? SS W ell, th e e a s ie s t exam ple is th a t in a n y case w h e re th e y 'v e b een s tu d ie d , an d th e y h a v e n 't been s tu d ie d in d e ta il, b u t th e m ajor o n e, I th in k , is th e 27 D ic h lo ra l d io x in , and th e re 's no d a ta as fa r*a s I know in th e lit e r a t u r e in d ic a tin g th a t it's a to x ic c h e m ic a l. It is r e la tiv e ly n o n - f to x ic . It 's , I w ould e x p e c t o r p r e d ic t, s e v e ra l o rd e rs o f m ag n itu d e / less to x ic , and c e rta in ly much less b ecause it w ould be e x p e c te d to 8240 0007iil POPOLO f (S S ) Q SS SS -2- be b ro k e n dow n p r e t t y q u ic k ly in th e e n v iro n m e n t. It w ould seem th a t if d io x in , in c lu d in g the e ith e r leth al ones o r th e re la tiv e ly safe ones o c c u r in the m a n u fa c tu rin g p ro cesses o f some o f th ese h e rb ic id e s , th a t we should ask some q u estio n s ab o u t how th e y do o ccu r an d how we can be ass u re d th a t m inim al am ounts w ill be th e re w hen th e y a re m anu factu red . Y e a h , I th in k th e fa c t th a t th e d io x in s h a v e b e e n is o la te d is im p o rta n t. T h e y w ere not isolated in com perable p re p a ra tio n s , in all p re p a ra tio n s , o r in m any p re p a ra tio n s from E u ro p e , and th e y w ere looked fo r b y good people b e fo re . I th in k th e y can be m ade to m inim ize o r elim in ate those d io x in s , and it does tu rn out th a t the d io xin s th a t have been id e n tifie d and th a t you w ould p re d ic t w ould be p re s e n t a re re la tiv e ly n o n -to x ic . So t h e 24--D , l u c k i l y , we w e n t o u t . S in c e th e y a re r e la tiv e ly in n o cu o u s in 2 U -D , w h y th e n is th e F e d e ra l * G o v e rn m e n t d o in g th e s e sam ple tests? W e ll, I th in k th e y 'r e d o in g th e t s ts b ecau se th e y 'r e as s e n s itiz e d as e v e ry o n e else is to d io x in s , and I t h in k , I h a v e a fe e lin g , an d I know some o f th e people th a t a re doing the w o rk , and I th in k the g o ve rn m e n t w an ts to k n o w . T h e y w an t to kn o w , a n d , if n e c e s s a ry , a d v is e the com panies and p e rh a p s ad vise th e p u b lic , a n d p e rh a p s it can be c h a n g e d . ! th in k th e re a re m ethods to p ro d u c e 2 4 -D .to e lim in a te o r alm ost e lim in a te th e d io x in b y -p r o d u c ts . ( S teve S afe, P ro fesso r o f B iocherr:- t r y at th e U n iv e rs ity o f G u elp h . * * * 8241oO?l=3 8242 RELEASE.' IF ASKED ABOUT TOXICITY# HE INTENDS TO REPLY AS .'FOLLOWS 1.- IN CONJUNCTION WITH THE HEALTH PROTECTION BRANCH OF THE CJVV TO V. CD. CO' , o ,_ ' DEPT. OF HEALTH AND WELFARE# THE DIOXINS IDENTIFIED AS BEING IN SOME r 2.4-D PRODUCTS ARE NOT THE HIGHLY TOXIC 2#3#7#8 TCDD ASSOCIATED ONLY WITH 2# 4# 5-T. 7 2. : THERE AR THREE TYPES OF DIOXINS THAT HAVE BEEN IDENTIFIED. f THESE ARE THE DlPOLYCHLORINATED DIBENZOPARADIOXINS (PCDD).'THE TRI PCDD'S AND THE TETRA PCDD'S.: 3. ' ACUTE TOXICITY TESTS FROM PUBLISHED TOXICOLOGICAL INFORMATION INDICATES THAT THE DIDI-ISOMERS OF PCDD ARE ONE MILLION FOLD LESS TOXIC THAN 2#3#7#8 TCDD. u*. I 4.' ACUTE TOXICITY TESTS OF THE TETRA ISOMERS OF PCDD INDICATES `THAT THEY ARE 50.000 TIMES LESS TOXIC THAN 2#3#7#8 TCDD.` 5.' ACUTE TOXICITY TESTS OF THE TRI ISOMERS OF PCDD ARE 15.000 TIMES LESS TOXIC Th Xn 2#3#7#8 TCDD. PLEASE NOTE NUMBER THREE#ILINE TWO#:SHOULD READ DI-ISOMERS.' 82^3 *tfr*- CG0731G X os fr* Ol 0003473 I' I O9 ON H S6ZI30M00 a VT Exhibit 895 i 9 6 2 183OM0O 1 Determination of 2,4-D Exposure .o ..Ov -t ' . Sr.' Rceived by Foresti^ Applicators o "Si- " Spring 1980 . 00 &) S3 !^ r- , 5fi*. ..f i I" ii - % i.*; .*i m L . .' K*-V.~ *i 1* ' 1`- i - * . T'*-*. * * ,;1. ^ '` v~*;-: ~ 'v-*-.*:'* .. ' ' -V - V '* T - -o> -, jn cooperation With * . . A-, , * ' ; Dow Chemical, U.S.A. ^ x:aV.* * i * jr t . - ,`v - October, 1980 v .*V . * . ''*** p -V *'*a.; w ;.. j '.-.j . ...VC : ^ Vf ; - .:{ - ; f . ' M - -, --Vrv, '' . . '' Sponsored by: . 8246 National Forest Products Association 0003474 oV 8247 fc > NPraotdiouncalaFAotrtaotcilallon Jtu r. tua Vi PfMioani. A**ourcanaEnvironment F o rn t Industrias Building 1619 Massachusetts Avanua. N.W. Washington. O.C. 20036 202/797-5658 November 14/ 1980 O O Mr. Edwin L. Johnson Deputy Assistant Administrator for Pesticide Programs Environmental Protection Agency 401 M Street/ S.W. Washington, DC 20460 CT> Cq .. po " r vj Dear Ed: The National Forest Products Association submits the attached research report entitled "Determination of 2,4-D Exposure Received by Forestry Applicators, Spring 1980" for EPA use in its Forest Chemicals Use Project and in response to EPA's fifra 3(c )(2)(B> notice in connection with 2,4-D registrations. This study was conducted with the cooperation and assistance of the Dow Chemical Company and the enclosed report includes a Dow paper . entitled "Dose Levels of 2,4-D in Forest Workers." This study confirms that forest workers absorb only low doses of 2,4-D during aerial application `of this herbicide. Resulting safety factors for exposed workers >re substantial -- ranging from 1,212 to 48,980 in relation to the Scientific Advisory Panel's 500 \ pom NOEL for reproductive toxicity -- even without special pre cautions during the loading and application process. The study also indicates that still lower exposure and larger safety factors can be achieved when special precautionary measures are taken including applicator use of disposable c o v e r a l l s , chgmieaiiy impervious gloves and boots, and strict personal hygienic practices^ Safety factors, under these special circumstances, range from 1,714 to 266,667. The study is similar to NFPA's "Measurement of 2,4,5-T Exposure of Forest Workers" submitted to EPA in February, 1979. You may recall that NFPA's February 14, 1979 cover letter accom panying the 2,4,5-T study proposed a follow-up investigation which would have examined the effects of added precautions during the 2,4,5-T application process. Since EPA fco gllnu fhA I1CA of 2,4,5-T for the post-suspension experiment. NFPA elected to conduct the foTlow-up study using 2,4-D. The enclosed study, like its predecessor study, was conducted jy T.L. Lavy, Ph.D. of the Altheimer Laboratory, University of Arkansas. The protocol for this study, developed bv Dr. L a w and a committee **o? torest y,pdui-ry was submitted to EPA for review and comment before the study was undertaken. NFPA is grateful for the assistance rendered by EPA personnel and found that their comments substantially contributed to a better research project. 8248 0003475 ' I. NFPA would welcome more extensive EPA involvement in future research activities of this sort. The forest industry believes that cooperative scientific effort involving both the regulatory agency and the regulated public is a more fruitful way of resolving the controversies that arise concerning pesticide use than the adversarial proceedings which have marked the history of pesticide regulation. D0WO681 2 9 8 I. GENERAL STUDY DESCRIPTION A. Crews The enclosed exposure study investigates the dose level of 2,4-D absorbed by forest workers as acon sequence of the helicopter application of 2,4-D sprays. Three spray crews, each ^"iprUoH nf w workers, participated in the .study* Each crew con sisted of a pilot# a mechanic, a batchman-loader. a supervisor, and two forest observers. Observers were included in the study to enable measurement of wha tever 2,4-D dose is received by individuals not involved in the spray application but who are proxi mate to the spray site. Each of the three helicopter crews participated in two different application tests. In the first test, designated Tl, measurements were taken on crew mem bers performing their duties in the customary manner using ordinary application precautions. Crew members were instructed to dress and to perform their duties in a normal fashion. The second test, designated T2, was conducted following conclusion of Tl. During T2, the workers are outfitted with spe cial protective clothing including disposable coveralls, chemically impervious gloves and boots, and clean hats. In addition, crew members were instructed to wash before rest stops and meals and were instructed to observe other stringent hygienic practices by research personnel in the field. B. Location Three different spray locations were selected for these studies, so as to r e p r esent the range of siteconditions encountered in Pacific No r t h w est f orestry. Crew 1 operated near Raymond, Washington in a forest site typical of the moderately steep slopes of the Washington Coast Range. Crew 2 operated near Gardiner, Oregon, in an area representative of the highly dissected topography of the Oregon Coast Range. Crew 3, operated near Cottage Grove, Oregon in the western foothills of the Oregon Cascade Range. 8249 0003476 i .i Two sites within 10 miles of each other at each. geographic location were chosen for Tl and T2 treatr ments witn Each site consisted of approxi mately 100 acres of Douglas-Fir which required release from competing vegetation. II. TEST METHODS D 0 W 0 C 8 1299 Lavy, et al. used three methods to estimate crew exposure to 2,4-D: (1) air s a m p l e s . (2) denim patches, and (3) .. urine samples. The detailed analytical results for each test method appear in tables 10 (air monitors), 14A-14B (patches), and 16A-18B (urinalysis). Analysis of those data, confirm Lavy et al.'s findings in the 2,4,5-T Exposure Study, that (1) airborne 2,4-D is an insignificant exposures avenue for forest workers and (2) that patc^h data is not a reliable means of estimating absorbed dose. These data also confirm that measurement of urinary 2,4-0 content is the most reliable means of estimating absorbed dosages. Accordingly, only the urinanalysis data are discussed below. III. RESULTS Table 21, reproduced in modified fashion below, sum marizes the estimated maximum initial dose received by each crew member for both Tl (regular precautions) r v and T2 (special precautions) utilizing measurements of total urinary 2,4-D. ABSORBED DOSE OF 2,4-D IN FOREST WORKERS ESTIMATED FROM URINARY EXCRETION OF 2,4-D mg 2,4-D/kg Body Weight Ordinary Special Precautions Precautions CREW 1 - Pilot Mechanic Batchman Supervisor Observer Observer 0.00179 0.00044 0.0021S nd nd 0.00055 nd* nd 0.00053 0.00038 0.00056 nd CREW 2 - Pilot Mechanic Batchman Supervisor Observer Observer CREW 3 - Pilot Mechanic Batchman Supervisor Observer Observer 0.0557 0.00232 0.0189 nd nd nd 0.00206 0.0136 0.0377 0.00692 0.0011 0.0013 0.0237 0.00516 0.0196 nd nd nd 0.00192 0.00388 0.0219 nd nd nd 8250 0203477 *nd not detectable at a detection limit of 0.04 ppm 4 DOW0601300 Fourteen of the thirty-six exposures did not result in detectable quantities of urinary 2,4-D. Of the 22 exposures with detectable quantities, the dose level ranged from 0.00038 mg/kg (T2) to a maximum level of 0.0557 mg/kg (Tl). Although the dose levels received by crew members employing usual precautions in Tl were quite low, the same workers generally experienced a statistically significant reduction in dose, or none at all, when utilizing special precautions in T2. Six workers who received some dose in Tl received no dose in T2. Of the fifteen crew members who received some dose in Tl or T2, eleven exhibited a decreased dose during T2. Four crew members, however, showed an increased dose during T2. As might be expected, intuitively, those crew members with the higher values were most intimately connected with the spray operation. Pilots, mechanics, and batchman received a significantly greater dose level., than supervisors and observers who were more removed from the spray operation. Since this latter obser C vation confirms a similar conclusion drawn by Lavy et al. in the 2,4,5-T Exposure Study, one can confidently conclude that spray crew dose levels repre sent a worst-case situation and that "involuntary" exposure opportunities for the general population diminish as a function of distance from the actual spray operation. IV. Safety Factors Although EPA has sought some additional toxicological information concerning 2,4-D through a section 3(c)(2)(B) notice, general agreement in the scientific community already exists on a no-observable effect level for 2,4-D reproductive toxicity. EPA's April 22, 1980 "2,4-D Fact Sheet" accompanying the Agency's announcement of its 3(c)(2)(B) actions acknowledged that "almost all animal tests conducted on the potential reproductive effects of 2,4-D show that . . . there is a no-effect level for injury to the fetus (fetotoxicity) from 2,4-D." Fact Sheet, Section II. 4. The Fact Sheet also stated that "based on the NOELs in the animal studies, EPA estimates that the level of exposure in a "worst case" situation (e.g. a person standing directly under a spray plane) would be 500-1,000 times less than the dose level that might cause an effect." Fact Sheet, Section IV, B.3. I j j j j ! 0^31 ; These conclusions were confirmed by the FIFRA Scientific Advisory Panel's review of 2,4-D literature to determine what further tests EPA should require pursuant to its Section 3(c)(2)(B) authority. The SAP unanimously i 0034? 8 -5- concluded that, "In our opinion 500 ppm should be con sidered as a no observed effect level (NOEL) for repro ductive toxicity in rats-exposed to 2,4-D and should be used in estimating the potential reproductive toxicity to 2,4-D to humans exposed to this compound." Scientific Advisory Panel Report at 4. [ 0l99QM00 The table, below, displays the safety factors for crew member by job classification using the SAP's 500 ppm NOEL converted to mg 2,4-D per kg body weight* l SAFETY FACTORS Pilots "BY JOB CLASSIFICATION Estimated Average Initial Dose of 2,4-D in mg/kg Tl T2 .0198 .00854 SAP NOEL For Reproductive Toxicity 24 rag/kg* Safety Factor Tl 1,212 T2 2,810 Mechanics .00545 .00301 24 mg/kg 4,404 7,973 Batchmen .0198 .0140 24 mg/kg 1,212 1,714 Supervisors .00231 .00013 24 mg/kg 10,390 184,615 Observers .00049 .00009 24 mg/kg 48,980 266,667 T1 (ordinary precautions) safety factors for crewmen ranged from 1,212 to 48,980. Pilots, mechanics, and batchmen who received the highest 2,4-D doses have ample margins of safety even in Tl when ordinary safety precautions were observed. Supervisors' and observers' safety factors were so large in T1 (10,390-48,980), that further improvement could only be of academic interest. In T2, the already substantial safety factors found in T1 were further improved and ranged from 1,714 to 266,667. It appears then, that the 500-1000 fold "worst case" safety margins announced by EPA in Section IV B.3. of its April 22, 1980 2,4-D Fact Sheet, are quite conservative. The Exposure Study clearly demonstrates that actual field applications without extraordinary precautions (i.e. Tl), can substantially exceed the 500 to 1000 fold safety margins EPA found adequate in its April 22 document. Although crew safety factors were substantially improved by the special pre- * The SAP's 500 ppm NOEL for 2,4-D reproductive toxicity was converted to 24 mg 2,4-D per kg body weight as follows: 8252 500 ug/g 2,4-D in feed X 12g feed/day 6000 ug or 6 mg 2,4-D dose per day. 6 mg 2,4-D per day . 24 mg 2.4-D/ka/dav 0003478 D0N0681302 `t -6- cautions o b s e r v e d in T2, there seems to be little point in. a dopting the T2 s p e c i a l p r e c a u t i o n s d a y - t o - d ay .field opera tions since the s a f e t y mar g i n s in Tl were already s u b s t a n t i a 1.. The National Forest Products Association would be pleased to discuss both the methodology and results of the 2,4-0 Exposure Study with EPA representatives. In addition, NFPA would be pleased to furnish EPA with an aliquot of the remaining urine samples so that the Agency can run confirmatory analyses. As always, we remain committed to providing EPA with useful information about forest use chemicals. We believe that the enclosed exposure study significantly advances the current state of knowledge concerning forest worker exposure to 2,4-D following aerial application of that herbicide. NFPA hopes that EPA will increase its level of participation with the forest industry in these dispassionate scientific inquiries so that future regulatory decisions about forest chemicals can be based on the best infor mation available. Respectfully submitted John F. Hall 8253 8254 t*i toxics law could stimulate innovation ' The 1976 Toxic Substances Control Act, long decried . by the chem ical industry a s a hindrance to innovation, may, in fact, stim ulate th e d ev elo p m en t of new and .. "safer chem icals. So finds a study prepared for EPA by M assach u setts Institute of T echnology's C enter for V 'P olicy A ltem atives.The study concludes that although ' .the impact of the law is not predictable, the agency can do much to thwart any negative effects. Among i- the suggestions to offset any discouraging effects a re generic prem anufacturing notifications for selected classes of new chem icals, "fast-track" prem anu-- V- facturing rev iew s for s a fe ch em icals o r m ajor in n o v a -; lotions, and governm ent subsidy of the testing and corrv .y; pliance c o s ts of new chem ical d evelopm ent. To co m - plem ent this report, EPA h as begun a three-year study T analyzing innovation in th e ch em ical industry. The MIT ; report can b e obtained from EPA's Industry A ssis- '* ta n c e Office in W ashington, D.Cw ,,. r*- t Industrial boilers destroy PCB's safely p a c ts. Further, h e say s, the standards w ent beyond?.?* - the recom m endations of the state health departmentT^" - The Air R eso u rces Board h a s indicated th at it will a p ^ S . peal this ruling, and will particularly challenge the contention of econom ic im pact A board sp o k e sm a n ^ tells C&EN that standards, a s o p p o se d to reg u la tio n s,-^ ' are based on health, not econom ic considerations:-^ ' *' y T*Kit House wrangling over committee seats .u The 33 seats the Republicans snatched from the. .. D em ocrats in the re c e n t election m an d ate a ch an g e V in th e num ber of m em b ers of e a c h party w ho sit on -jj e a c h of th e H ouse's 22 co m m ittees. But R ep u b lican s.jr are already crying "foul.": R ep. Bud S huster (R .-P a.),^ chairm an of the Republican Policy Com m ittee, charg- - e s th at S p eak er Tip O'Neill (D.-Mass.) is trying to . V stack th e th ree m ost important com m ittees in th e '3 - H ouse---Appropriations, Rules, an d W ays & M eans-- Vf* - .b y maintaining the current ratio of Republicans to V '-VDem ocrats on those three com m ittees,'w hile c h a n g - ^ ing the ratio on all other com m ittees to a p p ro x im a te ^ - -' th e overall ratio in th e House. A ccording to th e R e - ^ < Cil CTN CJ CO Ml ^ PA h a s found th a t polychlorinated biphenyls (PCB's) can b e destroyed safely by burning th e m in high-effi- ''ciency industrial boilers. T ests w ere perform ed last ^ May a t the C hevrolet plant in Bay City, Mich. A mix- publicans' calculations, they should pick up a total o f ^ r 12 s e a ts am ong th o se co m m ittees.-w h ich 'would ; m ake it harder for the D em ocrats to gam er the m ajor-V S ' ture of PCB-containing oil and No. 6 fuel oil w as ; burned having a final PCB concentration of about 50 -ppm ..M onitoring of th e em issio n s found no PCB's or ; other toxic substances, m eaning that at least 99.99% of th e PCB's had b e e n destro y ed . Finding a s a fe m eth- -y-od for disposal of PCB's h a s b e e n a problem for EPA "V 7 sin ce it w as given th e ta sk in th e 1976 Toxic Sub- Vi in sta n c e s-C o n tro l A c t T hese findings suggest th a t' t ; r many industrial boilers throughout th e U.S. can be v | - used to destroy PCB-containing w astes without risk to ' health or the environment. ; iv* ark service halts use of 2,4-D The National Park Service is suspending use of the Gulf refutes council's pricing charges ^ ^ i ^ ^ Gulf Oil C hem icals Co. h as issu ed a strong denial of . charges by the Council on W age & Price Stability that J . th e com pany did not comply with the voluntary price - guidelines in th e third quarter of 1979. During th e en tire first year the guidelines w ere in-effect, O ctober ^ . 1978 through Septem ber. -1979, th e C o m p an y 'say s that its profits w ere about $60 million less than tho se r perm itted by th e council's original rules. A ccording to - the company, eight months after the program began ' . the council changed the rules and im posed a " condition" that the com pany w as not to raise its a v e ra g e '^ -; p ric e s during th e q u arter e x c e p t to p a s s th r o u g h ^ ; ^ herbicide 2,4-D in its 325 parks and recreatio n a re a s. ';-V Vj;'.Park serv ice sp o k e sm a n D uncan M orrow sa y s th at this action co m es on the heels of pressure from enviVVV rrJ ronm ental g ro u p s, w hich cited sp o n ta n e o u s ab ortions V -'^y jran d birth defects a s adverse reactions to the w eed - J4tCk*Her. O ne o f th e m ajor m an u factu rers o f 2,4-D, Dow ^ C hem ical, s a y s th at in 3 0 y e a rs of m arketing th ere ' ' V sp ecified -co st in c re a se s. Gulf s a y s it com plied but that later the council changed th e rules again, inter-'; - preting th e "condition" to m ean that Gulf had to lo w e r' -fV .its p ric e s, with th e resu lt that th e com p an y would lo se m oney during th e quarter. Gulf sa y s it " finds this interns pretation unacceptable. ; :'*.'has b e e n "absolutely n o problem a s s o c ia te d with the . chem ical." EPA is studying 2,4-D. S o far the agency '. * " say s th e e v id e n c e of a d v e rse health e ffe c ts is incon- v elusive, and it h a s no p la n s to b an th e h e rb ic id e 's u se . ^Washington roundup ' * The Ju stice D epartm ent's antitrust division, without any CD- action, h a s closed a five-year-old investigation of alleged im proper pricing p ractices and com m unications in th e 'fT Two California air standards overturned Under a sp ecial procedure to h ear th e petroleum inindustry's law suit against the California Air R eso u rces ^ Board, retired sta te judge Eugene S ax ruled in a _ v. m em orandum o f intended d ecisio n th a t th e bo ard m ust rescind its strict sulfur dioxide and sulfate standards. In his ruling. Ju d g e S ax d e c la re s th a t th e board .... tV -C? adopted th e sta n d a rd s without a d e q u a te p ro c ed u res and without careful consideration of econom ic im -. ' aluminum industry. _ The A m erican Arbitration A ssociation say s it stands - ready to provide arbiters to help resolve disputes be- . tw een pesticide m anufacturers arising from the use of technical data produced by one and used by a n o th e r.. After months of wrangling, the House and Senate have - X ' agreed on a binding budget resolution setting federal Vv outlays for fiscal 1981 at $632.4 billion and revenues a t $ 6 0 5 billion, leaving a deficit o f $ 2 7 .4 billion. It is ^ unlikely that any of those figures will hold up. 1 C&EN Nov. 24 ,1 9 8 0 *'fr'.' S*n..' . - * .-? *** =v ' .'i - ^ oB cQ o 9 ) 8256 !rv*\ ^ns->r.T,*" E lsev ier/North-H ollanlrS i.-.*'? ,/v't - - 7s^ > 2'vT*r' 'tzkLs ~r. ? -*>$&&!! > . io c\? co (a CP Toxicology, IS (1980) 135-144 C Elsevier/North-Holland ScientificPublishes Ltd. C d " ROLE OF THE ENDOCRINE SYSTEM IN THE ACTION OF " 2,3,7,8-TETRACHLORODEBENZO-p-DIOXIN (TCDD) ON THE THYMUS ). f' M.J. een LOGTEN*,BJi. GUPTA, ELE. McCONNELL sad JJL MO OS E C N ational In stitu te o f E nvironm ental H ealth Sciences, Research Triangle Park, N C 27709 (V .S JL ) (ReceivedJanuary 28th, 1980) ) f (Revision receivedFebruary 8th, 1980) n (Accepted February 12th, 1980) SUMMARY Several experim ents were conducted to study the involvement o f the adrenal and the pituitary gland in the acute toxic effects o f TCDD. Adrenalectomized o r hypophysectom ized rats were treated w ith a single oral dose o f 10 o r 2 0 fig o f 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg body weight. The reduced growth rate, the hepatotoxic effects and thymic involution induced by TCDD were not prevented by the adrenalectomy. The pituitary gland did not appear to be involved in causing thym ic involution. In fact, the thym ic effects o f TCDD intoxication were even somewhat increased in hypophysectom ized rats. Treatm ent with growth horm one failed to prevent thym ic involution o r the influence o f TCDD on the liver. ). INTRODUCTION 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an extrem ely toxic com pound which has been found as an im purity in chlorinated phenols and other chemicals derived from chlorophenols. Trace am ounts of TCDD and other dioxins, e.g. 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin, w ere isolated from anim al flit which was mixed into the food o f chickens resulting in the death o f millions o f broiler chickens from a syndrom e referred to as chick edem a disease [1 ,2 ]. T h e re p o rte d oral L D So ranges from 0.6 n g/kg b o d y w t in m ale guinea pigs to 115 fig TC D D /kg in rabbits. T he LDS0 fo r rats is a b o u t 50 fig TCDD/kg [3 ]. In rats given TCDD 5 days/w eek fo r 13 weeks, the no-toxic 'Present address: National Institute of Public Health, P.O. Box 1, Bilthoven, The Netherlands. 135 8 2 5 8 0000 effect level based on liver enlargem ent was betw een 0.01 and 0.001 Mg TCDD/kg body wt. In a chronic study in rats the incidence o f some types of neoplasms were increased, whereas the incidence o f other types were decreased at dose levels o f 0.01 jig/kg body w t [4 ,5 ]. A t higher doses TCDO induced a reduction in grow th rate, progressive wasting disease, severe thym ic involution and im m une suppression [6--8]. Stress induced release of glucocorticoids was not considered to be responsible for atrophy of the thym us. In TCD D-exposed rats, decreased eosinophilia was observed in acidophilic cells in the adenohyphophysis, w hereas the serum levels o f grow th horm one (GH) were increased. These changes may indicate a dis turbance caused by TCDD in the relationship between the pituitary gland and the thym us, either by blockade o f the GH receptor sites on the thym us o r by a disturbed secretion by thym us epithelial cells [8]. To test the forgoing hypothesis, experim ents were carried ou t using adrenalectomized or hypophysectom ized rats. The interaction between TCDD and GH was studied also. 6 METHODS The 2,3,7,8-TCDD utilized in these studies was supplied by Dow Chemical Com pany, Midland, MI, U.S.A. and was 99% pure. It was dissolved in reagent grade acetone and subsequently diluted w ith co m oil. The stock solution was calculated to contain 10 tig TCDD/mL T he TCDD-acetone-corn oil solution was adm inistered via gastric intubation; th e dose being calculated according to the weight o f each rat (specific pathogen free female Fischer 344, Charles River, Wilmington, MA, U.S.A.). T he volum e given was either 0.1 or 0.2 m l/ 100 g body w t. Control animals were gavaged with an acetone com oil m ixture. Bovine growth horm one, NIH-GH-B17 (National Institutes o f H ealth, Bethesda, MD, U.S.A.) was dissolved in 0.9% sodium chloride solution im m ediately prior to injection. All rats except those hypophy sectom ized were individually housed in suspended wire cages in animal quarters 'maintained under a rigid sanitary regimen. Tem perature was main tained a t 21 1C and relative hum idity a t 50 5%. F our to 5 hypophy sectom ized rats w ere housed in each plastic cage to diminish body h eat loss. W ater an d fo o d (W ayne Sterilizable Lab-Blox, Allied Mills, Inc., Chicago, IL. U.S.A.) were available at all times. Dorsal adrenalectomy or hypophysectom y by the parapharyngeal approach was perform ed by the supplier. Surgical procedures were carried o u t at least 1 week before the adm inistration of TCDD. Adrenalectomized rats were given 1% sodium chloride in th e ir drinking w a te r th e h y p o p hy sectom ized rats received 5% glucose in th e ir drinking w ater. Body weights were recorded a t least twice a week. All rats were anesthetized with CO) gas and blood specimens obtained via cardiac puncture. Serum sodium and potassium concentrations were measured by the flame photom etric m ethod. Tissue samples for histopathologic evaluation were fixed in neutral buffered 10% form alin, paraffin-em bedded, sectioned 6 fim ( 136 8259 0000802 ` g thick and stained w ith hem atoxylin and eosin. Statistical analysis o f the 3f num erical results was preform ed by th e S tu d e n t's i-test. yre In th e first experim ent, groups o f 10 norm al and 10 adrenalectom ized D re ra ts w ere given a single gavage o f 10 Mg TC D D /kg body w t in co m oil. Similar groups o f 10 normal and 10 adrenalectom ized rats received com 0 if oil only. Five rats from each o f the 4 groups were killed 3 and 10 days later. i le The following tests were perform ed on blood sam ples: serum sodium and in potassium concentrations, packed cell volum e, hem oglobin c o n ten t, erythrocyte count, total and differential leukocyte counts. Lung, heart, S- spleen, liver, kidneys, thym us, adrenals, ovaries, uteru s, brain, th y ro id and .d p itu ita ry gland were rem oved, trim m ed, and w eighed. Specimens were th en is retain ed fo r histopathologic evaluation. In a second experim ent, 2 groups o f 5 norm al rats received either com oil ig o r 2 0 u g TC D D /kg body w t, 1 group o f 5 adrenalectom ized rats were given n c o m oil and o n e group o f 10 ad ren alecto m ized rats 20 Mg TCDD/kg body w t. Ten days later, the rats were killed, organ weights recorded, and the liver, thym us, and adrenals retained for histopathologic evaluation. In the first hypophysectom y experim ent, 8 norm al rats received com oil, an d 9 h ypophysectom ized ra ts received 20 Mg TC D D /kg b o d y w t. Ten days ll la te r, th e rats were killed, and th e liver, spleen, th y m u s an d adrenals w ere it w eighed. T hese tissues w ere also saved fo r histopathologic evaluation. is In th e second ex p erim en t w ith h y p o p h y secto m ized rats, th e effect o f n GH was evaluated. Ten norm al and 19 hypophysectom ized rats were injected g subcutaneously with 0.25 mg GH in 0.25 ml saline for 11 consecutive days. s Sim ilar num bers o f norm al and h y p o p h y secto m ized rats received 0 .2 5 m g V saline daily. One day after the first injection w ith either GH or saline, il one-half o f th e n u m b er o f rats in each group received 20 Mg TCDD/kg b o d y w t. T he o th e r rats were given com oil only. A fter 10 days, all rats were e killed, the organ weights recorded, and specimens o f the liver and thym us retained for histopathologic evaluation. d results A d re n a le c to m iz e d ra ts F irs t e x p e rim e n t 1 The body weight gain, serum sodium and potassium concentrations and I relative weight o f the thym us are presented in Table I. A fter 3 days there i was a decrease in body weight gain caused by TCDD in both normal and adrenalectom ized rats which persisted a t the 10-day observation period. In fact the effect o f TCDD on the body weight decrease o f adrenalectomized rats was even m ore pronounced. The serum potassium concentration in adrenalectom ized control rats was higher when com pared to normal con trols, probably due to the absence o f aldosterone. The relative weight o f the thym us o f both the normal and adrenalectom ized TCDD-treated rats was lower when compared w ith the control animals 137 8260 0000 M con o TABLE I BODY WEIGHT GAIN, SERUM SODIUM AN D POTASSIUM CONCENTRATION AND THYMUS/BODY WEIGHT RATIO OF NO R M A L OF ADRENALECTOMIZED RATS RECEIVING A SINGLE OR AL DOSE OF 10 ng TCDD/kg BODY WEIGHT The rati-werekilledliter3 or 10 day*.Valuer presented axemeans x S.D. Parameter Normal rats Adrenalectomized rats Com oil TCDD Com oil TCDD KSKed a fte r 3 days Number of rats 5 Body weight gain (g) 10 2 Sodium cone. (mmol/1) 145 7 Potassium cone,(mmol/1) 5.5 1.0 Relative weight ofthe thymus 0.26 t 0.02 5 4 x 1** 147 3 5.2 x 0.5 0.22 x 0.02* 4 13 t 3 134 x 3 6.8 x 0.7 0.31 5 2 t 7* 140 x 8 8.3 x 2.7 0.26 x 0.04 K ille d a fte r 1 0 days Number of rats 5 Body weight gain (g) 27 x 3 Sodium cone. (mmol/1) 138 x 3 Potassium cone. (mmol/1) 4.4 0.1 Relativeweight ofthe thymus 0.22 x 0.0 5 20 s 2** 140 6 5.0 1.2 0.14 * 0.02** 5 31 t 4 134 x 3 6.2 x 0.6 0.34 t 0.02 4 9 x 3** 128 x 5 7.2 X 0.7* 0.19 x 0.03* Values marked with asterisks differed significantly tern appropriate control values: *F< 0.01; *F< 0.05. Significance calculated by comparing TODD to com oil in both normal and adrenalectomixed rats. 0 There was no significant effect on the leukocytes, hemoglobin concentra tion, packed cell volume and the num ber o f erythrocytes. S econd e x p e rim e n t The results o f the second experim ent w ith adrenalectom ized rats are given in Table n . The effects o f 20 pg were m ore pronounced than the effects o f 10 jxg TCDD in th e first experim ent. N o t o n ly th e th y m u s to body weight ratio, but also the relative weight o f th e uterus decreased, whereas th e relative liver weight was higher. There was no significant effect (P < 0.05) o n th e weight o f the o th er organs. The increase o f th e w eight o f th e lungs in th e adrenalecto mized rats is th o u g h t to b e due to a decreased gluco corticoid level in the blood [9 ]. 0000304 'ON TP.n ;ht .7 .04 -.7* 03* jes: =to- :ra- are the dy as 15) TABLE E BODY WEIGHT GAIN AND ORGAN WEIGHTS, EXPRESSED IN PERCENTAGE OF THE BODY WEIGHT OF NORMAL OR ADRENALECTOMIZED RATS, RECEIVING A SINGLE DOSE OF 20 g TCDD/kg BODY WEIGHT The rati wet* killed 10 days after doting. Valuat presented are mean! i S.D. Parameter Normal rats Adrenalertomiled rats Corn oil TCDD Com oil TCDD Number of Initial body weieht (e) Body weight gam after 3 days (g) after 10 days (g) 5 117 i4 9 x2 23 x2 5 115 x6 5 2* 14 x5 4 106 x5 10 x4 29 *4 10* 110 x6 -1 x 6** 9 x 11* Relative organ weights Lung Liver Spleen Adrenals Thymus Ovanes Uterus Brain Pituitary 0.70 x oai 4.43 x 0.09 0.25 x 0.01 0.034 x 0.004 0.23 x 0.02 0.052 x 0.005 0.20 x oai 1.19 x 0.02 0.006 x 0.002 0.69 x 0.03 6.36 x 0.14*** 0.23 x 0.01 0.034 x 0.002 0.11 x 0.01** 0.048 x 0.005 oai x 0.02 IBS x 0.07* 0.006 x 0.001 0.83 0.10 4.34 0B1 0.28 x 0.03 0.28 x 0.02 0.056 x 0.016 0J22 x 0.10 1.29 x 0.05 0.007 x 0.001 0.82 x 0.09 5.43 x 0.86* 0.30 x 0.03 0B1 x 0.02** 0.045 x 0.007 0J.2 x 0.03 1.38 x 0JL4 0.006 x 0.001* 1 Three animal died after 5 and 1 alter 6 daya respectively. b Average of 4 1only. Values marked with asterisks differ significantly from appropriate control values: P < OBI; *f> < 0.06. Significance calculated by comparing TCDD to corn oil in both normal and adrenal- ectomixed rats. Histopathologic evaluation Microscopic changes in the thymus of normal o r adrenalectom ized rats exam ined 3 an d 10 days a fter a single dose o f 10 Mg TCDD w ere n o t remarkable. However, there was an indication o f an increased num ber o f m itotic figures and slight swelling o f hepatocytes in TCDD-treated rats. 139 8 2 6 2 GO0 Rats treated with a dose o f 20 pg/kg TCDD had a slight to m oderate swelling o f hepatocytes, hyperchrom atism o f individual cells and single cell necrosis in the liver as well as a slight involution o f thym us. These effects were accentuated in the adrenalectom ized rats treated with 20 {tg/kg TCDD. The thym uses o f these rats were m oderately involuted. Special staining o f the adrenals w ith Oil Red O for lipid did n o t reveal significant differences between the norm al and the TCDD-treated rats. Hypophysectomized rata 0 1 First experiment In th e course of the study, the hypophysectom ized rats treated with 20 Mg TCDD lost 5 6 g body w t, w hereas th e co n tro l hypophysectom ized rats gained 2 2 g. The relative w eights o f th e th y m u s w ere 0.05 0 .0 2 and 0.12 0.03, respectively. A pparently hypophysectom y does n o t protect against b o d y w eight loss and enhances th e th y m u s involution caused by TCDD. The relative weights o f the liver, spleen and adrenals from TCDD treated rats were not different from those o f the control hypophysectom ized anim als. Second experiment Daily injections of GH had a marked positive influence on the body weight in hypophysectom ized animals, b u t there was no clear protection against TCDD in either the norm al o r hypophysectom ized rats (Table III). The relative w eight o f the liver, thym us, spleen and adrenals are given in Table IV. T h e e ffect o f TCDD on th e th y m u s is even m ore pronounced in hypophysectom ized rats, in comparison to the controls. Regular injections w ith GH failed to significantly prevent the thym ic involution. In hypo physectom ized rats TCDD did not significantly increase the relative weight o f the liver unless there was GH stim ulation, and even then the increase was minimal com pared to normal rats given th e same am ount o f TCDD. TCDD caused an increase in the relative weight o f the spleen independent o f GH injection in hypophysectom ized rats only. Histopathologic evaluation TCDD injected in normal rats caused only a slight depletion o f thym o cytes from cortical region. The liver o f these rats showed slight to m oderate swelling o f the hepatocytes. The thym us of hypophysectomized rats treated with TCDD was markedly affected. There was a marked depletion o f cellular elements from the cortex, dilatation o f the blood vessels, and occasional hemorrhages. The liver o f these animals showed random single cell necrosis and m oderate swelling o f the hepatocytes. There were also focal areas o f centrolobular congestion in the liver. The microscopic appearance o f the thym us and liver o f TCDDtre a te d norm al rats did n o t d iffe r from th o se rats w hich had been given 0 ft*> 140 000C9C6 ;te TABLE III le se INFLUENCE OF TCDD (20 Mg TCDD/kg body wt) O N THE BODY WEIGHT GAIN OF ch N O R M A L OR HYPOPHYSECTOMIZED RATS d. Starting 1 day before theTCDD administration the ratswere given dailys.c.injectionsof al either saline or 0.25 mg growth hormone (GH). Values presented are * S.D. cs. Treatment Normal rata Hypophysectomized rats Number Initial Body wt gain Number Body wt gain of body after of body after animals wt Wt di 3 days 10 days 3 days 10days id id Com oil salinedaily 5 117 6 22 9* 101 -1 -2 et t6 2 i3 i7 *2 4 'y TCDD D saline daily 5 117 1 9 8b 101 -7 -14 id t 3 i 2M 4** i 5 t2" *6** Com oil G H daily 5 118 8 25 9 105 4 16 t3 t2 i4 4 3 :4 TCDD G H daily 5 118 2 16 9 105 0.4 8 m i 3 i 2** t 3** i 4 t2 t5" ). in * One animal died after5 days. b One animal died after8 days. in Values marked with asterisks differ significantly from appropriate control values; is ,m P < 0.01; mP < 0.05. Significance calculated by comparing TCDD to com oilinboth > normal and hypophysectomized rats. it additional injections with GH. TCDD had only a slight to moderate effect is on th e thym us in hypophysectom ized rats injected w ith GH. Six o u t o f D those 9 showed swelling of hepatocytes, occasional single cell necrosis, H and som e degenerative changes in the liver. DISCUSSION G lucocorticoid adm inistration is know n to produce a striking involution > o f th e thym us and a less pronounced atrophy o f the lym ph nodes and spleen :e [10- 12]. The atrophy o f the thym us caused by TCDD dose not seem to result from an enhanced secretion of adrenocorticosteroids, since involution y also occurred in our experim ents with adrenaiectom ized rats. If the adrenalie th y m u s axis was involved in the TCDD actio n , one m ight also expect an ;r atrophy o f the spleen and a hypertrophy o f the adrenals. However, in the `g p resen t studies no influence on th e spleen o r th e adrenals was n o ted , w hereas n in earlier TCDD studies, an increase in spleen weight and a decrease in )- adrenal w eight was found [6 ]. In rats co rticosteroid effects on th e lym phoid n system are associated with lym phopenia, eosinopenia, and an increase in 141 0000 107 TABLE IV OR GA N WEIGHTS, EXPRESSED IN PERCENTAGE OF THE BODY WEIGHT OF N O R M A L O R HYPOPHYSECTOMIZED RATS, RECEIVING A SINGLE DOSE OF 20 Mg TCDD/kg BODY WEIGHT Starting 1 day before the administrationofTCDD the ratiwere given dailyi.c.injections of either saline or 0.25 mg growth hormone (GH). The rats were killed 10 days after dosing.Values presentedare means x S J ) . Treatment No. Relativeweight of the of nts Liver Thymus Adrenals Spleen N orm al ratx Com oil salinsdaily TCDD salinedaily Com oil GH daily TCDD GH daily 5 4.51 0.31 5 6.28 0.34" 5 4.37 0.41 6 5.98 t 0.36** 0.22 0.02 0.10 x 0.01" 0.22 t 0.01 0.10 t 0.01" 0.027 x 0.005 0.023 t 0.005 0.027 x 0.003 0.024 t 0.001 0.258 : 0.02 0.246 0.01 0.292 x 0.05 0.258 x 0.03 H y p o p h y te c t o m i z e d rat Com oil salinedaily 8 TCDD salinedaily 7 Com oil G H daily 9 TCDD GH daily 9 4.56 x 0.29 4.33 t 0.97 4.14 x 0J20 4.99 * 0.24" 0.16 x 0.02 0.04 x 0.02** 0.22 x 0.03 0.09 t 0.02** 0.013 0.002 0.014 0.004 0.013 0.003 0.014 t 0.002 0.200 x 0.03 0.258 * 0.02** 0.242 x 0.02 0.286 0.04** Values marked with asterisks differ significantly from control values: " P < 0.01; P < 0.06. Significance calculatedby comparing TCDD and salineto corn oil,TCDD and G H to com oiland G H inboth normal and hypophysectomized rata. circulating polym orphonuclear leukocytes [13,14]. The experim ents reported in this paper and previous investigations in which rats were injected w ith 10 jig TCDD for 10 to 14 consecutive days [15] failed to show a significant decrease in peripheral blood lym phocytes accom panied by an increase in circulating polymorphonuclear leukocytes. In b oth m ice and guinea pigs, the sensitivity o f th e lym phoid system to th e action o f TCDD is even greater than w ith rats. In these anim al species 142 V o t 8265 000020 OF OF nona liter i.Ol; torn ;nts :ted wa an i to des there was also no evidence in favor o f a stress induced release o f glucocorti coids by TCDD [8 ]. This postulate was confirm ed in an experim ent w ith chem ically (M etapyrone) adrenalectom ized guinea pigs in which involution o f the thym us caused by TCDD was equivalent to that found in intact treated guinea pigs (unpublished data, 1975). M ineralocorticoids regulate th e electrolyte balance of the blood by favoring potassium excretion and sodium retention. An aldosterone defidency present in adrenalectomized rats results in a lower serum sodium and higher potassium concentration than in control animals. TCDD did not alter the serum electrolyte concentration in normal rats, another indication th a t (at least in rats) involvem ent o f th e adrenals is o f m inor im portance in the toxic effects produced. A fter hypophysectom y, thym us weight m arkedly decreased. In our experim ents, TCDD was able to evoke further atrophy of the thymus. This does n o t support m ajor involvement o f the hypothalamus-pituitary-thymus axis in the action o f TCDD. The weight o f the pituitary gland in TCDD treated animals also did n o t differ from th e controls. T he observed decrease in eosinophilia o f acidophilic granules in the anterior lobe of the pituitary gland is n o t in d irect agreem ent w ith th e foregoing findings [8 ]. Pierpaoli and Sorkin [16] have shown th a t thym ectom y o f the newborn mice provoked a degranulation o f the acidophilic cells o f the anterior pituitary gland. One cannot totally rule o u t th a t TCDD-induced atrophy o f the thym us may contribute to the observed alterations in the adenohypophysis. Regular injections of GH reversed th e involution o f the thym us which occurs in hypophysectom ized rats; the im pact o n the body weight is even m ore impressive. However, GH was ineffective both in norm al and hypophysectom ized rats receiving TCDD in preventing th e involution o f the thym us. Since GH did n o t prevent th e body weight gain retardation also, interference with GH action would not explain the toxic effects o f TCDD. As thym osin injections did n o t increase thym us weight and mitogenic responsiveness of thym ocytes an involvement of a reduced production o f thym osin, caused by TCDD is also very unlikely [1 7 ], Thyroidectom y also evokes an atrophy of th e thym us [18]. The involu tion of the thym us therefore, m ay be secondary to an influence of TCDD on the thyroid gland. However, until now, no substantial effect on the weight or the histology of the thyroid was observed. It has been known for some tim e th at the adm inistration of either andro genic or oestrogenic horm ones produce atrophy o f the thym us in norm al or castrated animals [19]. Hence, the acute involution of the thym us caused by TCDD could be due to enhanced endogenous secretion of gonadal horm ones. However, since TCDD evokes thym us atrophy in fetal and juvenile rats, it seems unlikely th at TCDD effects are exerted through effects on the gonads. From the present experiments it can be concluded th at the effect o f TCD D on th e th y m u s is n o t m ediated by th e adrenals o r pituitary gland. 143 ACKNOWLEDGEMENT The authors gratefully acknowledge the excellent technical assistance of Ms. M.W. Harris, Ms. JJD. Allen and Mr. R.E. Wilson. REFERENCES 1 GJt. Higginbotham, A. Huang, D. Firestone, J. Verrett, J. Ren and A.D. Campbell, Nature, 220 (1968) 702. 2 D. Firestone, Environ. Health Perspect., 5 (1973) 39. 3 B_A. Schwetz,J.M. Norris, G.L. Sparschu, VJC. Rowe, P.J.Gehring,J.L. Emerson and C.G. Gerfaig,Environ. Health Perspect., 5 (1973) 87. 4 RJ. Kotiba, P.A. Keeler, C-N. Park and P.J. Gehring, Tox. Appl. Pharmacol., 35 (1976) 553. 5 RJ. Kodba, D.G. Keyes, J.E. Beyer, R_M. Carreon, C.E. Wade, D.A. Dittenber, R.P. Kalnins, LJE. Frauson, C.N. Park, S.D. Barnard, R.A. Hummel and C.G. Humiston, Tox. Appl. Pharmacol., 46 (1978) 279. 6 J.G. Vos, J.A. Moore and J.G. Zinkl, Environ. Health Perspect., 5 (1973) 149. 7 J.G. Vos, J.A. Moore and J.G. Zinkl, ToxicoL AppL PharmacoL, 29 (1974) 229. 8 J.G. Vos and J.A.Moore, InL Arch. Allergy,47 (1974) 777. 9 R-A. Rhoades, XN. Gassenheimer and W.R. Blackburn, Proc. Soc. Exp. Biol. Med., 145 (1974) 987. 10 WX. Money, J.Fagerand R.W. Rawson, Cancer Res., 12 (1952) 206. 11 PJ4. Lundin, Acta Endocrinol., 28 (1958)suppl.40. 12 A. Fein,A. Ornoy and L. Nebel, J.Anat.. 117 (1974) 223. 13 DJI. Nelson, A-A. Sandberg, J.G. Palmer and F.H. Tyler, J. Gin. Invest., 31 (1952) 843. 14 MX. van Logten, De dithiocarbamaat-alcohoi reactie bij de rat. Thesis Utrecht 1972. 15 J.B.Weissbergand J.G. Zinkl, Environ. Health Perspect., 5 (1973) 119. 16 W. Pierpaoli and E. Sorkin, Br.J.Exp. Pathol, 48 (1967) 627. 17 J.G. Vos, J.G. KreeCtenberg, H.W.B. Engel, A. Minderhoud and L_M. van Noorie Jansen,Toxicology, 9 (1978) 75. . 18 J. Cornea, inTJ3. Luckey (Ed.),Thymic Hormones, University Park Press,Baltimore, U.SJL, 1973, p. 59. 19 T.F. Dougherty, Physiol. Rev., 32 (1952) 379. 144 0000310 A io VcJuir.2 4, Nar-iber 3, Scpicmhcr 1930 IlsN U H *-O jl3 NNO 7 5 2 8 0 0 DOW 089236 l'uhli.\hc<l u i i d t ' T thc Au'jnirs af lim Intelnnlinnul AcmU'my t>f J-.nvirmimeutuI Snfely FltllO RS FtciIith k CouKion Friedhelm Krte MANAftlNG r.UIIOR Ira Rosetibluin ASSOCIA'I K L I I OKI Miki Goto U't'i ner Klein Nv Yitl ] A CA D I M IC I' UI: SS . 11 . <i r r>SB 0000957 K - G> b b ECOTOX1COLOGY AND ENVIRONMENTAL SAFETY 4 , 3 4 6 - 3 3 6 (1 9 8 0 ) " ( IO) \ cn o DOW 089237 Accidental Release of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) at Sveso, Italy VI.TCDD Levels inAtmospheric Particles A lessandro di Do m en ic o ,* V ittorio SiLANO.t G iuseppe V iv ia n o . and G iovanni Z apponi Laboratorio di Igiene deI Lavoro, t Laboratorio di Tossicologia. tLaboratorio di Igiene del Territorio. tLaboratorio di Tecnologie Biomediche. Istituto Superiore di Sanit. Viale Regina Elena 299, Rome. Italy Received March 8. 1980 TCDD in atmospheric dust was monitored in the Seveso area between 1977 and 1979 using both dustfal! jars and high-volume samplers. Apart from the sampling site in Subzone A l. sporadic TCDD levels were detected at different times and different sites throughout the contaminated area. Variable amounts of TCDD were constantly detected at the sampling site located in the most heavily contaminated subzone. All findings were in the range of 0.06-2.1 ng of TCDD/g of dust, for dustfall jar specimens, and 0.17-0.30 ng of TCDD/g of dust, for samples from high-volume samplers. I. INTRODUCTION C ontinuous monitoring o f atm ospheric dust in the Seveso area was carried out to establish to what extent air-borne TCDD could contribute to contaminating nearby areas. Breathing in contam inated dust was also suspected as representing a potential health hazard for inhabitants residing near heavily contaminated areas. Moreover it was of interest to clarify the dynamics of mechanisms responsible for TCD D mobility in the environm ent. Due to expectably low levels of TCDD in atm ospheric dust, and to the sensitivity capabilities of presently available analytical m ethods, it was necessary to collect dust samples amounting to hundreds of milligrams. This was achieved using both dustfall jars and high-volume samplers. Some attempts to use electrostatic pre cipitators were performed, but these devices offered a number of inconveniences including poor reproducibility, low tolerance to atmospheric moisture, and special location and care requirem ents to prevent accidents. Preliminary findings have been previously reported by Viviano d a l. (I). II. EXPERIMENTAL Dustfall jars (Fig. I) were 10-liter glass vessels topped by a plastic metal screenlidded funnel with a collecting cross-section of approxim ately 0 .1 1 m*. T he top of the funnel was approxim ately 160 cm above the soil. Samples w ere collected for one m onth or the time needed for the vessel to be filled with m eteoric water and sediment. This sampling methodology enables dust particles smaller than 300 /Am. m ost of which are >10 /Am. to be collected (2 -4 ). A relatively small amount of soluble particles was dissolved in the liquid phase, whereas most Capyngfci O IMO b f AcariMMc P irn . lac. A * riffe * fe itfN M iM aar fa a iw n it TCDD LEVELS IN ATMOSPHERIC PARTICLES 355 TABLE 5 TCDD in Dust Sampled with High-Volume Samplers (Pooled Samples) Sampling site* .A B C Sampling duration (hr) 161 151 161 Airvolume sampled (mJ) 1.58 x 10* 1.45 x 10* 1.51 x 10* Dust weight (8) 2.19 1.66 1.79 Dust per airvolume ratio (mg/m1) 0.139 0.115 0.119 T C D D per dust weight (ng/g) 0.432 0.504 SO. 168 T C D D per airvolume (pg/m1) 0.060 0.058 sO.02 * For iie locations, see text. * s indicates uncertain detection. DOW089246 were pooled and analyzed (Table 5). The sensitivity of the method used w as, in this case, equal to 0.2 ng of TCDD/g of dust. IV. DISCUSSION The data reported show that both dustfall jars and high-volume samplers can be used to monitor TCDD levels in atmospheric particles. TCDD levels ranged from 0.06 to 2.1 ng of TCDD/g of dust from dustfall jars and from 0.17 to 0.50 ng o f TCDD/g of dust from high-volume sam plers. These findings suggest that the different dimensions of the particles sampled with the two devices are of m inor significance for TCDD contamination levels. Moreover, it can be observed that TCD D levels detected in some dust samples are considerably high and, if expressed with the units used for soil contamination (7), correspond to TCDD levels in the range of 10-300 /tg/m3 of soil surface. A comparison of TCDD levels in dust and soil samples taken at the same locations, indicates that air-borne TCDD does not significantly affect TCDD levels in the soil top layer. M oreover, data from dustfall jars show that TCDD levels in th e dust decrease with increasing distance from Subzone A1 moving along the main diffusion pathway of the toxic cloud generated by the accident. TCDD levels found in some samples suggest that some TCDD diffusion into adjoining areas may have been propagated by dust originating from contaminated areas. Calculations based on TCDD levels detected in atmospheric particles may provide a rough estim ate o f th e am ount o f TCDD breathed in by a person exposed to TCDD-containing dust for a given period of time. For instance, assuming a dust concentration in the air of 0.14 mg/m3 and a TCDD level in the dust of 1 ppb (an approximate average of the levels detected at different times in Subzone A 1), it can be estimated that an exposed individual, inhaling an average o f 10 m3 o f air in 24 h r, would also take in 1.4 pg of TCDD. ACKNOWLEDGMENTS We are gratefully indebted to the Segreteria Generale Tecnica (ISS) for ihe helpful assistance pro- 8 2 7 1vided. We also wish to thank Ms. G. Piva Micozzi for her technical help in the original drawings and Mr. A. Lczza for his photographic assistance. We desire to express our great appreciation to Lombardy Region Authorities for all the collaboration provided. The experimental work reported herein was carried out by the Isiituto Superiore di Sanila Rome) and the Laboratonu ITovinciale di Igicnc e ProfUassi (Milan). 00000G7 8272 t7 *- \\ \ \ AGRICULTURAL PRODUCTS . DEPARTMENT-9001 Midland, MI 48640 COPIES TO: I N D E X 14 M. T U C K E R 2 0 3 0 J. G L E E S O N 2 0 3 0 R. F L A N N E R Y 9008 R. R U S S E L L 9 008 R. C H A R L T O N 9008 E. H. B L A I R 2 0 2 0 K. W A T S O N R. M O F F A T T. H A A G S M A H O N G K O N G L. R I B I E R O S. P. B R A Z I L E. R. L A N I N G C O R A L G A B L E S R. C A P U T O S. P. B R A Z I L A. S C H A F E R H O N G K O N G B. M C C R E D I E 0. A. W O L C O T T o cn co cn ro ==--. JOHN DAVIDSON c n e*?e xone CC05332 THE T O R O N T O S T A R S u n d a y O c t o b e r 26, 1 9 8 0 Lr.Sr.'- J -- Cf.l. f 1 V I '-- TJV r-1 '"'.'..TT'i * * ............ *' By Ross H ow ard T o ro n to S ta r . . , > -A ' annually in C anada for controlling broad-leafed, D- ioxins discovered inn 22,,44--DD,, tthhee mm oosstt VV iiddeellyy ..VVw1 eeds and b ru sh i.n . f.a r.m e rs ' fields., along roa,d-- u s--e d1 .v..e..g..e...t.a..t.io n k iller in- C anada, d id n 't include ' w ays, pow er line right-of-w ays, and public p a rk s : 'dioxin TCDD, one of th e m o st deadly m an-m ade .* an d school y a rd s. - chem icals, says Sharon M cK ay of the federal agri A sim ilar chem ical, 2,4,5-T, already known t o : cultural m inistry. , contain dioxin TCDD, has been banned in O ntario "B ut all dioxins a re a problem and the discovery . and several other provinces because of health;- of a t least th ree different dioxins in 2,4-D is a sur risks. .j prise and a cause for concern," she said in an in terv iew . ,v Until now, environm entalists have unsuccessful- T he dioxins w e re discovered w ithin th e last ' ly opposed 2,4-D's w idespread use only. on th e m onth by federal researchers in tested sam ples of grounds of other suspected dangerous ingredients. 2,4-D. A. federal health m in istry scien tist said y ester- -. Until now, m o st' scientists and the chemical in d u stry believed 2,4-D to be com pletely fre e of d_ay- t.he. .d.i.o_x__in,,s findings and a .rating of th e ir dan. -^ dioxins and relatively safe for widespread use. ; * : v . g b u i ^ . f ? ? r f As little as six units of dioxin TCDD lion units of another substance, such as in one w ater, tcraiinl! cause hum an death, cancers or birth defects. F e d e ra l a g ric u ltu re and health officials w on't say which three of 75 different kinds of dioxin they found, or exactly how dangerous they are, but said concentrations ranged as high as four 'p a rts per million. j The dioxins discovery is expected to bring new i p re ssu re for lim its on th e use of 2,4-D, w ith sweep ing im plications for agriculture. "W ell h a v e to m ake some decisions before* C hristm as, because a fte r th a t it's too la te for* m anufacturers to- prepare approved products,-, w ith labelling about risks, in tim e for th eir use during the growing season," the spokesman said. ; T he 2,4-D herbicide is used m ost in western"; Canada but nearly 4 million kilogram s a r e `used* annually in O ntario, p articu larly by governm ent ' agencies, according to O ntario agriculture minis- i try reports. A lm ost 4 million kilogram s of 2,4-D a rc used DOVI 1053153 8275 DOW 1 0 5 0 4 7 8 THE SARNIA O B S E R V E R Wed n e s d a y October 29, 1980 Massive rise in cancer deaths predicted,* EDMONTON (CP) - There will be a massive Increase in cancer deaths as the effects of the chemical age start to catch up to North Americans, a U.S. professor said Monday. Dr. Samuel Epstein said cancer rates are Increasing as a result of exposures to large quantities of cancer-causing chemicals put Into the environ ment In the 19S0s. He Is a pro fessor of occupational and environmental medicine at the University o( Illinois In Chicago. Statistics from the National Cancer Institute In the United States and other U.S. sources show the cancer rate among 100.000people rose between one and (wo per cent annually bet ween 1969and 1976. "Within the last decade theIncrease In cancers has been equal to the Increase In the en tire 3S years between 1935 and 1970," E pstein told M0 delegates at a seminar on cancer at the University of Alberta. 'CANCER RATE UP' "We now have good evidence that we are going up steeply In cancer rates. We are beginning to see the emergence of very significant trends in a disease that Is killing many of us." Cancer kills about one in five North Americans, a figure that will seem trivial In 20 to 30 years when the cancerous ef fects of chemicals now in use become apparent. Epstein said. He said the environment can be cleaned without a loss of Jobs in the cnemical industry, wntch Is using three strategies In try ing to keep government regula tions from clamping down on cancer-causing chemicals. "The strategy Is to deny there Is a risk, control data on health effects and blame the victim and his lifestyle for cancers that do showup." Blaming cigarette smoking as a cause of cancer Is part of this "blam e-the-vlctim " strategy, said Epstein. Recent studies In the U.S. show a " greater link to occupationallyinduced lung cancers than to smoking." EVERYONE AT RISK He said workers In chemical plants, fanners and forestry workers who apply pesticides and people who live near chemical plants face the greatest risk. But everyone Is a potential victim of cancer caused by chemicals dumped Into the environment. "We just have a little more time than the chemical workers." Epstein criticized Industry's use of economics to defeat regulations and controls, using the risk-benefit ratio In arguments for continuing (he use of dangerous chemicals. "The cost of regulation will be seen now. But the benefits from those regulations won't be seen (or 20or 30years. And then It will be In the form of an absence of disease. "The benefits are benefits for Industry. But the risks are to the public or the workers, and there are no m atching benefits." High cancer-death rates can be avoided only by stiff safety, regulations and controls over new petrochemical plants, he aatd. C00532S 6Z*OQO!MOa 1 THE GLOBE AND MAIL T h u r s d a y O c t o b e r 3 0 , 1 9 80 Employers withhold truth about toxics, :MD warns workers By ROBERT STEPHENS Workers exposed to toxic and carci- Dr. Epstein said one of the favorite . nopenic substances a re little more strategies of industry was to "blam e 1 , than guinea pigs, and their employers . the cancer victim himself" by linking arc purposely withholding informa his disease to smoking, diet, and even ' tion about the very real risks of indus his genetic makeup. "Industry tries to ' trial cancer, a expert on occupational deny the evidence for occupational 1 health has warned. cancer." Dr. Samuel Epstein, professor of . He said industry also frequently occupational and ' environmental resorts to the argum ent that the costs . medicine at the University of Illinois, ' of complying with exposure regula told a conference in Toronto vester- tions will result in plant shutdow ns' day that workers who a re exposed to and higher unemployment. hazardous substances " are the throw aw ay segment of society." He condemned the governments of the United States, Canada and Britain for failing to regulate toxic substances He said chemical companies in the United States had fought regulations on vinyl chloride for years, and that their spokesmen had claimed the costs of compliance would be SSO-bil-. ,, . in the workplace. While regulations controlling the use of seven designat ed substances w ere proposed in Omar- ` io more than two years ago, these : regulations are yet to be passed. Dr. Epstein said the incidence of cancer is increasing among the gener al population at an alarm ing rate that reflects the huge growth in the pro duction of synthetic organic chemi- _ lion and 2.2 million lost jobs. "But when BF Goodrich cam e under the regulations in the spring of 1975 -- its cost was $35-million -- it actually began to make money on the recovenr of vinyl chloride, and then, complaining of unreasonable govern- ment interference, it had tlte nerve to raise its prices," Dr. Epstein said.. i cals beginning 30 years ago. One of the delegates at the confer He said the worker is being sacri- ence asked what workers could do to . ficed by government and Industry - protect themselves.from exposure to , because "they believe that economic ' dangerous substances in the absence growth is param ount." And he of government regulation, and Dr. charged that industry was engaged in Epstein replied: "If you have an op a massive coverup to keep its employ- tion, I'd say get the hell out of hazard . ees ignorant of the risks of cancer in . ous w orkplaces." the workplnce. C003327 f^r- - ' ' V* V->- . -sflSjSg^piw.lV\ J 'VfT*- T ' ^ - ^ .*V THE WASHINGTON POST i^v : *; :- - a !z,4-ii weeaKiuer use On All Its 325 Areas .o , VI I 4> V*T . %l UKMybJiouaAn*nHetOUmirWanrtgur The National Park Servi to H a kail next week to the use of the naJ tiem's most popular wtcrikillar, ?,4-P,' farmers and othrr targ-ioale user under several ' inanuhtiurm' brand names, including Wrtdone, Kxtrou, ;v W*ed*Rhp and Brush-Rhap, and to . homeowners Wd-B Con and Fw-_i- - in ih 325 park* and notation reas* ; Thechemical,oneof(liecunsliLueiib . ofthe herbicideAgmt Orange. that mu . prayedinVietnam,is incommoneom- ` metctal use, and to of it are wed ev eryyear nationwide to 1Hweeds along . highways, on golf onunws and an mil- fionsoflawns. Figures wereunavailable onhowmuchtlieParkServi usedna- ' tionally 1st year. Irut some 60 pounds . were usedto control dandelionson the MaQ, the White Hou grounds and otlan park lands here. ' The Pnvironmontnl Protection Agcncyis studyingthechemical, butof-i mula 40, Although it was.one rf the nonxrit. iwnts of Agent Orange. 2,4-D wa$ `the nbov^rsial part. Tliat was 2.4,6* T, whichWasfound tobecuntaminalod with deadly dioxins and Kqjc siihsc- qucnlly hern harmed from most use in the United Stales. ; Hundred* of Vietnam veterans haye. fdedsuit andhnvcsought rranpensefi.?! for a wide rangeof illnesses thev churn 'suited from tlieir exposure tu Agent: Oranga The EPA is holding hearings onwhether to ban all renaitiuu> use jjfg l * Cl -C -- CJ H* s.'. 4. m . 3frr * Jioals then atud evidence of ite bealtit efiheh k mrrvnriuave so far and there - are uo plans to curtail its use. _- Pork Service Director Russell Di- . chtwon confirmed thathr had written a memorandum to all park ttipc-rtn- . "tendenb ordering them tu liait use of ' -the herbicide immediately. Future use da to be Bowed only if the superin- tendenb coovin their regional direc- . 'trail that no aiternative methods are routable to accomplish indispensable weed coutroL'. ; ^ A spokesman far the park servi* Dunam Morrow, Mid (his was "nearly hut OOt quit', a hnn on 2,41), "hid. , it will lull it u&efor nowand in tha longrun. . . it willsubstantiallyreduce its usft.* .i Morrow fcd the action followed ' pressure from eoviWonental gtoop*; manyintheWashingtonarea,wliictiar- : gura that theherbicidehad beenfound to causa spontaneous hmtirina, bleed* mg of fetus and both defects, "its a mailer of Cuinklerable con- trnvrrsy,and theevidenceis inadquat. - to mats any firm judgment," Marrow 1 LJDl Blanchard of EPA's Prsfieid? Division said dioxins of the Agent Of*; knge sort ha to far lievvr been de*. (lectedin2,4-D. WhileIrsta ha\rshown ithat targe d*es of 2.4*D are toxic to )onimak, lie said, Small drew apjirar tohavenufclfMtI'he ogrnryhasa$kd |2,4-D manufacturer; for additioual teat, but conclusive reiulb are n>4 ex*: 'peded fur tvm years, HLwhard said.'. An April fact shret on the fesi.i?aid : KPATicJicvcathe rkksufamend oUier pesticide are higher and hrttfT doni-"" meuted than due* a&orinted with 2.4IX" Bbncturd svid the KPA W tosecanynewevidencetheparker^Kr ' may have. "If ut reire umihing thatmakes us lielieve usjvtronn is war ranted, well art quirkly,'" hr said. Krik.laasen of Friend of tlie Eurlh, oneoftliuseurtnunental inprrsuading DirkeiiMin of (hr.need Kir his anion, said exe-ling literature"is already over whelming" in providing evidence of prutlaiwwialjottion* and ftLal bkeil< ing. "Tlieie'a aleolutely no doubt it'a 0 problem tlicmiral," ho said. fy- r.f tt TT-V mid. "Therefore |D*ctens.ol decided. that it's better Urerevu tliesideofcon* C005323 13 8279 THE H A M I L T O N S P E C T A T O R W e d n e s d a y O c t o b e r 22, 1980 Amputee continues ..Ms fight for :;'a precedent : Story and picture by BRUCE STEWART. Spectator Staff ^ . CALEDONIA -- P e te r Ward lost his arm to : ..cancer earlier this year and has since lost a hid to link his problem to weedkiller he used at ,,'work. But the 44-year-old Caledonia area truck ` driver isn't giving up his fight as he feels a victory would help both him and others who .;(ha ve been exposed to chem icals at work. .. ' In April, M r. Ward had his arm am putated about four inches (10 centim etres) below the ,, shoulder after doctors discovered a malig' nant tumor. Since then Mr. Ward, who works for the town of Haldimand roads departm ent, has been trying to get compensation from the Workmen's Compensation Board. Although his request has been denied by the ' board's review branch, and he has lost an ' appeal of that decision, he is ready to launch a ' final appeal, with the heip of the Canadian - Union of Public Employees (CUPE). "1 would like to be able to set some kind of a "p reced en t with the Workmen's Compensation Board as there are many other people using ' these types of chem icals." he said. " " If we can get our nose in the door and get them to recognize this type of claim , it may "help others." Wages f * " I was hit by a chain" In the upper arm while " "^cutting down a tree and thought I had broken something." he sald. ';" But it turned out 1 ;hadn't, although my arm was in a sling for a r (while. But It got betted, although U bothered [-m e a little in tnc w inter." , , DOW i 0 5 0 4 6 9 A few years after the- accident, he spent i three weeks spraying roadside weeds for the ,,town of Haldimand, which replaced the old ' township of Seneca. / ' He believes the Weed(prays Included the .. 'I herbicide 2,4,5-T, which has now been banned {; in Ontario. It may havtf also included the con- troverslal herbicide herbicide 2,4-D, he s a id .. |; The herbicide 2,4,5-T has been the subject of . J controversy because ft contains dioxin, a n }<extrem ely toxic compound linked to brith .* 4 defects and considered cancer causing. - ............................... li It w as one of twp herbicides in Agent Or--l* f angej which was used to defoliate forests dur- i- ing the Vietnam w ar. But the 2,4,5-T used in V ietnam contained as much as 50 parts per ,, J million, while Canadian regulations limited it fj to less than 0.1 p a m p e r million. * " I was breathing in weedspray some of the * tim e and noticed. J ia t m y sandwiches tasted 1' funny," Mr. Ward said. " I had a mask buf 1 : , couldn't w ear it all the tim e because it was too hot and m y glasses would fog up." * Mr. Ward wants his doctor to search the . medical literature for research and experi- m ental data which would establish a link between the weedkiller and the tumor or the earlier accident and the tumor. -. f Dr. Kenneth McKenzie said yesterday he would be willing to try to set up a computer search of the medical literature to try to es tablish some link between the tum or and the ; . weed killer or the tum or and the njury. " T here might be some link but I don't know, it Is a very hazy area and It woulrj have to be looked into." he said. " I tola Mr. Ward th at if he o r the union were ready to pay f o r the search, I could set it up." .v "The type of tumor he had could have been l ; caused by anything. It could be a virus," he said. " In his particular case the tum or was In '* an area of the arm where they usually don't . ' occur too often. But It might be a coinci- " dence." tr Mr. Ward is now able to c a rry out a num ber "O r it could be caused by the traum a of an ;.:of functions with the hook attached to the ' earlier injury. But short of going through - stum p of his arm . He hopes to be able to re1 ;tu rn to work soon, and resum e most of his old hundreds of years to literature to support 'it. we really don't have a leg to stand on, unfortu- '^duties. nately." \ r He feels he should be reimbursed for the Dr. McKenzie said he hoped to m eet union wages he has lost while off work and compen- i . * officials about Mr. W ard's case and the possi <;sated for the loss of his arm . *' bility of a records search. it- Mr. Ward said he now thinks his tumor m ay have been caused by a combination of an c a r - . . ller inj ury at work and later exposure to weed k i l l e r at work. He says the tum or could have Meanwhile, Jack White, a national repre sentative for the Canadian Union of Public Employees, said tests in Sweden and New York have proven that neither herbicide 2,4,5- * ! also been caused by cith er the earlier injury T nor 2,4,5-TP cause c a n c e r.. j !Tor the weedkiller exposure alone. ** His upper a rm ^ a s .'in ju re d when he w as' He said the onus should be on the Wor km en's Compensation Board, however, to .cutting down a tree while working for the oid ,-township of Seneca on March 11. 1974, he said. prove that Mr. W ard's earlier injury didn't cause the tumor. .- The tum or developed in the sam e spot that '*.was injured in the 1974 m ishap. . Mr. White has written to Mr. Ward, asking him to obtain information from both of his doctors on what they believe caused the prob lem before an appeal is m ade to the Appeal ( 8280:. Board. W orkmen's Compensation Board officials were not available fur comment yesterday. Q Q & SZ n y^' f. THE HAMILTON S P E C T A T O R W e d n e s d a y O c tober 22, 1980 GW1050470 ...uaaywre Peter Ward won't give up his battle for compensation oo<?5qxl ' 8281 I ^ 0 9 0 I WOO ^{\y*yoo\ovi "3 Ouvir\ x Oc.Hj'o- lM ,tCto Herbicide's use injeopardy Killer chemical found in 2,4-D iualuvn mavf.r A herbicide widely used in Alberta and found in surface waters throughout western Canada contains diosin. ."me of the most dcadlv chemicals. say federal agriculture otfiaals. Department tetcrt have found the estrsmriy tosic diotin in some samples of the herbicide 2.4-0. Agriculture Minister Eugene Whelan Mid Thursday. I About 2 milium pound-* of the weed-controlling herbicide is used in i! Aibena annuall*. "If this u true then we're :n real I trouble." Keith Price. head of Alberta Agricultures weed control branch sa:d Thursday night. "There's nothing to replace it. I don't know what the farmers would Jo other than let the weeds grow.*" 2.4.D is used to cotitnd bruad-lcaf weeds in everything from lawns to cereal fields. About eight million pounds of it is used in Canada each year. This represents about 25 per cent of total herbicide use. Agriculture and health department officials in Ottawa are investigating the situation further and a decision will be made on 2.--D use before rest ycir s rowing seavon. The miy Canadian plant manufacturing 2.4-0 ,j Ururoynl near Sherwc%d Park. Glenn Martin. Unirmal plant mahaper. said he couldn't disclose how much 2.4-0 is nude at the Sherwood Park plant because "that's something our competitors would love to know." The Energy and Chemical Workers' Union is conducting a mijor medical survey at the plant in an attempt to pinpoint any correlation between workers* illnesses and their exposure to herhiviJc products. Ray Semes. Alberta Federation of Labor health and safety direct'*, said a royal commituon is needed to etamme uviets't use d chemicals. Me described the feccrd* government method %%f jpprmrj chemicals as a disaaicr.** Mr. Privc said Urtireyal is the viie Canadian manufacturer since Dw Chemicals in Pun Satkaichcwai phased out 2.4-0 pr*>duct:nn ihu summer. He said 2.4-0 is alu imported from the United S tatu ana Fcrope. The popular and cheap herbir.de hat been used ettensiseiy n this country >:hce the late I'Wa . "It's iurpiHed to be impossible :>i have diostn in 2.4-D.** Mr. Price mkI. "unless there's onte contaminant.** 0t r?H?vfv***sy".v>i*!.*_`o 2". 53 Dioxin levels in 2,4-D low-- official By U-i.\N M.WF1I The t.Kiis *f dw'fin found m samples *4 the hrrstvidc 2 A 0 is not as great u Mher tpe\ of the rbemical. .is federal acruuitare official C j n i v o t a press rclu '4 t*ucd a das eirlier. Wisne Omirod. as*wute ydircviur of the department's pesticide". dfkim. c*enp.ired Cdrr.'At kinds <du'sin with pliers "There's atvut ?.*! d.lfercnt kinds of spiders tn C m.ida. home are harmless and **me ire n*i.' aid Mr (rmi.'d '11 1 the v.tme as diosm. *n*.c kind are more otic th her *' Me a d the m#*t :ok rm cf du*in. 2. } * * - 2.C.C D . was mu km nj in 2.4.-D The dmun f*und were much lev toste. Bui dvr>fi*ncot effwuls are continuine to esrhue the *tinjn.*n ind s.il dn*ide h\ nest spring if j^'isrm cm t should he made wun 'he prod'j-l. used tu cunind brna*Mcaf ."ds m eser.ihme from i*ns to cereal field \ s u u u iu million pound .d 2.4-l> is used in CanaJa annodi with I 5 mtllmn p**-inds used :n Alberta Trases *4 i . 4 |) Save ecu found m surface wjiers ta?*ugh'<tn W%iem Cariad i. Mr 0*mrd said !hat 2 W i'$ 2.JD pvlus*s ie:cd ny S s department Uw**cd esci id .Ju*un He aidthat .is far as he know, u's die first time anyme ha found any .li,un in 2. M ) He said leseis u iliosm m 2.a-D ranceJ from fuur pans per million u* f.%< p.ms per Nilion Keith Pre. head of Alberta V?:.'; n itr i *verJ <.*mrol brsrh. cad V <li*cvn't tn"k *hc f.V.erd government's imdine *!! prevent xiv ..fl.cuUv to farmers m Alberti Ifc 'aid :bf Ji*tinv J*v \crKC.t*jif ( anada 15 r* v !*i ?' \ '>* v s sc tk.m 2.*.*., -2.Ca .L*. w.'ucn h i. s*-e-i -n seJ *#ii Nnh dciVsl 8282 0G05322 DOM 1 0 5 0 4 7 3 i THE O T T A W A C I T I Z E N F r i d a y O c t o b e r 24, 1980 Weedkiller has deadly;,chemical * . ' By The Canadian Pren . . Agriculture departm ent testers have found dioxin, one .of the m ost deadly o f chemicals, in some samples ; . of the herbicide 2,4-D, it was announced Thursday. Agriculture and health departm ent officials arc in- *' vestigating the.situation further and a decision will be . . m ade on 2,4-D 'usc before next year's growing season.- T he herbicide 2 ,4 -0 is used to control broad-Icaf weeds in everything from lawns to cereal Helds. A bout eight million pounds of 2,4-D is used in C anada each year. This represents about 25 per cent of total herbic; idc use. Agriculture M inister Eugene Whelan said "These findings clearly identify dioxin contam inants in some, but not all, 2,4-D sam ples examined. W ork is continu ing to gain a broader and more detailed understanding of these new findings. / 1 - " W hen some pesticide products were registered, to- 1day's highly sophisticated testing equipment did not 1* exist. T he investm ent my departm ent has m ade in high-priced laboratory equipment and in highly trained ' scientists is paying off with results like these. *. " I can guarantee the public that Agriculture Canada will continue to' work hard in keeping agricultural chc* . micals under constant review and to .provide answers to concerns that may arise as a result of the reviewing . process," M r. W helan said in a news release. 8283 C 05323 5 )1* 0 S O A r'AoQ THE SUDBURY STAR Saturday October 18,1980 .O 1 -fc* Umonrharges Uniroyal workers .n endangered by toxic chemicals E D M O N T O N ICP) -- The production of2,4.S-T and Workers *1 the.Uniroynl Ltd. pcntachlorophenol produces herbicide plant are being con small quantities of the dioxin taminated by toxic chemicals, TCDD, one o( the most deadly the .Energy' and :Chemical chemicals. ' Workers Union charged Fir- Basken saidtheunionobtain day. ed a copy of a study done last "We've noticed an abnormal year by the Alberta labor number ofpeoplewho havehad department which showed ab tolaketimeoffbecauseofcolds normally high levels of and lung problems," said Reg pentachlorophenol and Basken. national represen dlchlorophenol in the urine of tativeoftheunion. workers. He saidone ofthe2SUniroyal Those two chemicals can employees has uncontrollable cause birthdefectsIfpassed on tremors, another has problems Insperm, hesaid. with his memory and several DETECTPHENOL others have experienced mus Dave Gibson, director of the cleweakness intheirarms. hygiene branch of the labor He said the company has not deportment, said thereportdid done enough to prevent ex- find"some oftheurinesamples posure tothe herbicides. ofa minority oftheworkers in Among TTiS LHi'iillffalS pro dicated higher phenol levels duced at the plant are 2.4-D. thanwe want tosee." MCPA, pcntachlorophenol, But air tests showed no pro tetrach/orophcnoland 2.4.5-T-- blems. he added, and the only ahighly toxicchemical used by potential exposure came from the American military as a absorbing the phenols through defoliant durlpg the Vietnam theskin. War. .** Basken said the workers were nottoldofthetestresults. 'up to." Martinsaid. * .< The union has started a ; He dismissed allegations medical survey of all former :about poor safety standards. and current employees at the \ saying workers are supplied planttodetermine what kindof ;with masks, gloves, work hazards exposure to the clothesand rubber-soled shoes. chemicalsmightenuse. And allworkers trained Inhow The survey will study a .tohandlethechemicals. number ofpotential health pro Basken said thecompany has blems Including cancer, liver Installed washing machines for damage and nerve disorders. It .(he employees* clothes and a willalsolookIntothenumber of sauna to sweat the chemicals birth defects among the out of the workers* skin, but -* workers' children and miscar most of the men are still con- - riages among the workers' laminated. j >.-i wives. ."We notice mat they tend to A NO COMPLAINTS buy less weedkiller than most 'j Glenn Martin, manager of people-- theyjustgo home and the Uniroyal plant, said his company has not received any complaints about medical pro throw their shirt on the lawn," theunionofficialsaid.' * "J*m not kidding, ni bet a v- tt-i blems. survey of these guys' homes He said some monitoring testing had been done by and the would .grow show none of them can house-plants because of f Alberta government but the thestufftheytakehome Intheir .n company has not been given ;skinand clothes." detailed Information of the (In-' Basken said conditions atthe/ ,. dings. .plant have improved In recent *:! "We are going to talk to the year* but remain far fromm t-v * workers and see what they are ;ingsafe. fp : 8284 CG0S31S DOW>050466 THE EDMOHTON JOURNAL Tuesday Farm chemicals 4 Iwiiutafs mi the lot air used in pnhtis mh.Ii as 'No IVxt" strips. luuik' ami p.ioleii ittseitHhles. ami tanate. a ttup* iik v Is ule used <utwifr4 flerlfta run *ns * A ru.i|*r iiinpHiJe. Captan. wlml n still used* safety tests faulty in tin* priAMHt*. iindriwful |4 tests hi III I l.rh*. I huleen 4 those tests have mm leeu tiled invalid Captan is sus|*etid 4 caosiiif' .me As If ir>l ill i ruuth as lUl.ietl (Hinds 4 Captan is u\el u* Alberta ra* h )r.i. Ihe (filt-ul fi*rin* Or. Ales Mmrrs4t. head 4 tin* fu h rjf men! o n mi Lrnrrf fm etnim nl's Iteallh pioles lu loam It. sat Ins f.u |Ik sakls 4 |i< iiiiHU-fiS ihfl Report C *\T le|MftUH`ti! Itjs iHk*itd re-esaiMin.iii.Hi 4 4*a| Studies iliHiC l> Mil, two ilunlx 4 *lult are sii'lm led 4 Iwtt^ invalid W ittv .4 faults lo t vmiIii a I ' S UUh j- fhr poiK iJo fir . 1 irv<f sakts h* I hliisiii.il ltuu*si Ij K*- *l!l I I 4 KiHth- I I . 'ItC lie |.iniKUial *,iis testing riHiipjm _ Ity All.ui Mover V 1 . ' / v . 'tf-.v, 'V Y .-rrvii % V f `l -- &*1 It may eoxl ll.nld.Hlte** l i n t nitlhou tu retest MiNptsiul iiieum als. s^nl lit Mimmwu lite Irthial fiseriiutetil lias t|s u i }|4tlatMi s i far ttt tntcsit|Mtftig the III I \mhMo llll ltts| t'.niw imdet stt.pHMit <4 iIk* U S | ih) and lru|* aditmitsir.itiMt in I'Wb A spnletu.ttt. It4 tin* t'miM'MllMIlhl ptnivelHHt apenes mi iiaslnuphiu s.ud al***nl rtpht vtlett tt'jHMts re shte.hled tmetf tin* ilMMp.|(1 >I'.Ittl |4 lite stopKl.Hlt i ilir U S The Canadian piiseiuuieiit issued a news |kih ihr ( jiijilu n jfil yntetKan n weed l diet nh<n l*e nMinljf ik* trense in Atipusi, IV77, MiitintMj' tl* lure U sks cosenunents Im(( accused the smi.' vchfHtl had iW>t pamv O the pr4!etii Inti did not tay lu ihciiiHak f jm 4 up l o t result* and He felt ik L lif Unit Hn c e ll ere inv4ved mil* ih!k i% ami ilulrt t leil lilr himself h* an* 1 hit summer. Health Minister Miaiiijuc lleptu li.il! pnvtniMvn! l.aJ i r n J on oilier tiMHith. Mr ( Ij i L mm using issued a list i4 91 pcslwitles umlei suspieum H'l> In JppIMte III- ]; .4 III ilieituval known as I'afaipral. tMily after putsm e fn iii tl*r Saslatshewati . *cik.iN lit .S t'H 'ftj, t in re ifj*r tn v tt Wil' dents imutvinp il< vliriMiijS S>\u> < tedu leader K-H f l a i l WJs Jt I.hNlH' in thl* |j>l 'Pltll.f l.i% taidtn faspl<rno with iIkhbs Mnltio.1 4 Lxttmhr was applting (jtvrS flam lA elif iw Imhinc plant tint summer hen site betaine extremely m ii`iU>. She beran suffering from artl| UJ> j* hospital lor n s c rn u ie itl a n d uf*|>itiMi nh'ih I h' I s 4 'arh.inH'iil Iasi Cis4iMin, A S Ieit/t envii*unMi nunister, nays his |^itctimH*ttl `reins im ilc t severe week file,tl rrio rtu ttc Ihe posrrnrticiif n d a iiiM it." . | teiinM health to . nuie uuttullaitl lire with amt away Instil wwk lot i n wards- lire cltentrcal in the plant d<h*r was |)iMilli<tun, A inker at Untnual v lieibkHk plant near Sherwood I'arl *pilkJ mow penlathhiruphciHd Sasiatehewan't Ilavid I'ennun, from Ottawa. rnsifiHiineut it slctnamltu^ drpaiiik-iiI. I)i . wnur tuforiiialMMi <ni htx afnt and J.klet lie w j\hnl the thenik.il 41 hit ann hut pnt ln\ ja iic t Kiel no IIe chemical gi*< in his si in ami. jctimlnip to an l.nerpr and Chtfinkal Workers* Iftm n dtkial. the world** amt it 'jii\| ahimi useless ** While the three victims survived their iuiimis with pevtnidcs. tlere is no long term ftiaKtiicc that their ( \p m n tc o might eatsh up with then in l.ilvr tra it Alt the pesticides ere fMipinally )p|ttm til by Industria! Ilmiest lail*oraloriet. Ah.ml b.ilf 4 tire IU> pcsiiciek now mulct tiispism*ii ate used m Allwita. Carurhan *4fH.d> maintain Ilie firm tnhshm icJ live ralt for dead n w t in loof tcrm tafelv tots. <liliri results were pippled to slum fewer Inrllt defrsts and pemriK iintr.tftnns between l.ihotal**rv ittiintals that wete led iheitucak anil those that ere not I he piiitilem is a massive one for federal pm'Mmn'Hi *4Ih'mIs. wliohave inownalm ul the titualnm f.a three sears Norte 4 the* alies ted i ltciliHJls have leen witlulrawn lo*m tle mariel and M lk lias Iwcn V shmc to inliMin llx puhlw:. O cto b er 2 1 , 1980 in GO C \j CO I iKfcJ-i:i.|or>i A7 iL . I**. L*I ShepJpuanrde tlti Aug *1. | llie prjiliMr 4 lusiny Jr\.nt Ihhii |tjy (U nm .il f\'v<Kli`v lull Kr alkm cj i<n (Ik m o l d in I jiijiIj tm lesi Ksiilh Iohm bhrtjliifK t l> IIk i In'Hik jI iinliisiii. I lie o iliiH m * j i |H ooi| i|CiI h> l l t .i l i t i m l W t l l j i t Monster MmiMfor liepu' amu mm ron'iit vjiI> hi iIk >untiiH i llt.il U i M ImmIi <4 llw l o i v J im c h y i n if fo b - | m*Ih>Ou I Ilu4c*l 1 4 Illinois -- Inf ilw whmJ Iiihc l l i u i i i r th e Irisl * v fr w hmiiImI4c. M Iwi p r o * I m4c lli.il mlh flic lab lioj r i ii l f j fill vmie lime Imt h-nlii'l Ikch icsealtJ 0 C in jJ iin i wfilil tins vv41 I luvc a Itild fouo llm CnUii, n|ioial pnMn leUlums i4luef I Ite.ihb 111J Haic hi I iliikNiiim, saving llul im f.i\| (Ik liifMH'f inm iikf, Marc l.ahnnk*. jioitmine'J hi I1?7 |ImI invesiijMii lul U^'mn ii*ii llic Aiin iMao Ij Ii' Iosh'iis lc*fs. i m Ih m.nlio flic ik'h i irleas* Ifiwii L I ihhI< itnilnaiirg this While I'm pIvjNul i I j i up (Ins hit tni*f. ihc imnc itii|s>il !Ui |hiii%im1 Ik 1 1 J 1M1111 iciiuifi munsweicJ. M i r ^ U i i H ines* *`M i ili le r.H it H i I b r le s tin f! h> im h |K ii* k -iif l.ilnnao. l u l l a h .* assure \ % m ih a l iln * K * U ` U `f ( |*k * l *mI l i l l l ) >4'4M**|S f*f t ills a |'fO U I h *Ms) .i1ilnn:vli mi isietn MOV Ik nii|,*delv faibsale. il lu% lo-seiiin-less |iinU>i vMiviihIv shsi*sIwI Im nuns >eai I Ik ImIhsH.iI lloHesI i-.pi`in iiiir laf lfMf K'lnj |Ik it<4ui, is itt f.ni stv imiisI*fhes sscpinm lailic rule. , Suiils in n js iim m I 4s |*oMh- sjfils anJI sin h irJVHis slnMihl K- s|nf|rl mil ln 11 ii In n 1 imi sMtfjiHi* ViIk< M hi sutt|lv Noijt t4* r n s | hi 4 pii!U tiljiH<ns kp.ifomfii 4 n J iherc ili- i|iK'sinm nf h liiuium pist Hil *`mb f*m b nf'* nrti ln h*s| j n r * HI HIH*. tot S\st|MIS*l^*lsfls Sjfr " f ll>Mij: flies os.4s< him ms jifl 1I1.Melit elist I* Mil p i l n lim:. j I.h I al|-ls ikoun'sli.ilrt h* fins lone on iiMiiin fiehl t**\- I'm %;oiie pip.inl li* K Ih v iIi.ii the |mI< lhll rsiKiHiHtf *o. iml Ik lb; *'nnH*." I il hi>h HisifHiu^ ibt tl is (lie **%i'J'Ihhi Hi llw H ere's rH uisnleiaMe liiciaiuic jlmi fault* 1 Mi(lul-i4-mtcfcsl hi leslir.f.4uless*ess. s*tjt|icssi nuiiipubiNn 4 test |.ii4. 0 tie. m iln V S Wi iMib t .-uijiIj 'i rstnunns k t i 'f 4 ||< h u m h %J?Kls. Il' ImiJ In In lie; |l u | c u c nnl ailed lh.*s* iiMliers !!< riMMiwmflfjf pri(vfN<ii rent w the I?? irseateil llul II t k>|i'f| ino* lesl esulls flinm time Mhtr liU if a iM iio In s.tiise 4 sis|nsnm s | b j t |Ih H is U iu n k tM if hlSi4 iels ihs*hI. Ihil eseii if 11 uric pim rn Iiih' llul imli InJw hi*ir-l is imiiiis|H,nilist iIh* I.h I llul iIms inn Ij'iJ V J the Hsiiii* *4 imnv lh hi llll pcsin nles 4 * ni a?H`( 4 n4J 1 .n1 itMilel ts|i.tfUs Itceimg *h hs Mr l 4rln*i jssitfes hh- (ImI Ik ilfh 4ml Welf. "im h^J leepi HeimJ i*sf tins nuilrf 4 ml ihefs Hhnlt utiflii mhi'M'Is 4flesl iIh* brail t jf^ J u ils ** | lini'i l*nihi iIh* siihthiv 4 kUlt IIK'Ml II il I'J Icel Hxii rejssutl il I ImJ h' Ih*4iI lb . bhoriMni. Ii.ut 4 il,c h tlt'lal Ik jIiN | 't4 idHi In Vi. i*u IV II M l | ih i| H n Apn *liiii< ( 4 nhnli Ht.'les iIk !immis A m i nh.il in'slnnlrs srislrJ vn tins minis 4 ihJ lhl Itie kxisum ni.ot*', tun m ilie basis 4 sahiv, Imi m hImi ke < **l*ri -s*nnnK;s.** I ooos^r? THE EDMONTON JOURNAL W e d n e s d a y O c t o b e r 2 2 , Doctored chemical tests raise questions about yide-ranging dishonesty in labs (serfa P3rv r /r ii i t rh e irifw t/ m 0 ir n r x #y ina r i i f t r t , 1 h r f i r . i t a p f ir it r e H th e J o u r n a l J'lMMfirM'. O i l , o n r.i.c A t 7 /ir i h t foil ll lly .Mian M ajrr tndiiMri.il IlinleM l.yhnfalini(i (MH`| h-n K tn mi cniharrawnitiil in both ili< O a .iilu n jikI United S uici fiivcmmcnit and raises i|uiAiinni i IhniI the way in whit'll pesticulct are approted lor inc. When it wat dt'cnvercd in IV7h that IIIr had been doctoring both lone icrni and tltm llcrm Mfeiy Mudict on pcsliitdc* trial internationally. the U.S. f.oxrnmfnt lalen aback. 15 T in -.till mi operation hut only for r('(*.iliMifi*A of the iu' jxti t;ifdv i o n 1 n of die i n r three laht hae been nW and a hoyrr h th o ng vnjghl Kr ll*e remaining lah 'in NiHiltlKtH. III. Ilic lah in alw> fa itig immcrinit l.iMiiiv 'I Dr Alci Mormon. head of the Canadian g%rinrHiit't health protection branch. admitt lliat HIT Jwat ihvt'vtnj: rltOMitc ImK'iljr J'lm h t' on a p;ind Kale for live latl *dna*le. "Hut m o IDr the onlv company Jtjmng thit1 1 hat's (lie mtlilm3ir.k f.ip Dr. Mornton. " If ini' iiju if a rogue c*nipjiiy whivh for some iraton went trm tlrd linn )oi can ideal with that. Ilut if HIT is the lip ' 4 llie Kiln-re and llierc it t wnlopre.i*l chn.merv gmg on in commercial Ijltor'alonc* lliert we *hac a very vrim it pinMcni where *vhi cannot Irutl inhumation given by the private w to r to cnvetnmcnl supporting the wt of rhcmicalv T. **We don't know how tug tte problem is yip Wr've Iwvn ti vine hi 'concentrate on IIIf hut there %% ini fikuihl that we will he going ha*k to h*nk at ol|cr laboratories to Kr Whether or not we have monkey 'Imsitictt going on there.** L' Since the IIIT affaii began, tire fUS. Food and Ding *AdniinLitra|n*n has initialed a whole inflection cycle which iftH'ludes data audits am! nmole 'fstlHHi of ovornm ial letinc labt. Hn| in Canada. |l r v Richard Trcntne. co-ordinator if Agriculture Canada's crop rproivctMn resrarrh luamh. maintains Ihr citMing phw.es id Vcgntraiion it adc|iiaic. t MUw you pH into sitf<n I event #1hI d data yM dwln'l find 'j n m d f r he says. "The cutting /re tew procest isn't cavalier.* Under that priwctt, pesticide .posliKtt are etam inal by I.Apmullirrc Canaria, lleallN ami Welfare Canada. rnvinuinioii \Canada and Fisheries C'ana.U 'Final approval m i t wl.'d Agriculture Canada which itonn'l ,nrvetviri|y hate in a d fin health Mcparimcnl inptil. M n mmcooimmml cnunlrut. tin- principle m pontthilily for IIk safely of thcimcalt hat fallen vpm yt 1980 U U H lU D U ^ t ) / llr in:MiifrHlnrn. win then tuhmiit 1*v` dala lo povctntm'olt fK apprntal. (m oim tcnit ih*u'lifnIhe li-sltur, Amf in ibe t . w nf lit r* II il< (jiM ilian ftivrintiKOl ere %rm*p>o 4 ibe f. 0 iIj I.i *'ll j *hi ean*i irml iIk piivatc (iliir i!*`n ili.il halt y*u iiiMi % t i M I i m l i pohnr JriiiHmv" ays |lc. X|*mmi|. " |h c IiiM ihk it in In dfinul ilKinir)l<, Nil uuf mh H'lv ruii 41 cIh'imh.i I* |l< mh' m iw l k in I.II iIk*icMiue Well, ila-rc't a l*M I $ | millMtti every time A nr** t brumal omr\ up. If *c ! all rf llial tv'liujt i*l ((Ml luniliei| tlH'ttmalt a tear iIha vmimc tooling al a bill (<1 v v n il lunilfr*l nulli* if!fcitt 4 year <H*vftluucult Inu'l Im)( ih.tl litnl nf tmmey. **f Ik ibinl rplinn ft In ailil IlK p*iple hnib il. p* K id iiiln i k n l. ilH*aii*HA, l<*V o v iy cel i*i wltal ik * i< tli*n|t mi liny rio 'l d i a l mi V1** a:i| Kv< a* ay ill* d." ftitl federal N lir irtiK ?mut*t tlr Jhu |Rc|in;t l :*nl| <fAti1| buv IIk U l lh.il (Ik pmt'iniiKHt m i l mu iH im , ,'l|irri,'( |*vt ** Hiiini t'nitfKlt f itdvretit tm<lteil heir amt |Ik t h l i a are pirtt) hipti," Ik ta tv lie iIk ic jIh if inHibpv enifvt. pirail aoi" iIk *KMnr. Hikh miM eteimiie .iriiiiillHnl (k m ira lt usol in iIk ihffvrenl rrpnnt. Mr. ilc Imak w n there are to m. mv Mk*ri inn*" niftciining IIlf bit llial Ihc ctHinlrv it mmak f.iiruert .inti i*rr emMi*mncd at letting r.f(*imlt. IIk Satlnlihcaan rniirinmi'nl (leparlmcnl it lie nrilv prmiK.'Ml sr/iKv llial't part pfe.vtitrc **t iIk {`IcmI pnernincnl fur rw*e iitf*maiin. |)r Davnl lYniuhn. iIk -miiinimcnl department** x n u n tie.dlh eniitullanl, hat asled A;nulMirr ( `aada fir liealdi rep*i* (*fi |l l |' .tpprnteil th ^rw alt Viiatat. Ikhlnfovm ami peda* lilnrnphetud Inti a* Inltl in . *p i ih.tl ii(li*iiijiMfi I* ibe HMtt((lai'btrvt. lie vv* lic't p.iiliuil.ulj tnmefiied jbt*d Vtlavat IviMiiy a Mi mi4m fanner hIh* at h.ntilhii|t lite thrum at Ibit tprinf d|fd sIhkiIv afit'^t.iitlt fir* U I1 1 1 7 failure , In AlU ih . ItMifomueid Mumier Ja* I I W Immi v iit hv``t (indent |i* Id iIk fok'ral piieituncid titaitle "hal t t.df ami hat n a l in i k llll affair. - 'lo pull o r n i h n e *?f i k tb eltrt M he a birhH un*:il.r ifiMif tnitn uiifi iv in i'lcm c in h .x l it up.** satrt Mr I iv Vmii le f itirh :i. brad 4 i k pen (!*( ptnli'tiu*i (ml fctl t**fiiii| Inac.tb. N4t\ AUvtta'v .nrti!tirr (b;piilmrnl i} i^ n `l hate tin* Miff. I.ih.*.l*it*\ i* nnihiiiMii ii (if\ ihi| ile |r ti\ v'i|uMCl (a ihn u r "If c pulled t*iK rf ltese (k w H sU i4f (Ik m u l l nehl mm, h n iir fnr iiil.itvc, ihe*t *tihl be mi r.tpetrol crop I k flertht a*uiv Km H*it,| ilt-NiMi o I nr fapcsrrrl ml i'ilm iA tt pl tnls ft l k pmtiiHc imniU bate In k 'bul ihf.'.'*he at'. " I I k m l <4 IIk v*hl it miaIi ith lht l*> It't IIk fnb'fal pnefaiiK'id t irjnsibibt\ arul r hate MtafitkiKe tn llnm M Mr (rirrll Atfdlltt ib.ll flK A lk r lj ptcrnnKAl h it m* (.l-.-a 4 iIk pianiilt nf pr'liifr' n i tn ihit prnviate 411*1 *bi'f (*\rin*'MI H futalt ailmil ib.it they b* i Vn.. fu huav people p i rath finm pv'iKidet c.Kh tear Or Slanfev lircvnbitf. rb-wni.in (4 iIk O ni'ertii) 4 A lK fl.it health <lcp.itKirt. it ciHKt'itKil aKul the east r u n t lit Ihetechenmalt lie oat At Ihat nre.in*phit|li(te pcMK*let. mkH at lha/mui ibth i\ *n the 1*1X Iimi. A't 'brbtfy nttlifird n ene f..vt anil Ihii ihe pur h.re *4 f k v pesltcnfet i*er I k ' c*iiiin arc riila'ulcu'lv c.nv. He A n ihe teller i4irn lu t mi imlelee of ihe p n en et 4 the ptwflKl. In ci*nh.tl lint, the pr.tir< rurnity appty'fU ac .fe*HultiM.*| ikiiiH iib reci>Hiint *lt*vh ill f*ve tkalert m o*n|h*te * (itfrip w J i'iH'r riaif'C 'n peiaafe tafeiv. (K*tmeal\ ha'C l**%*n clat'ifinl uiukr ibllrfcal Kmliaft frf4iihnn ilmr p*emt ami faimert ill have to |n for kmik 4 iIk them kalt l k * me. (hitler tl*C^ it-r'tltiHtu. *i *!il K iter bipl.iv |*i:vitlt MMlls 4 fHs| pi.bul. .|s i ijsi* m V'mk *( | i| -i Ii*e ll il! I*e .!* T II*n. aa> | if *h| e mhI* . ff..* ft > tin bit|<* l*'-|`itc it it V*I ill'- a;i 4 fvri'k *bf i* rV (#.. si.in i 'if( mitt i f.\ lit* fall "lVf|4e b i.e h t n t e V 'H n p t n r ii* .l'**il p e .iH * > b s t t i e d s'i*Mtti (* t e . b-'iv i. H i ft i*it Iterme ihriu." fun M tK'iiM . U rfi'in i tip'r rb AlK rfa f a-.ii*nia p:l* .!* ilirmital* hi imi h f.niiH f hs In si. hit aim r hi huts K i'utal. v - k h e m*f.*i ireful Wh - t f .1 M..*kn. ?. iu l.lltllt'IS IIII*A UfllHA' tun filu**M*n. Ill Utt iS n i (Ik \ i* tase in Matnloha hA >en| n (|in`itf<flnr<' li I lk f U fan a tlm r oft-* I* i r p t l an* Mel: l l x t 'te df fr.| If.*u ) tkuiH tit |h e *|ie'SHatiie eat Hit t n i Mat Kd vtf^r he'* mi r*pa*e. Il.m t k'alline, ipA nm .m AJhrrfu't (firn u aa larri |ii|if.UMa. ta tt hit pitHip wi I.UUK'fV M use pMNAlei v ih ^it'tH* **v'.awe iV.'-re * *i udi4m.u*n *%the hnr (* e*f< 4 lire b `nut .(Is *To-.iall's are k i i ev il *i rIan*aifl**aumiuie'iritrnHr ham in ihe him 03 W CO *\ * 0005318 TIIE E D M O N T O N J O U R N A L W e d n e s d a y O c t o b e r 22, 1 980 0 0 IN 0 5 0 4 6 8 8287 /a LI C^ ould take some years; Lo know for surehow safe agricultural chemicals really are 1 1 %A i i .\ N M m : K (/.<.! in .iu rr. / Il vili he al busi ihrve ve.irt hefore 4 fiJcial (vrrnmcnl team 4 lnsi:ih$i%ti t*an u> hclher liv* lofiiimtnly u \cj agtnullutal chcmtcali i u tale lh*tven ihen anJ imiw, th tniiuitogitiv iti ha*e li ptmr ter fli>tj*.iiiilv nf page i4 faw data %ui*phed hy Industriai llhtuti l.jlkiriiiKio |IH T| 4 Nmildutwil. |ltiiiH \ in an effmt lo iMOIain hitli lu'Jict are tahd ami wlmh vtudies jre u h . " W r fiH iiiil flaws in h tilli vhm M e rm jn J lo n g -tcrm studies." u y > l) r . A lv i M4ftsifl. heatl 4 lt*e federai y m v in m e ttr h c a lllt prtHvtiMM i h i j i n h " M igln ni*' e v .m i'I ju d jrc h e iltc r ih < ilie iM it il jr e vj/ v i*r u n ta fe " | * i i m j mi, ile t**sH iili(tsls d i h jv c lo j* i cf j Ih h ii v i timlie% dune hy H IT . A lle r e v a m iim ig .1*11 sI in I icv, Ite u lili depar im e n i 4 lk ia ls I u t e ritte*! ! iln iits *4 tltc tn in v a lid . 1 he em m vut Hjv h ln iu < * li'$ h |> *n s ia li n** ili jd ans io a d d ano ther l*ur as v u h i a> ll*e> san he fo u o d llic y i l i a ll he lliO - le v c l w ie n ittis. "W r he! lo H t il a giteti jmnt.il is follo ed thrm;l a slntls. Ik'IIk lite pruUvid lr Ihe slinls j |**ll.trtl. Il a 2l*iiH*nli study J iiHitlu tvd. J tJ il carry hi th.it luig 4 as il nlv H mmiiln. or IS Uhmihs.** says |>r Mummia "f a n y*u acimml 1*4 <leal aninuls? Smiielime e lm*l ilul there ere m*er ammali al th end *<l a study Ihan ai lle Iv^immij.'* "Ilan*4 ll*es nnybi Iu te Imie ihe *tudv in pari, ilwv onv.ht Iu te nude il all up. ihcv ma lue ihaie Mmi a hllrreiti a) th.m iliev jnI lliev luti Imic ri ll*ev 4it'it v*rm I* Iu te h*ne (Irete klMthvs he le* Itine llian thvy ilaim " Ih v ii*ihat III| -a|i|irt*se*l i IhhhuI* are risei! ini *ur lr fite hillnm lidlais **lh 4 products sttltl in (hit oniaiiy cash Vc:ir. Ile sayt until hit Ir.im none .iIiniI ihe Mir Ij u . ll*e ilcpailiiKUl Im i In l*< careful llr.il **e iJini' i err to leniti of |mhltc udsne." " 'Ve Iute ititevitlerH'e ( IcimniNirale that these pesinolo represent a Inullli ha/aitj Iti users tr as rendues in iumI,** %j \ s Itc.dlh Minister Mtnmpie Mejsw. "If esiliente heemttes available llt.il ll*ew phNiKl* lo repretenl a health ha/jtd. immediate avliiHi tu prutccl Ihe ftulrltc will he ialiti." Ilul neither hit. Ilegin nr any *f k r i4fnia|s can vouch for long-ictni health eflvils. Ami until they van. lire leilerat gmeittmeni ili |*eml ih*ivinti i4 ihllars. in athhlurn lo frill.M*! r-penl already. in t learmg tip ihe situati*et. RipU em cnl ludici for Invalid HIT lata ili bate lo he i`nn|uilv<| hy i Ic*mhjI manufacturers anJ tome of illese Indies will tale at lung as linee >ort A lifetime study on a rat talcs ahonl l*t years ih antuher year analyzing lite lata. *ays Ih. Mitrrison. If you're using tuonley *r hig> il may lake finir or five years. IVlailv ahtHji b*m the lesis are fljcd remain vleuhy. Imi Dr. M*nritn pfi*i*led a lew samples for aglKullotal iheiimals used in Alheru. I*tih*ram. an esleitsivvly tinsi hcihrciile, as lire iihfcil of finir Mil simlies. No ngoral data no three Imif-term siinlie. A ln-\ear sluily iut a d*g as iiivjIhI. I mlostilfan. a ntmlerately ostsl ominule. Ihiitivn MU' slinlres hme. fmr iMv.tlnl. in salnl and seven III*: goveiitnienl has m* inf*inMiii*o mi t'elil n**w. feijtidngv Mmln-s |slulv of unmstvfsl and rrprmliKtise studies mvalul. I'apian, an esienvively n*nl fnnfunle liioMeert IHT nudivi h*oe. 1.1 arc imalnl. deplaecmriil siiuhv.s under *av fi*r uiiM inpn ilmfiev for ran and mne at vil a a leratohigy reptaccmcnl timi y. 'Ito-her. Dr hti*rrissn viys. ihrre o r |'i.d..d*t , Ds*i fiamiilaluHis lh.il restili fimo IMI In um als on the n u ll cl ut Canada, and r u h fHhmtJll*l| tan Is* uWiI in a immlicr 4 produits I *1|.ir^ tv a Ini 4 *h*` iln'nni.iS under uspnimi hy the fcilcral govsrmucm: \Mphaic, ,\l.nhi.*r. A!.map. Alar. Allid.sb'*#. 'm uso. \ 111*4, Atr^zine. Azmlnn. Ilanil'ns Ihurina.ienus. I.jiliail. |Hei:**s. Itinapairvl. Mi.*!*..lr*'M,m lt s. I apian. I jpijf.-I. CarKduian. i. irlii*mur.m. ( hl>4**|,ri'f'hjHi. Chhtrpvrdiis. ( l.l.aoth.ih'iid. ( tn ln n . ('vana/inc. Ispra/m e. Mulh:il. Ih ln iv . Ihsnndiphjm , Ihahf.ir. IXdljic. Ih.i/irim. |>iht4ii. lSshh*hnil. I>ifcn/v|ual. P*miJMim\ . llUhwh, L)m|UJ|, |-.t.K'|.*M.*. I n ib iti. j I inl. il. ill. j I iIu.I jic, I.iIihmi. 1`inJt ./>*. I .......... I I vmlr.illiitiH. I rnwIfiHhiiNi, I cnlm 11.>lr*'.n!r. | Kii,Af.i'.. l iJptl. I iHiiKlmjK . I iUplHiv,. <iltpl>iunc. I l jn jili. M iij/m .'.i. . I1 / . . 111. Mi'.pl*n. Mri.ihf.nnri'Hi. I NIilijimn). 'pi*.. Kltfltml.ill'. Mtft-.h MciIh-p k iM. .\ltfiiil.Hlfc. Mi I!.Nm.*i. N*'itf*. Nh'iiiintf J |.. 0*i.ir. I ) jn i\l (l.\J.*iiici<4i MtflHpl. r.rj;i.l r!>-i> I I'tfimcp M. l*cnl.M'Mt'*fl,"*l. IVimv'li.in. ri*toiitf.ltrluii. ni..\plumlin. IV! ..> |*,4w.ii. I't*Jiiioit'. ri*im*t*n. I'. *j'l' Jill. | >t.4;ur.lin. 1'nT.Khhir. I*i.i'.ui. I'u ti'iiin v Siiu/iiie. Sjiii>*tf. ............... . I ( M ill. Ttfilul.. ltfitiiil\lj.in. I . ih-A I ill. 4jti*'V 1 ii.illjlc. r.i.J . Vjp.*nj. V.'i'j.ltfi. Vvii.ki. \ i l j u t . fil -**.*.* 0005313 AH 8288 B2TSS5!3 0 ? S U B 5332 KCCTSfl 2,4,5,3 and 2,4,5,5s1 Banned On April 15, 1980, the Ontario Ministar of Er.yi.ror.asnt banned the use of the herbicides :,4,S,T end 2.4.5.TP. Studies have shown that the auhatancea can cause approximately six weeks after spraying occurred in the area. Swedish studies have shewn a link between increased levels of asnear end exposure to the eheeieals. |; irreversible health effects. This ban fbllovs slnilar bans in the USA, New Bruns wick and British Columbia. Other provinces are considering whether to place a ban on its use. The residue dioxin that is left ta- hind can get into the food chain n d cause prolonged exposure in the gtnei-1 public. I .Uses These cheaicals are used extensively as a control for broad leafed weed and bush and hardwoods. They are sprayed on the Action Required j. Merever sprsring af herbicide* j conducted Insist on knowing the type ef j chemical that you are using. Ask the i following questions: b sides of highways, on hydro right-of-ways 'and in.forest areas. - CUPS Dashers that nay have possible exposure include Hydro workers, nunicipality workers and school beard employees. The justification for this spraying is purely economic; spraying is cheaper than cutting. 1) M a t is the name of the chamia), . ' both the generic n e w (this will indi- r cate the type of cheslcal t.g.' 2,4,$,T and 2,4,S,TP are the generic nanas) | nd the trade nans (ellvex is a covca trade nana for these choalcale). il) Obtain the s a w of the wanfactuar. Municipalities, Provincial Governeants and Hydro authorities are the larg ili) If it is confined that it ip the above cheaicals, then refuse to uso rifs. est users of those chemicals. lv) Report all uses, and/or all aracs Health Effects whore it is stored, to your union. v) If you have, these present at you; The problem that exists with these worksite and they are being sold or cheaicals is that after spraying the sub stances tend to decompose very quickly. They leave behind however, an extraaely toxic substance known as DIOXIN. transportad elsewhere, find out where end report it to your union. vi) Mort there Is any chance of expo sure, insist on protective clothing, Dioxin is one of the w e t toxic fdbstanees known to nan. It ie estimated that one-twelve hundredth of one drop of dioxin is fatal co a human. The explosion at Sevcsso in Italy caused dioxin ta pollute the surrounding countryside turning it into a waete area. Military personnel jrtic were exposed to it in Viotnaa, where it was used as a defoliant in the jungles, are now experiencing aany health probleas. self-contained breathing apparatus and decontsmination after exposure. vii) Report any spiover who ie tuiethese wterlais in the provinces eha.-e a ban exista, to the Ministry of Labour and the Ministry of the Environnent. I NOTE: All reports to local unions should' be acted upon Info your Staff R*p.*a- tentative and the Xatienal Office. Can- ' Studies have shown that whore there la exposure to 2,4,5,T and TP there is an plain to your provincial governane. increase in cancers of the ausde and of 2, 4, S, T and 2, 4, S. TP ARE HEALTH the tissue. Reports from a town in Oregon indicate that there was an abnomally high HAZARDS THAT MAY EFFECT TOU OR TOUR rate of Miscarriages among pregnant women CHILDREN - DON'T USE THEM! AN Oehbsl OF Fu*-,c CsnFk4V*JCS SB -8289- w Mm,a i ^..w r* -0007318 8290 DOW 1136192 E v a lu a tio n o f 2,4-d ich lo ro p h en o xyace tic acid (2 ,4 -D ), 2 ,4 ,5 -tric h lo ro p h e n o x y a c e tic a c id ( 2 ,4 ,5 - T ) , and 2 , 3 , 7 , 8 - t c t r a c h l o r o d i b e n z o - g - d i o x i n (TCDD) t o x i c i t y i n C57BL/6 n ic e : *NJ vn o O' R ep ro d u ctio n and F e r t i l i t y in T re a te d h a le M ice and E v a lu a tio n o f C ongenital M alform ations in T h e ir O ffsp rin g James C. Lamb I V 1 , John A . M o o re1 and Thomas A . M arks2 , 3 N a t io n a l T o x ic o lo g y Program R e s e a rc h T r i a n g l e P a r k , NC 27709 2R e s e a rc h T r ia n g le I n s t i t u t e R e searc h T r ia n g le P a r k , HC 27709 3P re s e n t Address The U pjohn Company P athology and T o x ic o lo g y Research Kalam azoo, M ich ig an 49001 N T P -8 0 -4 4 ( DOW 1136193 T A B U OF CONTENTS 2lS* A b s t r a c t ............................................................................................................................ v I n t r o d u c t i o n ...................................................................................................... M a t e r i a l s and Methods ........................................................................................... 5 T e s t C hem icals and P u r i t y ....................................................................... 5 A n im a ls and H u s b a n d ry ................................................................................. 8 P r e p a r a t io n o f D i e t s ................................................................................. 8 E x p e r im e n ta l D e s ig n ..................................................................................... 10 T o x ic o p a th o lo g y .............................................................................................. 10 F e r t i l i t y and R e p r o d u c t io n .............................................................. 11 S t a t i s t i c a l E v a l u a t i o n ........................................................................... 13 R e s u l t s ........................ : .............................................................................................. 15 F eed Consum ption and Body W e i g h t .................................................... 15 O rgan W e ig h ts and H i s t o p a t h o l o g y .................................................... 15 F e r t i l i t y ............................................................................................................. 26 T e r a t o l o g i c a l E x a m in a tio n s .................................................................. 31 P o s t n a t a l L i t t e r E x a m in a tio n s ............................................................. 36 D is c u s s io n ....................................................................................................................... 46 B ib l i o g r a p h y ......................................................................................... A ckn o w led g em en ts....................................................................................... 1 52 57 CCOuAiOS i QC OC Qo O UOW1136194 LIST or TABLES Page T a b le 1 . A n a ly s is o f 2 ,4 - D Sample f o r D io x in . '............................ 6 T a b le 2 . A n a ly s is o f 2 , 4 , 5 - T Sample f o r D io x in s ........................ 7 T a b le 3 . 2 , 4 - D , 2 , 4 , 5 - T and TCDD C o n c e n tra tio n s in S to c k Corn O il S o lu tio n s and P ro je c te d Dosages in F e e d ........................................................................................................... 9 T a b le 4 . F e r t i l i t y and H a tin g E f f ic ie n c y i n T re a te d and C o n tr o l C57B1/6 M ic e , 8 Week T o t a l ................... . . . 27 T a b le 5 . E f f e c t o f 2 , 4 - D , 2 , 4 , 5 - T and TCDD on F e t a l D e v e lo p m e n t, Group I C o n t r o l.......................................................................32 T a b le 6 . E f f e c t o f 2 , 4 - D , 2 , 4 , 5 - T and TCDD on F e t a l D e v e lo p m e n t, Group I I .......................................................................33 T a b le 7 . E f f e c t o f 2 , 4 - D , 2 , 4 , 5 - T and TCDD on F e t a l D e v e lo p m e n t, Group I I I ..................................................................................... 34 T a b le 8 . E f f e c t o f 2 , 4 - D , 2 , 4 , 5 - T and TCDD on F e t a l D e v e lo p m e n t, Group I V .............................................. T a b le 9 . Summary o f M ost F r e q u e n tly O c c u rrin g D e fe c ts i n Fetuses S ire d by Males T re a te d vith 2 ,4 -D , 2 ,4 ,5 - T and T C D D ............................................ 37 T a b le 10. P e rc e n t Malform ed Fetuses S ire d by Males T re a te d vith. 2 , 4 - D , 2 , 4 , 5 - T and T C D D .................................... 38 T a b le 1 1 . E f f e c t o f 2 , 4 - D , 2 , 4 , 5 - T and TCDD on P o s tn a ta l Developm ent o f O ffs p r in g o f T re a te d M a le s , Group I C o n t r o l....................................................................................................39 35 ii 8293 DOW 113619 LIST OF TABLES (continued) Pace T a b le 1 2 . E f f e c t o f 2 , 4 - 0 , 2 , 4 , 5 - T and TCDD on P o s tn a ta l Developm ent o f O ffs p rin g o f T re a te d M a le s , Group I I ......................................................................................................... 40 T a b le 1 3 . E f f e c t o f 2 , 4 - D , 2 , 4 , 5 - T and TGDD on P o s tn a ta l Developm ent o f O ffs p rin g o f T re a te d M a le s , Group I I I ...................................................................................................... 41 T a b le 1 4 . E f f e c t o f 2 , 4 - 0 , 2 , 4 , 5 - T and TCDD on P o s tn a ta l Developm ent o f O ffs p rin g o f T re a te d M ales, Group I V ...................................................................................................... 42 07 T a b le 1 5 . Summary o f M a lfo r m a tio n R a te s (%) i n P o s tn a ta l S t u d y ^ ..................................................................................................... 43 T a b le 1 6 . Summary o f S p e c i f i c M a lfo rm a tio n s i n P o s tn a ta l Study 44 A p p e n d ix T a b le 1 . Summary o f A l l M a lfo rm a tio n s Observed i n Fetuses S ire d by M ales T re a te d v it h 2 ,4 - 0 , 2 . 4 . 5 - T and TCDD.......................................................... 49 Appendix T a b le 2 . In c id e n c e o f Fused S tern eb rae in Fetuses S ire d by Males T re a te d v it b 2 ,4 - 0 , 2 . 4 . 5 - T and TCDD.......................................................... 50 iii > 8294 ..DOW 113619,G LIST OF FIGURES Figure 1. Figure 2. F igure 3 . Figure 4 . F igure 5 . Figure 6. Figure 7. F ig u re 8. Figure 9. Figure 10. Figure 11. Figure 12. A verag e W eekly Food Consum ption............................................ 17 Mean. Body W eights f o r h a le M ic e ............................................ 18 A verag e W eekly W eig h t G ain ...................................................... 19 A v e ra g e L i v e r W e ig h t .................................................................... 20 A verag e Thymus W e ig h t.................................................................... 21 A verag e S p le e n W e ig h t.................................................................... i A verag e T e s t is and E p id id y m is W eig h t .............................. 22 23 A v e ra g e K id n e y W e ig h t.......................................................................... 24 A verag e B r a in W e i g h t ................................ 25 A verag e Sperm C o n c e n tr a tio n ...................................................... 28 A verag e P e rc e n t M o t ile Sperm .................................................. 29 A v e ra g e P e r c e n t Abnormal Sperm ............................................. 30 0004212 ' 8295 DOW 1136197 ABSTRACT T h is -study was u n d e rta k e n to d e te rm in e th e e f f e c t s o f m ix t u r e s (s im u la te d Agent Orange) o f 2 ,4 -d ic h lo ro p h e n o x y a c e tic a c id (2 ,4 -D ), 2 ,4 ,5 -tr ic h lo r o p h e n o x y a c e tic a c id ( 2 ,4 ,5 - T ) and 2 , 3 , 7 ,8 - t e t r a c h lo r o d ib e n z o - -d io x in (TCDD) on r e p ro d u c tio n and f e r t i l i t y o f t r e a t e d m ale m ice. h a le C57BL/6 mice were g iv e n fe e d c o n ta in in g v a ry in g c o n c e n tra tio n s o f 2 , 4 - D , 2 , 4 , 5 - T and TCDD such t h a t d a i l y doses o f a p p ro x im a te ly 40 m g/kg 2 , 4 - D , 40 m g/kg 2 , 4 , 5 - T and 2 . 4 Mg/kg TCDD (Group I I ) o r 40 m g/kg 2 , 4 - D , 40 o g /k g 2 , 4 , 5 - T and 0 .1 6 M g/kg TCDD (Group 1 7 ) o r 20 m g/kg 2 , 4 D , 20 m g/kg 2 , 4 , 5 - T and 1 .2 M g/kg TCDD (Group I I I ) w ould be a c h ie v e d . C o n tro ls (Group I ) were g iven a d ie t w ith o n ly th e corn o i l v e h ic le added to th e fe e d . In th e tr e a te d a n im a ls , d o s e -re la te d l i v e r and thymus t o x i c i t y w ere found and body w e ig h t g a in was s i g n i f i c a n t l y re d u c e d . L i v e r and thymus t o x i c i t y showed s i g n i f i c a n t o r com plete re c o v e ry when th e m ice w ere re tu rn e d to a c o n tr o l d i e t . Sperm c o n c e n tra tio n , m o t i l i t y and p e rc e n t sperm a b n o rm a litie s were e v a lu a te d and no s ig n if ic a n t e f f e c t was n o ted d u rin g o r a f t e r th e d o sin g p e r io d . A t th e c o n clu sio n o f an e ig h t week dosing p e rio d tr e a te d males were mated to u n tre a te d v ir g in fem ales (th re e p e r male p e r week f o r e ig h t w e e k s ), h a tin g fre q u e n c y , averag e f e r t i l i t y , p e rc e n t im p la n ta tio n and V r e s o rp tio n s ite s and p e rc e n t f e t a l m alfo rm atio n s were a l l measured in r e l a t i o n t o th e t r e a t m e n t . No s i g n i f i c a n t decrem ent i n f e r t i l i t y o r r e p r o d u c t io n was n o te d i n th e s tu d y . T h e re was no e v id e n c e o f germ c e l l t o x i c i t y . S u r v iv a l o f o ffs p r in g and n e o n a ta l developm ent were a p p a re n tly u n a ffe c te d by p a te rn a l exposure to th e sim u lated m ixtures o f Agent O ran g e. V RfiTflPTl Mnn INTRODUCTION C h lo r in a te d p h e n o x y a c e tic a c id compounds a re used e x t e n s iv e ly as h e rb ic id e s in fo r e s tr y and a g r ic u ltu r e . The Departm ent o f Defense p te s te d and used a number o f d i f f e r e n t h e rb ic id e s c o n ta in in g c h lo r in a te d phenoxy a c id s i n V i e t n am as d e f o l i a n t s ; th e s e in c lu d e d H e r b ic id e O ran g e, H e rb ic id e W h ite , H e rb ic id e P u rp le , H e rb ic id e P in k and H e rb ic id e Green (Young e t a l . , 1 9 7 8 ). The h e r b ic id e most e x t e n s iv e ly used was H e r b ic id e -- Orange, a 1 :1 m ixtu re o f the a -b u ty l e s te rs o f 2 ,4 -d ic h lo ro p h e n o x y a c e tic a c id (2 ,4 -D ) and 2 ,4 ,5 -tric h lo ro p h e n o x y a c e tic a c id ( 2 , 4 , 5 - T ) . I t has been e stim ated th a t 107 m illio n pounds were sprayed w ith th e m a jo r ity used in th e y e ars 1967 to 1969 (7 7 2 o f t o t a l h e rb ic id e sp rayed) (Young e t a l . , 1978). D uring th e syn th esis o f 2 ,4 ,5 -tr ic h lo r o p h e n o l (TCP) and subsequently 2 ,4 ,5 - T , b u t n o t 2,.4-D , a h ig h ly to x ic contam inant is form ed. This contam inant, 2 ,3 ,7 ,8 -te tr a c h lo r o d ib e n z o -p -d io x in (TCDD), has been found i n H e r b ic id e O range a t an a v e ra g e c o n c e n tr a tio n o f 2 ppm w it h i n d i v i d u a l a n a ly s is o f up t o 47 ppm r e p o r te d (Young e t a l . , 1 9 7 8 ). O c c u p a tio n a l o r e n v iro n m e n ta l exp o su re to ' humans to TCDD has been a s s o c ia te d w it h a number o f c l i n i c a l d is o rd e rs (F ire s to n e , 1977; IARC, 1 9 7 8 ). The h e a v ie s t exposures have in v o lv e d in d u s t r ia l ac c id e n ts which occurred in p la n ts s y n th e s iz in g TCP. The most c o n s is te n tly documented c l i n i c a l m a n ife s ta tio n has been ch lo racn e, a severe form o f p u s tu la r f o l l i c u l i t i s w hich is most fr e q u e n tly observed on th e fa c e , neck and upper e x tr e m itie s . O th e r le s s common c l i n i c a l f in d in g s f o llo w in g TCDD ex p o s u re in c lu d e p o r p h y r ia cutanea t a r d a , c e n t r a l and p e r ip h e r a l nervous system d is o r d e r s , d e p re s s io n and i r r i t a b i l i t y , h e p a t ic d y s fu n c tio n and a l t e r e d serum l i p i d c o n c e n - .. t r a t io n s (F ir e s to n e , 1977; IARC 1978; Young e t a l . , 1 9 7 8 ). CC0G14 DOW 1136199 5 2 A number o f Vietnam V e te ra n s have expressed concern as to h e a lth e f f e c t s t h a t may have r e s u lt e d ,from e x p o s u re t o H e r b ic id e Orange e i t h e r through a p p lic a tio n o f th e h e rb ic id e or through in h a b itin g d e fo lia te d areas (H olden, 1979; Raw ls, 1 9 7 9 ). A p a r tic u la r concern is th a t H e rb ic id e Orange exp o su re may be r e l a t e d to r e p o r te d d ecreases i n b o th l i b i d o and f e r t i l i t y (lo w sperm counts and abnorm al sperm fo rm s ) and t h a t i t may a ls o be resp o n sib le fo r b ir t h d e fe c ts observed in o ffs p rin g s ire d by v e te r a n s who w ere exposed t o A g en t Orange (B ogen, 1 9 7 9 ; H o ld e n , 1 9 7 9 ) . The t o x i c i t y o f TCDD and th e phenoxy a c id s 2 ,4 - D and 2 , 4 , 5 - 1 has b e e n s tu d ie d i n some d e t a i l . T h e . b i o l o g i c a l e f f e c t s o f th e s e c h e m ic a ls a re w e ll documented in a number o f mammalian t e s t systems (G eh rin g and B e ts o , 1 9 7 8 ; M o o re, 1 9 7 8 ). 2 , 4 - D , 2 , 4 , 5 - T and TCDD have a l l been in v e s t ig a t e d f o r t e r a t o g e n ic it y and f e t o t o x i c i t y when g iv e n to p re g n a n t f e m a le s .. 2 ,4 - D a c id and 2 ,4 - D e s te r s show s ig n s o f f e t o t o x i c i t y and embryo t o x i c i t y in ham sters and r a ts a t h ig h dose le v e ls , b u t i t is u n c le a r w h e th e r th e compounds a r e a c t u a l l y t e r a t o g e n ic ( C o l l i n s and W illia m s , 1971; Khera and M c S in le y , 1971; Schwetz e t a l . , 1 9 7 1 ). Exposure o f m ice to 2 ,4 ,5 - T during* pregnancy r e s u lts in c o n g e n ita l m alfo rm atio n s (C o u rtn e y and M oore, 1971; N e u b e rt and D illm a n , 1972; Hood e t a l . , 1 9 7 9 ). S tu d ie s i n ra ts (S parschu e t a l . , 1971) and monkeys (D o u g h erty e t a l . , 1 9 7 5 ), in d ic a t e t h a t th e t e r a t o g e n ic it y o f 2 , 4 , 5 - T may be a s p e c ie s 'd e p e n d e n t phenomenon, s in c e g e s t a t io n a l exposure t o t h i s compound produced fe to to x ic b u t n o t te ra to g e n ic e ffe c ts (G ehring and B etso, 1 9 7 8 ). E a r ly s tu d ie s w ith 2 ,4 ,5 - T samples w hich were contam inated w ith 30 ppm o f TCDD in d ic a t e d t h a t th e h e r b ic id e was t e r a t o g e n ic i n r a t s (C o u rtn e y ' 8298e t a l . , 1 9 7 0 ). Subsequent s tu d ie s by C o u rtn e y and Moore ( 1 9 7 1 ) , u s in g ccoG^ia DOW 1136200; 3 p u r i f i e d 2 , 4 , 5 - T , showed t h a t b o th 2 , 4 , 5 - T and TCDD were t e r a t o g e n ic i n t h r e e s t r a i n s o f m ice b u t i n r a t s o n ly TCDD was f e t o t o x i c and p o s s ib ly t e r a t o g e n i c . TCDD has been shown by o th e r la b o r a t o r ie s to be t e r a t o g e n ic a n d /o r em bryotoxic in mice a t le v e ls above 0 .1 p g /k g /d a y (Sm ith e t a l . . 1976) and r a ts a t 0 .1 2 5 -2 .0 p g /k g /d a y (Sparschu e t a l . , 1 9 7 1 ). A lthough f e t o t o x ic it y and te r a to g e n ic ity as s o c ia te d w ith g e s ta tio n a l exposures t o th e s e compounds have been e x te n s iv e ly s tu d ie d , t h e r e i s a p a u c ity o f d a ta as to th e e f f e c t s o f m ale exposure on f e r t i l i t y and developm ent o f t h e ir o ffs p rin g . In v e s tig a tio n s in male ra ts u n d ertaken t o d e te rm in e w h e th e r dom inant l e t h a l m u ta tio n s co u ld be caused b y TCDD w ere n e g a t iv e . H ow ever, th e in c id e n c e o f f e r t i l e m atin g s was d ec re a s e d b u t i t was n o t d e te rm in e d w h e th e r t h i s was due to th e s y s te m ic t o x i c i t y o f TCDD o r a d i r e c t e f f e c t on r e p ro d u c tio n (K hera and R u d d ic k , 1 9 7 1 ) . O th e r s tu d ie s t h a t have considered re p ro d u c tiv e competence in males have g e n e ra lly been m u ltig e n e ra tio n stu d ies o f anim als tre a te d during t h e ir e n t i r e l i v e s w i t h one o f th e compounds o f i n t e r e s t . I n th o se s tu d ie s n e ith e r 2 ,4 -D (Hansen e t a l . , 1971) nor 2 ,4 ,5 - T (Sm ith e t a l . , 1978) s i g n i f i c a n t l y reduced f e r t i l i t y when males and fem ales were g iv e n fe e d c o n t a in in g th e h e r b ic id e s . T h r e e -g e n e r a tio n s tu d ie s w it h TCDD demon s tra te d th a t in g e s tio n o f le v e ls g re a te r than 0 .1 pg/kg/day decreased f e r t i l i t y and l i t t e r s u rv iv a l in th e f Q g en e ra tio n ; exposure to 0 .0 1 P g A g /d a y decreased f e r t i l i t y in th e and g e n e ra tio n s , b u t n o t th e f Q g e n e ra tio n (H u rray e t a l . , 1 9 7 9 ). In th a t case, an in crease in the p ercen tag e o f resorbed im p la n ta tio n s ite s could be r e la te d to fem ale exposure to TCDD, b u t n o t to m ale exposure (H u rra y e t a l . , 1 9 7 9 ). > 8299 DOVi 1136201 4 The consequences o f c h e m ic a l t o x i c i t y on male, r e p r o d u c tiv e c a p a h i l i t i e s m ight in c lu d e lo s s o r decrease in f e r t i l i t y , abnorm al sperm m orphology, decreased sperm c o n c e n tra tio n a n d /o r m o t i l i t y , o r le s io n s in th e re p ro d u c tiv e t r a c t and a c ces so ry sex glands (Gomes, 1970; Hanson and Simons, 1 9 8 0 ). In a d d itio n to e ffe c ts on re p ro d u c tio n o r f e r t i l i t y , ch em ical exposure m ig h t cause g e n e tic m u ta tio n s in th e m ale germ c e lls w h ich c o u ld be expressed i n th e o f f s p r in g as an in h e r it e d anom aly, o r embryo and f e t a l d e a th ( J o f f e , 1 9 7 9 ; Hanson and Simons, 1 9 8 0 ). A n o th er mechanism to e x p la in f e t a l e f f e c t s v ia th e male would be t h a t th e ch em ical m ig h t a c t u a lly be tra n s m itte d to th e fem ale in th e sem inal plasma which could th en r e s u lt in a d ir e c t exposure o f the ova. The dom inant le t h a l (E p s te in , 1973; Generoso, 1973) and sperm m orphology (V yrobek, 1979) assays, used r o u tin e ly in m ice to e v a lu a te p o t e n t ia l chem ical m u ta g e n ic ity in m ale germ c e lls , w ere employed in t h is s tu d y . Both o f th ese t e s t systems in v o lv e chem ical exposure fo llo w e d by f e r t i l i t y te s tin g o r sperm e v a lu a tio n o f th e anim als f o r th e d u ra tio n o f th e spezm atogenic c y c le (a p p ro x im a te ly 35 days in m ic e ). Th is approach is n ecessa ry s in c e male germ c e lls a re c o n s ta n tly d iv id in g and d i f f e r e n tia tin g d u rin g t r a n s it from sperm atogonia to spermatozoa w ith each d e v e lo p m e n ta l s ta g e v a r y in g in i t s s e n s i t i v i t y and s u s c e p t i b i l i t y to * c h e m ic a l t o x i c i t y o r m u t a g e n ic it y . E x p e rim e n ta l .d esig n s w h ic h a re d ire c te d a t d e te rm in in g m ale germ c e l l t o x i c i t y must c o n s id e r th-i s sperm m a tu ra tio n process to assure th a t a l l stages o f developm ent a re te s te d . The f o llo w in g i n v e s t ig a t io n s w ere u n d e rta k e n to d e te rm in e i f compo s i t e ex p o s u re t o 2 , 4 - D , 2 , 4 , 5 - T p lu s TCDD ( i . e . , H e r b ic id e O ra n g e ), could a f f e c t re p ro d u c tiv e fu n c tio n in male m ice. c 83 00 5 MATERIALS AND METHODS T e s t C h em icals and P u r it y DOW 1136202 2 ,4-d ich lo ro p h en o xyacetic acid (2 ,4 -D ) OCHjCOOH Cl XJ 2 ,4,5-cric h lo ro p h en o xy acecic acid (2 ,4 ,5 -T ) I Cl ^ 0 2 , 3 , 7 , S - t e t r a c h lo r o d ib e n z o - ^ - d io x in (TCDD) 2 ,4 - d ic h lo r o p h e n o x y a c e t ic a c id ( 2 , 4 - D ) (AGR 1 7 1 1 1 4 , 9 8 .5 1 p u r e ) and 2 , 4 , 5 - t r i c h l o r o p h e n o x y a c e t i c a c id ( 2 , 4 , 5 - T ) (AGR 1 3 3 7 1 1 , 9 8 .7 1 p u re ) w ere s u p p lie d b y th e Dow C h em ical U . S . A . , M id la n d , M ic h ig a n . B o th sam ples w ere a n a ly z e d by Dow C h em ical f o r TCDD c o n ta m in a tio n who r e p o r te d no TCDD o r o t h e r d i o x in d e te c te d i n th e sam ples (T a b le s 1 and 2 ) . The f r e e a c id was used to e lim in a t e th e v o l a t i l i t y p ro b lem a s s o c ia te d w ith th e b u t y l e s t e r w hich would compromise q u a n t if ic a t io n o f dose a d m in is te re d and pose an exposure r is k to la b o ra to ry p e rs o n n e l. The free a c id form is r e a d ily absorbed from th e g a s t r o in t e s t in a l t r a c t . 2 , 3 , 7 , 8 - t e t r a c h l o r o d i b e n z o - - d i o x i n (TCDD) was s y n th e s iz e d by th e E n v iro n m e n ta l C h e m is try B ra n c h , N a t io n a l I n s t i t u t e o f E n v iro n m e n ta l .. H e a lt h S c ie n c e s , R e s e arc h T r ia n g le P a r k , N o r th C a r o lin a . The TCDD was 8301 re p o rte d to be o f g r e a te r th an 981 p u r it y by gas chrom atographic a n a ly s is CCG<i,3 6 TABLE 1 A n a ly s is o f 2 ,4 -D Sample f o r D io x in s 2 ,3 ,7 ,8-T etrach lo ro d ib en zo -p -d io xin H exach lo ro d ib en zo -p -d io xin Hep t a c h lo r o d ib e n z o -p -d io x in O ctach lo rodibenzo-p-dioxin C oncentration Not detected Not detected Not detected Not detected D etectio n L im it 1 ppb 1 ppb 20 ppb 5 ppb DOV11136203 V CWv> o 1 3 8302 DOW 1136204 7 TABLE 2 A n a ly s is o f 2 .,4 ,5 -T Sample f o r D io x in s 2 ,3 ,7 ,8-T etrach lo ro d ib en zo -p -d io xin H exachlorodibenzo-p-dioxins O ctachlorodibenzo-p-dioxin C oncentrarlos Not Detected Not detected Not detected D etection L im it 0 .5 ppb 0 .0 3 ppm 0 .3 ppm CC0GL20 8303 DOW 1136205 i 8 performed by NIEHS. The principal contaminate was 2,3,7-trichlorodibeazo-dioxin. A n im a ls and H usbandry Four week o ld m ale and 10 week o ld fem ale C57BL/6N in b re d m ice (C e s a re a n -O rig in a te d , B a r r ie r S u stain ed ) were purchased from th e C harles R iv e r Breeding L a b o ra to rie s , In c ., W ilm ington, M assachusetts. Upon a r r i v a l th e m ice were earta g g e d and housed in p la s t ic cages w ith s ta in le s s tops (r a le s , one p e r cage; fem ales, te n p e r c a g e ). A b s o rb -d ri hardwood bedding (B arnes S u p p ly , Durham, NC) was u sed , and cages w ere cleaned once each week. The anim als were kep t in c o n s ta n t tem p eratu re (2 0 + 2 C ) and h u m id ity (R .H . 50 + 10%) on a f ix e d c y c le o f 12 hours l ig h t - 1 2 hours d arkn ess. The m ice were allo w ed food and w a te r ad lib it u m . T h e powdered d i e t was open fo rm u la N IH -3 1 p re p a re d b y Z e i g l e r B ro s . Co. o f Gardners, Pa. P rep aratio n o f D iets S tock s o lu tio n o f th e t e s t chem icals were prepared in a corn o i l v e h ic le . The c a lc u la te d and a n a ly tic a l values a re g iven in T ab le 3 . The t e s t d ie ts were p rep ared each week f o r 8 weeks by adding th e appro p r i a t e s to c k s o lu t io n in t o th e fe e d (2% v o l / v t ) . The c o n c e n tra tio n o f c h e m ic a ls i n th e fe e d was n o t changed d u rin g th e 6 week exposure p e rio d s t u d y . Feed consu m p tion (gm /m ouse) was m easured once a w eek. A p p ro x im a te dose l e v e l s w ere p r o je c t e d u s in g consum ption o f 5 gm fe e d /d a y b y a mouse w e ig h in g 25 gm. The c o n t r o ls (G roup I ) w ere g iv e n a d i e t c o n ta in in g 2% c o rn o i l . Group I I c o n s is te d o f m ice t h a t re c e iv e d ab o u t 40 m g /kg /d ay o f 2 , 4 - D , 40 m g /k g /d a y o f 2 , 4 , 5 - T and 2 . 4 jg /k g /d a y o f TCDD f o r a t o t a l dose o f 2 . 2 4 gm/kg o f 2 ,4 - D and 2 , 4 , 5 - T each and 0 .1 3 m g/kg o f TCDD o v e r th e e n t i r e 8 w eeks. Group- I I I m ice were t r e a t e d a t a r a t e o f 40 m g /k g /d a y ccctzai 9 Treatment Group I (Control) II III IV TABLE 3 2,4-D, 2,4,5-T and TCDD Concentrations in Stock Corn Oil Solutions and Projected Dosages in Feed * ppm 1,1 ** mg/kg/day 2,4,5--T1 ppro* mg/kg/day ** 2 TCDD ppb* Hg/kg/d, 0(0) 10,000(9380) 10,000(9310) 5,000(4880) 0 40 40 20 0(0) 10,000(9590) 10,000(9480) 5,000(4830) 0 40 40 20 0(0) 600(505) 40( 39 ) 300(271) 0 2.4 0.16 1.2 ^Calculated prepared concentrations and in ( ) amounts detected by analysis. Dose levels based on ideal concentrations in feed and an average feed consumption of 5 gm feed/day/25 gm mouse. ^Samples of oil collected for 2,4-D and 2,4,5-T analyses were extracted with ethyl ether, derivatized with diazomethane, extracted with hexane and analyzed on an electron capture gas chromatograph (ECCC) by the Midwest Research Institute. 2 Samples of oil collected for TCDD analysis were saponified in ethyl alcohol and potassium hydroxide, then extracted with hexane and analyzed with an ECCC by the Midwest Research Institute. OD CO o Of CG0G222 i '=9029011 MOO DOW1136207 10 o f 2 ,4 - D and AO m g /k g /d a y o f 2 , 4 , 5 - T (same as Group. I I ) , b u t r e c e iv e d -o n ly 0 .1 6 M g /k g /d a y o f TCDD; th e t o t a l dosages o f 2 ,4 - D and o f 2 , 4 , 5 - T w ere 2 .2 4 gm/kg and 0 .0 0 9 a g /k g o f TCDD. The mice i n Group IV re c e iv e d 20 m g /k g /d a y o f 2 , 4 - D , 20 m g /k g /d a y 2 , 4 , 5 - T , and 1 .2 M g /k g /d a y o f TCDD, r e s u lt in g in a t o t a l 8 week exposure o f 1 .1 2 gm/kg o f 2 ,4 -D and o f 2 , 4 , 5 -T and 0 .0 6 7 mg/kg o f TCDD. A f t e r th e 8 week exposure p e rio d a l l m ice w ere fe d s ta n d a rd p e l l e t e d NTH 31 d i e t . E xp erim en tal Design Two hundred m ale m ice w ere w eighed and s o rte d (b y w e ig h t) in t o e i g h t groups (2 5 p e r g r o u p ). One h a l f o f th e m ale m ice (4 groups o f 25 each) were used f o r t o x ic it y e v a lu a tio n , w h ile th e o th e r h a lf (4 groups o f 25 each) were used fo r f e r t i l i t y and re p ro d u c tiv e s tu d ie s . A l l m ales w ere th e n a c c lim a t iz e d on N I1 - 3 1 la b o r a t o r y chow f o r th re e weeks b e fo re th e chem ical exposures were begun. Chem ical exposure began when th e m ales w ere e ig h t weeks o ld . Body w e ig h ts and fo o d consump t io n were recorded on a w eekly b a s is . The males were assigned to e x p e ri m en tal and c o n tro l groups such th a t w eig h t d iffe re n c e s between groups were m in im ized . The m ice'w ere th e n tr e a te d w ith one o f th e th re e tre a te d o r c o n tro l d ie ts fo r e ig h t consecutive weeks. T o z ic o p a th o lo g y One hun d red o f th e m ice w ere s tu d ie d d u rin g and a f t e r th e 8 week fe e d in g p e rio d . Four anim als from each o f th e fo u r dose groups were k i l l e d by d e c a p ita tio n a t 1 , 4 , 5 , 8 , 12 and 16 weeks a f t e r f i r s t r e c e iv in g t r e a t e d fe e d . Each mouse re c e iv e d a gross au to p sy e x a m in a tio n ; body and organ ( b r a in , l i v e r , s p le e n , k id n e y , thymus and t e s t is /e p id id y m is ) w eig h ts were m easured. These organs as w e ll as lu n g , duodenum, e a r , 8 3 0 6 ,-.-3 11 p r o s ta te , sem inal v e s ic le , c o a g u la tin g gland and u r in a r y b la d d e r were f ix e d i n 102 n e u t r a l b u ffe r e d f o r m a lin , deh yd rated and embedded in p a r a f f i n b lo c k s . S ix pm h i s t o l o g i c s e c tio n s w ere p re p a re d and s ta in e d w ith h e m a to x y lin and e o s in . The tis s u e s were examined f o r evidence o f h is to p a th o lo g ic change. A lso a t s a c r if ic e , th e vas deferens were removed and spermatozoa m ilk e d in to a 1 .0 ml volume o f 0 .9 * s a lin e . The c o n c e n tra tio n o f sperm p e r vas d e fe re n s was e s tim a te d w it h a hem ocytom eter im m e d ia te ly a f t e r c o l l e c t i o n . A d d i t i o n a l l y , th e p e r c e n t m o t ile (a n y movement v s . no movement) sperm was en u m erated . The sperm sam ple was th e n s t a in e d w it h 0 .2 5 2 e o s in Y f o r 30 m in u te s . The sperm were e v e n ly d is t r ib u t e d w ith in th e s ta in in g s o lu tio n using a P asteu r p ip e tte and fo u r s lid e p re p a ra tio n s were p rep ared from each sam ple. The smears were allo w ed to a i r d ry , were co ver s lip p e d and were examined a t 400 Z m a g n ific a tio n . Three hundred sperm w ere s tu d ie d f o r each sample and sperm w ere c la s s if ie d as n o rm al o r abnorm al u s in g th e c r i t e r i a o f Wyrobek and B ruce (1 9 7 5 ) and Soares e t a l (1 9 7 9 ). F e r t i l i t y and R e p ro d u c tio n F e r t i l i t y and re p ro d u c tio n assessments were conducted on the rem aining 100 m ice (fo u r groups o f 25).. A f t e r th e m ale mice had been tre a te d w ith th e t e s t chem icals f o r e ig h t weeks th e y were re tu rn e d to c o n tro l fe e d . B eginning th e n e x t day, each m ale was housed w ith th r e e v i r g i n fe m a le m ice (fo u r te e n weeks o f a g e ) f o r up t o 5 days each week f o r e ig h t w eeks. Bach fe m a le was exam ined each m orning f o r evidence o f m ating by d e te c tio n o f a v a g in a l p lu g (Bay 0 o f p r e g n a n c y ). Each m ated fe m a le was removed from th e c a g e , w eighed and p laced i n a cage w ith o th e r mated fem ales in th a t g ro u p . Females w hich d id n o t appear to have mated d u rin g th e 5 -d a y c o h a b ita tio n p e rio d 8307 ccOui-24 DOV1 1136209 12 were observed f o r th re e more weeks to p e rm it d e te c tio n o f p o s s ib le p reg n an cies f o r -which v a g in a l p lu g s were n o t observed. A pparent f a i l u r e o f a fe m a le to m ate o r c o n c e iv e was v e r i f i e d th r e e weeks a f t e r c o h a b i t a t io n by k i l l i n g th e a n im a l, rem oving th e u te ru s , and s ta in in g i t w ith ammonium s u l f i d e t o b e t t e r i d e n t i f y th e p re s e n c e o f im p la n t a t io n s i t e s (Xopf e t a l . , 1964). P o r each w e e k ly m a tin g t r i a l one fe m a le b re d to each m ale was p u t in a group to be s a c r ific e d on day 18 o f pregnancy f o r te r a to lo g y exam in a t i o n . A second b re d fe m a le fro m each m ale was p la c e d i n a group w h ich was a llo w e d t o d e l i v e r and r e a r h e r o f f s p r i n g . A l l re m a in in g dams fo u n d to have plugs were placed in a " te ra to lo g y backup group" to be subjected to t e r a t o l o g i c a l e v a lu a t io n i f th e dam s e le c te d f o r day 18 s a c r i f i c e was found n o t to have any l iv e fe tu s e s . The above pregnant mice were s y s te m a tic a lly d is trib u te d to the te ra to lo g y , p o s tn a ta l or "backup" groups such t h a t no one group was b ia s e d w it h dams w h ic h m ated f i r s t , second o r t h i r d . H ow ever, i f le s s th a n t h r e e dams had m ated , p r i o r i t y was g e n e r a lly g iv e n to th e t e r a t o lo g y g ro u p . A l l mated dams w ere w eighed on days 0 , 7 , 1 1 , 15 and 18 o f g e s ta tio n . On d a y 18 o f g e s t a t io n , th e dams d e s ig n a te d f o r t e r a t o l o g y exam ina t i o n w ere coded to p e r m it i d e n t i f i c a t i o n o n ly by number so t h a t la b o r a t o r y p e rs o n n e l c o n d u c tin g th e t e r a t o g e n ic a n a ly s is d id n o t know th e t e s t g ro u p . The m ice were k i l l e d by c e r v ic a l d is lo c a t io n and t h e i r rep ro d u c t i v e s t a t u s was d e te rm in e d . Im p la n t a t io n s i t e s i n each u t e r i n e h o rn w ere co u n ted and th e g e n e r a l c o n d it io n o f each conceptus was re c o rd e d . The d e te c tio n o f im p la n ta tio n s ite s in th e u t e r i o f a p p a re n tly nonpregnant fe m a le s was a c h ie v e d th ro u g h use o f ammonium s u l f i d e (X o p f e t a l . , 1 9 6 4 ). L iv e fe tu s e s were weighed in d iv id u a lly , sexed in t e r n a lly (s u r g ic a l in c is io n below n a v e l) , and examined f o r e x te r n a l m a lfo rm a tio n s - T-v* 8308 13 DOW 1136210 fe tu s e s w e ig h in g < 0 .5 ' g , o r w e ig h in g le s s th a n t w o - t h ir d s th e mean o f th e ir la rg e r litte r m a te s , were designated as b ein g "s tu n te d ". A t le a s t o n e -h a lf o f th e fe tu s e s o f each l i t t e r , a l l "s tu n te d " fe tu s e s and fe tu s e s having e x te rn a l m a lfo rm a tio n s , were examined f o r v is c e r a l a lte r a tio n s (S ta p le s , 1 9 7 4 ). The bodies o f a l l fetu ses were then . processed fo r s k e le ta l exam ination (S tap les and S c h n e ll, 1 9 6 4 ). The ^ heads o f each fe tu s subjected to v is c e ra l exam ination (w ith the excep tio n * o f any fe tu s e s w hich had e x te r n a l head m a lfo rm a tio n s ) were c u t o f f a t th e base and examined by th e fre e -h a n d s e c tio n in g te c h n iq u e d e s c rib e d by W ilson (1 9 6 5 ). The re m a in in g dams ( p o s t n a t a l group)were a llo w e d to d e l i v e r t h e i r l i t t e r s . L iv e and dead o ffs p r in g as w e ll as b i r t h w e ig h twere recorded (d ay 0 ) . The pups were rew eighed on days 4 , 7 and 21 andv i a b i l i t y also was re c o rd e d . The dams and t h e i r o f f s p r in g w ere k i l l e d on day 2 1 . The above procedures were rep eated w eekly f o r e ig h t weeks r e s u ltin g in a t o t a l o f e ig h t s e ts o f d a ta . lo u r weeks a f t e r th e co n clu sio n o f th e b reed in g s tu d y , (week 20 o f th e e x p e rim e n t), th e male mice were k i l l e d and au to p sied in a. manner id e n t ic a l to th a t d e s c rib e d f o r th e males s a c r ific e d f o r to x ic o p a th o lo g ic e v a lu a tio n . S ta tis tic a l E valu atio n S ta tis tic a l evalu atio n s o f possible p a irw is e tre a tm e n t-c o n tro l d iffe re n c e s in food consum ption, body w e ig h ts , organ w e ig h ts , f e r t i l i t y , m ating e f f ic ie n c y , and sperm number, m o t ilit y and a b n o rm a litie s were made b y D u n n e tt's t e s t ( H i l l e r , 1 9 6 6 ). A n a ly s is o f v a r ia n c e p ro c e d u re s w ere em ployed t o assess th e s ig n if ic a n c e o f d if f e r e n c e s among g ro u p s , w eek-to-w eek v a r i a b i l i t y , and week by group in t e r a c t io n s . A nalyses o f a b n o r m a lit ie s among th e o f f s p r in g were c a r r ie d o u t em p lo yin g p a ir w is e o 8309 DOVI U36211 i 14 com parison o f c o n t r o l v e rs u s t r e a t e d groups w it h th e Mann W h itn e y U t e s t . The a n a ly s is o f m alfo rm atio n s -considered th e average p e rc e n t m alform ed fe tu s e s p e r l i t t e r . V 8310 CvOGZS? DOW 113612 15 RESULTS Feed Consumption and Body W eight The p r o je c te d food consum ption o f 35 gm/week (5 gm /day) p ro ved to be a c o n s e rv a tiv e e s tim a te in a l l groups throughout th e p e rio d o f chem ical exposure (F ig u re 1 ) . Lower food consumption fo r a l l groups is in d ic a te d i n w ee k -2 because o n ly a f r a c t i o n o f th e week (5 d ays) was m easured. The a d d i t i o n o f 2 , 4 - D , 2 , 4 , 5 - T o r TCDD d id n o t s i g n i f i c a n t l y d ec re a s e fe e d consumption d u rin g th e f u l l e ig h t week dosing p e rio d in any tre a tm e n t g ro u p , as compared to th e c o n tr o ls . S t a t i s t i c a l l y s ig n if ic a n t changes i n fe e d consum ption w ere o n ly found i n s p o ra d ic cases and no g e n e ra l tre n d o f decreased feed consumption could be a ttr ib u te d to the a d d itio n o f e i t h e r phenoxy a c id s o r TCDD. Body w e ig h t and w e ig h t g a in , how ever, showed s i g n if ic a n t re d u c tio n s i n th e tr e a te d anim als when compared to c o n tro ls (F ig u re s 2 and 3 ) . T h is r e d u c t io n i n body w e ig h t was most pronounced i n group I I ( 2 . 4 Mg T C D D /k g /d a y and 80 mg phenoxy a c id /k g /d a y ) from weeks 3 th ro u g h 8 o f th e s tu d y . The Group I I an im als reco vered most o f t h e i r w e ig h t d e f i c i t when re tu rn e d to c o n tr o l d i e t . G e n e ra lly a l l o f th e mice appeared h e a lth y throughout th e course o f th e s tu d y . O n ly two an im als d ie d d u rin g th e tw e n ty weeks, one i n group X 17 a t 5 weeks and one i n group I I a t 19 w eeks. T h e ir d e a th d id n o t appear to be tre a tm e n t-re la te d . Organ W eights and H is to n a th o lo g y The mean organ w e ig h ts o f an im als k i l l e d on weeks 1 , 4 , 5 , 8 , 12, 1 6 , and 20 a re shown in F ig u re s 4 - 9 . S t a t i s t i c a l l y s i g n i f i c a n t in c re a s e s i n l i v e r w e ig h t (F ig u r e 4 ) w ere observed i n a l l t r e a t e d groups and was p o s i t i v e l y c o r r e la t e d w it h th e amount o f TCDD exposure ( i . e . , 2 . 4 > 1 .2 CC06 8 3 1 1 3 DOVI U36213 16 > .16 pg/kg TCDD/day, groups I I , IV and I I I r e s p e c t iv e ly ) . A f t e r co n c lu sio n o f exposure, th e l i v e r w eig h t re tu rn e d -to w a rd n o rm al, alth o u g h Groups I I and I V c o n tin u e d to show s i g n i f i c a n t l y e le v a te d v a lu e s even a t week 2 0 . The liv e r s o f tr e a te d mice were e n la rg e d , l i g h t e r in c o lo r than norm al and m o t t le d . The thymus was d ecreas ed i n w e ig h t, w h ich a ls o ap p eared to be a f u n c t io n o f th e l e v e l o f TCDD r a t h e r th a n phenoxy a c id exposure (F ig u re 5 ) . A lth o u g h th e thymus w eig h ts were s i g n i f i c a n t l y (p < .0 1 ) reduced in Groups I I and IV r e la t iv e to c o n tro ls th ro u g h o u t th e tre a tm e n t p e rio d (weeks 1 - 8 ) , th ym ic re c o v e ry appeared com plete and w eights were n o t s t a t i s t i c a l l y d if f e r e n t from th e c o n tro ls by 4 weeks a f t e r th e l a s t e x p o s u re . No s i g n i f i c a n t t r e a t m e n t - r e la t e d e f f e c t s w ere observed in the spleen (F ig u re 6 ) , te s tis (F ig u re 7 ) , kid n ey (F ig u re 8 ), o r b r a i n (F ig u r e 9 ) . H is t o p a t h o lo g ic a l e v a lu a t io n showed no t r e a t m e n t r e la te d changes in any organs, w ith the excep tio n o f th e l i v e r . Even th e thym us, w h ic h .h a d d ec re a s e d i n s iz e to as much as o n e - t h ir d t h a t o f th e c o n tro l thymus, appeared h is to lo g ic a lly norm al. The m ild to x ic e ffe c ts observed in th e liv e r included h e p a to c e llu la r s w e llin g , s c a tte re d s in g le c e l l n e c ro s is , in c re a s e d numbers o f m it o t ic f ig u r e s , excess e x tra m e d u lla ry h e m a to p o ie s is , and le u k o c y tic i n f i l t r a t i o n . These changes w e re most a p p a re n t i n group I I ( 2 . 4 M g /k g /d a y TCDD; 80 m g /k g /d a y phenoxy a c id s ) and l e a s t a p p a re n t i n Group I I I ( 0 .1 6 M g /k g /d a y TCDD; 80 m g /k g /d a y phenoxy a c id ) . These signs o f t o x ic it y dim inished s u b s ta n tia lly by the end o f th e t w e lf t h week o f th e study (fo u r weeks a f t e r chem ical exposure was c o n c lu d e d ). 8312 UJ Q tf) O Z3 OO U- 2 \ ^J 5 2 ofUJi z 5: UJ I-- cr 3CD CL <2 ^ zW(7) <0 o o n o GO CO H-* CO -- I____ l -2 -I WEEK OF TREATMENT Figure 1. Average weekly food consumption before and during the treatment period of the 6tudy for the males. Values are mean + S.E.M. -liberi MOO ST298TIMOO CO CO H cj u 903D (BmOeDtYaniWSE.IE.GMH.)T oo - 3 - 2 - 1 0 I 2 3 4 W5 EE6K 7OF8ST9UDIOY II 12 13 14 15 16 17 18 19 20 Figure 2. Mean body weights for naie mice in all four treatment groups. Significant reductions (p<0.05) in weight, as compared to control, for groups II and III were present in weeks 3-6, group IV in weeks 6-8. Values are mean t S.E.H. 4 r I I 19 DOW 113621G WEIGHT GAIN t S.E.M. (gm) F ig u re 3. A verag e w e e k ly w e ig h t g a in . W eight g a in was s i g n i f i c a n t l y (p < 0 .0 1 ) reduced i n Group I I r e l a t i v e to c o n tr o l d u rin g weeks 4 , 5 and 8. R ap id re c o v e ry was observed such t h a t no s i g n i f i c a n t d if f e r e n c e was p r e s e n t by week 12 i n th e s e a n in a ls . V a lu e s a r e mean + S . E . M . , n 4 p er group. 8315 f.r I 20 CJ 05 LIVER WEIGHT i S.E.M. <gm) WEEK OF TREATMENT Figure 4 . A v e ra g e l i v e r w e ig h t . L i v e r w e ig h t was s i g n i f i c a n t l y ( p < .0 5 ) in c re a s e d in Group I I (weeks 1 - 2 0 ) , Group I I I (weeks 1 - 5 , week 16) and Group IV (weeks 4 -2 0 ) r e l a t i v e to c o n tro ls . V alues a re can + S .E .h ., n = 4 p e r group, weeks 1 -1 6 , n * 25 p e r group in week 20. r\ -- 21 THYMUS WEIGHT t S.E.M.(gm) 8T89ETI MOfl 0.000 02 WEEK8OF 1T0REA1T2ME1N4T 16 18 20 Figure 5. Average thymus w e ig h t. Thymus w e ig h t was s i g n i f i c a n t l y (p < .0 1 ) reduced in Groups I I and IV r e l a t i v e to c o n tro ls (weeks 1 - 8 ) . Com plete re c o v e ry was observed in a l l groups by week 1 2 . Values a re mean + S .E .M ., a = 4 p e r group on week 1 - 1 6 , n * 25 p e r group in week 2 0 . - 8317 GGQ{j34 22 E_ 0.!0 ~o> 0.08 l- X2 0.06 Li 2 Q04 I Ha LlJ !j 0.02 .1212o Gl <0 0 1 2 3 4 5 6 7 8 9J--1I--011I--1I_2_!I3_14 15 16 1718 1920 WEEK OF TREATMENT Figure 6. Average spleen veigfat was not significantly changed by treatment. Values are mean + S.E.M., n = A per group in weeks 1-16, a = 25 per group in week 20. ...< 8318 ccocioa 23 DOW 1136220 AWNEDIGEPHITDIODFYTMIESS(TIgSm) Figure 7. A verage t e s t i s and e p id id y m is w e ig h t was n o t s i g n i f i c a n t l y a f f e c t e d bY tr e a tm e n t. V a lu es a re mean + S .E .M ., n = A p e r group in weeks 1 -1 6 , n = 25 p e r group in week 20. ...` 8319 G o O G Iis 24 CO O l\0 tO Q25r % 020 H X 2 0.15 Ll I > LJ QIO *Q Q05 i iza U lo 12 0 1 2 3 4 5 6W7EE8K9O< F1t0T11R E1i2A1T<3M1i4EN1I5T16 1718 192I0 Figure 8. A verage k id n e y w e ig h t was n o t s i g n i f i c a n t l y changed by tr e a tm e n t. V a lu e s a re mean + S . E . h . , a 4 p e r group i n weeks l - i 6 f n * 25 p e r group in week 20. Pi-1 0 7 0.45 o Cl a C' CJ t o Q0 CO ro 0.40 E I-o 0.35 X o LU 0.30 < 0.25 (Z m 0.20 I DA mo GZ- I I 1 1 I - I __ I__ I__ I-- I-- I-- I O I 2 3 4 5 6W7EE8K9OF10T1R1E1A2TIM3IE4NIT5I6I7 1819 20 Figure 9. Average brain weight waa not aignificantly altered by chemical treatment. Values are mean + S.E.H., n * A per group in weeks 1-16, n = 25 per group in week 20. Z2Z96TIWOQ N> In DOVI U 3 G 2 2 3 26 F e rtility The average p e rc e n t m atings and o v e r a ll f e r t i l i t y o f th e males th rough 8 weeks o f th e s tu d y a re g iv e n i n T a b le 4 . T h e re was a s i g n i f i cant re d u c tio n in the m ating frequency in males from group I I I (80 mg A s /d ay phenoxy a c id , 0 .1 6 p g /k g /d a y TCDD). T h is e f f e c t was n o t s i g n i f i c a n t i n Group I I whose phenoxy a c id exposure was s i m i l a r and whose TCDD exposure was 1 5 - f o ld g r e a t e r . T h e r e fo r e , no d o s e -r e la te d e ffe c t could be a ttr ib u te d to th is decrease. A lso , the p e rc e n t f e r t i l e m atings and t o t a l f e r t i l i t y were n o t s ig n if ic a n t ly reduced in Group I I I o r i n any group when compared to th e c o n t r o l. When f e r t i l i t y was e v a lu a te d on a week by week b a s is , no tre a tm e n tr e la t e d changes were observed . F e r t i l i t y was a ls o s tu d ie d on an i n d i v id u a l p e r male b a s is and no s i g n i f i c a n t changes were d e te c te d w it h in tr e a te d males as compared to c o n tro ls . A t th e conclusion o f the study sperm c o n c e n tra tio n and m o t i l i t y and p e rc e n t abnormal sperm were measured (week 20, F ig u res 1 0 -1 2 ). These values were an alyzed , on an in d iv id u a l male b a s is , to determ ine whether any c o r r e la tio n e x is te d between low f e r t i l i t y perform ance (p lu g fre q u e n c y , p e rc e n t f e r t i l e m atings and t o t a l f e r t i l i t y ) and low valu es f o r sperm q u a lit y (c o n c e n tra tio n , m o t i l i t y , p e rc e n t abn o -m ial). I n a l l groups th e re was no c o r r e la t io n betw een th e p aram eters m easured. T h is would in d ic a t e t h a t , even though th e r e was considerable v a r ia b ilit y w ith in these param eters, v a ria tio n s in f e r t i l i t y co u ld n o t g e n e r a lly be a t t r ib u t e d to s p e c if ic changes i n sperm q u a l i t y . The v a lu e s f o r sperm c o n c e n tra tio n (F ig u re 10) and sperm m o t i l i t y (F ig u re 11) flu c tu a te d c o n s id e ra b ly from week to week. P e rc e n t abnormal sperm were le s s v a r i a b l e (F ig u re 1 2 ) . No t r e a t m e n t - r e la t e d changes were observed in these param eters. The marked re d u c tio n s in sperm co n cen tra t io n (F ig u re 10) and in c re a s e in sperm m o t i l i t y (F ig u re 11) which were i 0Qi>239 DOW 1136224 27 TABU 4 Fertility and Macing Efficiency in Trancad and Cenerei C5731/6 Mica 8 Hank local Traaeaaac Crespi Macing2 Brequeacy Perda Matings (percent)^ Total4 Berciliry (persene) I(Coacni) 74.6 1.6 56.2 2.2 42.0 1.9 H(80;2.4) 70.3 2.4 58.3 2.9 41.0 2 . 6 ZZZ(80;0.16) 67.8 2.4* 55.3 2 . 3 37.7 2.2 IT(40;1.2) 73.0 2.0 60.8 2 . 9 41.2 2.3 ^Calculated dally exposure la given la pareschases as cecal ag phenory acids/kg/day, -Ug TCBD/kg/day barcane plug* ebaazvad/eecal fanales housed with alea. /Persene fardi aciaga/fanales with plugs. Persane fardi aciaga/cecal fosales housed d e h ales. P<.05 ralacivu ce eeacxela Tainas ara nasa * standard error of cha asa, n * 23 per group. 8323 0 0 0 & .4 0 28 ttooCO 05 crc so cr i- LJ O O O cr LU CL 05 WEEK OF TREATMENT Figure 10. A verage sperm c o n c e n tra tio n . Sperm c o n c e n tra tio n was q u it e v a r i a b l e and th e o n ly s i g n i f i c a n t re d u c tio n r e l a t i v e to c o n tr o ls was i n week 16 ( p < .0 5 , Group I I ; p < .0 1 , Group I V ) . The marked r e d u c tio n i n a l l groups a t 20 weeks may have been r e la t e d to th e m atin g o f those a n im a ls . V alues a re mean + S .E .M ., n s A p e r group in weeks 1 -1 6 , n = 25 p e r group in week 20. s 29 DOW 1136226 ; 01 2 3 4 5 6W7E8EK9OF10T.1R1E1A2T13M1E4N15T 1617 181920 Figure 11. Average p e rc e n t m o tile sperm. No s i g n i f i c a n t change was observed in th e p e rc e n t m o tile sperm (p < 0 .0 5 ) when t r e a t e d and c o n tr o l valu es were compared. The drop in m o t ilit y seen from week 4 to week 16 may have r e s u lte d from n o t b re e d in g those m a le s ; in c o n t r a s t , th e week 20 (m ated) v a lu e s were much h ig h e r . V alu es a re mean S .E .h ., n = 4 p e r group in weeks 1 -1 6 , n = 25 p e r group in week 20. 8325 %ABNORMAL SPERM 30 0 1 2 3 4 5 6 7 8 9 1011 12131415 161718 1920 WEEK OF TREATMENT V F ig u re 12. Average p e rc e n t abnormal sperm. T reatm ent had no s ig n if ic a n t in f lu e n c e on th e p e rc e n t abnorm al sperm ( p < 0 .0 5 ) . V a lu e s a re mean S .E .M ., n 4 p e r group i n weeks 1 - 1 6 , n * 25 p e r group in week 20. CG0SS'438326 UlHV 1136228 * ' 31 observed from weeks 16 to 20 o f th e study m ight be a t le a s t p a r t l y e x p la in e d by th e f a c t t h a t th e m ales -whose sperm were checked on week 20 had been through an 8-week in te n s iv e m ating program whereas th e males m onitored in the e a r l i e r weeks were v ir g in s . T e ra to lo g ic a l Examinations The r e s u lt s o f th e t e r a t o lo g y exam in atio n o f th e dams mated w ith tr e a te d o r c o n tro l males f o r each group by week are d e ta ile d in Tables 5 - 8 . A comparison o f the ta b le s in d ic a te s th a t th e average number o f im p lan ts p e r l i t t e r , average number o f re s o rp tio n s p e r l i t t e r o r average number l i v e fe tu s e s p e r l i t t e r (Tab les 5 -8 ) were u n a ffe c te d by th e m a le 's chem ical exp o sures. F o r exam ple, th e mean v a lu e s f o r c o n tr o l and Group I I (most h e a v ily exposed) were 7 .1 vs 7 .4 im p la n t s ite s p e r l i t t e r ; a ls o in Groups I and I I th e re were 4 .9 vs 5 .0 l i v e fe tu s e s p e r l i t t e r and 2 .1 8 vs 2 .3 7 r e s o rp tio n s p e r l i t t e r . ' The average f e t a l w e ig h t was s i g n i f i c a n t l y (p < 0 .0 5 ) g r e a te r in a l l tre a tm e n t groups as compared to c o n tro ls . The t o t a l number o f dead fetu ses ( i . e . , o ffs p rin g which weighed more th a n 0 .3 gm; o f f s p r in g w eighing < 0 .3 gm were l i s t e d as a 4 r e s o r p tio n s ) was 1 i n Group I , 2 in Group I I , 1 i n Group I I I and 0 in Group IV f o r th e e n t ir e 8 week s tu d y. The r a t io o f male to fem ale fe tu s e s was a ls o d e te rm in e d ; no tre a tm e n t group e x h ib ite d any s i g n i f i c a n t change (p < 0 .1 0 ) i n th is r a t io as compared, to th e c o n tro l. C ongenital m alform ations were not s ig n if ic a n t ly increased in the o ffs p rin g o f tre a te d versus c o n tro l males (Tables 5 -1 0 ). V is c e ra l m alfo rm atio n s were observed w ith le s s freq u en cy than e x te r n a l and s k e le ta l m alform ations in a l l groups. The incid en ces o f th e most fr e q u e n tly observed m alfo rm atio n s a re summarized in T a b le 9: eye d e fe c ts (a n o p h th a l mia and m ic ro p h th a lm ia ), jaw anom alies (a g n a th ia , m ic ro g n a th ia ), were observed in 1 .4 to 2 .4 p e rc e n t and 1 .2 to 1 .6 p e rc e n t o f th e fe tu s e s , QQo . w U /C i 0 8 0 6 2 -4 4 Nunber of (taalca eaanlned Maternal weight gain Niiuher of (plant* per Ut t e r Nniaber r| reaorptlona per litter Niuaber of live fetuaea per litter Average (etal weight per litter Hale/feat^le Viareral llal fornalionai Number of fetuaea eaaaiined Nunber with vlaceral nalforaationa Skeletal and External Halforaiatlona! Nunber of fetuaea exanined Nunber with ualfomationa 6229611111100 Table 5 Effect of 2,4-D, 2,4,S-T and TCUD on Fetal Developatent Croup I Control Week of Study 12 3 45 6 7 CO S! CO Total 9 9 weeka 1 13.1 2 1.0 0.1 1 0.5 2.16 1 0.3* 5.9 t 0.7 1.04 1 0.03 59/52 22 12.9 2 0.7 7.7 2 0.4 2.41 2 0.32 5.3 1 0.5 1.06 2 0.02 47/60 22 12.7 2 0.7 9.0 t 0.4 2.19 2 0.32 5.9 2 0.5 1.05 2 0.03 63/64 25 12.0 2 0.9 7.4 1 0.6 2.16 1 0..25 5.2 2 0.6 1.00 t 0.02 69/60 23 10.0 1 0.7 5.4 1 0.5 2.39 1 0.25 3.0 2 0.5 1.03 2 0.02 39/32 19 10.1 1 0.7 5.9 2 0.4 2.16 1 0.33 3.7 1 0.4 1.04 2 0.03 32/39 22 11.4 2 0.9 7.2 2 0.5 2.27 2 0.3 4.9 2 0.5 0.99 2 0.03 52/53 19 12.1 2 0.9 6.6 2 0.6 1.60 2 0.30 4.9 2 0.6 1.01 2 0.03 42/52 171 11.9 2 0.3 7.1 2 0.2 2.19 0.11 4.9 2 0.2 1!o 3 2 0.01 404/419 60 62 69 73 39 39 62 52 to 0 0 0 1 10 0 0 2 0 f 113 117 129 129 70 70 109 94 030 2 3 4 4 4 0 4 5 26 Value* are a a m + at andatd error of tli* M a n . 0006245 / Table 6 Effect of 2,4-D, 2,4,5-T and TCUD on Fetal Developaent Group II Week of Study 12 3A 5 6 7 8 Total 8 wceka Nuaiber of feaalca exaalned Haternal weight gain Nuaber of laiplanta per .Utter thuaber of reaorptlona per litter Nuaber of live fetuaea per litter Average fetal weight per litter Hale/feaale Viaceral Halforaatlona: Nuaiber of fetuaea eaaalned Nuaber with viaceral aalforaatlona Skeletal and External Halforaatlona: Nuaber of fetuaea exaained Nuaber with aalforaatlona 19 14.1 t 0.3 9.2 t 10.4 2.37 1 0.27 6.8 t 10.3 1.00 1 0.02 62/67 16 21 12.7 t 0.9 12.2 1 0.S 7.4 1 0.6 S.2 1 0.4 1.94 1 0.37 2.71 t 0.40 3.3 1 0.7 3.6 1 0.3 1.14 t 0.03 I.0S t 0.03 39/60 61/48 17 II.5 t 1.0 6.2 i o.6 1.76 t 0.22 4.3 t 0.7 1.09 i 0.02 36/39 22 ' 10.8 t 0.7 7.1 i 0.4 2.53 t 0.36 4.3 1 0.4 1.02 1 0.03 43/54 20 10.4 i 0.9 6.2 1 0.3 2.30 t 0.43 3.9 t 0.6 l.ll t 0.03 43/34 17 12.6 1 0.9 7.5 1 0.4 1.88 t 0.38 3.6 1 0.6 1.02 1 0.02 42/54 14 12.0 1 1.0 7.0 t b.7 3.43 1 0.71 3.6 t b.7 1.10 t 0.03 28/26 148 12.0 1 0.3 7.4 1 0.2 2.17 t 0.14 5.0 1 0.2 1.08 t 0.01 356/376 66 S3 61 42 34 42 47 28 393 ^ 0000002 0 2 1f 129 99 115 78 100 77 96 50 744 2 6 4 0 5 1 7 1 26 Valueo ore neon + otandard error of the Moan. C*i0fc*S46 GO Co t\D CO 0'G29eiI Alfld TCS9GTL NVOQ Table 7 Effect of 2,4-D. 2,I,5*T and TCDD oil Fetal Development Group III Week o f Study Total 1 2 3 4 3 6 7 k 8 weeka Humber of femalce examined Maternal weight gain Number of Implanta per litter Number of reaorptiona per litter Number of live fetuaea per litter Average fetal weight per litter Halc/female Vlaceral Halformatlonai Number of fetuaea examined Number with vlaceral malformatlona Skeletal and External Malformatlona: Number of fetuaea examined Number with malformatlona IB 12.9 t 0.9 8.4 4 0.6 2.65 4 0.31 3.7 4 0.7 1.06 1 0.0] 67/30 IS 12.9 i 0.9 7.6 4 0.3 2.27 4 0.46 3.4 4 0.6 l.ll 4 0.02 41/39 ' 21 11.9 4 0.7 7.3 1 0.4 2.14 4 0.33 3.3.4 0.3 1.13 4 0.02 SS/S3 17 12.0 4 0.9 6.6 4 0.6 1.63 4 0.2S 3.0 4 0.3 1.09 4 0.0] 33/50 19 10.7 4 0.8 7.2 4 0.3 2.84 4 0.37 4.3 4 0.4 1.09 4 0.02 46/35 22 10.9 4 0.8 6.6 4 0.6 2.14 4 0.34 4.3 4 0.5 | .03 4 0.03 51/47 21 10.2 4 0.6 6.8 4 i0.4 2.05 4 0.30 4.8 4 i0.4 1.00 4 0.02 51/49 12 12.2 4 l.l 7.0 4 0.6 2.]] 4 0.72 4.7 4 0.7 1.09 4 0.03 29/26 145 11.6 4 0.3 7.2 4 0.2 2726 4 0.1 4.9 0.2 1.08 4 0.01 356/349 S3 44 60 44 47 58 56 32 394 13000 00 15 1 97 tl 112 5 82 98 100 56 711 2 1 4 2 3 0 5 1 20 Valtieo ore aeon + otandard error of the awan. 00 Co CO o / Effect of Table 8 2,4,5-T and TCIM1 on Fetal UevelopaieiiL Croup IV l/cck of Study Total 1 2 3 4 5 6 7 1 6 weeks Huaiber of fcnatea exaarined Naternal weight gain Hiiolier of laplanla per litter Huaiber of reaorptiona per litter Huariier of live fetuaea per litter Average fetal weight per litter Hale/fenale Visceral Halfornationet Huaiber of fetuaea exaaUned Huaiber with viaceral ualfonaationa Skeletal and External Halfornationai Niuulicr of fetuses exaolned Huaiber with nalforaiationa 18 11.6 1 0.8 8.9 ft 0.7 4.00 ft 0.S0 4.9 1 0.6 1.12 1 0.04 33/46 23 20 12.9 ft 0.8 11.5 ft 0.7 7.3 ft 0.6 7.0 1 0.6 1.77 ft 0.29 '1.30 ft 0.28 5.6 ft 0.6 5.7 ft 0.5 1.16 ft 0.03 1.09 ft 0.02 59/69 58/54 24 12.2 ft 0.8 7.6 ft 0.5 1.88 ft 0.30 5.8 ft 0.6 l.ll ft 0.02 63/75 21 9.9 ft 0.8 6.0 ft 0.5 1.95 ft 0.37 4.1 ft 0.5 1.10 ft 0.03 45/41 21 9.9 ft 0.8 6.5 ft 0.5 2.43 ft 0.35 4.1 ft 0.4 1.07 ft 0.03 40/46 IS 11.9 ft 0.8 7.5 ft 0.6 2.39 ft 0.48 5.1 ft 0.6 1.05 ft 0.03 42/46 19 11.9 1 0.9 5.9 ft 0.7 1.58 ft b.30 4,5 ft0.7 1.07 ft 6.03 36/44 164 II.5 1 0.3 7.0 1 0.2 2.11 0.1 5.0 + 0.2 1.10 1 0.01 376/420 u> Ui 41 67 62 77 50 50 50 46 443 10 2 1 1 1 0 0 0 5 ;b 129 113 139 86 66 92 62 805 2 5 5 3 2 0 4 4 25 V a lu e a o re aiean a ta n d o rd e r r o r o f t lio autan. <48 CX) CO ses9eilMOO CO DO\H1136233 36 re s p e c tiv e ly . C le ft p a la te and h e a rt or m ajor blood ves s e l anomalies were observed in a l l groups in somewhat low er in cid en ces (T a b le 9 ) . The t o t a l p ercen t malformed fe tu s e s (T ab le 10) ranged from 3 .1 to 3 .6 p ercen t a n d .th e w eekly p e rc e n ta g e d id n o t show any t r e a t m e n t - r e la t e d in c re a s e s in co n g en ital m alfo rm atio n s. A comprehensive l i s t i n g o f m alform ations observed during th e study has been in clu d ed (Appendix T ab le 1 ). P o stn atal L it t e r Examinations When fem ales were a llo w e d to c a r r y t h e i r l i t t e r s to te rm , th e s u r v iv a l and development o f t h e i r o ffs p r in g were s tu d ie d . The number o f l i v e pups and t h e i r mean body w e ig h t were compared i n t r e a t e d and c o n tro l o ffs p rin g (Tables 1 1 -1 4 ). The la c k o f a to x ic e ffe c t is graph i c a l l y dem onstrated by comparing valu es f o r c o n tro l (Group I ) anim als to th o se f o r th e a n im als exposed to th e h ig h e s t dose o f phenoxy a c id and TCDD (Group I I ) . There was a marked r e d u c tio n i n th e number o f l i t t e r s from day 0 to day 4 in a l l groups. In group I the number o f l i t t e r s ^ f e l l from 80 to 44 and i n group I I from 90 to 6 0 . T h is was accounted f o r in a l l groups by cannabalism by the m others. A fte r day 4 , the loss o f l i t t e r s was g r e a t l y d e c re a s e d . O th e r p aram eters show l i t t l e d if f e r e n c e between Groups I and I I ; on day 0 , th e number o f l i v e pups p e r l i t t e r were 4 .4 0 and 4 . 1 9 , number o f dead pups p e r l i t t e r was 0 .9 2 i n b o th groups, and th e average pup w eights were 1 .3 7 and 1 .3 9 . A t day 21 the number o f l i v e pups p e r l i t t e r were 5 .1 5 and 4 .5 9 and th e averag e pup w e ig h ts were 7 .4 8 and 7 .6 0 , r e s p e c t iv e ly , f o r groups I and I I . No e f f e c t on p o s tn a ta l v i a b i l i t y o r growth could be a t t r ib u t e d to th e exposure o f th e a d u lt male m ice to phenoxy a c id s o r to TCDD. The pups w ere examined e x t e r n a l l y on day 0 f o r m a lfo rm a tio n s (T a b le s 15 and 1 6 ) . D u rin g th e e n t ir e e ig h t weeks th e t o t a l m a lfo rm a tio n CG0643 - 8332 DOW 1136234 37 TASLZ 9 SisBoarj of Most Frequently Occurring Defects ln Fetuses Sired by Males Treated with 2,4-0, 2,4,5-T asd T O D Treatment Croup I n El IV Asopchalsla/ sieropcbalsla 4gnatbla/alcrognathia Cleft Palate Heart/Vessels Asosallea 1.4(12/830) 1.301/830) 0.6(3/830) 0.20/435) 1.904/744) 1.2(9/744) 0.7(3/744) 0.5(2/393) 2.004/711) 1.4(10/711) 0.7(3/711) 1.0(4/394) 2.409/805) 1.6 03/805) 0.7(6/805) 0.7(3/443) Values arm paresse lacldaaet of specific ssoaaUes; so. specific salforaacloBa per no. observed Is gives la parestbeses. GGOGSoO DOW 1136235 38 TA3IZ 10 Percent Malferaad Pacuaa* Sired by Males Treated with 2,4-0, 2,4,5-T ad T O D Week I inTreacaenc Croup IX IT 1 1.8(2/113) 1.6(2/129) 3.1(3/97) 2.6(2/78) 2 2.6(3/117) 6.1(6/99) 3.7(3/81) 3.4(7/129) 3 3.1(4/123) 3.3(4/113) 3.6(4/112) 3.3(6/113) 4 3.1(4/129) 0.0(0/78) 2.4(2/83) 2.2(3/139) 3 3.7(4/70) 3.0(3/100) 6.1(3/82) 3.3(3/86) 6 0.0(0/70) 1.3(1/77) 0.0(0/98) 0.0(0/86) 7 3.7(4/108) 8.3(8/96) 3.0(3/100) 4.3(4/92) 8 3.3(3/94) 2.0(1/30) 1.8(1/36) 4.9(4/82) local 3.1(26/830) 3.6(27/744) 3.2(23/711). 3.6(29/803) Values ara perant mal foraad fetuses, a m b e r malford per a m b e r observed is (Ives la pareacfcases. Ho values are significantly different free control (p<0.05). v > CGO&1 Table 11 Effect of 2,4-0, 2,4,5-T and TC00 on Poatnatal Development of Offapring of Treated Halea Croup I Control Week of Study 1 2 3 4 `5 6 7 Total 8 weeka Day 0; Number of llttera Number live pupa per litter Number dead pupa per litter Average pup weight Day 4; Number of llttera 1 Number live pupa per litter Average pup weight Day 1: Number of llttera Number live pupa per litter Average pup weight Day 21: Number of llttera Number live pupa per litter Average pup weight 17 3.94 t 0.70 1.47 t 0.43 1.39 t 0.03 IS 4.67 t 0.80 1.33 t 0.45 1.34 t 0.02 15 6.00 1 0.62 0.20 1 0.20 1.37 i 0.48 10 5 2.60 t 0.85 4.00 t 1.10 1.10 t 0.41 1.00 t 0.78 1.41 t 0.02 1.36 1 0.04 10 5 3.70 l 0.91 5.40 1 0.51 0.44 f 0. IB 0.20 1 0.20 1.38 l 0.05 1.33 t 0.03 3 5.00 t 2.51 1.33 t 1.33 1.30 i 0.d3 80 4.40 1 0.32 0.92 t 0.16 l;37 t 0.01 8 5.00 t 1.20 1.87 1 0.10 1 5 6.60 t 0.93 2.22 t 0.19 10 5.30 1 0.75 2.04 t 0.15 4 5.50 t 0.50 2.43 t 0.10 4 4.75 i 0.75 2.71 t 0.24 6 4.00 i 0.78 2.32 1 0.28 5 5.40 1 0.51 2.35 t 0.19 2 7.50 1 o.sb 2.25 t 0.39 44 5.30 t 0.33 2.22 t 0.07 8 4.29 1 0.99 3.13 t 0.29 59 1 6.60 t 0.93 5.78 1 0.64 3.64 t 0.33 3.60 1 0.19 4 5.50 i 0.50 4.07 i 0.18 4 4.75 t 0.75 4.71 t 0.39 5 4.00 t 0.95 4.67 t 0.26 5 5.40 t 0.51 4.03 1 0.24 2 7.50 1 0.50 3.59 1 0.35 42 5.32 t 0.31 3.83 1 0.12 8 4.75 t 0.98 6.43 i 0.51 4 6.00 t 0.91 7.02 t 0.75 9 5.78 1 0.64 7.34 1 0.32 4 5.25 1 0.63 8.74 t 0.21 4 3.50 t 1.04 8.62 t 0.54 5 4.00 1 0.95 7.71 1 0.65 5 5.40 1 0.51 8.07 t 0.51 2 7.50 t 0.S 6.41 t 0.12 41 5.15 1 0.32 7.48 t 0.21 Vnlueo are mean + etandard error of tlie Bean* 9fe89eil MOO .. eS9ETl P O T a b u 12 Effect of 2,4-D, 2,4,5-T and TCDD on Postnatal Development of Offspring of Treated Maieg Croup II Week of Study Total 1 2 3 4 5 6 7 i 8 weeks PY 0 - Humber of llttera Number live pups per litter Number dead pups per litter Average pup weight Dry li Humber of U t t e r s Hiuaber live pups per litter Average pup weight fiflLli Number of litters Niuaber live pups per litter Average pup weight Day 21: Humber of litters Nimher live pups per litter Average pup weight U 4.76 t 0.33 O.AB t 0.40 1.39 1 0.03 16 4.88 t 0.68 1.06 t 0.30 1.39 t 0.04 14 3.29 1 0.74 0.64 t 0.27 1.33 t 0.02 3 2.80 1 1.20 1.00 1 0.78 1.47 t o.os 16 3.13 1 0.59 0.79 i 0.26 1.42 t 0.03 II 1.33 t 0.74 1.23 t 0.45 1.42 t 0.09 1 6 3.67 1 0.92 1.33 t 0.80 1.38 i 0.07 3- 4.00 t 1.41 1.00 1 0.45 1.36 t 0.b4 90 4.19 t 0.29 0.92 t 0.14 1.39 1 0.01 II II II 3 14 3 3 4 60 4.63 1 0.46 3.23 t 0.36 5.36 t 0.61 4.67 i 0.67 4.64 1 0.38 4.50 t 0.50 3.67 1 0.33 4.25 t 1.44 4.79 1 0.25 2.21 t 0.11 1 II 4.20 t 0.44 3.61 t 0.19 2.30 t 0.14 II 4.73 t 0.63 3.63 1 0.25 2.11 t 0.06 II 5.36 t 0.61 3.38 t 0.10 2.39 i 0.19 3 i4.67 0.67 4.12 t 0.29 2.47 t 0.10 14 *4.64 0.58 4.08 1 0.22 2.44 t 0.18 3 3.67 i 0.88 3.03 i 0.90 2.36 1 0.18 3 3.33 t 0.68 4.19 1 0.21 2.47 t 0.21 4 4.25 1 1.44 14.04 6.24 2.33 t 0.05 60 4.58 1 0.25 3.79 1 0.09 10 4.00 1 0.49 7.28 t 0.48 10 3.00 t 0.58 7.71 t 0.24 10 5.10 i 0.64 7.20 1 0.39 3 4.67 t 0.67 a.ii t 0.43 13 4.92 t 0.53 i8.43 0.21 3 3.67 t 0.88 5.30 t 0.14 3 i3.33 0.67 8.43 t 0.11 4 4.25 1 1.44 7.58 t 0.52 56 4.59 1 0.25 7.60 t 0.16 Valiieo ore ktan 4 atandard error of the moan. . *> CO Co o Co 05 Table |J Effect of 2,4-0, 2,4,5-T and TCDD on Poatnatal Development of Offapring of Treated Halea Group III Week of Study Total 1 2 3 T - 5 l 7 I 8 week Bay Ot Nuadier of littere Number live pup* per litter Hiuaber dead pupa per litter Average pup weight Bay 4; Numbet of littere Number live pupa per litter Average pup weight Bay I: Hiuaber of littere Humber live pup* per litter Average pup weight 14 5.64 t 0.52 0.51 t 0.34 1.32 1 0.02 II 3.91 i 1.01 1.55 t 0.43 1.39 1 0.06 12 5.67 t O B J 0.27 1 0.14 1.37 1 0.27 9 6.11 i 1.03 0.11 t 0.11 1.36 i 0.04 10 3.B0 i 0.B0 0.60 i 0.34 1.32 1 0.06 II 2.73 t 0.75 0.50 1 0.27 1.39 1 0.05 II 3.B2 t 0.89 0.90 l 0.41 1.37 t 0.02 3 1.67 i l.ij i.o o t o .4b 1.38 81 4.44 t 0.32 0.67 t 0.13 1.36 i 0.01 12 5.30 t 0.47 2.03 * 0.09 3 4.33 0.67 1.76 t 0.89 B 5.25 1 0.10 2.19 t 0.16 4 5.25 1 0.75 2.25 i 0.16 B 4.25 i 0.49 2.50 t 0.10 5 4.60 t 0.40 2.79 1 0.0S 7 5.57 i 0.53 2.73 1 0.07 1 5.00 2.at 12 5.00 t 0.44 3.25 t 0.21 3 4.33 1 0.67 2.79 i 0.17 a 5.13 1 1.04 3.52 i 0.93 4 5.25 i 0.75 3.67 t 0.23 a 4.25 1 0.49 4.16 1 0.13 5 4.60 i 0.40 4.67 t 0.14 7 5.57 t 0.53 4.54 1 0.13 1 5.00 4.66 48 4.91 1 0.25 2.37 1 0.06 48 4.92 1 0.24 3.82 t 0.12 Humber of litter* Hiuaber live pup* per litter Average pup weight 12 3 7 4 a 5 6 1 5.00 1 0.44 4.00 t o.sa 5.43 t 0.97 5.00 1 0.71 4.25 1 0.49 4.60 i 0.40 5.50 t 0.62 4.00 6.83 1 0.22 7.43 1 0.64 7.12 i 0.37 B.39 1 0.25 a.15 t o.ia 7.66 t 0.24 a.59 i 0.28 10.31 Value* are u m t etamlard error of tlie aiean. 46 4.87 t 0.23 7.67 1 0.15 CO Co 8829611 MOO 6E396TI MOQ / Table 14 Effect of 2,4-D, 2,4,5-T an<l TCDD on Poatnatal Pevelopaent of Offapring of Treated Halea Croup IV ____________________________________________ Weeli of Study_____________________________________________ T2 5 4 :5 i 7f Total t wecka Pay Oi Niuiber of llltera Nuaber live pupa per litter Nuaiber dead pupa per litter Average pup weight Li Nuaber of llltera Nualier live pupa per litter Average pup weight Day 7i Nuaiber of llttera Nuaber live pupa per litter Average pup weight 19 4.a4 1 0.64 0.95 ft 0.29 1.36 ft 0.02 23 5.35 ft o.6a 0.74 ft 0.20 1.36 ft 0.03 14 II 5.29 ft 0.ft3. 3.82 ft 1.06 0.79 ft 0.38 1.09 ft 0.32 1.39 ft 0.03 1.44 ft 0.05 15 3.67 ft 0.56 0.79 ft 0.28 1.39 ft 0.03 10 2.60 ft 1.19 1.50 1 0.50 1.43 ft 0.05 ' II 4.45 ft 0.71 0.27 1 0.14 i.ia 1 0.03 5 3.80 ft 1.66 o.ao ft b.49 1.43 1 6.06 ioa 4.41 1 0.29 0.84 ft 0.11 1.39 ft 0.01 10 5.57 ft 0.43 2.24 ft 0.16 10 5.40 ft 0.67 2.41 1 o.oa a 6.00 ft 0.66 2.60 1 0.97 4 6.25 ft 1.03 2.30 ft 0.13 9 3.33 1 0.50 2.40 ft 0.19 4 5.75 ft 1.49 2.94 1 0.50 a 4.BB ft 0.55 2.54 ft 0. |6 3 4.67 i 6.88 i2.38 6.28 56 5.13 1 0.27 2.41 1 0.08 10 5.00 ft 0.47 3.2B ft 0.31 10 5.40 ft 0.67 4.08 ft 0.15 a 6.00 ft 0.66 4.06 ft 0.18 4 6.oo i i.oa 3.88 ft 0.24 9 3.33 ft 0.50 3.98 ft 0.41 4 5.75 ft 1.49 3.80 1 0.33 8 4.88 ft 0.55 4.24 ft 0.25 3 4.67 ft 0.88 3.99 ft 0.46 56 5.04 ft 0.26 3.94 1 0.10 Pay 21: Nualier of llttera Nuaher live pupa per litter Average pup weight 10 5.00 ft 0.47 6.99 ft 0.34 10 5.30 ft 0.63 8.15 ft 0.33 8 5.75 ft 0.59 7.53 ft 0.40 4 6.00 ft 1.08 8.20 ft 0.09 9 3.33 ft 0.50 8.53 ft 0.68 4 5.75 ft 1.49 6.66 ft 0.74 8 4.75 ft 0.59 8.34 1 0.37 3 4.67 ft 0.88 7.38 1 0.97 56 4.96 ft 0.25 7.80 ft 0.18 Valuea are aeaii + atandard error of tlio aean. oo CO CO OO NJ>S . DOW 1-13G240 43 TA2LZ U Sinmiry of Malfomacloa Rataa (Z) in Postnatal Study^ Vaak I Traacacat Croup H rn I 5.4(5/92) 2.1(2/96) 1.1(1/87) 2 2.2(2/90) 3.2(3/95) 5.0(3/60) 3 1.1(1/93) 4 0.0(0/37) 6.0(5/83) 5.3(1/19) 6.6(5/76) 8.9(5/56) 5 4.0(1/25) 1.1(1/88) 4.5(2/44) 6 2.2(1/45) 0.0(0/32) 2.1(1/48) 7 7.1(2/28) * 13.3(4/30) 3.8(2/53) S 5.3(1/19) 8.0(2/25) 0.0(0/8) Total 3.0(13/429) 3.8(18/468) 4.4(19/432) ^All factual (11va or daad) vara aasuaad to ba at flak. 17 1.9(2/105) 0.0(0/140) 2.4(2/85) 13.0(7/54) 2.7(2/73) 2.10/47) 3.8(2/52) 4.30/23) 2.907/579) 8339 C00GS36 DOV1 1136241 44 TABUE 16 SuaaarT' o S p edile Malformation* in Postnatal Study IU Anopthalala/ CT<ipthll.<. 1.9(8/429) 2.6(12/468) Agnachla/aicrognachla Cleft Lip/palato 1.4(6/429) * 0.2(1/429) 1.3(6/468) 0.4(2/468) All 1 0.0(0/429) 0.0(0/468) *Cn ejconcaphaly; on* clubbed rlfht blad llab. m 2.5(11/432) 1.9(8/432) 0.0(0/432) 0.5(2/432)* 17 1.7(10/579) 1.4(8/579) 0.0(0/579) 0.0(0/579) V GOSS.' 8340 DOW 1136242 45 r a t e i n th e s e m ice was betw een 2 .9 and 4 . 4 p e r c e n t. The o n ly in d iv id u a l v a lu e s w hich .approach s t a t i s t i c a l s ig n ific a n c e are th e m a lfo rm a tio n ra te s f o r week fo u r group IV (40 m g/kg/day phenoxy a c id , 1 .2 p g /k g /d a y TCDD) (T a b le 1 5 ) v e rs u s c o n t r o l. I n t h a t case th e c o n t r o l a n im a ls had no m a lfo rm a tio n s and th e t r e a t e d had 13% m a lfo rm a tio n s ; a l l o f th e s e were e ith e r eye o r jaw anom alies. As seen i n th e p r e n a t a l e v a lu a t io n s , eye and ja w m a lfo rm a tio n s accounted f o r the m a jo rity o f th e d e fe c ts noted (T a b le 1 6 ). Anoptha lm ik o r m ie x o p th a lm ia were seen i n 1 .7 to 2 .6 p e rc e n t o f th e pups and a g n a th ia o r m icro g n ath ia were seen in 1 .3 to 1 .9 p e rc e n t o f th e pups fo r a l l treatm en t groups. GGO&^oB DOW 1136243 4 DISCUSSION I n th.es s t u d ie s -we have e v a lu a te d th e t o x i c i t y o f t h r e e m ix tu re s __ r o f 2 , 4 - D , 2 , 4 , 5 - T and TCDD on r e p r o d u c tio n i n m ale m ic e . M a tin g fre q u e n c y , f e r t i l i t y , germ c e l l m u tag en esis, and f e t a l o r p o s tn a ta l developm ent were a l l considered in th e s e le c tio n o f to x ic o lo g ic a l e n d p o in ts . Male m ice were c o n tin u o u s ly exposed to h ig h doses o f 2 ,4 -D p lu s 2 ,4 ,5 - T mixed w it h 2 o r 30 ppm TCDD i n th e phenoxy a c id f o r 8 w eeks. These TCDD le v e ls re p re s e n t average and h ig h c o n tam in atio n le v e ls w ith in H e rb ic id e Orange used in Vietnam (7oung e t a l . , 1 9 7 8 ). T h is stu d y employed th e fr e e a c id s o f 2 ,4 -D and 2 ,4 ,5 - T r a th e r th an th e b u ty l e s te rs w hich were components o f H e rb ic id e Orange because o f th e low er v o l a t i l i t y o f the a c id s . The e s te rs are ra p id ly m etabolized to th e fr e e a c id in b o th p la n ts and a n im a ls , and th e r e fo r e , th e system ic t o x i c i t y can be a t t r ib u t e d to th e fr e e a c id (G ehring and B etso , 1978) and should be com parable on a m o lar b a s is . The dose le v e ls employed e x h ib ite d m oderate to low d ir e c t t o x i c i t y i n exposed m ale m ice as evid en ced by decreased body w e ig h t g a in , changes in thymus and l i v e r w eig h ts and m orphologic changes in th e l i v e r . The m o r t a lit y , how ever, was q u it e lo w . The s e v e r it y o f th e s e t o x ic e f f e c t s appeared to be p r i m a r i l y r e l a t e d t o th e TCDD c o n te n t o f th e s im u la te d " H e r b ic id e O range" m ixtu re. D e s p ite th e use o f continuous, m oderately to x ic , chem ical exposures th ro u g h o u t th e co m p le te p e r io d o f s p e rm a to g e n e s is , no s i g n i f i c a n t in c re a s e i n r e p r o d u c t iv e a b n o r m a lit ie s i n th e 2 , 4 - D , 2 , 4 , 5 - T o r TCDD exposed groups w ere o b s e rv e d . TCDD has p r e v io u s ly b een d e m o n s tra te d to a l t e r sperm atogenesis in C57BL/6 m ice (M cConnell e t a l . , 1 9 7 8 ), how ever, th a t s tu d y used a s in g le h ig h ( l e t h a l ra n g e ) dose o f TCDD. A d d i t i o n a l l y , 8342 DOW 1136244 5 47 t e s t i c u l a r le s io n s were o n ly found in c l i n i c a l l y i l l a n im a ls , as opposed i o th o se v h ic h su rv iv e d 'exposure t o s im ila r doses (M cConnell e t a l . , 1 9 7 8 ). A lte re d sperm atogenesis has a ls o been rep o rted in ra ts (Xociba e t a l . , 1 9 7 6 ), guinea p ig s (M cC onnell e t a l . , 1 9 7 8 ), and monkeys and c h ic kens (N orback and A lle n , 1 9 7 3 ), a lth o u g h th e s e were a g a in t o x ic exposures. In th e p re s e n t s tu d y , m o rp h o lo g ical changes were n o t observed i n th e t e s t i s o f t r e a t e d m ic e . Thro u g h o u t t h i s s tu d y t e s t i s w e ig h t was n o t a f f e c t e d , n o r was sperm m o t i l i t y o r p e r c e n t abnorm al sp erm ato zo a. Mean sperm c o n c e n t r a tio n , ho w ever, was s l i g h t l y reduced a f t e r f i v e and . e i g h t weeks o f d o s in g , a lth o u g h th e e f f e c t was n o t s t a t i s t i c a l l y s i g n i fic a n t (p > 0 .l0 ). The l e v e l s o f TCDD chosen f o r t h i s s tu d y were w i t h i n th e range t h a t had a lr e a d y been shown to r e s u lt i n c l e f t p a la t e and k id n e y anom alies when g iv e n to p re g n a n t C57BL/6 fem ale m ice (Moore e t a l . , 1 9 7 3 ). M ix tu re s o f phenoxy a c id s p lu s s p e c i f i c l e v e ls o f TCDD were used i n o rd e r to b e t t e r m im ic human exposures to E e r b ic id e O range. A d d i t i o n a l l y , p re v io u s i n v e s t i g a t o r s (N e u b e rt e t a l . , 1 9 7 3 ) showed t h a t adding as l i t t l e as 0 .1 p g /k g TCDD to 2 , 4 , 5 - T in c re a s e d th e t e r a t o g e n i c i t y i n m ice o f 2 , 4 , 5 - T i n o ffs p rin g o f exposed mothers above th a t expected by a sim ple a d d itiv e e f f e c t . The dose o f TCDD i n t h i s s tu d y i s a t o r above th e 0 .1 p g /k g /d a y l e v e l . A ls o , i t sh o u ld be em phasized t h a t human exposures in v o lv e d m ix tu re s o f 2 , 4 - D , 2 , 4 , 5 - T and TCDD ( H e r b ic id e O ra n g e ). C e r ta in c h e m ic a ls , when g iv e n to a d u lt m a le s , can cause f e t a l d e a th o r a l t e r norm al development in o ffs p r in g s ire d by those males ( J o f f e , 1979; Manson and Simons, 1 9 8 0 ), how ever, such e ffe c ts were n o t e l i c i t e d i n th e e x p e rim e n ts we r e p o r t by e x p o sin g m ale m ice to th e 2 ,4 - D , 2 , 4 , 5 T and TCDD m ix t u r e s . As ev id e n c e d by th e numbers o f im p la n ts and r e s o r p t io n s , n e it h e r embryo t o x i c i t y n o r dom inant l e t h a l m u ta tio n s could be DOW 1136245 48 a ttr ib u te d to exposure to these ch em icals . The u n a ffe c te d valu es f o r p e rc e n t .abnorm al sperm, which I s a - t e s t f o r m u ta g e n ic ity {V yro b ek, 1979) a ls o lead s one to th e c o n c lu s io n th a t th e ch em icals , as g iv e n , were n o t m utagenic tow ards th e m ale germ c e l l s . T h is c o r re la te s w e ll w ith p re v io u s m u ltig e n e r a tio n s tu d ie s (h u r r a y e t a l . , 1 9 7 9 ) and dom inant l e t h a l assays (K hera and R u d d ick, 1 9 7 1 ). The valu es f o r p e rc e n t malform ed fe tu s e s also in d ic a te d th a t 2 ,4 -D , 2 , 4 , 5 - T and TCDD had no in f lu e n c e on th e o f f s p r in g o f exposed m a le s . The s tu d y was d e s ig n e d such t h a t , i f th e o v e r a l l p e r c e n t m alform ed fe t u s e s (3%; see A p p endix T a b le 1 ) was d o u b le d i n one o f th e e x p e r im e n ta l g ro u p s , t h e r e was a 90% chance t h a t i t w ould have been d e te c te d . T h e re was a 70-80% chance o f d e te c tin g a f o u r - f o l d in c re a s e i n c o n g e n ita l d e fe c ts in any one week. F o r any s p e c ific m alfo rm atio n o r class o f m a lfo rm a tio n s th e co rresp o n d in g powers would be somewhat le s s . F o r exam ple, f o r v is c e r a l d e fe c ts (background r a te 0.44%; see T a b le 5 ) the e x p e rim e n t had a p p r o x im a te ly a 90% chance o f d e t e c t in g an o v e r a l l r a t e as h ig h as 3% i n an y p a r t i c u l a r tr e a tm e n t g ro u p . The o n ly v a r i a t i o n w h ic h we c o u ld f i n d e le v a te d i n t r e a t e d v e rs u s c o n t r o l o f f s p r i n g , i n th e e n t i r e s tu d y , was th e in c id e n c e o f fu s e d s te m e b r a e (A p p e n d ix T a b le 2 ) . I n t h a t c a s e , we o b served a s t a t i s t i c a l l y s i g n i f i c a n t ( p < 0 .0 5 ) in c r e a s e i n fu s e d s te rn e b ra e i n Group I I I a t week 3 and i n Group IV a t week 4 . The in c id e n c e i n th e c o n tr o ls a t th o se tim e s , how ever, was u n u s u a lly low (0 in b o th weeks 3 and 4 ) . T h is ty p e o f s k e le t a l v a r ia t io n has been d e s c rib e d as o c c u rrin g as o fte n as 5-15% o r more in o ffs p r in g from u n tre a te d pregnancies in m ice and a lth o u g h i t is fre q u e n tly observed, th e in c id e n c e is q u ite v a r ia b le and th is anomaly is co n sid ered a v a r ia t io n and n o t a m alfo rm atio n (W ilso n , 1 9 7 3 ). C G G SS i DOW 113G246 49 JUPFSSDg ju a ix 1 Snmary of Ail Malformations Observed la Focus* Sired by Males Treated with 2,4-0, 2,4,5-T ad T O D Treatment Group I IT m TV Visceral Malformations^ Haart/Vcsscls Anomalies Kidney Ageaesls Liver-cvo lobes only Lung-lobes 2/3 aocaal size Eight kldaey-1/2 aoraal size 0.2(1/453) 0.2(1/455) 0.0(0/455) 0.2(1/455) 0.0(0/455) 0.5(2/393) 0.0(0/393) 0.0(0/393) 0.0(0/393) 0.0(0/393) 1.0(4/394) 0.3(1/394) 0.0(0/394) 0.0(0/394) 0.0(0/394) 0.7(3/443) 0.0(0/443) 0.2(1/443) 0.0(0/443) 0.2(1/443) Skeletal and External Malformations2 Anopchalml a/elcropthatola Agnathia/micrognathia Cleft palace Cleft Up/nose Open eye Exeacaphaly/hydrocephaly No tongue Dobillcal hernia Elbe fused/alsslag Spinal centra doubled/'misaligned Spinal arches fused Mandibles fused Skull banes missing Eye bones mlsslag Fecial banes fused Kinked Tall 1.4(12/830) - 1.3(11/830) 0.6(5/830) 0.0(0/830) 0.5(4/830) 0.2(2/830) 0.0(0/830) 0.1(1/830) 0.1(1/830) 0.1(1/830) 0.0(0/830) 0.0(0/830) 0.0(0/830) 0.0(0/830) 0.2(2/830) 0.1(1/830) Total Malformations2 5.2(43/830) Total Malformed Fetuses2 3.1(26/830) 1.9(14/744) 1.2(9/744) 0.7(5/744) 0.0(0/744) 0.0(0/744) 0.4(3/744) 0.0(0/744) 0*3(2/744) 0.3(2/744) 0.0(0/744) 0.0(0/744) 0.0(0/744) 0.1(1/744) 0.1(1/744) 0.5(4/744) 0.0(0/744) 5.8(43/744) 3.6(27/744) 2.0(14/711) 1.4(10/711) 0.7(5/711) 0.3(2/711) 0.0(0/711) 0.1(1/711) 0.1(1/711) 0.3(2/711) 0.0(0/711) 0.1(1/711) 0.1(1/711) 0.1(1/711) 0.1(1/711) 0.0(0/711) 0.4(3/711) 0.0(0/711) 6.6(47/711) 3.2(23/711) 2.4(19/805) 1.6(13/805) 0.7(6/805) 0.0(0/805) 0.0(0/805) 0.2(2/805) 0.0(0/805) 0.1(1/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 0.0(0/805) 5.7(46/805) 3.6(29/805) ^Values are percent incidence of specific aaoaailaa; ao. specific malformations per no. -observations Is givea la pareacheses. ^Values are pereeae Incidence of naifornacions or malformed fetuses; ao. malformations - or aalforsed fetuses per ao. observacloas is given la pareacheses. 8245 CG06S63 DOW 1136247 50 AP?=!fiZX TASLS 2 Incidence of Fused Sternebrae In Fetuses Sirsd by Males Treated with 2,4-D, 2,4,3-T and I S O Week Z 1 0.90/113) 2 1.7(2/117) 3 0.0(0/129) 4 0.0(0/129) 5 1.1(1/70) 6 1.10/70) 7 3.7(4/108) 8 2.1(2/91) Total 1.301/830) *p<.05 w . controls. Treatment Group n 121 1.6(2/129) 3.0(3/99) 0.90/115) 2.6(2/78) 2.0(2/100) 5.2(1/77) 2.1(2/96) 2.00/50) 2.307/711) 1.00/97) 3.7(3/81) 7.1(8/112)* 2.1(2/83) 3.7(3/82) 3.1(3/98) 0.0(0/100) 0.0(0/56) 2.8(20/711) 17 1.30/78) 1.6(2/129) 2.7(3/113) 5.0(7/139)* 2.3(2/86) 3.5(3/86) 2.2(2/92) 1.20/82} 2.6(21/805) 'U'"'; r*T` OUtJOtaOO DOW 1136248 51 Certain anomalies are associated with embryotoxicity, not teratogen icity or mutagenicity. However, with chemical -exposure only to the males, not pregnant females, embryotoxicity would not be expected in their offspring. If exposure of the embryo directly to the chemicals had occurred, via seminal plasma or sperm, one would expect to observe increased embryotoxicity in the first weeks of the study, when the chemical levels in the body (or ejaculate) were the highest. One would have also anticipated that during the first weeks of the teratology study germ cell toxicity would most likely have been detected, because the spermatozoa that were evaluated in the first week of mating had been exposed to the chemicals throughout ail stages of the spezmatogenic process. If the spermatogonia had been affected by the exposure, the effect would have been most apparent in the last weeks of the mating, because at that time, we were evaluating spermatozoa which were sperma togonia during the entire 8 week dosing period and only began to proceed through the spezmatogenic cycle near the end of chemical exposure. Thus, there does not appear to be a residual or transient effect of 2,4-D, 2,4,5-T and TCDD at the concentrations in this study, on the fertility of exposed male mice. In addition, exposure to these chemicals did not appear to influence the fetalor neonatal development or the viability of offspring sired by these mice. 78 3 4 52 BIBLIOGRAPHY DOW 1136249 1. Anonymous. (1980). Fallout from agent orange dogs a herbicide, Bus. Week, pp. 114-118. l 2. Backstrom, J. (1978). The phenoxy acid problem in Sweden, p. 108- 121. In: C. Ramel (Ed.), Chlorinated Phenoxy Acids and Their Dioxins-Mode of Action, Health Risks and Environmental Effects. NFR, Stockholm. 3. Bogen, G., (1979). Symptoms in Vietnam veterans exposed to agent orange, J.A.M.A., 242:2391. 4. Collins, T.F.X., and C. H. Williams (1971). Teratogenic studies with 2,4,5-T and 2,4-D in the hamster. Bull, of Environ. Contam. and Tox., 6:559-567. 5. Courtney, K. D . , D. W. Gaylor, M. D. Hogan and H. L. Falk (1970). Teratogenic evaluation of 2,4,5-T. Science, 168:864-866. 6. Courtney, X. D., and J. A. Moore (1971). Teratology studies with 2,4,5-trichlorophenoxyacetic acid and 2,3,7,8-tetrachlorodibenzo-p< dioxin, Tox. Appi. Pharo., 20:396-403. 7. Dagg, C. P. (1966), Teratogenesis, pp. 309-328 In: E. L. Green (ed.), Biology of the Laboratory Mouse. McGraw Hill, New York. 8. Epstein, S. S., (1973). Use of the dominant-lethal test to detect genetic activity of environmental chemicals. Environ. Health Per spectives, 6:23-26. 9. Firestone, D. (1978) The 2,3,7,8-tetrachlorodibenzo-para-dioxin problem: a review, pp. 39-52. In: C. Ramel (ed.) Chlorinated Phenoxy Acids and their Dioxins - Mode of Action, Health Risks and Environmental Effects. NFR, Stockholm. '' i DOW1136250 53 10. Gehring, P. J. and J. E. Betso (1978) Phenoxy acids: effects and fate in mammals, pp. 122-133. In: C. Rasel (ed.) Chlorinated Phenoxy Acids and their Dioxins - Mode of Action, Health Risks and Environmental Effects. NFR, Stockholm. 11. Generoso, W. M. (1973). Evaluation of chromosome aberration effects of chemicals on mouse germ cells. Environ. Health Perspectives, 6:13-22. 12. Gomes, V. R. (1970). Chemical agents affecting testicular function and male fertility, pp. 483-554. In: A. D. Johnson (ed.).The Testis. Academic Press, Hew York and London. 13. Hansen, V. H., M. L. Quaife, R. T. Habermann, and 0. G. Eitzhugh (1971). Chronic toxicity of 2,4-dichlorophenoxyacetic acid in rats and dogs. Tox. Appl. P h a m . , 20:122-129. 14. Holden, C. (1979). Agent orange furor continues to build. Science, 205:770-772. 15. Hood, R. D., B. I. Patterson, G. T. Thacker, G. L. Sloan, and G. M. Szezech (1979). Prenatal effects of 2,4,5-T, 2,4,5-trichlorophenol, and phenoxyacetic acid in mice. J. Environ. Sci. Health, C13(3):189< 204, (Abstr.). 16. I.A.R.C. (1978). Long-term Hazards of Polychloroinated Dibenzodioxins and Polychlorinated Dibenzofurans. J. A. Moore (Chairman), W.H.O., Lyon. 17. Joffe, J. M. (1979). Influence of drug exposure of the father on perinatal outcome. Clinics in Perinatology, 6:21-37. 18. Khera, K. S., and W. P. McKinley (1972). Pre- and postnatal studies on 2,4,5-trichlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid and their derivatives in rats. Tox. Appl. Pham., 22:14-28. G u 0 (i2 6 6 8349 54 DOW 1136251 19. Khera, K . S. and J. A. Ruddick (1973). Polychlorodibenzo-p-dioxins perinatal effects and the dominant lethal test in Wistar rats, pp. 70-84. In: . H. Blaire (ed.), Chlorodioxins-Origin and Fate. American Chem. Soc., Washington, D.C. 20. Kociba, R. J . , P. A. Reeler, C. N. Park and P. J. Gehring (1976). 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDO): results of a 13-week oral toxicity study in rats. Tox. Appl. Pharm., 35:553-574. 21. Kopf, R . , D. Lorenz, and E. S a le s v k i (1964). Der Einfluss von Thalidomid auf die Fertilitt von Ratten im Generationsversuch ber zwei Generationen. Naunyn-Schmiedebergs Arch. Exp. Pathol. Phazmak., 247:121-135. 22. Hanson, J. M. and Simons, R. (1979). Influence of environmental agents on male reproductive failure, Chapter 6, pp. 155-180. In: V. R. Hunt (ed.), Work and the Health of Women. C.R.C. Press, Florida. 23. McConnell, E. E., J. A. Moore, J. K. Haseman, and M. W. Harris (1978). The comparative toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs. Tox. Appl. Pharm., 44:335-356. 24. Miller, R. (1966). Simultaneous statistical inference, McGraw Hill, New York pp. 76-81. 25. Moore, J. A. (1978). Toxicity of 2,3,7,8-tetrachlorodibenzo-para- dioxxn, pp. 133-144. In: C. Ramel (ed.) Chlorinated Phenoxy Acids and their Dioxins - Mode of Action, Health Risks and Environmental Effects. NFR, Stockholm. 26. Murray, F. J . , F. A. Smith, K. D. Nitschke, C. G. Humiston, R. J. Kociba, and B. A. Schweiz (1979). Three-generation reproduction study of rats given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet. Tox. Appl. Pharm., 50:241-252. .R 55 DOW 1136252 27. Neubert, B., and I. Billmann (1972). Embryotoxic effects in.mice treated with 2,4,5-trichlorophenoxyacetic acid and 2,3,7,8-tetra- chlorodibenzo-p-dioxin. Naunyn-Schmiedeberg's Arch. Pharmacol., 272;243-264. 28. Neubert, 0., P. Zens, A. Rothenvallner, and H. J. Merker (1973). A survey of the embryotoxic effects of TCDB in mammalian species. Environ. Health Perspectives, 5:67-79. 29. Norback, B. H. and J. R. Allen (1973). Biological responses of the nonhuman primate, chicken, and rat to chlorinated dibenzo-p-dioxin ingestion, Environ. Health Perspectives, 5:233-240. 30. Rauls, R. L. (1979). Bow finds support, doubt for dioxin ideas. CSEN, Washington, pp. 23-29. 31. Schwetz, B. A., G. L. Sparschu, and P. J. Gehring (1971). The effect of 2,4-dichlorophenoxyacetic acid (2,4-D) and esters of 2,4- 1) on rat embryonal, foetal and neonatal growth and development. Fd. Cosmet. Toxicol., 9:801-817. 32. Smith, F. A., B. A. Schwetz, and X. D. Nitschke (1976). Teratogen icity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Tox. Appl. Pharm., 38:517-523. 33. Soares, E. R . , W. Sheridan, J. K.- Haseman, and M. Segall (1979). Increased frequencies of aberrant sperm as indicators of mutagenic damage in mice. Kutation Res., 64:27-35. 34. Sparschu, G. I., F. L. Bunn and V. X. Rowe (1971). Study of the teratogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. Fd. Cosmet. Toxicol., 9:405-412. 35. Staples, R. . (1974). Betection of visceral alterations in mam malian fetuses. Teratology, 9:A37-A38 (Abstr.). CG06G8 8351 DOVI 1136253 56 36. Staples, R. E., and V. L. Schnell (1964). Refinements in rapid clearing technic in the KOH-alizarin -Red S method for fetal bone. Stain Techaol., 39:62-63. 37. Wilson, J. 6. (1965). Methods for administering agents and detecting malformations in experimental animals. In: J. 6. Wilson and J. Warkany (eds.) Teratology Principles and Techniques. The University of Chicago Press, Chicago pp. 262-277. 38. Wilson, J. G. (1973). Environmental and Birth Defects. Academic Press, H.Y. p: 188. 39. W yrobek, A. J. (1979). Changes in mammalian sperm morphology after X-ray and chemical exposures. Genetics 92:sl05-sll9, May Suppl. 40. Wyrobek, A. J. and W. R. Bruce (1975). Chemical induction of sperm abnormalities in mice. Proc. Hat. Acad. Sci., USA, 72:4425-4429. 41. Young, A. 1., J. A. Calcagni, C. E. Thalken and J. W. Tremblay v (1973). The Toxicology, Environmental Fate, and Human Risk of Herbicide Orange and-It's Associated Dioxin, U.S.A.F. O.E.H.L., Aerospace Med. Div. (AFSC), Texas. 1. DOW. 1136254 57 ACKNOWLEDGEMENTS ~We acknowledge the valuable statistical consultations of Dr. E. Abeywickrama, Dr. B. Gladen and Dr. J. Haseman, tbe assistance of Dr. E. E. McConnell in evaluating bistopathological specimens and editing tlie manuscript, the technical assistance of Ms. M. L. Dellinger, Ms. D. Frazier and Ms. M. Ross, and Ms. W. Peterson for preparing the manuscript We thank Thomas Mangum for his valuable technical support during this study. We also wish to thank Melissa Marr and Patricia Fisher for perforating the statistical analyses of the teratological and postnatal data. The technical assistance of Freida Gerling, Betty King, Loretta Langhoff, Burnes Bay, Lynn Smith and Vickie Wilson is gratefully acknow ledged. This study was partially supported by contract number N01-ES-2127 from the National Institute of Environmental Health Sciences and the National Toxicology Program. 8353 Ilo. y 1 ;L 12633 9%9SIZHOQ (RF'ZHAW) (1980) TRANS. MID. NO. 12*693 NTC. NO. WARSAW. PANSTUOWY ZAKLAD HIGIENY. ROCZNIKI. WARSAW. V.31(6)611-14 (19801-- ___________________________ Absorption 9^ 2 4-<JlL'lilu I1UPneno:;yaceticacidj^throush the skin. v'*"------ --------- ------- ----------- AUTHOR: Senczuk* Witold TRANSLATOR: Lilienheim DATE: November 1981 REQUESTED BY: L. Griswold* 1803 TRANSLATION NO.: 81-11-7 / A 1V1 t\ p J O O '**r** i \j co en . -w ri Witold Senezuk, Halina Poeo~zelska, Monika Debska A3S0RPTI0N 0? 2A-DICHL0RPHZN0XYACSTIC ACID THROUGH THE SKIN Texicoloey Department of the Institute of Bicanalysis and medium analysis of the Medical Academy of Poznan Director: Frof. Dr. W. Senezuk Trans. Record io ti P-'!D. . t* V CODEN & P z - H A W Percutaneous absorption of S-.^-dichlorphenoxyacetic acid by indirect method was investigated, determining the amount of 2.*t-D in the urine of rats. The production of pesticides and their application ive rise to wide possibilities of poisonin with these compounds (1,2,3,5), and this prompted the determination of the decree of pe-cutaneous absorption of one of cost frequently used pro tective aeents, namely 2.*+-dichlorphenoxyacetic acid (2A-D). Experimental Part Material and Method The tests were carried out on 28 rats of the Wistar species, weiehine each 200 p ICe. The animals were divided into seven eroups of four rats each eroup. Commercial preparation ,sPielik"(.2.lf-dichlorphenoxyacetic acid: translator; containing about 85/S of sodium salt of 2 A dichlorphenoxyacetic acid was used for the tests. The prepar ation was used in the form of aqueous solutions of different 2.^-0 concentrations. Results of Determinations 1. Determination of 2 A - D acid in the urine dependine on the concentration of the tested compound in the solution The tests were carried out with the use of aqueous solutions of "Pielik" containine 0.5, 1, 2, and 5% of 2 .h -D acid. After six hours there was determined the amount of 2.^-D acid excreted with urine. The results are shown in table 1 and in Fir. 1. 2. Determination of 2.*t-D acid in urine dependine 8356oh the period of exposure The influence of the exposure period (2, b and 6 hours) on the excretion of 2.^-D with urine was determined by usine aqueous solution of "Pielik" containine of the tested acid. The results of the determination of 2 A - D acid in the collected portions of urine are shown in table II. Fie. 2 eraohically 0009753 9V9S IZMOQ. 2 illu s tr a te s th e r e s u lts T a b le 1. R e s u lts o f th e d e te r a i n a t i on o f 2 . ^-D a c id in u ^ in e d ep en d in e on th e c o n c e n tra tio n o f th e com pound in th e s o lu tio n S o lu tio n % Anount of 2 A -D A n iaa l 1 s t da y 2nd 3 rd No (2*f h o u r s ) d a v d a y a c id in u -rin e ( n r ) jo in tin e a fte r th re e days DON 2 1 5 6 4 6 5 * 0 .5 3 4 av erag e Sniiniii * U av erag e 1 9 n 4 2.0 . av eraee 1 4 3 4 Snnluiti i 1 1 4.(1 i av eraee ! *9 3 4 S n 'iifiu * av eraee 3 . 1 3 4 0. 1 . i. ut 1.!I7 3 .4 1.11 7.1* 5.3 3 .ns I.S 2. l.li 2 .3 l.*2 .I* fljl I.X 2.1 4.4.*< .4 ,* 2.7 n.r. 4.U 4.1(1 1.4 2.X l.n 1.77 2.4 i.n * (4 1.0 l.H O 3.1 H.7 l.s I.X 3.1(1 4.X ft.M 2.1 33 4.ini 4.7 2.I *.K n .M 4.M7 1.2 i. l.n 1.1 1.07 1.(1 1.2 0.11 0 ,11 0 ,3 3 I.X 17 2.1 U l.so 7.2 2.11 2.7 2.7 3.SO 4.(1 2.1 li.X 7 ** * i.^ S 3 ,,7 3 .3 4.11 3.(1 3.X1 li.X 3.S t.x n.3 3.(17 x.l 12.4 3.0 3 .4 8.72 lx.o 13.-1 1.(1 K.O 12.23 13.1 7.1 10.2 Is . 1432 Table II. Results of the determination of 2.^-D acid in urine dependine on the exposure period Amount of 2 . 5 acid in u^ine (me) Period of Animal Istoay 2nd -3rd .jointine after Exposure No (2 lf hours)dav day 1 three days_______ 1 . 4- 3 M .tlllUi a v e ra e e 1 4 .3 ** nlllM a v e ra e e 1 * 4 3 av eraee 41..07 2.3 3.0 2.03 I.X 1.4 1.0 3.2 2.(17 U.(l 3.0 4.X 2.0 4.13 I.X 3.X 1.7 1. 1.07 13 3.3 2.3 Kl.3 3.13 I.X 3.X 2.1 3.3 -1.1X1 1.0 1.7' II.H II.X 1.113 1.4 1.3 -, 4.0 4 7,2 2.18 2*7 4 3.SO 33 10.2 3.11 .4 3.07 7,3 X.2 .(> 17.7 0,40 IX. 13.1 ii.r. X.ll 12.23 8357 0009754 9 9 4 9 9 1 ZMOO i i 3- - Discussion of the Results It has been determined that the amount of the substance excreted with urine is proportional to the 2.*+-D concentration in the tested solutions(Fie.l). As the 2 A - D concentration increased, the amount of this compound excreted with urine, as compared with the precedine eroup, i.e. of lower 2.*+-D con centration of 2.*+-D increased by* about 5% This related to 0.5 to concentrations, but after exposure to 5% concentration, in comparison with the eroup of animals exposed to solution, 17/S less 2 A - D acid were excreted with urine. Also the period of exposure influenced the amount of 2.*f-D acid absorbed by skin. This relation was proportional for 2, *f and 6 hour exposure (Fie. 2). This can provide a basis for further research in determinine the biochemical absorption index. Fieurel. Excretion with urine of 2.^-D acid dependine on the con centration of the compound in the solution Fieure 2. Excretion with urine of Z.^-D acid dependine on the period of exposure. r f\l 0009755 - 1+ A Russian sunnary corresponds to the following English stma ^ y , 291r9S I ZM0Q W. s " e i i c i u k, 1 1 . P o e o r z c T s k a , M. D g b s k a AUSORPTION OF 2.4-DlCIILOHPJIKNOXYACETIC ACID THROUGH THE SKIN Su m-m a r y The degree of percutaneous ihsnrptiun of one of the most frequently used hrrlHcides - - 2.4-diclil<irplicnox);ici,li<: arid -- was investigated. The in v estig a . lions were carried nut with different ronccnlraliuns of this acid in aqueous so lutions of ..Piclika" and in relation to the duration of exposure. Wistar rats were used in these experiments. The dermal exjsisure wax done hv the tail method. The urinary excretion of the acid was determined ly gas chromatography after previous extraction of the acid from urine and its eslrifiealion. PlSM lENNICnvO 1. Uobiugiu 0 . A - S yrkin A. /i- Lupinosoio J. W., Zajccwa L. A.: D ie js lw ijc na organism czielowicka i ziwotnych gicrbicidnw-prnizwodnych chlnrficnuksiuksusnoj kislnly. Farinakol. i T oksikril- lflfi'l. 32. 747. -- 2. Jiraxck l l , Kalcnxky J - Kubec K - Acne chlorina a porphyria cutanea tarda pri vyrobe hcrbicid. Cs. dcrm ulol., 1973. 48. 3116. -- 3. Rodionov A. f).. ( 'humnrhcnkn A. AT- K urilenko I. S an itary -- to xicologic features of a herbicide of sodium, am m onium and dim cthylam m onium salts of 2.4-dichloropheuoxyacetic acid. Gig. SaniL, 1967, 32, 100. -- 4. SencTitk VV.. I'oporzelska ll~ liudow a chcimczna a toksykiKlyiiainiczne wlasciwoitci poehodnych kwas6w fcnoksykarboksyiowych. C zq ii If. M elody oznaezania poehodnych- kwasu fenoksyoctowcgn i fcnokxyprnpionnwcgo w mnezu i krw i. Roczniki P Z ll. Praca oddana do d ru ku . -- 5. Z ankiew icz W - lu tkow ska N.: Zatrucie P ielikiem . M cdycyna Pracy. 1967, 18. 446. ________________ Literature 1. Influence on the organism of humans and animals of herbicides on the basis of chlorphenoxyacetic acid, Pharmacology and Toxicology 1969, 32, 7^7 2. Percutaneous absorption in the production of herbicides 3. see above in Enelish Chemical structure and toxidynamic properties of derivatives of phenoxycaboxylic acids. Part II. . Method for determination of derivatives of phenoxyacetic and phenoxypropionic acid in urine and blood. PZH Annuals. Faper remitted to printing. 5. Poisoning with 'Fielik', Occupational I-fedicine July 17, 1980 60-780 Poznan, Grunvaldzka street 6 ' 3 3 5 9 0009756 w' Nr 6 Di. "n. 1, giu ri brani .-am in o- ''iiarmac. >[ rato- Tuxicol. mcthoa ::ne, do ri.. 1973. .io acid i;.. 1949, i- a v e l i e 'iru in ::* IV, .md il* J. D.: -- 10. .. r.-rauiM- Vlif. 12. : tx k ty a- d ru :.... w .Inej iiiT -- 14. 21. 57. Muc/Ii. I'7.ll, i n T. X X X I, M I <j tl 7 W IT O L O S E S C Z U K . H A U N A P O G O K Z E L S K A , AJO.V/KA D S B S K A W CH LA N IA N IE KW ASU 2.4-D W i;CH LO RO FEN O K SY O CTO W ECO PR2EZ s k o r ; Zuklad Tnksykologii Jnstytutu Binanulizy i Badania Srndowiska Akadcmu Medyczncj w Pnznaniu K ierow nik: prot. dr luib. W. Se nc^ak Z barian o w ch la n ia u ie przcz sk n ; k :ca su 2.4-durucMoro/enofc.'yoctou:etfO mrrodq poiredniq azaaczajqc tloic J.J-D a ntnczu jccrxirte. P rodukcja pestvcydw i ich stosow anic slw arza duze m ozliwosci zatr u c ia ty m i z w ia z k a m i |1, 2, 3, 5), sL-pl c e ln w v m b y lo o k re s le n ie stu p n ia w chlaniania przez skre, jodnego z czvsciej uzyw anych srodkw oehrony ro slin , a m ianow icie kw asu 2,4-dw uchlorofcnoksyoctow ego (2,4-D). CZ5SC DOSW1ADCZALNA Material i metodyka Badania vcykonarrn na 28 szezurneb. xzczepu U 'im ar. t> music cialn 200 g 10 g. Zw icrzcta ptdi.eltiii ita 7 crup pii 4 s z ra iry . On batiali uzyto p rcparalu handlnwegti ,, P ie lik " awierajqccgii ukotii Si*.' v ili sndnuvj kvoasu 2.4-dwuchlnroicnoksynctuwcS". P re p a ra i uzywann w (xislaci rnztw nrow voiidnych ro inych stvzuiuach 2,4-D. Oc'inv zvoicrzai p> dnkladnym univciii i nlilie/.eniu powierzehni. zunurzann \v proIm ukat'h '.uiu'ierajneych nknl. 20 ein* Icitlaueu" in /.lw iirii ti tenip. 37- 4 0 'C*. Pu kr>'slonym czasie ckspnzycji (p. nizejt zwierzctu p i/ f i m - . 'i i i'i dn klalek melalmlit /.nyrli tvpu ,,S im ax". p e/.ym pi.'.e/. 72 gmlziiiy /In e ra ii" .l..lt<t\ve im reie uiur/.ii. D m t i../v dziennic ixtd.iuano zw ivrzetm n vindit do oiiidku |> 5 cui* vvody. Zavvartusc k -.v.i - u 2.4-D \v intte.-ii kifil.iiitt rni-lmla ln..n.il>i*.t.*fti ........ . |> itpr/tiinim w.Vfk-trahtiwaiuu bada::i*B,> zwi;|.:ku z umo/.u i jeii" f - l iy f ik .i e j i |4|. W Y M K I O /.NA CZKN 1. O z n a c z a n i e k w a s u 2.4-D \v m o c z u w z a le z n o s c i od s t viv n iu b ad a nego iw in zk u w r o z t \v o r z e B adania w ykonnno przv uzyciu w odnvch rnzuvorw ,,Pielika" zaw ira jq c y c h 0,5, 1. 2, 4 i .Via k w a su 2,4-D . P o fi g m izin ach o k re sla n o Uose w vraloncgo z m oezem kw asu 2,4-D. W vniki przcdstaw iono w la beli 1 o ra z n a ry c in ie 1- 2. O z n a c z a n i e k w a s u 2,4-D w m o c z u w z a l e z n o s c i od c z a su ck s puz v e j i W plyw czasu vkspozvcji (2, 4 i 6 godzin) na w v d alan ie z moezem 2,4-D okrcslono stosujqc w odnv roztw r ,, P ie lik a " znw ierajqcy 4% bado nego V9 <J 09 09 CO I K ?!? i' b~ Ai'r 12 W. Scczuk i inni Nr 6 T a li < 1 1. tW iiiU i it/.liitiv.jiitit liu u m i 2 4.1> r u Til w r.ilr/lNMM n! Mt) Nliyi'illit nr/.'r/4f H iM iw r .a iiw Xr 11m* k u it u 2 4*1> IINMV.II (ih;) * *" T 1 iitliii 11 <1i4 ni 11 f (Iii)hi |m i tiiilw rli i ** n.5 a 4 S ntiiiiit 0,0 1.0 1.0 1.0 ti.iT 1.4 1.5 2.X i. 1.77 1.2 l.o 1.0 l.l 1.1*7 n.5 n.5 4 .li n.r " ~ n .si j 1.0 .1 4 __- - . . . Sn^iiiu i 2 2.1 3 4 N ntlniii .1.4 1.0 7 .1 n . 1.2 2. i.o 2.5 I.J*2 2.4 1.0 * * 1.0 I.M I 5.1 M.T 4.X 1.* 5.1o i. 1.2 .* 0.1 0,3.7 l.x 17 2.0 1.1 1.JM" .s n .s U.X 5,5 .7.117 S.l 12.4 a.o 5.4 0.72 1 4 4.0 3 4 Sriniiiki <1.0 .m 4.X 2.0 4.4.*i 4..H 7.X 2.1 .1.1 4.01 74 2.0 2.7 2.7 a. 1S.O 1.1.4 ll.lt SJt 12.25 i 4 .7.0 n 4 7..7 n.r* 4.0 4.1 4.7 2.0 ;> li.H 4.07 ' 4.0 2.1 li.X 7.2 7.23 -- " i-- ------ 15.1 7.4 Ili.2 ls.0 14212 ^ 6 s m izMoa pr/ p / * 11 V kw asu. W yniki oznauzania kw asu 2,4-D w zebranych porejach m oezu p rz i-d sla w io n o w ta b u li 11. Ilu s lra c jq jrafieznq w y n ik iiw ju st ry c in a 2. OMOW1KN1E WYNIKW \ Slw iordzono, zp Uose su b sta n e ji w y d alo n ej z m oczem je s t p ro p o rejo n a ln a d o s tq z c n ia 2 ,4 -D vv b a d a n y c h rn z tw o ra c h (ry e. 1). W m iare; w z r o stu stqzenia 2,4-D Uose leg o zw iazku w ydalonego z m oczem , w p o r w n aniu z grupq poprzedniq, tzn. o nizszym stzeniu 2,4-D w zrastala o ok. 50%. D o ty czy lo to st z e n od 0,5 do 4%; n a to m ia st po ek sp o z y c ji n a ro z tw r 5%, w p o r w n an iu z g ru p q zw ierzq t ek sp o n o w an y ch na ro z tw r 4%, z m oczem w y d alilo siq o o k . 17% m n iej k w a su 2,4-D . 8361 I t } 0003758 i - N; ti Nr 6 W chlanianie kwasu 2.-l-d'*'uchIroicnoksyocto\vcco 613 t* * < J- iS Rye. 1. W ydal..nie i tnnvzem krx<u 2.4-0 w w roitworze. ni stv /cn ia /.\vi:|zku Czas ekspozycji w plyw al rvvniez na ilosc kw asu 2,4-D w chlonifjtq przez skory. Zaleznosc ta byla proporcjonalna dia 2, 4 i 6 godzinnej eks p o z y c ji (rye. 2). M oze to sta n o w ic p o d staw .; do d n lszy ch b a d a n ad o p ra cow anicm biochum iczncgo w skaznika w chinniunia. T i 1** I t . W yitiki m nitnuiniii k %.> *, |1 |) H cauiftu W C -u t* k yv-ji i'*i / H Nr n . NM; kW(IM| J.,4*11 W |||4M*7.M fOllfl I i(u1mi 11 ikilm 111 iltilkl I* trr.**li kilim'll i * 3 4 *i. tllM 1.0 4.7 2.3 3.1) O.fc :i,s '.7 1.1 t.*7 .a 1.7 U .S IK S 1 <;. 3.3 10.2 3.0 3,4 I 'J 1 :: 4 ****lllitl 1 .* 3 4 1. 1.4 i .:i 3.2 2.1)7 II. 3.0 4.H 2.1) 4.43 ) ;', l**,3 3.13 4> 3.S 2,1 3,3 (.Mil 1.4 l-'i . 4,1) 1 . 2.1 < ;i,*n 7,.* 17,7 |K,H 13.4 su s.o 12,23 i. 1:V.*..fJf'!Zl.*7* Ii ; ! ? 8362 i J. J3. 'sfe -M & V*<f sr ?t*#*. V-'" .--- -M * t* J r I t fc;- irt;.-*--1 Nr 6 IN cn CD ji.vnir/r^i t. /...*: _____________ l_____________l---------------------- 1 24 6 Czas ekspozycji (godz) Rye. 2. W vd alan ie czem kwase 2.4-D leznosci od caa-u zycji. z mow zaeks|>o- B. C f ii u 'i y x, X . n o r o x t c . i i i c x . 1 , M . 3 c m 6 c k a P E 3 0P C 1 1H H H E P E 3 K O /K V 2 .4 -a ilX -!IO P l E H O K C liy K C y C H O W K H C .IO T b l Ph k i x p .<):i|x,je .i .ia c u ctciiciii pcviiHjitmt -icpci minty o.moro in uairfm.-nv 'i.ii-m npnmciimomi.'x rcpCmwaoii, 2.4-jitx:iop<t>ciiOKCiiyKcyciiort kiic-iotm (2.4-D i. llcv.ie.wiiaiimt npoiKj.iit-itu-i, ii lamu-aMuc-rn or KomtciiTpamiii -jniii kuc.iotij n no.iiiOM pacntope npcnaparn Jle.ntK" a Tnicxe ot apeMcim asciio-uimm xuocra llpltttCIIHCMI.IX )KMIIOTIII.IX IK|M.IC .111111111 BlICTap) 11 JCItCTUItC 2.4-D. K o u i'iecm o ni.iAC.i*CMoro c momom 2.4-D onpeacjianit sieroAOM raaonoii xpouaToipuipmt noc.ic cro -jKcrpamut hj momii h arcpiKbincamtH. \V. Senczuk, H. Pojurzclska, M. Ocbika AB SOR PTIO N OF 2,4-D lC H LO K PH K N O XYA C ETlC A C ID TH R O U G H T H E S K IN Suinmarv T h e degree of percutaneous absorption of 011c o i the most frequ en tly used I i. rl mi des -- 2.4-dichlorpliciioxyacetir acid -- was investigated. The investigati'in - w ere carried nut w ith different enncenlraliuru ot this acid in aqucuus so lutions ot ,,P ic lik a " and in rrla tm n to the duration ot exposure. W'i n a r rats w ere used .n these experim ents. T he derm al ex|Hisure was done hy the tail method. The u rinary excretion ot the acid was determ ined hv gas chrom atography a fte r previous extraction of the acid from urine and its iM rifirn tio n . i j P lS M IE N M C n v O 1. lio b iu g in D. A - S |/rkin A. /- Lupinosoir J. W ., Z aje ew a L. A.: D ie js tw ijc na organism czielowicka i ziwotnych sicrbicidnw-proizwodnych chlorficnoksiuksusnoj kisloty. Farin akol. i T oksiko l- 1W>. '2. 747. -- 2. J ira se k L - Ka lcr.n ky J,, K u b e e K., Acne "chlorina a porphyria cutanea tarda pri vyrobc hcrbicid, Cs. derm a lu l,, 1973. 48, 206. __ X Rodionqv A. f).. C h n m n r h c u k n A. V- K u rilen ko I. I.: S an itary -- to xicologic features of a herbicide of sodium, am monium and dinicthylauunonium saltv of X 4-dichlorophi,i:oxy:icelic acid. Gig. SaniL, 1967, 32, 100. -- 4. S c n r r u k tV,, I 'o g o rz tlsk a It.: Budowa chemiczna a toki.ykodynam icznc wlasciwosci pi*;li>>diiych kwa.6w fenoksykarboksvlowych. C zq& I I . M ctody oznaezania pnchodnych kw asu fenoksyoctowcgo i fenoksvpropionowego w moczu i krw i. Roczniki I'Z II. Praca oddana do d ru ku . -- 3. Z a u k ie u ic r \V,, llu tk o -x sk a N j Z atru cie P iclikiem . M cdycyna Pracv, 1967. 18, 446. D n . 17.07.1980 r. 60-730 Poznan, ul. Grunwaldzka 6 ( Q Q |Q C hlorm nnom i- Pr< Io m iarv n vv te c h tn Ocvii:: ry nk'il' f n b r\ 1. Prz< . nylu. np. na.r w y n ie-tl rn w n iev m n n i . ' \V 1..- 0 SllllI' >tnn\! i wii-ks/* w atroli 1 sk>r--' N ick kajiny w t< j i tyc/.if ny sknickt" \V i: na w\ chlork PCW nyin i nizszn - j . |> b a u-: to m (i 0009750 I 2m ^ ^ rfoY J"/ " OBOG METABOLISM REVIEWS, U(2), 149-190 <1 - K -ysiS- Pharmacokinetics and Ecodisposition of Polyhalogenated Hydrocarbons: Aspects and Concepts MAHCEL H. BICKEL and STEFAN MUEHLEBACH Department oi Pharmacology University of Berne Berne, Swttxarland T. INTRODUCTION: THE FATE OF XENOBIOT1CS............... 150 It..- THE APPEARANCE OF D D T .................................... A. New Compounds and P roperties ...................... B. Pharmacokinetics of P ersistent Polyhalogenated Com pounds.............................. C. Ecodisposition of Persistent Compounds . . . . , 152 152 153 155 HI.' THE APPEAHANCE OF P C B s .................................. A. Compounds and P r o p e r tie s ............................... B. Ecodisposition of PCBs ..................................... 157 157 157 IV. FROM PERSISTENT TO UNMETABOLIZABLE COMPOUNDS............................................................... A. Chlorination and P ersisten ce ........................... B . Unmetabolizable Lipophilic Compounds......... C. Consequences of Unmetabolizable Compounds 161 161 164 167 V. THE APPEARANCE OF TCDD................................. A. Compounds and S o u rces..................................... B. Toxicity ............................................................ C. Pharm acokinetics, Ecodisposition, and Ecotoxicology....................................................... VI. CONCLUSIONS ........................................................... 170 170 173 175 o f < 179 Acknowledgments ....................................................................... 180 References ............................................. ........................ 180 149 Copyntbi C 19*1 by Mrccl Dekker. lac. 4 150 BfCKEL ANDMUEHUESACH L INTRODUCTION: THE FA1 aobxdtxcs*. Early physiological sod pharmacological amdie clearly demon strated that many drugs and foreign compounds when administered are not excreted unchanged and have to be mftgbolized in order to be elim inated. In fact, before the end of the 19th century all the m ajor path ways of drug metabolism had been discovered [ l , 2] and were at that tim e considered to be detoxication m echanisms. Owing to the funda mental work of B. T. Williams and B. B. J ro d ie , a better understand ing of the fate of foreign compounds was reached in the middle of the 20th cen u ry and subsequently became important fo r pharmacology, pharmacotherapy, and drug development. Williams not only system atized xenobiochemistry [2 ], but also deduced the general principles -governing the fate of foreign compounds la th e body. It became-clear that only hydrophilic compounds can be excreted in urine and bile owing to the peculiarities of the m ajor excretory organs, in oostrast, lipophilic compounds a re metabolized to polar metaholltSBC Thus, elimination of a xenobiotic can be achieved by excretion, ^metabolism, o r both. Typically, a drug will be eliminated from the body by proc esses following first-o rd er kinetics. Metabolism of xenobiotics does not lead to chn<eni degradation but ra th e r to formation o r unmasking of fawwHnnai groups at selected metabolically vulnerable positions of a molecule. These Phase I reactions (oxidations, reductions, hydrol yses) a re unable to biotransform highly lipophilic xenobiotics such a s hydrocarbons, thereby increasing their polarity. Once functional 1*0 6A The following abbreviations a re used: acceptable daily intake 2,4,5,2',4',5'-hexachlorobipheayl 2.2- bis-(p-chlorophenyl)-acetic sold 2 .2 - bis- (p-chloropheny1)-1 ,1-dlohloroethylene 2 .2- bis- (p-chlorophenyl)-1, l , l-trlchloroethane Environmental Protection Agency Food and Drug Administration 3-methvlcholanthrcne phnobarbital 1 polychlorinated biphenyl polychlorinated dlbenzodioxln polychlorinated dibenzofuran pentachlorophenol 2,4,5-trichlorophcnoxyacetlc acid 2 .3 .7 .8 - tetrachlorodibenzo-p-dioxin 2 .3 .7 .8- tctrachlorodlbenzo-furan C? 1 POLYHALOGENATED HYDROCARBONS i 151 TIME flC . 1. Types of pharmacokinetic behavior: (a) "ordinary" xeno' biotic*, e . g . , drag* (T i/2 * hours o r days); (b) p ersistent xenobiotics, . ( . , DDT <?4'/r ** months or years); (e) ideal nnmetabolizable lipo philic xeaoblctic; and (d) unmetabolizable lipophilic aenoblotic, e . g . , .2 ,4 ,5 ,2 \ 4 , ,5 ,-hexachlorobtphenyl (&-CB) [64, 102]. groups are present. Phase n reactions (conjugations) may take over, giving ris e to the formation of highly polar and excretable m en Oolites. Brodie, on the other hand, was m ore concerned with the enzymes catalyzing Phase 1 reactions and with physicochemical and evolutionary aspects of drug metabolism. In a se rie s of classic papers [3-5], Brodie and his early associates summarized a decade of research and came to conclusions and outlooks which seem to have withstood the test of tim e and a flood of additional information. Thus, since lipophilic drugs have been shown not to be excreted unchanged to any significant degree, they must of necessity be metabolized. Otherwise, a lipo philic drug (like quinacrine) with a volume of distribution as high as 1000 U kg and a renal clearance a s low as 1 m L/m ln would have a half-life of some 90 years [6 j. The liver m icrosomal drug-metabo lizing enzyme system , which was discovered by Brodie and his asso _ elates, could be characterized a s extrem ely nonspecific yet highly se lective for lipophilic xenobiotics. As we are now witnessing in the ease of opioid and other recep to rs, the question then arose: What can the natural substrates for this enzyme system be? According to Brodie's hypothesis, a great number of lipophilic organic compounds such as steroids, alkaloids, and terpenes, present in food, would gradually accumulate, perhaps to toxic levels, in the body unless mechanisms were present to dispose of them. In the process of ( ( evolution, development of the microsomal oxidative enzymes must ^ therefore be considered a s one of many biochemical adjustments that made possible the conquest of land by form erly marine forms of life. In conclusion, the m icrosom al drug-metabolizing enzymes IOHMS90M -^BICKEL AMS MUEHLEBACH TOST prevent higher o rg u iim e from beingijpa3uslly poisoned by lipophilic (natural or synthetic) compounds end thus arc sn essential protective system , comparable perhaps with the'*"""* system. This fascinating theory has drawn little opposition, which may be dae to the fact that it has not been possible to challenge it experimen tally [7 ], for these hepatic and eztrahepatlc enzymes can neither be surgically removed nor can they be blocked by inhibitors, at least not for long enough to allow for accumulation of lipophilic senobiotlcs and observation of the appearance of deleterious effects. The aim of this review is to show that the simplistic scheme of faydrophilic-excretable and lipophilic-metabolizable organic com pounds has been disturbed by the advent of DOT-like persistent com pounds and must now be enlarged by a third group, that of bpophiliounm eta bo11tab le compounds. The last-nam ed type of xenobiotic ex hibits a new -dnd of pharmacokinetic behavior and has certainly ac centuated the problem of global ecodispoaition. Finally, this new class also contains m em bers of extrem e toxicity which have added o r could add to the severity of the unieersal eeotoxieological condi tion. Old and new facts will be used to discuss and a sse ss new a s pects, concepts, and outlooks rather than merely reporting recent findings and progress in one limited field. Thus the quotations for the time before, say, 1970 will be drawn largely from the review liter ature, and the list of recent original works quoted will not be exhaustive. Our literature search was concluded in early 1980. n. THE APPEARANCE OF DDT A. New Compounds and Properties In 1939 DDT came out of a screening procedure for insecticidal activity. The compound, dichlorodiphenyl-trichloroethane (chloropheaothane) had in fact gathered dust on a shelf for alm ost 70 y ears before it had been rediscovered and put to worldwide use. The suc cess of DDT became immediately cle a r during its use in World W ar n , the first w ar in history not to be followed by devastating epidem ics. The postwar years and the 1950s added further to DDT's success story owing to its worldwide use la the fight against vector-borne " diseases like typhus, yellow fever and, particularly, m alaria which waa being eradicated in vast a re a s. It hss been estim ated that 50 million lives have been saved and 1 billion cases of Illness averted by DDT, thus this "drug" can be second only to penicillin and other antibiotics. This aspect must not be forgotten in an e ra ready un critically to ban and damn DDT and other pesticides. RR POLTHALOGENATED HYDROCARBONS 179 noticeable residue* In human tissues simply reflect* the low level oi exposure a s compared with, say, DDT or PCBs. However, largescale monitoring and improved analytical sensitivity m ar reveal TCDD residues in humans tomorrow. If so, what would residues at the ppt level mean? A cautious assumption would be that with compounds like TCDD, any residues may be harmful. Such a statem ent is based on facts like extrem e species difference* in toxic sensitivity which do not allow an extrapolation to humans of even the LD value. Fur therm ore, it Is based on documented long-term effects like terato genicity and carcinogenicity in animals and, finally, on our ignor ance with respect to a no-effect level. Thus, in the absence of hard disproving data, it seems wiser for the time being to assume that TCDD is unmetabolizable, that it has entered the biosphere, and that human* do have tissue residues. R esults of epidemiological studies of directly exposed people a re still controversial [23G, 237 ] but w ill certainly provide useful information in the future. There is even more to this than ju st the problem of TCDD and - T C B F .' It has taken a long tim e to detect both the existence and the toxicity of these chemicals, years during which individual* and popu lations w ere c lo s e d to them. The disturbing question therefore a ris e s of whether such a situation can re c u r. Owing to one particu la r fact this does not seem to be too unlikely. This fact is the er ratic structure- toxicity relationships which exist within the series of polychlorinated dibenzodioxins o r dibenzofarans (Table 2), 1. e . , the general possibility of the appearance of excessively toxic mem bers within chemical fam ilies of relatively harm less compounds. This is indeed one of the most important lessons that the TCDD story has taught us. Dispersion of high-toxicity compounds cam ouflaged by a harm less "c a rrie r" can happen again in the manufac ture and use of some other chemical product at any tim e. After all, poiyhalogenatcd compounds have surprised us more than once by creating ecotoxicological hazards which are becoming increasingly difficult to cope with by traditional technical and legislative means. VI. CONCLUSIONS 1. Lipophilic xenobiotlcs cannot be excreted but a rc eliminated by being metabolized. Hence, according to Brodic, these compounds rem ain in the body o r accumulate in the absence of metabolism, so that drug-metabolizing enzymes must be regarded as a protective system against the accumulation of lipophilic xenobiotlcs, such as those contained in natural food. 2. If metabollcolly vulnerable groups of a lipophilic organic molecule a re blocked by halogen atom s, the compound may become 180 BICKEL ANS MEHLEBACH llOSSIZMOd p ersisten t, l. e . , very slowly m etstelized. Owing to th eir lipophilio- ity, persistence, end lipid storage C om pounds like DDT and related insecticides have become subject to global ecodisposltlon and biocon- centratlon. 3. Polychlorinated biphenyls (PCBe), another class of poly- halogenated hydrocarbons, have also undergone global ecodisposl- tion and concentration in the bioaphere, even though these industrially used compounds had never been intentionally introduced into the en vironment. Their appearance in human and animal residues has re vealed unsuspected pathways of ecodisposltion. 4. By blocking all metabolically vulnerable groups of a molecule according to established criteria, a persistent compound may become an unmetabollzable one. Studies with model compounds like 2 ,4 ,5 ,2 ',- 4 ', 5'-hexachlorobipheny1 have shown that its metabolism is indeed negligible, diet total excretion (mainly in the feces) of unchanged ma te ria l accounts for only a sm all fraction of the adm inistered dose, and that the m ajor part is stored in the adipose tissue where it is not avail able for elimination. These imwwtionMhu lipophilic compounds thus represent a new class of pharmacokinetic behavior. In addition to its potential for ecodisposltion and bioooncestration, this class of com pounds also proves Brodie's hypothesis in demonstrating accumula tion and retention of lipophilic compounds which cannot be substrates of the drug-metabolizing enzymes. _ 5. The herbicide 2 ,4 ,5-T, the wood preservative pontachlorfr- phenol, and PCBs contain traces of the extremely toxic polrhalogen- aied compounds TCDD and TCDF. As contaminants of widely used products, they have already entered the global ecosystem . By being persistent or even unmetabollzable, they have the potential to enter / food chains and undergo bioconcentration. Finally, by being exces- J ively toxic they have opened a new dimension in ecotoxlco^ogy. f Ackncwledgmenta The authors a re indebted to D rs. H. B . Matthews and W. B. Jondorf for Inspiring discussions and help. REFERENCES C l] A. Conti and M. H. Bickel, Drug Metab. Rev. . 6, 1(1977). [ 2 j It. T . Williams, Detoxication Mechanisms. 2nd e d ., Chapman and Hall, London, 1959. [ 3 j B. B. Brodie, J . Pharm . Pharm acol. . 1 (1956). [ 4 ] B . B . Brodle and C. A. M. Hogbea, Ibid. , 345 (1957). 2f t 2 ,18 i10 AN EPIDEMIOLOGICAL FEASIBILITY STUDY ON THE EFFECTS OF 2.3.7.8.-TETRACHLORODIBENZO-PARA-DIOXIN (TCDD) ON FINNISH FORESTRY, ROAD AND RAILWAY WORKERS Preliminary findings < CC < 00NN By Antti' U. Arstila, M.D. and Tapani E. Sorvari, M.D., Department of Public Health, University of Jyvaskyla, Finland 8373 0002278 V. t 2 INTRODUCTION During several occasions human populations have been exposed to compounds, which contain as a contaminant small amounts of 2.3.7.8.-tetrachlorodibenzo-para-dioxin (TCDD). Such com pounds include herbicides such as 2.4.5.-trichlorophenoxy acetic acid (2.4.5T) and an antiseptic compound, hexachlcro- phene. It is now known that TCDD is one of the most toxic compounds ever synthetized, and its acute toxicity is for instance of the same magnitude as that of many well known toxins, such as diphteria toxin or tetrodotoxin. TCDD has received world wide attention as a potential health hazard for humans because it was noticed that many widely used herbicides contained small amounts of TCDD and when on several occasions large num bers of wild and domestic animals were killed after acute exposure to TCDD. Although the acute and chronic toxicity of TCDD has been exten sively studied, little is so far known of its longterm effects on humans. The present study was undertaken to test whether it is possible to make epidemiological and clinical field studies on Finnish persons exposed to TCDD-containing herbicides for long periods. Also it was the purpose of the present study to examine whether there were any clear-cut differences in the anamnestic and clinical health status of the exposed persons as compared to control persons living in the same areas and belonging to similar social groups. This study was carried out with persons who had spread TCDD-containing herbicides, such as 2.4.5T, for many weeks each year during several year s . It is interesting that according to two Swedish studies, higher than average numbers of malignant tumors were found among-- the same kind of workers. _ 0002279 rrr r*^ f r*a a o n )3 MATERIAL AND METHODS The study was carried out with 31 exposed persons from Finnish forestry, road and railway workers living in Central Finland around the city of Jyvskyla. All of the exposed persons were Finnish Government employees and most of them had been exposed to herbicides during several summers. The average exposure time varied each year from one to three months and the herbicides were in most cases spread manually during five days a week. The amounts of exposure for each person are shown in Table 1. The hnrb-icides used were mostly 2.4.5T and 2.4D until 19 76 when it was replaced by MCPA in about half of the cases. The use of protective clothing, respiratory masks or gloves were almost negligible; About half of the exposed persons had used gloves and paper masks only occasionally during the last three years or so. The 'control group consisted of 23 railway workers employed by the Finnish Railways from the same area as the exposed persons. Similarly to the exposed workers, these persons worked out of doors throughout the year. The control group was matched to the exposed group by age. The smoking habits of both groups were quite similar as seen in Table 1. The epidemiological study consisted of interviews with each person (one hour per person) by a work health nurse. For the anamnestic interviews, three different questionnaires were used. One was an occupational health questionnaire used by the Finnish Railways, another was designed to ask exposures and symptoms mediated by air, and the third questionnaire was designed for tracking exposures and symptoms caused by toxic chemicals. Detailed medical records were available from all control persons as well as about half of the exposed persons. Half of the ex posed forestry workers did not have organized occupational 8375 0002280 -4- health care and there were little or no written records on their previous health status or on their exposure to chemicals. The ex posed and control persons were examined by the same physician. The examination of the dermatological status was made by a dermato logist. The laboratory tests (Table 2) included blood haemoglobin, haematccrite, sedimentation rate, total leucocyte count, total thrombocvts count, serum glucose, serum creatinine, SGOT, SG?T, SDH, serum LDH isoenzyme pattern, quantitation of immunoglobulin classes (A,G,M), relative amounts of T and B (K) cells in the blood, urine colour, urine albumine, urine glucose, urine pH and urine sediment. In addition, vitalograph was taken. Chest X-rays were studied by a radiologist. ct -c NO In 1970-76 the most widely used herbicude was Vesakon Tuho Special manufactured by Kemira Co. It contains 2.4.5T 750 g/1. In 1976 the content of TCDD in 2.4.5T was 0.04-0.07 ppm. RESULTS AND CONCLUSIONS The major anamnestic results are shown in Table 1. There were no significant differences in the age of the exposed and control persons, nor their smoking habits or their consumption of alcohol. The average time since the first exposure was ten years and the average total exposure in weeks was forty-nine, thus making an annual mean exposure time of 4.9 weeks. Anamnestically the exposed group had about twice the number of cardThySscular, respiratory and skin diseases and respiratory allergies (Table 3 ) . On the other hand, it was found that approximately half of the exposed persons were tranferred from heavy to easier forestry work (includung the spreading of the herbicudes) because of health problems, such as cardiovascular or ____ _________musculoskeletal diseases. ~~83"76 One of the exposed persons had a mentally retarded child as compared to none in the control group (Table 3). In the chysical examination 0002281 < including the palpation of the abdominal organs, respiratory and cardiac auscultation, dermatological, neurological and ophthalmological examinations, no clear-cut differences were found between the groups (Table 4 ) . Anamnestic symptoms of acute toxicity in the expcsed group are shewn in Table 5. For statistical conclusions, this material is, however, far too small. As shewn in Table 4 elevated blood pressure was found in six ex posed persons and in seven control persons. The heart was radiologically enlarged in four out of fifteen exposed persons and in three control persons. In vitalographic findings and in radio logical examination of the lungs, no differences were observed between the two groups. uUWj ( In the dermatological examination done by a dermatologist, no skin lesions typical to chloracne were found. The results of the blood analyses showed no obvious differences between the two groups. There were, however, two exposed persons, who had'the lowest 3 lymphocyte values: 6.5 % and 6.1 %. One of these persons had also the lowest thrombocyte value 133 xlO 9/l. However, the immunoglobulin amounts of these persons were in normal range. In the urine analyses, no obvious differences were found between the groups. Summarizing, this study shows that it is possible to get both anamnestic and epidemiological as well as clinical data on the past and present health status of Finnish employees exposed for long periods to herbicides containing TCDD. In this study no obvious or significant differences were found between the exposed and contre1 groups. It i s , however., evident that this material is far too small to'make any conclusions in .cv-u. It is also suggested that this type of approach could be one possibility to further evaluate the potential and so far undocumented chronic effects of TCDD on humans. NOTICE: POOR COPY DUE TO DEFICIENT ORIGINAL 8377 00022S2 o i Table 1. l CHARACTERISTICS OF THE CONTROL AND EXPOSED GROUPS Persons Controls Number Mean Exposed Number Mear Persons studied Age (years) Tobacco Alcohol Cancer 15/28 16/28 0/28 45 Exposure Time since first exposure (years) Number of weeks exposed Annual exposure time (weeks) 21/31 16/31 1/31 43 9 43 4.8 Table 2. LABORATORY TESTS Haemoglobin (g/1) Haematocrite (%) SR (mm/h) 9 Total leucocytes (xlO /l) Leucocyte differential count (%) 9 ^hrcmbocytes (xlO /l) T and B lymphocytes (%) Blood glucose (mmci/1) Serum creatinine (umol/1) Serum GOT (U/l) Serum GPT (U/l) Serum LDH (U/l) Serum LDH/HBD (U/l) Serum LDH^_-isoenzymes (enzyme fraction) Serum immunoglobulins A,G,M (g/1) ET GoCM(bn 0002283 Table 3 ANAMNESTIC FINDINGS Diseases Cardiovascular Lung Respiratory allergies Gastrointestinal Skin Controls Number i 5/28 1/2 8 0/28 7/2 8 8/28 18 4 0 25 29 Exposed Number 13/31 5/31 8/31 8/31 11/31 % 42 16 26 26 35 fiT o n Mental retardation (Children) Y Number of children 0/64X 0 1/31 3 Table 4. ABNORMALITIES FOUND IN CLINICAL EXAMINATION Organ (system) iControls Exposed Cardiovascular Lung Liver Skin Neurological Eye 7 7 0 2 1 1 6 7 2 5 2 2 Table 5. ANAMNESTIC SYMPTOMS OF ACUTE TOXICITY Organ (system) Number % Respiratory Gastrointestinal Neurological Skin 9/31 6/31 13/31 12/31 29 19 42 39 a / * * ^//[ j,',* / n . >' ik *// / !/ /. / -- r '>' f '1 ' Uj 59 ca %s OCT e g fi. w. hj ^ O c,-) fcr g iuui 8379 00022S-I E d itora! O A jl D0W0637274 The Buri.il o f the T - o Million Dollar Teaspoon 2*2 =4 vO o* oa EPA has reportedly contracted for the disposal of 30 million pounds of lawn fertilizer containing silvex. The cost of the "grave"? S2.1 million. The EPA release reads, "This contract involves disposal of dry* fertilizer-based products which contain no more than 1.5 percent of the active ingredient, silvex, which the Agency estimates to contain about 25 parts per billion or less of the toxic contaminant dioxin (TCDD). Over 95 percent of the material being disposed of consists of inert carriers for the fertilizer and weed-killer (such as com cob grits or Vermicu lite)." Registrants of the products are to transport the mate rials to the disposal site and that could increase the cost considerably. According to my calculations, the whole "kitten caboodle" contains about 5 grams of dioxin -- one teaspoonful. Boy, are we ever a bunch of scaredy-cats, spending over S2 million to bury a teaspoonful of anything. The grave, referred to as a "single burial cell," will re portedly hold 240,000 cubic yards. According to figures from the local trainmaster, that's about 1,500 box cars. With 100 cars per train, that's 15 trainloads. Perhaps what we should do for slow-learners is park them by a railroad crossing to watch a 100-car iii train pass by -- at the speed they .usually do for you -- then another, and another, until 15 trainloads have passed by. And in all that time, one itsy bitsy teaspoonful would have passed before their eyes --not in one car, not in one train, but in all 15 trainloads. Just think of the time, effort, energy' and cost --to dispose of such a tremendous trifle --one teaspoonful. What should we call it, " Blum's folly"? But that's just part of the story. There are about four million containers of various sizes with almosr a million gallons of liquid silvex. EPA has considered having these containers emptied and rinsed and the material incinerated at sea. According to one estimate, the silvex going to sea would contain about two teaspoons of dioxin. One EPA official reportedly estimated the total cost to taxpayers for silvex disposal and indemnities at S30 million. So that's 530 million tojdisposc of three teaspoons - one by land and two by sea. Wouldn't Paul Revere rurn over in his grave if he could see what foolishness the bureaucracy of his great country is up to. And what really gets your goat is the way we squander money frivo lously, and needlessly on such regu latory activities while funding for educational programs for pesticide applicator training are being cut. Who will pick up the burden for that program initiated by the feds? Vou guessed it, the feds would like to dump it in the states' laps. And where will the states get the funds -- the most likely place is by charging those who are being regulated and never asked for the proi*tim rh# We certainly don't have anything against education. In fact, some good old arithmetic for some of those folks in EPA might be a good place to start. The average mind probably hasn't caught up yet with terms like parts per trillion. If you say 10 pans per something -- well, 10 sounds like a fairly big number. But 10 pans per trillion is like 10 seconds in 320 centuries. Come on EPA, get your rear in gear and do your homework. You're supposed to provide some responsible leadership instead of catching butterflies with bear fraps. 2.4- D What concerns many of us now is EPA's domino game. They suspended many uses of 2,4,5-T and silvex just before the RPAR decision was ready. The major basis for their decision has been largely shown to be faulty. But perhaps their math book says 1 wrong + 1 wrong = 1 right. They acknowledged that dioxin had not been found in 2,4-D, but now 2,4-D is under scrutiny and subject to guilt by associa tion. 2,4-D provides one of the lowest cost, most efficient methods for controlling weeds. If you are truly concerned about water quality, remember that the trend is toward reduced tillage --to save soil and energy. As we reduce .tillage, 2.4- D, still our major postemergence herbicide, will become all the more essential. I like Steve Jellinek's story about the G.I. who walked into a French village after the American's had bombed it to drive out the Germans. He said, "Boy, we sure liberated the h____out of this place." At the rate EPA is going, that's about how our farmers and even the food consumer will feel if EPA continues their bombardment. If EPA wants to listen to the potheads who want to get rid of any chemical that kills marihuana, or to the mafia, that's their privilege, as long as that's all they do is listen. But remember that the Good Lord doesn't let man discover a 2,4-D very often. .And if we fritter away the discoveries he does allow us, we know not when he will let man use his mind for such great discoveries again. "The concern fo r man and his destiny must always he the ch ie f ir.ieiest o f all technical effort. S'e-aer forget it among yo u r diagrams and equations. " -- Albert Einstein "When a country chooses its technology, it chooses its fu tu re. " -- E. F. Schumacher q381 "F.PA, jours is a crave responsibility. Don't dig one for 2.4- D." 3| 3382 DOW CONFIDENTIAL INFORMATION R &D REPORT Cfll K-002372 Ul#iAT5P. CCi* D O W C H E M I C A L U.S.A. HET K-002372-(22) R&D REPORTS SHOULD REMAIN ON THE PREMISES OF THE DOW CHEMICAL COMPANY CC*iA TM (N T 9 atk a : u i : January 7, 1981 LAtl. N S T T n i w i M NC. Toxicology Research Laboratory_________________________ 1,9,5 3,1,3,7,2,2,2 CRI NUMBER >Zfr90MD0 TitCHNICAL GRADE 2 ,4-DICHL0R0PHEN0XVACETIC ACID (2,4-D): RESULTS OF A 77 13-WEEK SUBCHRONIC DIETARY TOXICITY STUDY IN THE CDF FISCHER 344 RAT PAGES IN FULL REPORT . TmOR >iJ \j ^ 7 w^ p#r 1 * S.J. Gorzinski, C.E. Wade, D.C. Morden, o.G. Keyes, E.L. Wolfe, D.A. Ddttenber, ~ TZ al l k` S-J. ^ 7 .{itK C R 'l IK N iT U K E ^ B.A. SchU wt . leA iz DESCRIPTIVE SUMMARY WITH CONCLUSIONS, C/ .. .. R.v. Kalnins, D.J. Schuetz and R.1. Kociba This report is: n INTERIM JZLFINAL and mainly: VI I x l NEW n REVIEW $ Z Groups of 15 male and 15 female 6-week old CDF Fischer 344 rats were given diets formulated to provide doses of 0 (control), 15, 60, 100 or 150 mg/kg/day of tech nical grade 2,4-dlchlorophenoxyacetlc acid (2,4-D) herbicide for 13 weeks. Data were obtained on the following parameters: overt signs of toxicity, body weights, food consumption, food conversion, clinical evaluations (clinical biochemistries, Jbematology, urinalyses), organ weights, organ to fasted body weight ratios, gross Examination at necropsy and histopathological examination of tissues. Growth retardation and decreased food intake were evident for males and females given 150 mg/kg/day of 2,4-D. Food conversion was also slightly reduced in the top dose males and females. Serum glutamic pyruvic transaminase activity (SGPT) was statistically significantly increased in both sexes fed 150 mg/kg/day and females fed 100 mg/kg/day; total thyroxine (T4) values were reduced significantly for females at the highest 2 dose levels whereas T4 values for males were unaf fected at any dose level. Hematological values and urinalyses were not affected at any dietary level of test compound. The absolute (g) and relative (g/lOOg) kidney weight values were statistically significantly increased in all experimental groups of males fed 60 mg/kg/day and greater. Males given 15 mg/kg/day had a significant increase in the relative but not absolute kidney weight. Relative kidney and liver weights were increased for females given 150 mg/kg/day whereas only the relative kidney weight was increased at 100 mg/kg/day. Minor histopathological alterations of the liver were noted in both sexes given 100 or 150 mg/kg/day. At 60, 100 and 150 mg/kg/day both males and females had dose-related microscopic changes of the convoluted tubules of the kidneys. These slight changes of the renal tubules were not seen in male or female rats given 15 mg/kg/day. CD DISTRIBUTION: cOCO PM-NTS3 ft -J i^OEc .R 7Mj;N7 r i P & O ADMINISTRATION c e n t r a l r e p o r t ! n : ; x - .* c o p i e s (566 Bldg. - Wtalsnsi i 838 3 (continued) Oitlfibution lift is continv#d sn ortoeh.d , e f t . In conclusion, the results of this study with technical grade 2,4-D indicate the primary target organ to be the kidney. Dose levels of 60 mg/kg/day and higher exceeded the maximum tolerated dose as evi denced by morphologic changes in the kidneys of both sexes. The 15 mg/kg/day dose level was interpreted as a no observable effect level (NOEL) in the female rats whereas in male rats this dose level pro duced only a slight increase in relative kidney weight. C3 I O CD CO fM C! O * 0003585 DOW CONFIDENTIAL INFORMATION 7170 '>1 DOW0664251 TECHNICAL GRADE 2,4-DICHLOROPHENOXYACETIC ACID (2,4-0): RESULTS OF A 13-WEEK SUBCHRONIC DIETARY TOXICITY STUDY IN THE CDF FISCHER 344 RAT ,1 By: S. J. Gorzinski, C. E. Wade, D. C. Morden, D. G. Keyes, E. L. Wolfe, D. A. Dittenber, R. V. Kalnins, D. J. Schuetz and R. J. Kociba Reviewed By: B. A. Schwetz Toxicology Research Laboratory Health and Environmental Sciences, U.S.A. Dow Chemical U.S.A. Midland, Michigan 48640 8386 000358R -23- DISCUSSION The growth retardation observed in males and females fed 150 mg/kg/day was associated with a slight decrease in food consumption and food efficiency (both sexes); this may suggest a degree of unpalatability of the experi mental diets and treatment-related systemic toxicity. D0 WOO8 4 2 7 7 Increased SGPT activity for males and females given 150 mg/kg/day.nd females given 100 mg/kg/day was considered treatment-related and suggests an effect possibly on the liver. The decreased serum alkaline phosphatase activity in the top dose females appears to be caused by non-specific decreases in food intake. Osihi (1979) has reported decreases associated with restriction of diet. Thus, the reduced value seen only 1n the top dose females may be related to the decreased feed intake where consumption was approximately 2 g/rat/day less than that of the concurrent controls. Serum T^ values were decreased in female rats of the highest 2 dose levels. This is interpreted as a treatment-related effect consistent with a previous literature report by Florsheim and Velcoff (1962) of decreased serum levels of protein bound iodine in rats given higher dose levels of 2,4-D. None of the other clinical biochemistry results were considered to be the result of treatment with 2,4-D based on the reason included in'the results section. Organ weight data indicated that the kidney was the primary target organ with dose/treatment-related effects at all dose levels in male rats and at the highest dose level in the female rats. Histopathologic examination 8_ 3 8 7 0003612 i D0W0684278 -24- also identified the kidney to be the most sensitive target organ with minor kidney alterations in male and female rats given the highest three dose levels of 60, 100 or 150 mg/kg/day; these effects seen on the kid ney may be related to saturation of the elimination mechanism. r F In conclusion, the results of this study identified the kidney, and to a lesser extent the liver, as target organs for rats ingesting up to 150 mg/ kg/day of 2,4-D with the kidney being the more sensitive Index for ktoxi ci ty. >^ Dose levels of 60 mg/kg/day exceeded the maximum tolerated dose as evidenced by cellular alterations in the kidneys of both sexes. The 15 mg/kg/day dose level was interpreted to be a no-observed effect dose level (NOEL) for female rats whereas in male rats this dose level produced no effects except for a slight increase in relative kidney weight. i i t L WRITTEN BY: i Si 3. 7 3 8 1 S. J. Gorzinski, M.S. Study Director Research Leader Toxicology Research Laboratory D. C.Morden, B.S. Biologist Toxicology Research Laboratory C .J L -iu la d .. 7 JU . r >__ C. E. W a d e 1 Research Biologist Toxicology Research Laboratory ~T> Jr-- : D. G. Keyes, B.S., M.T.(ASCP) Senior Research Medical Technologist Toxicology Research Laboratory E. L. Wolfe,'B.S., M.T.(ASCP) Medical Technologist Toxicology Research Laboratory D. A. Dittenber, "B.S., M.T.(ASCP) Research Medical Technologist Toxicology Research Laboratory t iL. L E L t 82 f- 0003613= D0W06S4-279 -25- ___ _ ^ p . V. Kalnins, B.S., M.T.(ASCP) ' y Research Medical Technologist Toxicology Research Laboratory _ CYJ_________ h i - V Rl.. J. $>ciba, D.V.M., PFh.D. Associate Scientist Diplomate, American College of Veterinary Pathologists Toxicology Research Laboratory / - ?-<?/ D. J 2. ./ g c r t i e t , B.S.^Jl.T.(ASCP) Senior Research Medical Technologist Toxicology Research Laboratory REVIEWED BY: B 7 2f B. A. Schwetz, D.V.M., Ph.D. Director, Toxicology Research Laboratory Health and Environmental Sciences, U.S.A. 1803 Building Dow Chemical U.S.A. Midland, Michigan 48640 t 8389 0003614 ;u3 Trji '?w3 .'>1"21 :""i'~ " ' as' CAHAM STAr^iT - .-.^Ji" . c:.AH>riCAT7C'i TO rOlLC* Frew: r-*Z. isbcr inu j'' ^ Tft.'ih-uc TT irons Qv..-y.-;A r u sty 7:7, 13S1 Tress r-siAii:;'; 7:<; 7 .--i--O i.vrj- r e l e a s e d .T<-sn. 37 n o o n * T a x i l y i l o w s : ` . 5.,<i-D measures cutiiheo: Ottawa Jan, 77/31 - .\gyL ?.:uicure .Minister sugonu Whelan today enisleiron measures a 5mod at phasing out sraa 2,4-D herbicide products. Last October, Mr* -vhelan announced that ngrio. Canada scientists had discovered that some types of the popular weedkiller ware contaminated-with dioxins.' There are cany different forma of dioxin. The most toxic 'o r a - 2,3,7,3-TCDD .- was n o t .found, in any 2.4-1} samp it!:;; tested* The measures.- outlined. today, jars: . Ifsmpdiata ban on the sale by-basic; manufacturers of technical -esters of 2 , 4 - d that havo been;shown .to contain dioxins* ' * '- phasing out; of ail sales o f a volatile-, form o f .ester-hosed. : .. 2,4-D colled btstvl ester* -vcrnt'1 studies have: identified concerns -:7 .\r^tayer rapid evaporation and- drift-'o f .;such-'products', leading"to possible I.'-'-.' ` ^'-demnne tc.-non-tersel: crops*. :/K ' A ': i A-:' i : >W. .-/.'action .to ensure that ail 2 ,.4-B- material.;is;free. ;of dioxin ;/.: 'C.-'V -.: ;- - . ; ;.^Se...are: extremely .encouraged: by- fche oormiiance^iready 'show*;?' l-`.by industry with-'.a*ir.'seasraa**' i-i-r! s h n ^ ail d-^*;:-?Bas**i1c"';. 1 ;% "*v.* *v liuti iy59048 not. pnsurCyth dioxin-. ;;.I - I.il:'/i;-.ii":/;-/--1y/;.-1/i---rf r- ` Ivrir> i j-:rt. c r i -?rf_ ' *X i\lT f ilm ; IS . t 'O -....;;y! ; ^ 'visy i t a - comp toly uncontaiainated;products^;, y e a r . .>n sdi^interiia;: users'.pvuot:r o c c c n ^ o t h i s . ^ dt :S*V3CBV t tis iitX ii }- ?1 ;into; f!5&i5U,- M-t1!,: i,^v J':24^0 :thi3; year- ' .:- : - ^ i - v . i f S ^ K S n ? i '1*I : ;i\>V .8*. i. ` 't/:::':'r =v' . A ^ :: . . cr--*a:.ii'-[r" t. r: "-.-vi-ir;+vV:" .. i: 391 1; 0003975 *X .an't ettjnxsiss- enough ..the-value- s i -3,4-- D 't3 Canadian;`Agriculture ho -.-iia ,. 'About eight million- pounds -.;isoused in JCarndn. ws-ch'year-" the '.bulk of. it .tipcontro 1 wccis that >-vjpuLd. cthe rwi'Se -1! 7.iy; '.` V h' *.. v *.` *\ !-. t \ - . *V : ' - * 1 ** reduce ocurr. crop yields' \..T-h, V- hi.v;-;. -.../ ::' v ; A M-' vi 1' / V i"- . ' = '; Mr. Khelan explained that because Agric. Canada, was first agency in veria to discover dioxin contamination of 2,4-Di.there was incomplete info available cm what the presence of dioxins ir-eans in terms of health. Scientists inAgrie...Canada*s food production and;-inspection branch made the discovery , rising-"state^of-- ths-art technology. The finding-vats made public at an ..international conference on dioxins-in Rome --last October. ''' "' S t C- I '/''hr. ' ' ' ' ''.. : . ' Based' on. present knowledge, health and Keif are Canada experts .beli'ove that the types of dioxin fOunu are raueh loss toxic than , the--;;2>3,7,S-TCED recently, found in herring gull./eggs and considered ,-to; -iaa? extrem ely danqarous. vtiVV. ' . ` ; .'.! i: U '.We;`'re -anxious to do. all we possibly:can to sdke s\irs that all ;- '2 f4-D products are free o f 'dioxin conraninationas ouickly as *.!i; * .j * \ '" . possible, *r. ^fhelaii cold,. `Via have worked in consultation with , federal colleagues i n TiCO.itn-'and Welfare-'.'Canada`..and,'Environment Canada as wall as Provincial Agriculture, Environment and Health Pcpts.*' Agriculture Canada- tests. found that 2,4'P. product#',based on basic .material cai led esters are of-.on contaminated with;dioxins. `The majority of the rvs-iv? eermbn sroducts based'..o n ."ater.ia 1 s called `.amines are dioxin-fr-:, -he tests showed. H o s t u s e d in agriculture :a ar-iro brsrd. All horse-and-gardehv products arc b*::*ua on- arias materia.*. l-.b-:;:. ; clc.-ariy biotitify- whe'thej^ihe product amino or c*tcr *; *. I . ; <*. . 8392 "J 0003976 0SriRftl iinr* I rcsiice that these Treasures !.-riil not please everybody, ' Mr. M he lari said, *II -simply is not possible to phase into onrrplately dioxin-frae S.i-D this year* Me' ua however have'every confidence * that this objective --ill be reached next year.-*'- ' : .: 'A'complete ban on coot a~ ina toe' forts of 2,4-D.v.ould have resulted .in drastic shortages of the weedhiiler T and that/in/turn would V; have jeopardized'1our farmers' ability, to. produce 3.. K feel that these measures effectively respond to'ithe; new "info/that cmerasQ last fallr while at- the sane;trme .ensuringveontrnued V/:-levels, of crop production', H r i viheian said. 'As. wi'tii'all pesticides, /'/aii'/ussrs are reminded t c c o r e f u i l y rbii-nwiabel ./directions when . //yusihg. 2 , 4-D products. ./I: ' -V-t ... _>y ..y.//,- .-1: -. ' :v--\ . . ti'-.rbrysiore info .-media ./nay contact,./:'..'/./';. /y/-..y/T'y *./ . . - . V .: ;/ ...; : / ^ / . ^ y ^ t O j r a ^ d ^ Pestici.Ses Section /,A g r i c u l t u r e . ' o r ./ 1" .- .i.* .. . 1* '? *V. ' 'S'* *- - `''David. Smithers,/.informtion Services, AgrxcuIture ;/ / 95-3963 -----..? . . . . - % ' ... . : ;/'V.-- ' ; -. // .1 l ^ 1-" - .' ..' ' 'V ..-'lV--V:V)' /r,:. :V- ../m v:: -yv/ **...; : vi-: **v r;//V y :r y` Si? , ` s ' * * .** ! 4 ;i;-iSaean- lussi-er Deputy; Minister ;>/ ':/.!. .' " ':;..'- ... Tt :"'-V '' ;. : ii::'i/'-.: y: .V': >'i ,r\-- ilejricuifcure Ottav/a 0 5 2 - 3 2 3 3 *' ` ''* ;//?.* *. _.v;. -; ..... /w.W . ; * . . y. ' v- ' ; , i ; ;1t... /S ' ' i ; y-'/'yyi'v.-.. 8,?S 3 'VI. 0003977 ay 8394 Vol. V January 28, 1981 No. 4 OVV655949 MN 0 6 6 9 9 5 r Canada To Phase Out Some 2,4-D Products f In a telegram to DAA Ed Johnson dated 1/27/81, Canadian Agriculture Minister Eugene Whelan outlined measures that his Government is taking aimed at phasing out some products containing the herbicide 2,4-D. Agri culture Canada's measures are: (1) an immediate ban on the sale by basic manufacturers of technical esters of 2,4-0 that have been shown to contain dioxins; (2) a phasing-out of all sales of a volatile form of the esterbased 2,4-D called butyl ester (Department studies have identified concerns about rapid evaporation and drift of such products, the telegram states); and (3) action to ensure that all 2,4-D material is free of dioxin con tamination by 1982. "We realize that these measures will not ensure that only dioxin-free 2,4-D is used this season," Whelan said. "Our aim is to phase into completely uncontaminated products by next year* These actions are based on the Canadian findings, announced last fall, of three types of dioxins in 2,4-D product samples taken in the Canadian marketplace. The dioxins found are: 2,7 dichlorodibenzo-p-dioxin; 1,3,7 trichlorodibenzo-p-dioxin; and 1,3,6,8 tetrachlorodibenzo-p-dioxin. Some of the samples tested were free of dioxins, but when the contaminant was present concentrations ranged from 5 parts per billion (ppb) to approxi mately 8,000 ppb. None of the samples tested contained the highly toxic 2,3,7,8 tetrachlorodibenzo-p-dioxin which is often present in 2,4,5-T. EPA is coordinating its review activities on 2,4-D with Agriculture Canada, but the Agency says that there is no justification for regulatory action to change current uses of 2,4-D in the United States because products tested here were either dioxin-free or contained extremely low levels (less than 100 ppb.) EPA has a number of review activities under way to assess the safety of 2,4-D. More details are contained in a fact sheet on 2,4-D issued 1/23/81. Copies of the telegram and fact sheet are being sent to the Regions. For more information or copies of the fact sheet, contact Jan Wine, 703-557-7973. * . i ' r e o i r s d ^ p y A e ^ o n a , ! S u c o o r t . S n a c c h . . OPP 5 5 1 - 7 ? 6 6 0 dim s 5 i r o *O The Development and Prognosis of Chronic Intoxication by Tetrachlordibenzo-p^lioxin in Men 05 2 o ^ 'to ro Ni 1C JANA PAZDEROVA-VEJ LUPKOVA, M.D. MARCELA NEMCOVA, Ph.D. JANE PICKOVA, Ph.D. LUBOR JIRASEK, Ph.D. Faculty of General Medicine Charles University Prague, Czechoslovakia EDGAR LUKAS, P|h.D. Institute of Hygiene and Epidemiology Prague, Czechoslovakia ABSTRACT. During 1965 to 1968, 80 workers who had been engaged in the production of 2, 4 , 5-sodium trichlorphenoxyacetate and butylester of trichlorphenoxyacetate acid became ill. The causcztlthe illness was 2 , 4 ,7 , 8-tetrachlordibcnzo-p-dioxin. A 10-yr study has been conducted for 55~exposed individuals. The majority of the patients developed chloracne, and 11 manifested porphyria cutanea tarda. Approximately one-half o f the patients suffered from metabolic disturbances, .e., pathologically elevated Jipids with abnormalities in the lipoprotein spectrum, and two-fifths of the patients had pathological changes in the glucose tolerance.test. One-third of the patients had bio chemical deviations indicative of a mild liver lesion. Histo logical examination revealed light steatosis, or periportal fibrosis, or activation of Kupffcr cells. Fluorescence of the Jiver tissues was present in ultraviolet light. In 17 persons symptoms of nervous.system focal damage existed, with predominance of~peripheral neuron lesion of the lower extremities (verified by EMG examination). The majority Bf~patients~suffere(Tfrom various psychological disorders. As of this date, two patients have died of bronchogenic < | //"'^lung carcinoma; one of liver cirrhosis; one of a rapidly - t"'" ^ developed, extremely unusual type of atherosclerosis pre- r J r ' cipue cerebri; and two patients have died in traffic acci dents. The conditions of most other patients have improved. ' PERHAPS THE most potent man-made toxin presently known is 2 , 3,7,8-tetrachlordibenzo-p-dioxin (TCDD), a solid substance that is insoluble in water and slightly solu ble in fats and chlorinated solvent. It is a heat-stable, amphoteric substance, and exerts its biological effects at extremely low concentrations. TCDD is not translocated in plants, and has a half-life in soil of about 1 yr. Microbial degradation of TCDD is reported to rarely occur in nature. Irradiation of TCDD in water produces few changes after 14 days.1 Due to its extreme toxicity, its chemistry has not been fully evaluated. There are considerable differences in species susceptibility, but in all laboratory animals the lethal effect is slow and ensues several days or weeks after a single dose.3 TCDD is formed as a by-product during the synthesis of 2,4,5-trichlorphenol, which involves the hydrolysis of 1,2,4,5-tetrachlorbenzene using methanol and caustic soda at atmospheric pressure. TCDD is formed in the distillate by the condensation of two molecules of sodium trichlorphenoiate influenced by the highly exothermic decompo sition of sodium-2-hydroxyethanol. Trichlorphenoxyacetic acid (2,4,5-T), a herbicide produced commercially prior to 1965, contained 30 mg/kg TCDD. Currently, 2,4,5-T, con taining < 0.05 mg/kg TCDD is produced in several countries and is available in commercial quantities.1 Several accidents have occurred during the industrial synthesis of 2,4,5-trichlorphenol and 2,4,5-T, the conse quences of which are well described in the literature.3' 7 The most recent large-scale TCDD intoxication that occurred in Seveso, Italy in 1976 renewed the interest of specialists and the general public. Since we have acquired considerable information during the 10 years we have observed patients with chronic TCDD intoxication, we have chosen to present our findings in this study. Q o, & lanuarv/Fetaruarv 1981 IVnL 16 No 11 < w V 1 J'GTGii) M OO Table 1.-P h ysiologic, Neurologic, Psychiatric, and Dermatologic Observations for F ifty-F ive Males w ith TCDD In to xica tio n * Percent o f patients (/V = 55) Medical lesions Porphyria cutanea tarda Only uroporphyrinuria Hypercholesterolemia H yp e rlip em ia Hyperphospholipemia Diabetes m ellitus Low glucose tolerance test value Hepatic lesions increased to ta l blood proteins Increased plasma ^ g lo b u lin s a , globulins Decreased plasma albumin Neurological lesions Pathological changes w ith o u t any connection w ith exposure ____ exposure to TCDD ----- Polyneuropathy -- Encephalopathy Psychiatric changes Severe neurotic symptoms and signs w ith disorders o f vegetative nervous system Neurasthenia syndromes w ith depressive component Depressive syndromes w ith endogenous component Pscudeoneurasthenia syndromes in patients with arteriosclerosis o f central nervous system Skin lesions Chloracne o f d iffe re n t severity *A II results were obtained at the beginning o f in to xica tio n. 20 '21 56 67 42 8 19 20 13 36 44 33 8 23 7 64 11 8 14 / MATERIALS AND METHODS The Department of Occupational Diseases University Hospital in Prague admitted 55 males for the first time in 1968 and 1963 suffering from chronic TCDD intoxication, who had been engaged in the production of sodium 2,4,5trichlorphenoxyacetate and butyl ester of 2,4,5trichlorphenoxyacetate acid. This incidence of mass intoxi cation occurred during a time when alkaline hydrolysis of tetrachlorbcnzene at atmospheric pressure was used to increase and shorten reaction time, and probably during the same time the mother liquor, which was originally dis posed of, was put back into production. The concentration of TCDD in the work atmosphere was never measured; however, TCDD was found in the final product--Arboricidc E^-and several years later, was also found in the building and qn wall paintings. Originally, 80 of 400 persons who were engaged in this production becamejli. Only 55 of those persons have been observed on a long-term basis; the remaining 25 persons either refused to be examined in our hospital or moved, leaving no address. Those who moved were usually for eigners who returned home. The mean age of the 55 intoxi cated individuals was 36.3 [standard error (SE) = 11.2] at the time the outbreak of illness occurred. We do not pro vide any further details about production conditions and the course of the illness during the initial 3 to 4 yr in this article, since these were described in our 1974 report;7 therefore, we shall only provide the most important data required for understanding the development of the illness. RESULTS The first symptoms of intoxication which occurred at the time of exposure were: gradual, but rarely sudden, formation of chloracnc; a feeling of sickness; fatigue; weakness in the lower extremities; and frequently, pain under the right coastal arch. In 10 patients, however, the first symptoms of intoxication appeared several months after work with TCDD was completed. The intoxication affected several organs and systems (Table 1). It should be noted that only the most severely affected patients exhibited all of the above-listed symptoms, and the extent of organ damage was not uniform for these patients. The severity of illness was not related to the duration of expo sure, job status, or age. 6 Archives o f Environmental Healtt/ ) 0 0 oowtivyiy Table 2.--Cause o f Death fo r Six Patients with TCDD In to xica tio n Age (yr) 1. S7 Duration of Exposure Intoxication 9 mo 2 yr 2. 59 3. 47 4. 31 3 yr 2,5yr 15 shifts 2 yr 3 yr 4 yr 5. 63 7 mo 5 yr 6. 40 32 shifts 9 yr Severity o f TCDD Intoxication Cause o f Death and Post-Mortem Findings Severe type o f TCDD intoxication. Unusual type o f very severe arteriosclerosis o f cerebri, liver, pancreas, and kidneys. Dementia cerebri. Immediate cause o f death: bronchopneum onia. Severe type o f TCDD intoxication. Bronchogenic carcinoma. Severe type o f TCDD intoxication. Bronchogenic carcinoma. Slight signs o f TCDD in to xica tio n. T ra ffic accident--com m inuited fractures o f . lower extremities. * Im mediate cause o f death: fa t embolisation to lungs. Severe chioracne and slight signs o f lip id metabolism disorder. T raffic accident--fractura coli femoris. Cause o f death: bronchopneumonia hypostatica. Severe typ e o f TCDD in to xica tio n; about 3 yr before death; complicated with hepatitis epidemica, type B. --------- - ' M acronodular cirrhosis w ith signs o f portal hypertension, ascites. Cause o f death: hepatic coma. The progression of illness was not linear. In some patients, symptoms and signs of intoxication that were present from the very beginning of the illness, became more severe during the 3-4 yr that followed intoxication. In others, however, organs and systems that were functionally normal during the beginning of illness later became impaired. Deterioration occurred suddenly, the eliciting factors sometimes being intercurrent illness, stress, or unusual physical exertion. In other patients, however, deterioration could not be ascribed to specific factors, but was probably attributable to the spontaneous course of the illness proper. Deterioration and subsequent improvement did not occur consistently in individual organs and sys tems. During 5 yr of intoxication, the health status of most patients was stabilized; some patients' status even improved. During this time 6 patients died, the causes of which are listed in Table 2, and S refused our systematic medical care. The authors are therefore providing medical care to 44 of the original 55 patients; all patients' condi tions have improved, but no patient is entirely healthy. Most of these individuals gradually re-entered the work force, and established themselves in society. During their illness, 18 healthy children were born. The wives of two patients had spontaneous abortions in their third month of pregnancy, but the cause is not known because the fetuses were not autopsied. The impact of the intoxication varies. There are still January/February 1981 (Vol. 36, No. 1) pathological deviations in lipid metabolism in most of the patients. Figure 1 shows mean values of total cholesterol measured when the illness was first noted and "to-date" values, both compared with a control group. Figure 2 shows similar results for phospholipid measurements. At the beginning of intoxication, lipid values were pathologic in more than one-half"of the patients (mean = 13.85 g/L). Currently, the mean values of lipids do not significantly differ from controls. Lipoproteins could be examined only in recent years; we found elevated mean values in the pre-beta fraction [VLDL (Fig. 3)J . In the blood pro tein spectrum, pathologically increased alpha 1 and gamma globulin levels have normalized, but there are still elevated mean values of total blood proteins in comparison to con trols: 7.5404 (SE = 0.5499) against 7.0296 (SE = 0.4462 (P= .01)]. For all internal examinations we used the Stu dent's t test for statistical evaluation. Currently, one-fifth of the patients has a pathological diabetic glucose tolerance test and another one-fifth has a pathological flat glucose tolerance test. Pathologically high excretion of uroporphyrins, together with other signs of porphyria cutanea tarda, were present at the outset of intoxication in one-fifth of the patients. The same fraction had a slightly increased uroporphyrin excretion in urine (to IOOug/24 hr) without any skin manifestations. Excre tion of coproporphyrin in urine was, only rarely, substan tially affected; mean values of delta-aminolevulnic acid in f f> , ^C 00034 Kt\ .%Tf>i)MOa CHOLESTEROL 10 - Table 3.--Results o f Neurological Examinations fo r Individuals Exposed to TCOO Onset ( * = 55) A t Present (/V = 44) Normal neurological examination Pathological changes w ith o u t any connection w ith exposure to TCOO Polyneuropathy Encephalopathy 62% 8% 23% 7% 51% 9% 31% 9% SlCHIflCANT DirriftiNCE Fig. 1. Values o f cholesterol in serum o f patients at the "beginning o f in to xica tio n" and "these days" in correlation w ith "c o n tro l group." urine were, during the first years of intoxication, signifi cantly higher than in controls. At present, pathological excretions of uroporphyrins and skin manifestations of porphyria cutanea tarda are very rare. Similarly, functional liver tests (i.e., bilirubin, thymol pyruvic transaminase in serum, bromsulphaiein test) are seldom pathological, whereas in the beginning of the illness, one-fifth of the patients had mild hepatic lesions. Liverjiecropsy and biopsy showed that even for the most severe forms of intoxication, onjy sjight jnorphological deviations in terms of mild steatosis or periportal fibrosis occurred; even when most severely affected patient, who was the first victim of intoxication, showed only slight activation of Kupffer cells. Only one patient, who died in hepatic coma attribut able tojconoommitant infectious hepatitis B (HBAG posi tive), displayed large-nodule active cirrhosis with manifes tations oTpoftal hypertension and ascites. In all decreased patients and for those in whom liver biopsy was performed, liver tissue fluorescence in ultra-*y violet (UV) light was present, even in cases where repeated examinations revealed normal values of urinary porphyrins. Throughout the entire observation period of the whole patient group, goal-directed examinations did not indicate any signs of toxicjesions in the myocardium or kidneys, and hemopoiesis was not affected. There were no patho logical values of phosphatase alkaline scrum and iron in serum, nor ophtalmological impairments that could be attributed to the effect of TCDD. The results of repeated neurological examinations arc presented in Table 3. During the initial 3-4 yr of illness, the lesion in the peripheral neuron of the lower extremi ties deteriorated, which in most patients, was present from the onset of intoxication. In some cases, polyneu ropathy appeared only during the course of the illness; in these patients it could be reiiablv documented that clinical and electromyographic examinations were normal at the s outset of intoxication. In addition, in four patients there was peripheral lesion N VII, which occurred either in con nection with polyneuropathy of the lower extremities, or was isolated. After 4 yr of illness, the neurological picture stabilized; three patients even showed improvement. Encephalopathy sometimes develops in persons aged 5065 yr, accompanied by organic psychosyndrome on the basis of atherosclerosis of cerebral arteries. Very rarely is ischemic heart disease concurrently present. The patient who presently has the most severe form of the illness is also afflicted with paroxysms of temporal epiiepsis and Fig. Z Phosphorus o f lipoids in serum at the "b eginning o f in to x i c a tio n " and " these days" in correlation w ith "c o n tro l group." 0003 Archives of Environmental Heilth Table 4 .--Psychiatric Changes Observed in TCDD-Ex posed Individuals Beginning o f Intoxication [N = 55) A t Present |N = 44) Neurotic symptoms, neurasthenia syndromes w ith depressive com ponent, depressive syndromes w ith endogenous component 83% Pseudoneurasthenfa syndromes in patients w ith arteriosclerosis o f central nervous system 16% Without any psychiatric symptoms o r signs 3% Neurotic symptoms w ith o u t any depressive symptoms and anxiety symptoms 58% Developed to severe type w ith signs o f dementia cerebri 18% W ithout any psychiatric symptoms o r signs 24% external and internal hydrocephalus; polyneuropathy has remained unchanged throughout the 10 yr. The neurological picture of the illness is complemented with results of repeated psychiatric examinations (Table 4). Psychiatric disorders also progress on the basis of cerebral atherosclerosis, predominantly in patients over 50 yr of age. However, a severe organic psychosyndrome with dementia is also present in a 30-yr-old patient. The depressive and anxiety components of neurasthenic dis O O c: orders have completely disappeared, and the number of patients who show no signs of mental disorders has increased. Chloracne, which in the beginning of the illness was the most constant sign of intoxication, has healed in one- cc fifth of the patients; one-half of the patients has only iso lated cysts and comedones. Fifteen percent, however, still have florid manifestation of chloracne with large cysts, abscesses, and comedones. The pathological changes often affect the genital region, thus senously curtailing sexual activity. Severe forms of chloracne, though healed, have left gross defects in the form of scars which have perman ently disfigured the patients. DISCUSSION f There is no doubt that TCDD intoxication is one of the most severe occupational and non-occupational poison ings. There are two reasons for this: (1 ) TCDD is highly toxic; and (2) the noxa interferes with many metabolic SIGNIFICANT difference Fig. 3. Value o f plasma lipoproteins in correlation w ith control group. January/February 1981 (Vol. 36, No. 1) . * hl OsO'4 5 2 processes which still remain disturbed ax a lime when TCDD, in view of its short biological half-life of 21 davs, should be eliminated from the organism. There is a con siderable species-specificity in the sensitivity of laboratory animals to this toxic substance, and the impact on indi vidual organs differs in different species. In monkeys, as in humans, a permanent sign is skin lesions, while hepatic impairment is in the background. The long-term and relatively complex observation of our patient sample with chronic TCDD intoxication per mits us to express a hypothesis on the nature and prog nosis of this illness in man. There is no doubt that TCDD was present in the air of the workshop, and because of the constantly changing technology, its concentration in air was inconstant. TCDD caused intoxication which in turn, nonuniformly affected a number of important organs and systems. The course of the illness was more severe in individuals when the illness started during exposure than when the first symptoms appeared several months after cessation of this study. Even though most of the patients did not experience all symptoms and signs of intoxication, and some patients showed only symptoms and signs in different combina tions, we assume that in this type of intoxication all the systems and organs mentioned in this study were simul taneously affected, although some only slightly. This assumption is supported by several facts. Fluorescence of liver tissues in UV light, which is a sign of pathological porphyrin metabolism, was present_in all cases of necropsy and biopsy, i.e., in persons in whom long-term monitoring of porphyrin excretion in urine and delta-aminoievunic acid values were constantly within normal limits. Probably a slight subclinical lesion was present. Further evidence was furnished in repeated neurological examinations. Polyneuropathy of the lower extremities was manifest in some patients only in the third or fourth year of illness; we have definite clinical and electromyographic evidence that the first examinations conducted when the illness commenced were entirely normal. The manifestation of these lesions was promoted by unspecific stress (e.g., greater physical exertion, intercurrent inflammation of upper respiratory pathways, stress situations, etc.), none of which could, by itself, produce a similar illness. Simi larly, slight hepatic lesions and diabetes mellitus-manifcst or latcnt-appeared in some patients 1 or 2 yr after intoxi cation, and were related with some unspecific stress, or sometimes they occurred independently. The alteration of many metabolic processes and functional disturbances of several organs indicate a high probability that TCDD affects general enzymatic processes that arc present and necessary for the activity of more systems. Other than the direct toxic effect of TCDO on nervous tissues, we also assume that indirect intervention may exist, i.e., impaired metabolic processes in lipid and hydro carbon metabolism. The incidence of polyneuropathy was more frequent in patients with manifest or latent diabetes. Changes were also marked in the central nervous system on the basis of atherosclerosis of cerebral arteries, the development of which might be ennanccd by hypercholes terolemia, hyperlipemia, hyperpnospholipcmia, and higner pre-beta fraction (VLDL) in the iipoprotein spectrum. 10 GTf)9MOGI* Unfortunately, we could not arrange the autopsy of all deceased patients in a qualified, university surgery where detailed attention could have been given to atherosclerosis. The patient who was the first to die, and who had demon strated the most severe clinical and laboratory signs of intoxication, was thoroughly examined in this respect and autopsy revealed very severe, entirely untypical athero sclerosis. Detailed information is given in our study of 1974.7 The mass occurrence of psychic disturbances, pre dominantly anxiety and'depression, was in the first years CC of illness mainly due to exogenous influences: fear_of death; disfigurement; invalidity; maritaf problems; and in young individuals, the difficulty of entering intimate, close relationships because of the disfigurement resulting from chloracne. Gradual adjustment to the illness, its . ' improvement (especially on the visible skin area), and return to normal work and social life all contributed to decrease psychic disturbances, thus facilipting better adaptation to life. It does not appear that chronic intoxication in our patients unfavorably affected the quality of offspring. All of the 18 children bom to intoxicated individuals were free of the developmental anomalies; their postnatal development has also been normal. Two spontaneous abortions in 10 (10%) pregnant wives of our patients is less than the number of worldwide spontaneous abortions relative to the number of pregnancies (15-20%).7 In recent years the possible carcinogenicity of TCDD has been widely discussed.1 Even though two of our patients, died ofJjronchqgenicJung carcihorriTafter 2 and 3 yr of the intoxication, no definite conclusions can be drawn in view of the small number of persons in the group. This illness is characterized by its non-uniformity, both in its developments and its effects on individual organs. Deterioration was always sudden, followed by less gradual improvement. This is a rather cheerless balance of an ill ness, where the mechanism of origin and cause of unusual development we know virtually nothing. Being aware of this poor understanding, we were very careful in our therapy and concentrated on the prevention of further possible stressful situations that could have aggrevated the illness. We attempted to remove all ncurotoxic, hepatotoxic, and dcrmatotoxic substances from the work and living areas. Each patient received a list of drugs known for their hepato- or neurotoxicity, and those drugs suspected of producing porphyria cutanea tarda, which he was instructed to avoid. Rarely did we apply medicines to alleviate symp toms which were particularly distressing. The treatment of chloracne is discussed elsewhere by the dermatologist, Jirasck.8,5 In our paper we wished to indicate the importance of having a thorough understanding and knowledge of unde sired by-products resulting from synthesis or manufacture of various products, being alert to changes in technology and to systematically protect the health of workers. REFERENCES 1. World Health Organization. 1977. Monographs on the valua tio n a t the Cjrcm oqenic Risk o f Chemical to Man, V o l. 15, Archives of Environm*fri non > vr '.V i pp. -41-102. Lyon , France: International Agency fo r Research on Cancer. 2. Reggiani. G. 197S. Medical problems by the TCDD contam ina tion in Seveso, Ita ly. A rch T o*icot 40: 161-88. 3. Bauer. H.: Schulz, K. H.; and Spiclgerg, V. 1961. Occupational intoxication during the production o f chlor-phenol compounds. Arch Gewerbepath Gewerbehyg (in German). 18: 538-55. 4. Goldmann, P. ). 1972. The most severe acute chloracne: Mass intoxication bv 2,3,7,8 TCDD. International Symposium o f fa cto ry doctors in chemical industry (in German). M cdichcm . 5. .Combos, B.; Pechnovi, A.; Koziak, B.; M oscoviiov, E. 1969. Porphyria cutanea tarda and chloracne during the production o f chlorinated carbohydrates. Brat Lck List (in Siov.). 51: 640-45. 6. May, G. 1973. Chloracne from the accidental production o f tetrachlordibenzodioxin. Br / tn d Med 30: 276-83. 7. Pazderova, ).; Luks, E.; Nemcova, M.; Spacilova, M .; Jirasek, L.; Kalensky, J.; John, ).; Jirasck, A.; and Pickova, J. 1974. Chronic intoxication bv chlorinated hydrocarbons, formed in the production of 2.4,5 sodium trichlorphenoxyacetate. Pracov L in (in Czech.). 26: 332-39. 8. lira'sek, L : Kalensky, J.: Kubec, K.; Pazderova, ).; L u k i, E. 1976. Chloracne, porphvria cutanea tarda and other signs o f in toxication by herbicides. H a u ta rrt (in German). 27: 328-33. 9. Jirisek, L.; Kalensky, J.; Kubec, K. 1973. Acne chlorine and porphyria cutanea tarda by the production o f herbicides. C Dermal (in Czech.) 48: 306-17. o O c: l_ Subm itted for publication February 29, 1980; revised; accepted fo r publication A pril 24, 1980. Requests for reprints should be sent to: Jana Pazderova'Vejlupkova, M.O., Ph.D., Klinika nem oci z povola'ni, Prague 2, 12821, VySehradska 49 Czechoslovakia. i Tetrachloroazobenzene in 3,4-Dichloroaniline and Its Herbicidal Derivatives Propanil, Diuron, Linuron, and Neburon ROBERT H. HILL, JR., Ph.D. ZELDA J. ROLLEN, B.S. RENATE D. KIMBROUGH, M.D. DONALD F. GROCE, B.S. LARRY L. NEEDHAM, Ph.D. Center for Disease Control Public Health Service U.S. Department of Health and Human Services Atlanta, Georgia ABSTRACT. The presence of 3,3' ,4,4' -tetrachloroazobenzene (TCAB) was determined by high performance liquid chromatography in 3, 4-dichloroaniline and herbicides made therefrom. The concentrations of TCAB in 3, 4-dichloroanilines and in different herbicides from a variety of manufacturers ranged from 9 to 1400 pg/g (ppm). The chloracnegenic potential of these products, as determined by rabbit ear test, suggests that it is in the same range of 2, 3, 7, 8-tetrachlorodibcnzodioxin, a known potent chlor acnegenic agent. RECENTLY, some outbreaks of chloracne in groups of chemical workers have been attributed to 3,3\4,4tetrachloroazobenzene (TCAB) and 3,3',4,4-tetrachloroazo.wbcnzcne (TCAOB) as contaminants in 3,4dichloroaniline and its herbicidal derivatives.1,2 These contaminants arc by-products of the commercial syn thetic process.' In addition, several workers have reported that tiie herbicides degrade in soil to produce TCAB and TCAOB.' Chlorinated azobenzenes arc structurally s i m ^ lar (isosteric) to the chlorinated dibenzodioxins and dibenzofurans, which aiso cause chloracne. Poland has reported that chlorinated dibenzofurans, dibenzodioxins, January/February 1981 (Vol. 36, No. 1) O frO .liC A i /. archives o i* fui* .0 U JANUARY/FEBRUARY 1981 VOLUME 36 NUMBER 1 0 0 ? ,6 9 The Development and Prognosis o f Chronic Intoxication by Tetrachlordibenzo-p- dioxin in Men Tetrachloroazobenzene in 3 ,4-Dichloroaniline and Its Herbicida! Derivatives: Propanil, Diuron, Linuron, and Neburon Effects in th e Rat of Inhaling PVC Dust at the Nuisance Dust Level (10 mg/m3) Chlorine Dioxide Water Disinfection: A Prospective Epidemiology Study High Barium Levels in Public Drinking Water and its Association with Elevated Blood Pressure Changes in the Mineral Composition o f Food as a Result o f Cooking in "Hard" and "S oft" Waters Inhalation o f NOz and Blood Borne Cancer Cell Spread to the Lungs Erythrocyte Protoporphyrin IX as a Diagnostic and Therapy Evaluating Tool in Lead Poisoning Jana Pazderova'-Vejlupkova', Edgar Lukas Marcela Nemcova, Jane Pickova Labor Jirdsek R obert H. H ill, Zelda ]. Rollen Renate D. Kimbrough, Donald F. Groce Larry L Needham R. J. Richards, L M. Cobb, C J. Hardy F. A. Rose, T. D. Tetley George . Michael, R obert K. M lday Jeno P. Bercz, Robert G. M ille r D aniel G. Greathouse, Date F. Kraemer James B. Lucas G. R. Brenniman, W. H. Kojota P. S. Levy, B. W. Carnow, T. Namekata B. S. A . Haring, W. Van D e lft A rnis Richters, Kestutis Kuraitis M iguel Angel Ziga-Charles ]. Diego Gonzlez-Ramirez G ilberto Molino-Ballesteros 5 11 14 20 28 33 36 40 `"00 Albemarte Street, N. W. ihin/tton. D.C. 20016 ..tum Postage Guaranteed 1- ISSN 0003-9896 0003455 & 3 .3 7 2 . Safety Services Department ^ o IN cn cn cn A STUDY TO ASSESS THE O CCUPATIO NAL EXPO SURE TO 2,4-0 HERBICIDES Date: January<isl3> Report: SSD-81-1 / Health &Safety Division 0008952 14 1 1 1 fl 1 J fl 1 1 1 1 fl 1 1 fl fl fl fl TABLE OF CONTENTS 1.0 OBJECTIVES 2.0 SCOPE 3. INTRODUCTION 4.0 METHODS OF STUDY 4.1 Study Development 4.1.1 Breathing Air Sampling 4.1.2 Biological Monitoring (Urine) 4.1.3 The Urinary Model 4.2 Sampling Strategy 4.2.1 Air Sampling 4.2.2 Urine Sampling 5.0 RESULTS 6.0 DISCUSSION 6.1 Exposure vs Spray Operation * 6.2 Major Exposure Pathways 6.3 Significance of Air Exposure 6.4 Significance of Urine Concentrations 6.5 Tordon vs 2,4-D/2,4-DP Exposures 6 . 6 Weekly Urinary 2,4-D Variations 6.7 Comparison with 1979 Urinary Levels 7.0 OBSERVATIONS AND CONCLUSIONS 8.0 RECOMMENDATIONS / 8407 0008955 DON2155453 imsizMoa. * -14- 7.0 OBSERVATIONS AND CONCLUSIONS As a result of this study the following conclusions can be made. 7.1 The major route of worker exposure to 2,4-D herbicides is through dermal absorption.- Comparison of the breathing air and urinary data indicates at least 35 times more 2,4-D is absorbed through the skin than is inhaled with the breathing air. 7.2 The averaoe breathing air concentrations were 0.01 mg/nr which is 0.1% of the current TLV of 10 mg/m3 for 2,4-D exposures. The maximum air concentration for a single day was 0.1 mg/m3 which is 1% of the current TLV. 7.3 The average worker excreted 2.1 mg/day of 2,4-D in urine. This is 2% of the maximum daily allowed exposure- via inhalation. The maximum urinary elimination encountered was 43 mg/day. This maximum falls within the range of moderate exposure to 2,4-D. 7.4 Mist-blower operation provided the greatest air exposure to workers at 55.2 ug/m3. The right of way spray operations average 13 ug/m3 2,4-D and the roadside operations provided the lowest worker air exposures to 2,4-D at 6.4 ug/m3. 7.5 Improved work procedures, protective equipment and training provided to the workers reduced the maximum average weekly urine 2,4-D concentrations by a factor of 3 times over those measured in. 1979.. This reduction may also reflect increased worker awareness to possible hazards of these herbicides. 5:10.8 0008983 ZBUSIZMOO, * I m i -15- 8 . 0 RECOMMENDATIONS Work procedures and protective equipment used by herbicide applicators should be reviewed keeping in mind that the major worker exposure pathway is through skin absorption. Inhalation exposure to 2,4-D has been shown to be minimal. 8 . 2 Further reductions in 2,4-D intake can be achieved by washing of exposed skin areas and changing of . clothing which has been exposed to 2,4-D residues ^as soon as practically possible after exposures. There is a great variability in urine elimination rates throughout the day. Better exposure values can be obtained if 24 hour urine samples are collected rather than spot samples through the day. The 24 hour samples can be better related to the urinary model for total exposure calculations. 8.4 The 1981 herbicide monitoring program can be restricted to urine monitoring as air exposures have been shown to be negligible. Urine monitoring should be continued to check work control methods and to continue our data base. t 0008S81 si 8410 i fD0H2I 55 14 1 THE HEALTH EFFECTS OF HERBICIDE 2 ,4 ,5 -T A Report by the American Council on Science and Health CO 0008743 0008744 The American Council on Science and Health is an independent educational association promoting If)DU *9 U L 1 5 5 1 4 2scientifically balanced evaluations of chemicals,V W Richard Main,.ftr.Sr (Consultant ,s', ,, the environment and human health. Sidney Shindell, N.D. LL.B, Medical College of Wisconsin The Council is a nonprofit associb tion exempt from federal income tax under Sec M o n 501 (c) (3) of the Internal Revenue Code. AJ>1 contributions Terrence Smith, M.P.A. American Council on Science and Health i are tax deductible as provided by law. Henry F, Smith, Jr., Ph.D. Individual copies of this report ire available at University of Pittsburgh a cost of $10.00. Prices for ten or more copies are available on request. Kenneth V. Thimann, Ph.D. University of California, Santa Cruz This report on 2,4,5 - T was researched and written by Mary Katherine Hayes, M,S,r Rejearch Associate for the American Council on Science and ft<!alth (ACSHl, CSH gratefully acknowledges the comments and contri butions of the following individui Is who reviewed this report and its contents! Elizabeth M. Whelan, M.P.H., Sc.D. American Council on Science and Health William L. Williams, Ph.D. University of Georgia Ernest E. Campaigne, Ph.D. Indiana University Robert M. Devlin, Ph.D. University of Massachusetts ! E.M. Poster, Ph.D. University of Wisconsin Virgil Freed, Ph.D. Oregon State University William R. Havender, Ph.D, University of California at Berkeley William E. Hazeltine, Ph.D. butte County, California, Mosquitc Abatement District Thomas H. Jukes, Ph.D. University of California at Berkeley Robert H. Kupelian, Ph.D. Rutgers University 0 0 Robert MacVicar, Ph.D. Oregon State University March 1981: first printing r O July 1981s second printing (updaled) 8413 OF CONTENTS Introduction Position Statement Chronology of Events Involving 2,4,5-T Herbicide Production Statistics Uses 2,4,5-T Chemistry Chemical Synthesis of 2,4,5-T Chemical Stability of 2,4,5-T Summary Hazards Spray Drift Residues Tonicity Summary Polychlorinated Dioxins 2,3.7,8-TCDD Chemistry Summary Toxicity Kociba et al^ 1979 McCopneIX and Moore 1979 Allen and Van Miller 1977 Kociba et al^ 1978 Summary Teratogenicity Mutagenicity Carcinogenicity Human Experiences with 2,4,5-T and TCDD Dow Chemical Plant Workers Monsanto Plant Accident, Nitro, West Virginia Arkansas Cleft Palate Study Humboldt County Denny, California St. Louis, Missouri, Horse Arena Seyepo, Italy Alsea I Alsea II Hanify, Metcalf, Nobbs, and Worsley (1981), Swedish Occupational Epidemiologic Studies Summary Agent Orange History Present Complaints about Its Alleged Effects Agent Orange-- Future Plans Scientific Studies Summary EPA Regulatory History Conclusion ) 1 2 3 5 6 10 11 13 13 14 14 14 IS 21 22 23 23 28 29 33 38 40 41 45 46 59 59 65 65 67 68 68 70 71 72 75 75 78 80 87 68 88 69 89 90 91 92 94 0008745 12155 M3 INTRODUCTION This paper by the American Council on Science and Health was prepared as a result of the controversy con cerning the suspension and possible cancellation of reg istration of the herbicide, 2,4,5-trichlorophenoxyacetic acid. Use of the herbicide is currently being questioned and indeed may cease permanently after scheduled hearings by the Environmental Protection Agency (EPA), which began March 14, 1980. Registered in 1948, the herbicide, 2,4,5-T, is not a newcomer to weed control. But studies within the last ten years involving both human and animal exposure to the herbicide have raised questions regarding potential health hazards accompanying its use. In 1978, the EPA issued a Rebuttable Presumption Against Registration (RPAR) (EPA 1978) and Continued Registration of herbi cides containing 2,4,5-T, initiating the process to question the need for continued registration. However, on February 28, 1979, the EPA exercised its option by citing an "imminent health hazard" and called for an immediate Emergency Suspension of 2,4,5-T (EPA 1979c) on rights of way, forests, and pastures. Exempt from this suspension order were rangeland and rice paddy applications. Proponents of the ban argue that the herbicide is very toxic to humans. They illustrate their point with a variety of studies that attribute an increase in mis carriages, birth defects, and certain forms of cancer to exposure to 2,4,5-T. Opponents of the ban defend the use of the herbicide. Interested parties in this camp feel that the scientific evidence does not substantiate the claims made by critics of the chemical. They therefore feel that the EPA's proposed cancellation is unfounded. At the heart of the matter lies the chemical 2,3,7,8tetrachlorodibenzo-p-dioxin (TCDD). Regarded as one of the most potent toxins known to man, TCDD is a consistent contaminant of 2,4,5-T. The American Council on Science and Health seeks to present a balanced and unbiased assessment of this cur rent public health issue. In preparation of this paper, the Council has diligently studied the history and past and present uses of this herbicide both<in the U.S. and abroad. Furthermore, it has scrutinized available data 1 on the effects on human and animal health. In qdditipn, * it has reviewed information about 2,4,5-T in the'popular press aqd from interested parties on both sides of the issue. The American Council on Science and Health appreciates the problems encountered in making a definitive decision regarding the use of 2,4,5-T. A thorough analysis of the 2,4 f 5-T dilemma is complicated by a paucity of human evidence, the need to extrapolate from animal data and a lack of sophisticated detection equipment. The Council recognises valid arguments submitted by both parties involved in this dispute. The Council presents its paper as its own opinion and interpretation of the infor mation studied and hopes that it addresses all pertinent arguments in this important public health matter. I I CO 2 0008746 POSITION STATEMENT Based on its review of the scientific evidence, the American Council on Science and Health (ACSH) concludes that there is insufficient evidence to Bupport a ban on 2,4,5-T. No scientific reports presented to date have shown any convincing relationship between the traditional use of 2,4,5-T and adverse health effects in humans. The toxicity of 2,4,5-T and its contaminant, 2,3,7,8TCDD (2,3,7,6-tetrachlorodibenzo-p-dioxin), has been dem onstrated under laboratory conditions at doses far high er that those to which humans are exposed. Estimates of human health risk derived from animal experiments are un* r e l i a b l e . Furthermore, those risks which have been cal culated for 2,4,5-T and 2,3,7,8-TCDD are extremely small. ACSH recommends that the current uses of 2,4,5-T in rice fields and rangeland be continued and the suspended uses in forests, railways and highways, and landscaping be reinstated. ACSH recognizes the problems posed by 2,4,5-T's unavoid able contaminant, 2,3,7,8-TCDD, and urges that every ef fort be made to further reduce contamination during the manufacturing process. ACSH recommends that applications of 2,4,5-T, particularly aerial spraying, be strictly mon itored to minimize unnecessary environmental and human exposure. ACSH believes that stringent safeguards for the manufacture and application of 2,4,5-T will effective ly reduce any potential adverse effect of 2,3,7,8-TCDD wniie allowing for the continued use of the herbicide. 8 'PC ? ? if Chrone. <fY of Events Involving 2,4,5-T 1945 - developed as an herbicide ^O O H 2 I 5 5 U 5 1948 - registered with USDA as a pesticide 1949 - accident at Nitro, West Virginia, 2,4,5-T plant 1957 -- 2,3,7,81-- "TCDD impurity-in 2,4, 5-T made knovn^ 1962 - Vietnam defoliant spraying commenced 1966 - USDA and FDA order residue tolerances be estab lished for most pesticide chemicals in or on food crops 1967 - deadline for obtaining tolerances for residues of most pesticide chemicals including 2,4,5-T on food and feed products and by-products 1969 - 2,4,5-T and 2,4-D were reported to produce birth defects in animals 1970 - USDA requested further teratogenic studies 1970 - Department of Defense cancels use of 2,4,5-T in defoliation procedures in Vietnam 1970 - USDA cancelled all use of granular 2,4,5-T formu lations for use around the home, recreational areas and similar sites and all food crops intended for human consumption 1970 - USDA suspends use of 2,4,5-T in lakes, ponds, ditch banks, and all liquid formulations for use around the home, recreational areas, and similar sites 1 97 0 - Congress directed DOD to contract with National Academy of Sciences for study of ecological and physiological effects of use of herbicides in Vietnam 1970 - use of 2,4,5-T banned in Italy; it is also banned iq Sweden and the^Netherlands 1971 - accident at racecourse in St. Louis, Missouri, involving exposure to TCDD resulting in animal death and human illness; 2,4,5-T not involved 1971 - FIFRA Advisory Committee recommends continued use of 2,4,5-T on forest, range, rice, rights of way; stipulates TCDD (dioxin) content be reduced to GO en 0008747 0 .1 ppm, 2 , 4 , 5 - T be a p p lie d no more th an ce a y e a r , and a p p l i e d ja ( m m n ^ r '-that* w i l l n o t c o n ta m in a te humans ' ' ' 1971 - EPA prohibits use of 2,4,5-T on most food crops 1972 - Amendments to Federal Insecticide, Fungicide1and Rodenticide Act (FIFRA) enacted requiring registration of all pesticides and their use plus certification of applicators-- Administering Agency for FlfRA is EPA 1972 - Dow Chemical obtains an injunction against EPA enjoining further action against 2,4,5-T IS The study "Primary Carcinoma, of -the .Liver in Vietnam" released in medical journal Chlrurgie by Dr ...Tan Thflt Jung. 1973 - U.S. Court of Appeals overturns injunction; can cellation proceedings continue 1973 - Notice of Intent to hold Hearings on all uses of 2,4,5-T. Public hearing scheduled for April, 1974, following completion of intensive monitor ing for TCDD in part per trillion (ppt) range 1974 - National Academy of Science Report - "Effects of Herbicides in South Vietnam - Part A Summary and Conclusions" issued 1974 - information hearings expanded to include all insecticides and herbicides using 2,4,5Trichlorophenol in their manufacture 1974 - EPA withdraws from cancellation and information gathering proceedings because of its inability to accurately monitor food for TCDD residues 1974 - EPA establishes Dioxin Implementation Plan to identify good analytical methods for detecting TCDD in ppt range 1976 - explosion at ICMSSA Chemical Plant in Seveso, Italy, releasing an estimated 1.7 kg. (3.74 lb.) TCDD in an area with population of 100,000 1977 - decision to continue use of 2,4,5-T in New Zealand issued by government 1978 - Ministries of Agriculture, Fisheries and Food (MAFF) of United Kingdom - Advisory committee announce that herbicides containing 2,'4,5-T were safe, "if used in the recommended way for the 3 recommended f^jpesef* continued! tt*av.Uin* approval given for their 1978 - Agent Orange Victims, International formed by y.S. Vietnam veteran 1978 - EPA publishes Rebuttal Presumption Against Registration (RPAR) and Continued Registration of ?,4,5-T, citing research that indicates 2,4,5-T and TCDD cause tumors, birth defects, and fetal deaths. RPAR allows continued use pending final decision 1978 - firing of ABC-TV's 20/20 News Magazine two-part program detailing 2,4,5-T and Agent Orange 1979 - suspension hearings commenced on April 19, 1979 1979 - hearings stopped on May 15, 1979, after all registrants withdrew from the hearings 1979 - "Politics of Poison," a documentary on 2,4,5-T shown on NBC San Francisco affiliate KRON-TV 1979 - Dispute Resolution Conference on 2,4,5-T held sponsored by the American Farm Bureau Federation I 1979 - availability of EPA Position Document on 2,4,5-T 1979 - hearings before'House Sub-committee on Oversight and Investigations on Involuntary Exposure to Toxic Herbicides and Pesticide Products 1979 - Pendulum and the Toxic Cloud by Thomas Whiteside published, dealing with the Seveso, Italy, dioxin accident 1979 - Notice of Intent to Cancel Suspended Uses of 2,4,5-T by the EPA 1979 Alsea II report submitted to the EPA which pro vided grounds for initial suspension action by the EPA 1979 - EPA issues Emergency Suspension Order for 2,4,5-T on rights of way, pastures, forests, home gardens, aquatic weeds, ditch banks, and ornamental turf; exempt from this suspension were rangeland and rice paddy applications 1979 FIFRA Scientific Advisory Panel reviews nonGO suspended uses of 2,4,5-T and issues opinion 0008748 15 S I %6 1979 - PBS airs "A Plague on Our Children" as part of jl ,( itp p o ^ l ^ r i e s dealing in part with 2,4,5-T 1979 - EPA issues Final Determination Concerning, the , RPAR for certain uses of Pesticide Products and Notice of Intent to hold a hearing I960 - Dow Chemical filing against U.S. Government claims negligence in misuse of Agent Orange ahd failure to inform servicemen of potential dangers of exposure to Agent Orange 1980 - Cancellation hearings of 2,4,5-T began March 14, 1980 1980 - Operation Ranch Hand - in depth study of Vietnam veterans scheduled begins 1DON2155117Herbicide Production Sta tistics Forty years ago, while researching the properties of naturally occurring plant growth hormones, scientists discovered the phenoxy herbicides (Peterson 1967). Considered as synthetic plant growth regulators, the phenoxy compounds were developed to mimic the properties of a naturally occurring plant growth regulator, indoleacetic acid, Concurrent research in the United States and Great Britain revealed the capabilities of certain phenoxyacetic acids, including 2,4-dichlorophenoxyacetic acid (2,4-D), as active herbicides, selectively killing many broadleaf weeds in cereal grain, grasslands, and coniferous forests (Bovey and Young 1978), (Nutman, Thornton and Quastel 1945), (Blackman 1945). The mili tary furthered their investigation by studying phenoxy herbicide use as a vegetation control weapon in 19441945. By 1946, 2,4-D was used extensively to control weeds in turf, small grains, and corn. However, its efficacy did not extend to brush control. Research for an effec tive substitute began. Use of 2,4,5-trichlorophenoxyacetic acid began,after its registration by the Amchem Products Company, Ambler, Pennsylvania, on March 2, 1948. In the years that followed, 2,4,5-T made its mark as the material of choice for effective brush control on rights of way, rangeland, forestry, and certain weeds in rice, wheat, corn, and sugarcane (CAST 1978). Although many phenoxy compounds have herbicidal capa bilities, mpst are not commercially available because of prohibitive cost or narrow effectiveness range. Phenoxy herbicides presently in use today in the U.S. include 2.4- D, 2,4,ft-T, MCPA, Silvex, 24-DB, MCPB, dichlorprop, mecoprop, 2,4-DEP (Weed Society of America 1974), and dichlorprop-methyl (Federal Register April 7, 1980). 2,4-D predominates in the U.S. today, due to its low cost and high effectiveness. Other phenoxy herbicides are employed only in instances where they exceed the capability qf 2,4-D. In 1975, the United States used 59 million pounds of 2.4- D, 6.7 million pounds of 2,4,5-T, and two million pounds of Silvex (Stanford Research Institute 1976). MCPA, 2,4-Dp, dichlorprop and mecoprop find important but limited use for specialized applications (Klingman and Ashton 1975). 2,4-DEP, a chemical related to 2,4-D, acts principally through soil transport (Crafts 1975), but it is not used, with the same, frequency as 2,4-D. --C O 0008749 . One hundred companies hold federal registrations and formulate 424 products containing 2,4,5-T. Eleven companies have applied for federal registration of 21 products containing 2,4,5-T previously registered only in certain states (EPA 1974). In 1969, 11,626,000 pounds of 2,4,5-T acid, esters, and salts were produced in the United States alone. In 1970, the quantity rose to 12,335,000 pounds. Between; 1971 and 1974, 738,907 pounds of 2,4,5-T were imported into the U.S. averaging a total of 148,000 pounds per year (EPA 1974). The phenoxy herbicides gain entrance to the target site by penetrating the plant foliage, roots and soft stem tissue. When applied as a drench in diesel oil, they can soak through the dry bark of trees and enter living tissues (Crafts 1964). Accumulating in the actively growing parts of roots and stems (Crafts 1964), they cause the leaves and buds to twist and curl and new growth of stems and leaves are malformed. Sensitive young plants may die in a few days. Hardy shrubs and trees may succumb only after weeks or months or may survive without injury (Bovey 1977). A phenoxy herbicide enters a plant in an imperfect and uncontrolled way. Once inside the plant, it interferes with the regulation of growth processes normally gov erned by the plant's own naturally occurring growth hormones (Ashton and Crafts 1973). The phenoxy herbi cides interfere with cell division (mitosis) and cell enlargement, food utilisation and various other processes necessary to stabilize life. Scientists do not know the precise mode of action of either synthetic or natural plant growth regulators. They do know that phenoxy herbicides are far more toxic to green plants than to animals. Plant growth regulating compounds act on plant cell compounds such as cellulose and lignocellulose which are not present in animals. 5 USES DOM2I55IM Land management personnel utilize phenoxy herbicides in variogs situations. The following discussion lists kinds of upes and the preferred herbicides for the job. Timber Management - Foresters have included the phenoxy herbicidesamong their timber management tools since the early sixties (Bentley 1967). Forests cover a third of the U.6. (approximately 750 million acres), and two thirds of this land is usable for commercial timber purposes. The remaining, approx imately 350 million acres, either produces too little timber for commercial classification or has been utilized for other functions, namely wildlife, water yield, grazing, pr recreation (CAST 1978). . According to Walker (1973), competing undesirable vegetation causes about 300 million acres of commercial timber land to operate at less than two thirds of its timber production capacity. Over one hundred million acres of historically high yield areas, now support no significant timber growth because competing vegetation robs treeq of vital space, sunlight, and nutrients. Phenoxy herbicides applied here literally shift the advantage to the desired trees, increasing productive land for forest purposes and allowing re-establishment of mature.forests. Traditional forestry methods emphasize hand cutting for thinning and culling of forest stands (Newton 1973), a procedure proven satisfactory as well as economically sound. But nationwide manual attendance of such large forest areas is economically and physically unfeasible. Kimmins and Fraker (1973) have cited 280 references to herbicide uses in forestry, and Johnson and Lawrence (1977) have listed more than 80 references in a more recent review. In California, herbicides are extensive ly used to control weeds in Douglas Fir forests, Ponderosa Pine iqixed conifer forests, and Red Fir forests. Personnel used herbicides in two ways in forests: site preparation for stand establishment and conifer release. The site preparation method involves treatment of land before planting desired conifer seedlings. Fires, logging, and other natural or intentional situations often leave a forest area overgrown with herbaceous and 0008750 woody "undesir^d" growtfi which must be controlled Cor successful seedling establishment. This area is first prepared by clearing the site and crushing or burning the waste. A broad spectrum herbicide is applied durin the next spring to prevent new growth. After the coni fer seedlings are planted, foresters then employ a selective herbicide for continued suppression of rapidly growing plants. This application takes place within one to two years after the desired plantings during the late spring season, a peak time for rapid growth and resprout ing of broadleaf competitors. Some areas may be treated with herbicides prior to the initial burning and planting. With either of these treatments, conifer seedlings establish themselves with in six to twelve months. Occasionally land management personnel may find it necessary to re-treat areas because undesired growth has returned (Bentley 1967), (Schubert and Adams 1971), (Gratkowski 1975). In California, low volatility ester formations of 2,4-D and 2,4,5-T, alone or together, are used for brushfield control, while amltrole, atrazine, dalapon, dicamba, and simazine regulate herbaceous plant or grass growth in site preparation (California Department of Foods and Agriculture 1978). The conifer release method of herbicide control protects conifer seedlings from competing vegetation which robs young conifers of sunlight, nutrients and moisture. To accomplish this, aerial application of phenoxy herbicides takes place in early spring or*late summer when conifer buds have not broken or hardened* avoiding any damage or injury to new growth (California Department of Foods and Agriculture 1978). Repeated treatment may be necessary depending on the species of brush or hardwood involved. Because conifers are relatively tolerant of 2,4,5-T, it is the herbicide of choice for broadleaf control. When the control of certain grasses and herbaceous growth is necessary for conifer release, the herbicides atrazine and simazine are used. Conifers are tolerant of these compounds unless their root systems come in.contact with them. In addition to suppressing new growth, conifer release management may also involve control of mature hardwoods, such as oak. On an overstocked plantation or forest, conifers may be thinned out through direct injection of the herbicide into the base of a tree or direct applies- 7 c k iT s ir r n r r jiiT n w im i* . erms* $**$*!$ -isssas*xi .ss****** i VoL 390 SOAm* mi iKr.i trim :jc- .*11 taMfsroos suggs that h tea a taataUdag degreeof activity again a broad spectrum detailed taveatigationa of individual woritan to make up for the deficiencies of Dioxin a sarcoma risk ofvkal I m m and tumours. But activity it tha epidemiological aurvay of 1977-71. Rcasaesiineclinical data isnotthc only the aot caouMt, or ooMbunt enough. k 0 That invoked only 41 of the 90 woritan reason for monitoring the health of dbmsa to give a final verdict without mors known to have bean expoaed. but revealed workers exposedto dioxin. Recent letter] triala. Aiao, aa genetically-manipulated (almoat a decade after tha event) tome in 7he Lancer(P. A. Honchor end W. E. baLtsrla an to yield atflldent amounts of ahnonnaiitiaa of blood chemistry and Halperin. 1,261,11January 1990; and R. tte tenor0subtypesofalpte-lnicrfaraa.tte immune function -- but none of tha R. Cook. 1.6. 14March I960)highlight panmitatioaa of subtypes and iliaaaiw expected chromoaomal aboonnaHtiee ia another reason. btaonrn huge* circulating lymphocytes. Theauthonoftheletters pointout that Maaawhlla, large-eerie triads of bata- The newt that Coaiha was unwilling to in four induHry-sponsorcd mortality iatarfaroa (from flbrobUsu) lag slightly dkdoee information about this aurvey studies of dioxin-exposed workers in the behind. The large haa y to nan. served to alert the atutoty Employment United States. IQSdeaths wererecorded. Financad aad organised by tha National Medical Advisory Service of the Health In four of these cases, death was caused loathutaaof Haahh(NIH), thetrialwilluaa aad Safety Executive to the existence of by soft tissue sarcomas. These are rare 90,000 million unha of teta-interfsron. such data, which was disclosed 00 a forms iff cancer and for mo the enough for aavatal hundred patterns. Tha confidential bask after three weeks. Tha etiologies ere unknown. kuarfaron la being supplied by Flow service haa also persuaded Coalite that ha Soft tissue sarcomas have also been Laboratoriaa ihfc., which won tha i2 medical adviser. Dr George May, should idcaiifte^`in another cohort of workers aUHon contract a year ago. Fint deliveries publish someof the results. considered to have been exposed to wareduna frw waakaago, but NIH appaar Theemploymentservicehasla themean dioxin. According to two Swedish to ba la no hurry. Tbit la hicky for Flow time bean encompUmeatary about tha epidemiologists. Dr Lennart Hardcll and Laboratoriaa, whoaa own production baa aurvay which, k says, k deflekat ia ha Anita Sandnrom of the Centra of not bean point amoothly. Fortunately, failure to follow up pa employees aad hi Oncology the University of Uaaa. they have a aubcontract with the Wan the Inadequate matching of tha control exposure to the dioxin contaminated Oenaaay company of Dr Reatschkr populations. Tha aurvay covered 41 herbicide 2,4,3-T (2.4.3-trichloro- Arsnrimhtai OmbH which haa continued workan known to have beta exposed to phcnoxyacetk acid) or chlorinated to amaaa beta-interferon made by ha own, dioxin, 94 who might have beta exposed phenols6 to 20 yarn previously could ba leanadvancad, techniques. aad 31 intended aa a control group but responsible for the sixfold g n at Thenext bigcontract, aiao for NIH, wilt drawn for convenience from sanior office, incidence of soft tissue sarcomas ba for gamma-interferon (from calla of the laboratory aad works staff, mo ofwhom recorded in a survey of Swedish forestry immuneayrtem). Far laaaiaknown, at laaat ware being tavesdgatad for Mood lipids at workers (British Journal o f C m ctr 99, publicly, about this type ofinterferon, but the time. 711; 1979).____________ A tedrH sy Biocan aad Oeneatach are rumoured to ba Tha 1977-71 survey showed blood-lipid oa tha varpe of dotting tha relevant ptnee. disorders, with elevated concentrations of Coalite k thus fer from complete. One Other commercial intareata centra on aanaa rholmtarol aad triglycerides. aad clinician describes the re-examination of mtibodiw th i intff* depraaaad levels of high-density lipo the29 workerseat "totallyuseless ptaceof farona. Several new monodonala again p ro tein . Tha easym e y-glutam yl work" which cannot be expected to yield dthar alpha or bata-lntarfarona were tnnapaptldaaa, diagnostic of liver func any meaningful results. announced in Rotterdam, but only tha tion, was abnormally high ia tha expoaed Coalite's managingdirector, MrCharles original monoclonal (aceN a tu rt 2*5, 446; group. Oa the otter head, levek of two Needham, has been approached by several 19t0) la aa yet commercially available. The fanmuaogiobuiias (IgD and IgM) ware dinidans prepared to cany 0 funter sailers ara-tha Britiah company Calltach depressed Intheexposed group,auggestirg investigations. Coalite's reluctance to Limited, ao far ha only product. It will ba Impairment of immuas aa wall aa tear agreeto publicationofthe recallsfromaay MrprWaf If the C iih^h fttilfffH dM function. fttture comprehensivemedical sersen of to Sa mflaidwfalwubwlwiiwB^dnfai*a aFuumfa faN e wmi^ifut The rigahlcaaee of tteaa findings is far workers has, however, forced a t lea oaa Item d a , with the consensus /mong dintriin to abandon hk proposal. Dioxin hazards physicians la the field that 'unher Mr Needham, described by his secretary investigations art aaadad. Tbsyt'gue ttet a*aoiclyresponsibleforpramrelatione, has Secrecy at Coalite the p danca of the phenomena aa- aot bssa available for comment. One covered by the earlier study riwuld be consequence of criticism of the 1977-71 Secrecyaboutthemedicalccnaaqiiancatto confirmed--but ako tte t funter surveys survey, aad of Coalite's continued woritan aapoaad to dtadn condnum at tha should be atosicmafbllyccinrolled. insktenre oa secrecy, k that the financial nun com ply wow i n o u a n w Dr George May, Coalite's company sponsorofthesurvey(an Independentnon Products Limited. Documents now to tend doctor, coafima tte t tteaa workan governmental source) win be unwilling to diow thatCoalkawflnotagraeto tha ftattar Inchided hi the original survey have since provide further support. medical hu anIfIon of workpsopk if tha teen offend a second madknl exantina- As ite law stands, CoaBte may havette phyridaai concernedhad thatthetaculBam tioa, but tint "not everybody availed la word. Hitherto, tte company tea bssa eventually pubddiad. tbemsatves of, tte , opportunity" . la the able to exploit aa ambiguity in tte 1974 Coalka'a ehynaaa k not aaprecadaatad. avam, 39'of the original sample of 41 Health rad Safety M Work Act wtea La year,tte company withheld Infant ton deciding whether or ooc to n im m fitttHfil on an apldamlologicai aurvey of woritan am atsofteawnogloteliBwartaot aiada. Information oa itsarorkforce(seeN a ta n * aapoaad to dioxin (2 ,),7 ,l> Theraa n aophms, however, for further March 1910, p.2). The routine power of hivawlgatios of the Coaiha workers, the Healthaad Safy Executiveto demand (Darbydifae) plam la 196S-71 (aaaMarum, S arrnrdlng to Dr Oaorgt Sonia, deputy medial records of workan Uksty to have March 19009. The otpoaure Mowed an director of the Employment Medical teea affected by a product lapse wtea expioaioninavaaaaiuaadforthemanufacture Advkory Sendee, who saystte t hk service manufactureope. Although Section27of of 2,44-trichlorophaaol and tha woritan tea aot haaa prm nad with any "reaiktic tte a a allows tte executive to dkdoas effected bydtadn developedtharidn dkaaaa r J m sM " propoaak for a loag-tana whatever information k requires (see M iiwnim a t ite health of tha Coalka Nsrunr I May 1990, p.4), epidemiologist Tha fraah ttoubk which haa ariaea workan. The raam am aat of tha stats of at tte executive consider that a ts case k Coaiha raauha from tha need for more health of dioxin-expoaed workan at required to darify the law. AtetakHay OHM 8421 0010966 Z$ Z .3 0 8422 MN07 3 280 AGRICULTURAL PRODUCTS DEPARTMENT - 9001 Midland, Ml 48640 COPIES TO: INDEX C. GOODMAN 9008 J. Y T Z E N 9008 R. G A NTZ 9008 W. MULLISON W. BRAUN 1803 W. WRIGHT CHICAGO B. A L L I S O N W AL N U T CREEK J. GERONIMO KANSAS CITY D. PORTEOUS AT L A N T A M. KALLAL BATON ROUGE J. P O D N A R BATON ROUGE M. NORRIS R. M O F F A T G. J O N E S H O N G K O N G K. W A T S O N R. F E A R S 9008 J. W E L K E R MINNEAPOLIS E. B L A I R 2020 G. W E A T E P. G E H R I N G 2020 R. C H A R L T O N 9008 E. R. R U S S E L L 9008 R. C O O K 1803 A. W A T S O N MINNEAPOLIS J. BETSO.1803 B. S C H W E T Z 1803 R. K O C I B A 1803 F. LANGLEY R. HENDLER PHILADELPHIA D. M O R G A N J. W A L S T A D G. M I L L E R D. D I ETZ C. B L A C K M. ANDE R S O N O. A. W O L C O T T R. M A T T H E W S F. T S C H I R L E Y F. B A L D W I N J. W I T T F. DOST M. N EWTON . R. F R A N S R. G. H A R V E Y G. F. W A R R E N FROM:* J O H N D A V ID S O N 517-6364826 L, HO L M R. W E I S E N S E L L R. W U R M W. S T R I N G E R 0007481 ( c i * 8423 ' ` RESEARCH Contact : Judy McBride (301) 3^-3541 P-16 V550863 J.S. DEPARTMENT OF AGRICULTURE SCIENCE AM) EDUCATION ADMINISTRATION NORTHEASTERN REGION WORKERS' EXPOSURE TO 2,4-D STUDIED ATLANTA, Ga., April 2-- How much 2,l*-0 enters the body of an average 175~pound worker who applies this herbicide 30 days a year for 30 years? The estimate is less than 1 gram. The conclusion Is based on a study that measured the amount of 2,^-D (2,li-dichloropher.oxy acetic acid) in the urine of workers Involved In ground or aerial applications, according to Ralph G. Nash, a U.S. Department of Agriculture chemist who Is a specialist in analyzing pesticide residues. Evidence suggests that the amount of 2,^-D excreted is equal to the amount absorbed, Nash told an audience at the American Chemical Society's National Meeting here today. He cited studies by J. B. Kohl I and colleagues (reported in Xenoblctlca, 197*0 and M. W. Sauerhoff (reported in Toxicology 1980) which indicate that this herbicide is not metabolized in the human body, but rather passes through unchanged after a large dose is ingested. Studies on a similar herbicide-- 2,*,5"T-- substantiate this finding, he added. "The present .study gives us an estimate of exposure for a segment of the population In closest contact with 2,**-D," says Nash of USDA's Science and Education Administration (SEA). "And our figures can generally be interpreted as the upper limit of exposure for more toxic pesticides. Because users of 2,l-D consider the herbicide to have a low order of toxicity, they are less likely to wear protective clothing than when applying more toxic pesticides," he noted. Some pesticides, however, may be more rapidly absorbed, and more toxic, he cautioned. The study was conducted in spring 1980 among two groups of workers who 8424 applied 2,**-D to wheat fields in two areas of the country. Ground applicators in North Dakota applied the herbicide only once and provided daily urine samples 0007482; - MORE I t \ Science and Education Administration Agricultural Research Center Beltsville, Maryland 20705 April 1981 P-16 2- Contact: Judy McBride (301) 3*4-35*1 for six days afterwards-- enough time for complete excretion. A different sampling procedure was used with the second group to optimize the validity of the findings. Aerial applicators in Washington State applied the herbicide intermittently for 2 weeks and provided urine samples every other day for 12 days. Both groups used routine dress and procedures when applying 2,4-0. Absorption was presumably through the skin, Inhalation, and possibly some Ingestion. The North Dakota samples were analyzed in Nash's laboratory at SEA's Agricultural Research Center in Beltsville, Md., while the Washington State samples were analyzed at SEA's Agricultural Research Laboratory in Yakima, Wash. Working with Nash were pesticide specialists P.C. Kearney and S.N. Fertig from Beltsville; and J.C. Maitlen and C.R. Sell, from the Yakima Laboratory. Results showed that absorption Is directly related to the type of job, the amount of herbicide applied and the length of time it is handled. These who mixed and loaded (and, In North Dakota, applied) 2,4-D had the highest total absorption-- 0.02 milligrams per kilogram of body weight (or 1.6 milligrams for a 175-pound person). The least exposed group-- pi lots-- absorbed less than one- third that amount. The Information from this study and other similar studies will be evaluated by the U.S. Department of Agriculture, other Federal agencies, and the Environmental Protection Agency (EPA) which, last spring, requested additional safety data from 2,4-D manufacturers. Absorption data will be compared with toxicity data-- how much is harmful or safe-- when the chemical Is reevaluated. 2,4-D, which Is the active ingredient in many products from six major companies and several smaller manufacturers, was registered about 1946 and has been used widely and safely for more than 35 years. It is used extensively to kill - MORE - 0007483 U(1W1- 55U865 Science and Education Administration Agricultural Research Center Beltsville, Maryland 20705 April 1981 P-16 Contact: Judy McBride (301) 344-3541 -3- weeds In crops, rangelands, and noncropland areas. Some groups have expressed concern about the reported finding in Canada of minute quantities of dioxins in certain formulations of 2,4-0. It should be noted, however, that while 2,4-0 has been reported to contain small amounts of relatively nontoxic dioxin compour the highly toxic 2,37.8-TCDD has never been found in this herbicide. The study with aerial applicators will be continued during 1981 to further assess methods of reducing the level of exposure reported in these studies. 9999 0007484 8426 8427 31 THE * * * * DOW C O N F ID E N T IA L ** * DOW C H E M I C A L C O M PA N Y Q U A LITY ASSURANCE QACACI S P E C IF IC A T IO N C O N F IR M A T IO N COPY * O FFIC E 28749 DATE PRINTED: 2-JUN-81 PA6E: 1 PRODUCT: 28749 QAC 290 REVIEWED 29 HAY 81 REPLACES 28749 16 HA.R 81 name: esteron cr> 245 herbicide DESC: AMBER OILY* EMULSIFIABLE LIQUID. APPL SOVT/IND STOS: EPA RE6. NO. 464-205 : EPA EST. NO. 464-M I-l : FED SPEC 0-H-210C* TYPE II* CL2 MSO: 303 PROD*N PTS U .S. :HH OEPT r\> 31 CJl 00 00 o UT PR0D*N DATES : latest: 29 NAY 81 prior : 2 SEP 80 DATA 5 TERM*L raw matl : sales: test method : 2 SEP 80 : 9 JAN 76 ---- --TEST ITEMSTM-- :2*4*5-T.RICHL0R0PHEN0XY ACETIC <2*4*5-T> :ACID* PROPYLENE 6LYC0L BUTYL ETHER ESTERS* : min. unit:: r 569.2 : ----- 5-- p :2*45-T ACID EQUIV.* MIN. UNIT5X :45.o t-- P' :2*4*5-T ACID EQUIV. UNIT:LBS/6AL :3 .97- 4.1 : ------ 4 :INERT INGREDIENTS UNIT5S > :3o.s :-- r-- :2*3*7*8-TETRACHL0R0DIBEN20-P-DI0XIN p UNIT5PPM * 5<0.1 BASED ON r-- i'~ p 52*4,5-T ACID . .: : 52*4*5-T ACID EQUIV UNIT5LBS/SAL : 3 .97-4.1 :-- :--- 4 IEHULSION CREAMRATEQ 1 HR. 100' PPM HARO WATER unit: hl : 0 .6 MAX. 5-- *. :o.6500 PPM HARD;WATER U N IT H L * 5287490 :28749ft 528749B 528749B 528749B \ 5AS 15B-2 ' :-- W . ?. ^ - : -* - * * . "> : ' ' Vf '"Y, , ;> . . ' -V-v-idr -*%.* '-i ' :--------- COMPOSLTKUt.CNOMINAL>-- fi : 2 *4,5 - T * PROPYLENE 6LYC0L BUTYL ETHER IPS V5--- 7i . -5*7* BE) ESTERS UNIT5X 5 6 9 .0 :^ -- 5027613-72-5 ,,iff.- :2*3*6-TRICHL0R0PHEN0XYACETICACID* P6 BE 5K ESTERS'-V- unit: V; 5 1 .4 ; r ~ i* 5REQUESTED 52 4 -0 ICHLOROPHENOXYACETIC ACID PS BE ESTERS unit: 50.7 --- . --- :* SO01320-18-9 - ' :2-HETH0XY 4 5-DICHL0R0PHEN0XYACETIC ACID* 8.42^ (R) *IND* IC*ATDES0 yA TRACDEOMANRKF OI FD TEHENOOTWI CAHELMI*CA*L* COMPA NiYn m P D D i t r c m i nu c I THE **** DOW C O N FIDENTIAL DOW C H E M IC A L C O M PA N Y Q U A LITY ASSURANCE QACACI S P E C IF IC A T IO N C O NFIRM ATIO N COPY O FFIC E PRODUCT! 287#? CONTINUED* NAMES ESTERO* IN* 245 HERBICIDE PROO*N^-^ t DATA S' TERH*L. IRAN MAT*LI SALESS Z mm Zm -- COMPOSITION (NOHINAL* -- (CONTINUED* :pc be' ester s U N I T S * ' 'I-,' 1*0 - < t ~ . . * .i r -- ' 4-HETHOXT 2*5-DICHL0R0PHEN0XYACETIC ACID* PC BE ESTERS . . UNITS* . /; .'C rJ' ~' 5-METHOXY 2*4-DICHL0R0PHENQXYACETIC*AClD* SPft BEL ESTERS _ l `Q > v- IPQLYGLYCOL. 5?-137tTRIOECYLALCOHOL " E *Q .> '. REQUESTED REQUESTED 2874?" or .00 QO* <0 -- KEROSENE/ UNITS* 2 7 ^ .- MISCELLANEOUS* S P E C IF IC 6R A V ITt.C S /B 8 S Q 7<A P P R O *^? b c il in c ^-p o in t * ( ib p . _________ ... . . . V . i - V r . , - . ----------- " ' VAPOR PRESSURE R +H-. : B B O Q S -ZB -fc.. t / l T " -^*T *-y FLASR PO1RT: ... "' W . T ------ RAU MATERIALS tr-w: -- STOCCASTIT D -13I -*?r 2*4*5--T ACI& BUTOft&PRQPYt^ E37EK&i_ ^ , ;.. ' J- ' - f f 7 C 2 1 - R 2 z+ - 027613-72-5 POLYCLTCOL * ". ' * -- ' 6 7722-RZ 4 SPONTff -:^ v . / : / T/ r ^ - / V $ S ^ S 8 | B 3 4 3 -R ir* KEROSENE E - ji- 0 0 2 0 0 8 -2 *^ ' Pl? 17543] PI 1 0 3 2 5 1 ? " PIC 118351.4' p rr n o 1518 PIT IX0751& PIS. 2T35226 - 5 PIS* 10935S7L? 55^6A^0NUK1 ASPAN!SH,LABEL* PROO*N`NttTE^' -r (1 ). REVISION 27 HAT S r TO' CHANCE TEST LIMIT FOR EMULSION CREAM RATE NO CHANCE. NECESSARY IN SALES'SPECIFICATION AT THIS- TUIE Ef /' ; <21 NO FURTHER PRODUCTION EXPECTED OF. THIS PROOUCT-QUANTITIES ON O^ ^ j CR) INOTCATES A TRADEMARK OF THE DOW CHEHICAL COMPANY ; ' THE * *- * Q 0 II. C O NFIDENTIAL *** OOy C H E M IC A L COMPANY Q U A LITY ASSURANCE Q A C A CI S P E C IF IC A T IO N C O N F IR M A T IO N COPY * O FFIC E 287** PRODUCTS 28749 (CONTINUED* NAME: ESTERON (R*. 245 HERBICIOE PROO*N NOTE (CONTINUED) PAGE: 3 HANO TO BE SOLD UNTIL SUPPLY/DEPLETION, (3) FORMULATION IS M-350G* s approvers: u. l* gold a ERASER approval of changes cc IC A TED A B O V E :.**" APPROVERS of INDIVIDUAL SPECS: PROON: U.L GOLD' QAC 2S MAT 8 t PRODN: N.R KRACHT METHODS 22 APR 80 PROON: G.R., VEURINK PROD*- 22 APR ftl PRODN: L KLOCRE PR00^ 2 2 APR 81 PROON: J,*R* 6LEDHILLACPO ,2 3 .APR 81 PROON! J*S UOOOS GAC/OA* 28- MAT: 81. PROON: E^l*. KING- RAD *18 MAV 81L; ' PROON: J .U . ORENCKPOHL AO A 2G MAY 81 prddn: c . d. UOOOS PSC- .22 MAT 1: prodn: R.U* MORGAN AG REG. 22 MAT 81 proon: a . M . FRASER QAQ-29>MAT 81 sales: U .L . GOLD: QAC.Z9AUG. SR sales: c . d uoods p sc ^ sfc uir so Jf*P ,*V .* SALES! Q.tt*. FRESERXL^SfT^ ^NAl^GOv : * -. S A L E S r r .ORENCXR0Hi^A^a*^Z?aUir.8r':'-, . SALES: J.S*. UOODS> SALES: J.M* FRASER^a.Jfcc DEPT* f, 2^SEir 80 ZJl oe 00 ec *1 --..v ^ i ^ * v r *"*'''-1!?'",rf' ^ ........ ... APPROVALS TV '"'-sfu j JT SL CRT INDICATES A;TRADERARN$ OFtTHE-HDok-CHEMIDAL- COMPANY- : LAST PACE',-.. M w M ? ,! ,\ ?* ' **-* r~"\ - -V . 4 ^ ; . 'Zi*?? '... 4 c-;: , ; o o o 7 4 8 P,3 A D MANUFACTURING SPEC IFIC A TIO N W'STRIBUTION FOR APPROVAL (j/l/vFl JJ/bNCtf potfL 600/ . ~ ' <->-- / t'-- /ieJ /7r<T/ -- A / W -------------- f S ree.orj 2 ivS5 a3S: M /a/ W C M i h d i ^ v ----------------- *>. res- ta .T a t4 ***t-------:----------- * /3.- .. iKy- ? < /-- ~ 12 - /1 -a Please review the attached specification and send to the next person listed. 1 . Review specification as listed. 2. Note a pproval with signature, /t;W s i-* ./ p^eyLt^r C^rU. , ~ > , ~ c O c*L***^tj 'i.Kj TJ.c : .-u;. ^ location and date. 3. If not approved, note necessary -- a/C P a>vu m r - r ^ o D --- changes and initial. When distribution has been completed: ( Return to: sag. uncm. rroa n. 83*1 B u ilding o TVO* C3 l\3 PO CO CO m oo CA Vv;- * .___ . . I__ f- 8432 o c e s t s ? 33 33 MEDICAL -< S > * INFORMATION MATERIAL; ESTERON" 245 BE HERBICIDE SYNONYMS: "TOU J U flg U ll SHifih K T I l e r T , K-4498 COMPOsmON: ' s e e b elo w MATERIAL NO: SOLUBILITY: p h y s ic a l STATE: -4498 amber H om 'd TOXICOLOGY -- ANTICIPATED HUMAN RESPONSE -- BASED ON: EYES: S lig h t t r a n s i e n t I r r i t a t i o n a n d /o r co rn eal I n ju r y . i. amual oata b x stauc * human data o *. utcaa sk in : Prolonged c o n ta c t: s l i g h t I r r it a t io n . Repeated c o n ta c t: moderate ir r i t a t i o n , d ry in g , even a bum Not lik e ly - to be absorbed in to x ic amounts. ORAL:Moderate to low s in g le dose to x ic ity . oo o o D_ _ _ . Dow guide f o r naphtha 250 mg/m3 v ap o r, 10 mg/m3 a e r o s o l. " BS *COMPOSITION: 59.1 2 ,4 ,5 -T , Butoxyethyl e s t e r 32.05S arom atic o r a ro m a tic /a lip h a tic blended o il (p e tro le ra naphth; 5.85S e m u ls ifie rs SAFAC RE-610 and GAFAC PE-510 d ie se l V T .---------------------------- BSTE------------------------- BSKAEiiCt -------------------------------------------------!-----------P at K eeler I 12-30-81_____________based on In g re d ie n ts and s im ila r p ro d u c ts SUGGESTED -- TREATMENT AND HUMAN EXPERIENCE EYES:Hay cause i r r i t a t i o n . In ju ry i s u n lik e ly . S ta in f o r ev id en ce o f c o r n e a l.in j u r y . SKIN: Hay cause I r r i t a t i o n . Not l i k e l y t o be absorbed in a c u te ly to x ic am ounts. E f fe c ts may be cum u lativ e. RESP: A n e sth e tic o r n a r c o tic e f f e c t may o ccu r. * Hay cause re a c tio n s im ila r to petroleum o r p e tro le u m -H k e s o lv e n t. Danger o f chem ORAk:pneumonia must be weighed a g a in s t t o x i c i t y when c o n sid e rin g emptying th e stom ach. I f lavage is performed suggest endotracheal and/or esophagoscopic co n tro l. SYSTEMIC: A n e sth e tic o r n a r c o tic e f f e c t may o c c u r. May In c re a se m yocardial 1 r r i t a b i l 1 t ; Avoid e p in e p h rin e o r s im ila r a c tin g drugs i f a t a l l p o s s ib le . No s p e c if ic a n tid o t! Treatm ent based on th e sound judgm ent o f p h y sic ia n and th e in d iv id u a l r e a c tio n s o f ST:----- we'" iau----- ESTE----- ig a e s a r ---------------------------------------------- SUGGESTED FIRST AID PROCEDURES EYES: i r r i g a t i o n Im m ediately w ith w ater f o r 5 m inutes 1s good s a f e ty p r a c tic e SKIN: C o n tact w ill p ro b ab ly cause no more than i r r i t a t i o n . Wash o f f in flow ing w a te r o r show er. Wash c lo th in g b e fo re re u s e . iNHALATiONflemove to fresh a i r i f e ffe c ts occur. I f resp ira tio n stops give mouth-to-mouth resu scitatio n . ISJ r*o CO INGESTION: Do n o t induce v o m itin g , C all a p h y sic ia n a n d /o r t r a n s p o r t to emergency facility . 0008370 SY? H.C. ScharnwebefV* C-MTS M a n e ft.T.17 12-30-61 persFERCZr M E D IC A L -< 3 5 > - MATERIAL: ECTERON 245 BRUSH AND WEED KILLER* SYNONYMS: fc-JBUb"TM CQMPQSmON: SEE BACK * . '__________ INFORMATION MATERIAL NO: M-3506 SOLUBIUTY:Einulsifiable in v PHYSICAL STATE: Liquid TOXICOLOGY ^ ANTICIPATED HUMAN RESPONSE -- BASED ON: EYES: Slight *to moderate pain, slight transient conjunctival inflammation and iritis. i.animal'data o ? human oatas 3. struc 4 . liter SKIN: Prolonged contact, intact skin, unconfined: slight erythema. Repeated skin contact slight to moderate erythema and edema. Skin absorption capacity not evaluated (Based on minimal tox study).';* * ORAL: Moderate to low acute oral lethality (LD50 rats approx. 1 g/kg body weight. ^ (Based on minimal tox study). o RESP: One hour exposure of 20 rats to an aerosol'of M-3506 resulted in no adverse effects. BY Pat Keeler DATE:. * REFERENCE * 6-24-80 *Rcvised * SUGGESTED -- TREATMENT AND HUMAN EXPERIENCE Stain for evidence of corneal abrasion or injury. SKIN: N RESP: CO May cause reaction similar to ORAL: petroleum or petjroleup-like solvent. Product moderately toxic. Danger of chemical pneumonia must be weighed against toxicity. If lavage is performed suggest endotracheal and/or esophagoscopic control. SYSTEMIC: Human effects not established. Probably could cause serious illness with spontaneous recovery. Based on minimal data. B7T .T M 10-30-78 IFEKEnCET T SUGGESTED FIRST AID PROCEDURES EYES: irrigate with flowing water immediately and continuously for fifteen minutes. Refer to medical personnel. SKIN: Wash off in flowing water. Decontaminate clothing and accessories before reuse. Good personal hygiene. INHALATION: Rempve to fresh air if effects occur. Consult medical personnel. 00 G8371 INGESTION: Do not induce vomiting. Call a physician anc/or transport to emerge facility. 1 MATERIAL: ESTERON 9 245 CONCENTRATE BRUSH SYNONYMS: M-3557 ANL) U lLcr COMPOSITION:^" emulsifiable fonmlation 2, 4, 5 MATERIAL NO: M-3S57 SOLUBILITY: Eaulsifies in H, PHYSICAL STATE: TOXICOLOGY -- ^ANTlbiPAtED HUMAN^&E^PtTNSE -- BASED ON: EYES: be a mild irritant but should cause no more t>in slight transient corneal effects. 1. animal data 0TM*3^TmT; * h u m a n o a t a q 4..liter SKIN: May cause mild to moderate irritation on repeated contact. Not absorbed in toxic amounts. ORAL: Moderate single does oral toxicity. LD50 (rat) in the range of 700 to 1000 <p mgAg. *<*" 0* & RESP* TLV: No guide for control established. Considered to be low in hazard by inha .. ` Solvent low in volatility.-: * V:Pat Keeler f A^/4/77 EFEHENCET SU GGESTED -- TREATMENT AND HUMAN EXPERIENCE EYES: May cause mild irritation. May cause corneal injury or burn. Stain for eviden of corneal injury. If cornea is burned instill antibiotic steroid preparation frequently. Conult ophthalmologist. SKIN: May cause mild irritation. Wash clothing before-reuse. RESP: No tox data. Human effects not established. ORAL: cause reaction siailir'to petroleum or'petroleum-like'solvent. -May cause chemical pneumonia if aspirated into lungs. N6t likely to be absorbed in acutely toxic amounts. If lavage is performed, suggest endotracheal and/or esophagscopic control. SYSTEMIC:Anesthetic or narcotic effect may occur. May cause kidney damage. May cause liver damage. No specific antidote. Treatment based on sound judgment of physician and individual reactions of the patient. rBYT W. A. FisKbeck ii: 10-30-78 SU G G ESTED FIRST AID PROCEDURES Ri EFERENC: [ EYES: jyyigate with flowing water immediately and continuously for fifteen minutes. Refer to medical personnel. SKIN; Contact will probably cause no more than irritation. Wash off in flowing water of shower. INHALATION- Remove t0 f TM * 1 if effects occur. Consult medical personnel. INGESTION: Do not induce vomiting Call a physician and/or transport to emergency facility. 8436 0008369 BY: ---------------------- BATE: W. A . F i:h b e c k | 10-30-78 iEFERENCET 8437 I ) REPORT OF THE COUNCIL ON SCIENTIFIC AFFAIRS T its ;g Report: A (T -81) Subiect: Presented by: Referred to: Health Effects of "Agent Orange" and Dioxine Contaminants William D. Dolan, M.D., Chairman Reference Committee E (John J. Gaughan, M.D., Chairman) * 05 to cn 00 1 2 3 4 5 6 7 8 9 10 n 12 13 14 15 I6 17 18 19 v 20 21 22 23 24 25 26 27 28 The American Medical Association's Council on Scientific Affairs, in response to a request from the Medical Student Section, has reviewed the medical evidence regarding the toxicity and long-term health effects of Agent Orange and its associated contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). This Executive Summary, which was prepared by the Council on Scientific Affairs Advisory Panel on Toxic Substances,* sunmarizes the findings in its Technical Report on the subject, which is available on request. BACKGROUND During the latter stages of the US' involvement in Vietnam, herbicidal mixtures of 2,4,-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), otherwise identified by the military as Agent Orange, were sprayed over certain areas of Vietnam for the express purpose of defoliating the jungle and destroying one of the enemy's means of concealment. Similar spray programs have been used in the US as a means of forestry management. For the past 30 years, mixtures of 2,4-D and 2,4,5-T have been used extensively by the homeowner and farmer for ridding lawns and agricultural acreage of unwanted broadleaf vegetation. Large numbers of persons have been exposed to varying amounts of 2,4,-D and/or 2,4,5-T, as well as the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in the normal course of employment. Also over these years, there has been a number of industrial incidents wherein workers, as well as civilian populations, have been subjected to accidental exposure to these compounds. There are now * John R. Beljan, MD; Nelson S. Irey, MD; Wendell W. Kilgore, PhD; Kazuo Kimura, MD, PhD; Raymond R. Suskind, MD; Jaroslav J. Vostal, MD, PhD; R.H. Wheater, MS, Secretary i 0007102 T *T S 9 $ iM l CSA Report A - page 2 1 pending a number of litigious actions and government regulatory 2 responses that are based upon alleged adverse health effects from such 3 exposures. 4 5 The most serious of these allegations by Vietnam veterans and 6 persons who were involved in accidental industrial exposures assert that 7 Agent Orange, or compounds of a like nature, may have caused malignant 8 tumors, sterility, spontaneous abortions, birth defects, disfiguring 9 skin diseases and other illnesses. In spite of the voluminous data on 10 the biological effects of the phenoxy-type pesticides and the associated 11 chlorinated dioxins, there is still very little substantive evidence for 12 the many claims that have been made against these compounds. Data from 13 experimental animals do indicate that TCDD is a toxic material; however, 14 while suggestive, the animal data are not necessarily applicable to 15 man. Still, a number of those exposures to TCDD of industrial and 16 17 general populations documented to offer that some have occurred have been insight into the effect osfufTfCiDcDieonntlmy awne. ll 18 19 Agent Orange, or Herbicide Orange, was a label given by the US 20 military forces to a 50:50 mixture of the n-butyl esters of 2,4-D and 21 2,4,5-T together with a minor amount (12) of the free acid of 2,4,5-T 22 and varying amounts of the contaminant TCDD. Agents Green, Fink and 23 Purple also were used as defoliants by the military forces from 1962 24 thru 1964, a time when very few American troops were committed to the 25 field. Another formulation, Herbicide Orange II, was similar to Agent 26 Orange except that the isooctyl ester of 2,4,5-T was substituted for the 27 n-butyl ester of 2,4,5-T. In addition to Agent Orange, other spray 28 defoliants used in Vietnam included Herbicide White, whose active ingre- 29 dient was picloram (or the triisopropanolamine salt of 30 4-amino-3,5,6-trichloropicolinic acid). This substance is very 31 persistent in the environment and highly carcinogenic in rats and 32 mice. Lesser amounts of Herbicide Blue, which contained sodium 33 cacodylate* (26Z) and cacodylic acid (5Z), were used. Though the long- 34 term effects in humans of either or both of these compounds is 35 uncertain, picloram and cacodylic acid should be considered along with 36 the above agents that were encountered in Vietnam. > 37 38v TCDD may form as a by-product of the synthesis of 2,4,5-trichloro- 39 phenol (TCP), a precursor of 2,4,5-T, when 1,2,4,5-tetrachlorobenzene is 40 subjected to alkaline hydrolysis at elevated temperature and pressure. 41 If the reaction temperature is allowed to go above 180 C, the 42 sodium-2-hydroethoxide (formed from the ethylene glycol solvent and 43 caustic soda) decomposes exothermically and promotes the dimrisation of 44 sodium trichlorophenate to TCDD. The presence of TCDD as a contaminant 45 of 2,4,5-trichlorophenol was discovered in 1957, when workmen involved 46 n Che manufacture of TCP developed chloracne. 0007103 __________________________________________________________________ * Sodium cacodylate is the sodium salt .of cacodylic ac|.d (hydroxydimethylarsine oxide) --*-- ..... -. 8439 j CSA Report A - page 3 DOW1462515 1 About 20 years ago, _omoercally available 2,4,5-T contained any 2 where from 1 to 70 ppm of'TCDD. When the industry became aware of the 3 contaminant's existence and toxicity, production operations were 4 monitored and altered to reduce the level. Current manufacturing 5 operations are able to control the amount of TCDO in commercial 2,4,5-T 6 formulations to less than 0.01 ppm (with occasional batches as high as 7 0.05 ppm), a level believed to be non-hazardous to humans and other 8 organisms. Data relating to an acceptable maximum level are presently 9 under regulatory review by FIFRA (Federal Insecticide, Fungicide and 10 Rodenticide Act); the recommended maximum concentration is now placed at 1 1 0.1 ppm. 12 13 Commercial formulations of 2,4,5-T and 2,4-D were used safely in 14 agriculture for over 30 years with no recognizable evidence of carcino 15 genicity or birth defects in humans. Those adverse effects that did 16 .-occur from massive doses of either pure 2,4-D or pure 2,4,5-T were 17 manifested soon after the exposure, and the victims recovered with no 18 signs of. long-term damage. When the first symptoms were to present 19 months or years after the last exposure to these compounds, it was 20 evident another causal agent had to be responsible. That agent was 21 later suspected to be TCDD. Though closely related chemically to 2,4,522 T, 2,4-D is.not generally contaminated with TCDD. 23 24 BIOLOGICAL EFFECTS 25 26 Two of the more pronounced biological effects of some of the 27 chlorinated dioxins are their tendency to cause chloraene (especially, 28 in the rabbit, nude mouse, monkey and man) and the accumulation of fluid 29 (ascites) in the pericardium and peritoneal cavity of chicks. 30 31 Chloraene in man is typified by comedones in a malar distribution; 32 the pns- and postauricular portions are often accompanied by hirsutism 33 and sometimes by. melanosis and a secondary inflammation. The disease 34 was first described in 1899; its cause was discovered in 1918 to be due 35 to contact with certain chlorinated hydrocarbons. Chloraene has now 36 become one of the more common forms of occupational dermatitis. Other 37 acute toxic reactions to dioxin include liver and renal damage, por 38 phyria cutanea tarda, hyperpigmentation, hirsutism, polyneuropathies 39 (eg, sensory impairments and weakness in lower extremities) and neuras 0 thenic -or depressive- syndromes.'--Thus-far,-'long-term effects, except for 41 persistent chloraene, have not been seen. 42 43 Chloraene is not caused by 2,4,5-T and 2,4-D per se; if the 44 condition occurs upon exposure to either or both of these compounds it 45 is most likely that the contaminant TCDD is responsible. Chloraene 46 usually appears within 2 to 3 weeks after the first exposure. Mild 47 chloraene clears up within several months after cessation of exposure; 48 severe chloraene, on the other hand, has been known to persist for as 49 long as 30 years following the last exposure. Persons most responsive 50 are those who are prone to develop acne vulgaris. If one's exposure to 51 TCDD is severe enough, cysts form and, on occasion, inflamation and 52 scarring will occur. If there is no medical history of chloraene, then 0 A 53 the likelihood of a significant exposure to, or adverse health effects O'i -.SBS"-- GG07104 462516 CSA Report A - page 4 from, TCDD is remote. Hence, chloracne is the clinical marker of TCDD exposure. Chronic exposures to TCDD lead to degeneration of the liver and 5 thymus in experimental animals: one sensitive index of exposure is 6 atrophy of the thymus. Porphyria, altered levels in serum enzymes and 7 weight loss are also observed. Major organs to be affected are the 8 liver, blood forming organs and the reticuloendothelial system. 9 Progressive weight loss, the first clinical sign of toxicity in the 10 monkey, may be accompanied by alopecia, facial edema and a dry, scaly 11 dermatitis over the rest of the body. 12 13 The metabolism of TCDD in man is unknown, and for the present 14 there is only limited information available on the metabolic pathways 15 'afid metabolites that may occur in other mammals. TCDD is distributed 16 equally among the fat and liver of mammals, to a lesser extent in the 17 kidneys, and is eliminated via the fces. Samples of fat from beef 18 cattle and samples of milk from cows that had grazed on 2 ,4 ,5-T-treated 19 pasture or rangeland, in Addition to human milk from an area where 20 2,4,5-T herbicide:were used repeatedly over a period of 20 years, had 21 small to undetectable (not more than 10 ppt) amounts of TCDD. 22 23 Ho clearly defined mutagenic effect has been observed in vitro 24 with TCDD. TCDD does induce genetic changes by the Ames test with _S 25 typhimurium and E coli but not with repair-defective strains; there is 26 no evidence (from dominant lethal and cytogenetic evaluations in v ' 27 rodents) that such changes occur in whole animals. 28 29 Of perhaps more relevance to sum are the in vitro studies on 30 maaaalian cells-- ie, HeLa; Balb-3T3, normal mouse fibroblasts; SV101, 31 virus (SY40)-transformed 3T3 mouse fibroblasts; human foreskin fibro 32 blasts; and normal human lymphocytes. Ho significant growth inhibition 33 in the cell cultures nor discernible ultrastructural changes have been 34 observed by electron microscopy. 35 36 The teratogenicity and fetotoxicity of TCDD were discovered in 37 1969, in the course of a study on the biological activity of 2,4,5-T. .38 The sample being used was later found to be contaminated with TCDD. The 3 9 ^ incidence ofcieit palate was greater*in "two particular mouse strains 40 (C57BL/6 end AKR), while the C57BL/6 mouse and the rat developed a 41 higher incidence of cystic kidney. All doses given the rat led to 42 gastrointestinal hemorrhage in the fetus. The increased ratio of fetal 43 liver to body weight in the mouse suggested that TCDD was fetotoxic in 44 this particular species. 45 * 46 A majority of studies using high doses of 2,4,5-T with 0.1 ppm of 47 TCDD or less showed cleft palate in mice, but no other species, and 48 embryotoxicity in the mouse, rat, hamster, sheep, monkey and rabbit. 49 There is no scientific evidence that 2,4-D, 2,4,5-T or TCDD has caused 50 reproductive difficulties or hazards in the human. No conclusive wP' 51 evidence is yet available that phenoxy herbicides or TCDD are mutagenic 52 or teratogenic in man. 'f* V. --t 11 i n r r l a w s _LSl ^mf cAi j B^j aui SM i j ji . 0007105 CSA Report A - page 5 1 TCDD can induce cancer or serve as a cancer promoter in some 2 strains of rats and mice. In contrast to some other chemical carcino 3 gens , the carcinogenicity is always accompanied by considerable systemic 4 toxicity. 5 6 From an environmental view, TCDD breaks down rapidly on leaves of 7 plants, in water and on the surface of soil, especially through the 8 action of sunlight. In soil it generally has a half-life of about 230 9 days; some soil microorganisms can degrade it, especially if other 10 chlorinated hydrocarbons are present. 11 12 EXPERIENCE IN MAN 13 14 One of the most extensive human experiences with the adverse 1 5 > effects of TCDD in man involves the residents of Seveso, Italy. In July 16 of 1976, TCDD was accidentally released from the ICMESA*. trichlorophenol 17 synthesis plant when a safety disk in a steam-heated reactor vessel .. 18 ruptured .^The plume of reactor-contents,-, .including TCDD,, rose 160 feet 19 above the factory .and fell in a cone-shaped pattern about a mile long 20 and a half-mile .ride. This is the largest single population to have 21 been exposed to the compound. Over 37,000 persons rere potentially 22 exposed to varying doses. 23 f i y wk ,v. 24 Two years after the incident occurred, the acute and mid-term 25 health effects were assessed; the mild chloracne, which occurred mainly 26 in a small group of children, healed quickly. Subelinical peripheral 27 nerve impairment was reported; there was also some liver involvement, 28 but rithout apparent functional disorder. Neither imunoresponse nor 29 susceptibility-to infectious diseases was altered. 30 31 The most recent progress report on the long-term epidemiologic 32 survey of the residents of the Seveso area emphasizes the preliminary 33 nature of their findings and reiterates the conclusions of prior 34 investigators. -Except for the skin, no organs or body functions rere 35 impaired. No derangement of gestation, no fetal lethality and loss, no 36 gross malformations, no growth retardation at term and no cytogenetic 37 abnormalities have yet occurred. 38 T T :The--first-^f-several -accidental -releases-of-TCDD-and-other - 40 dioxins, attending the manufacture of 2,4,5-trichlorophenol (TCP) or 41 2,4,5-T occurred in 1949 in the US. At least 11 other industrial acci 42 dents or exposure incidents have occurred since then, both here and 43 abroad. To date, an estimated 579 rorkers are knotm to have been 44 exposed, including 156 employees in the ICMESA plant at Seveso. 45 i 46 CURRENT STUDIES 47 48 There are how a number of studies underway by agencies of the US 000710649 government and industry, rhich may resolve questions on the kinds and C & .~ tc ..c r * Industrie Chimiche Meda Societ Anonima " *W|M * >->tffff m a ?rT 'rti; h <t i r CS Report A - page 6 *'V 1 2 3 4 5 05 to 6 or 7 8 00 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 -38- 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 extent of human damage from exposure to low levels of TCDD: Thru its Department of Environmental and Drug-Induced Pathology, the Armed Forces Institute of Pathology (AFIP) is examining biopsy and autopsy tissue of all Vietnam veterans. To date, only 152 eases have been assessed: the dominant diseases are epidermal inclusion cysts and chronic, non-specific dermatitis. If any malignancies were to have been induced by TCDD, they should be appearing by now, yet there have been no unusual morphological features nor clustering of tumors by diagnosis or site as to implicate Agent Orange. A soft-tissue sarcoma study also has been proposed that will be < --conducted jointly by the Armed Forces Institute of Pathology and ' th Rational Cancer Institute. '^' -The Air Force,'-through-Project Ranch Band, will administer* and " examine the 1,200-personnel who-were involved in the actual handling and spraying of Agent Orange. They, and the control population of'20,000, are to be followed over the next 20 years. The1University of California, Los Angeles, was awarded a contract by the Veterans Administration for the design of an epidemiologic std of Vietnam veterans. Approximately 45,000 Vietnam veterans who expressed concern about the hazards of Agent Orange have been examined by the VA; data on 25,000 of these men have been placed in a special Agent Orange Registry, which may serve later to identify them and to provide medical information as well as indications of health trends over the long term. The Chioracne Task Force was established to sift out those cases of -dermatitis that either resemble or are truly chloracne. Cases of the former type will be re-examined by dermatologists who have an expert knowledge of the disease. Thus far, there are only 700 cases of "skin conditions" out of the total of 3,500 filed claims k----- for-damage-from*Agent-Orange r**- ---- :------- :------ 1------ ---- RECOMMENDATIONS The Council on Scientific Affairs recommends that: (1) The above studies on exposed, or allegedly exposed, persons continue to be supported and, if feasible, enlarged to include the cooperative engagement of all internationally known exposure data, as recomaended by the International Agency for Research on Cancer (IARC). f (2) All physicians be alerted through AMA publications to the classical signs of chloracne and the possible signs and adverse effects of TCDD exposure. They should be encouraged to enlist in the present efforts to identify and treat those persons who have had serious exposures to TCDD, and to cooperate in the collection of vital information that is needed for the ongoing human epidemiologic studies. *W ......1 t rr-ffiif 000V107 84 5 >3 S ' N05 <OOW 1 526037 CURRENT REPORT 1601 be assessed on lots found to be deficient in quality or quanti reproduction or offspring were observed in any of the tests, / ty. The money collected would be paid to the pesticide users, according to CMA. when known. Testicular changes were observed in two out of 20 male rats Vincent Giglio. director of the departm ent's Division of at the highest dose level, but this did not appear to affect Inspection. March 3 distributed a letter to pesticide control reproductive performance. Nor was it clear if these changes officials from other states seeking comment on the proposal were related to benzene exposure, the group said. and inquiring about practices followed by other states. The study results were submitted to the Environmental For further information, contact Giglio a t the Florida Protection Agency, the National Cancer Institute, the Oc- ; Department of Agriculture and Consumer Services, Room cupational Safety and Health Administration, the National 232. Mayo Building, Tallahassee, Fla. 32301. Institute for Occupational Safety and Health, the National Institute of Environmental Health Sciences, the Food and Drug Administration, and the Consumer Product Safety Health Hazards Commission. REDUCED SPERM COUNTS F O UND BY NIOSH IN PRODUCTION W O R K E R S AT KENTUCKY PLANT Workers in a Kentucky plant who were exposed to toluene diamine (TDA) and dinitrotoluene (DNT) during the produc tion of TDA w ere found by the National Institute for Oc cupational Safety and Health to have reduced sperm counts. The findings were made after the discovery of abnormal sperm morphology in one worker in the TDA unit at Olin Chemical Corp., Brandenburg, Ky., according to the in stitute. Some 30 workers participated in the study, including nine workers currently exposed to both substances. 12 who were exposed in the past, and nine with no history of exposure, the institute reported. The currently exposed workers had " significantly reduced sperm counts" compared with the non-exposed group, the in stitute said. Wives of the exposed workers indicated that spontaneous abortions had become more frequent after their husbands were first exposed, the institute commented. It cautioned, however, that " this finding had only borderline statistical significance, and may have been affected by factors such as age and inaccuracy of recall." Implications Indetarminata The findings " can neither be considered conclusive nor can they be dismissed as insignificant," the institute com mented. Because'the population size was small, a " large number" of additional subjects m ust be studied to cor roborate the findings, it asserted. NIOSH said it plans to locate other plants using TDA to determine if the problems that were identified exist elsewhere, and to recommend that the National Toxicology Program conduct additional animal studies to assess further the reproductive toxicity of the substances. *. Benzene N O EFFECT O N REPRODUCTIVE PERFORMANCE FOUND IN STUDIES CO N D U C T E D FOR INDUSTRY Benzene has no effect on the reproductive performance of laboratory anim als, according to a study recently completed for the Chemical M anufacturers Association and the American Petroleum Institute. The study, conducted by Bio/dynamics Inc., E ast Millstone. N .J., subjected m ature male and female rats to benzene a t 1 to 300 parts per milHon for six hours a day, five days a week, during a 10-week period prior to mating with untreated animals. Female rats continued to be exposed during the mating and gestation periods and days five to 21 of the lactation period. No statistically significant adverse effects on Dioxins SECOND D O W SARCOMA CASE FOUND; COMPANY SUGGESTS SMOKING AS FACTOR Dow Chemical U.S.A. March 11 reported that it found a se cond case of soft tissue sarcoma among Dow workers expos ed in the past to dioxins. The company stated, however, that the conditions to which the employee may have been exposed " do not exist in the workplace today." The worker also was a cigarette smoker, "which may have a bearing on this incident," Dow said. According to Dow, the employee began work in the produc tion area of a trichlorophenol plant in the company's Michigan Division in 1951. An outbreak of chloracne appeared in that process area in late 1963 and 1964, ap parently due to contamination by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the company reported. The worker cited by the company developed chloracne, and was diagnosed by his personal physician in late 1979 or early 1980 as having a malignant fibrous histiocytoma, Dow said. Production of trichlorophenol by Dow in the U.S. ceased in 1979, the company said. It added that its overseas production facilities have been modified over the years so that exposure to the contaminant TCDD " virtually has been elim inated." Smoking Soon Factor Dow noted that another trichlorophenol-production worker was found in an earlier company study to have died from fibrosarcoma. This worker, and two Monsanto workers who also had been exposed to dioxin and had died from soft tissue sarcom a, were noted by researchers with the National Institute for Occupational Safety and Health, who said that the deaths represented a higher than expected m ortality rate (Current Report, p. Feb. 27, p. 1517). A review of the two Dow and two Monsanto cases revealed some "common characteristics," Dow maintained: All four workers were cigarette smokers. Three of the employees had substantial exposure to trichlorophenol, and all four probably had substantial ex posure to TCDD. Two of the workers developed chloracne, and another had facial derm atitis not diagnosed as chloracne. Although the report on the fourth employee does not in dicate if he had chloracne, it mentions that a num ber of other employees in his work a rea a t that time did have the condition. No definitive cause/effect relationship can be drawn, but the data suggest that persons who exhibit chloracne as a result of substantial TCDD exposure, and who were 4 4smokers, may be at increased risk of developing soft-tissue sarcom as, according to Dow. 3-20-81 Copyright ' 1981 by The Bureau o f National A ffairs. Inc. Oia-7973/S1/$OOSO 0007309 ^ f 1J502____________________________________________ CHEMICAL REGULATION REPORTER DOW 1 526038 i Cancer Rata Said Lass Temporary tolerances were renewed for glyphosate and ' Dow reported the second case of malignant fibrous its metabolite aminomethylphosphonic acid on forage histiocytoma to the Environmental Protection Agency legumes at 0.4 ppm. and the liver and kidney of cattle, goats, March 6. to provide "technical compliance" with the ToxicSubstances Control Act. The information " does not, in our judgment, scientifically demonstrate a substantial risk at this- lim e." according to a memorandum signed by Etcyl H. Blair. Dow vice-president and director of health and en vironmental sciences. .None of the four studies evaluated in aggregate by NIOSH researchers found " any increased overall m ortality, nor significantly increased m ortality due to cancer," Dow main tained. When combined, the studies " reveal an apparent in crease of soft-tissue sarcom as (albeit histiologically dis tinct)." but the "overall cancer was substantially less than that expected in the general population." the company said. Noting that NIOSH has further dioxin studies under way, Dow said it was making the latest data available so that the information could be included in the studies. hogs, horses, poultry, and sheep at 0.1 ppm. The tolerances expire Jan. 29. 1982. Specific end Crisis Exemptions Exemptions for the use of pesticides in em ergencies were issued to: Animal and Plant Health Inspection Service, to use naled to eradicate the oriental fruit fly in California. Arkansas, to use Machete and Propanil to control grasses and weeds in dry-seeded rice fields. California, to use Botran and orthophenylphenol on kiwi fruit to control A l t e r n a r i a a l t e r n a t a a n d B o t r y t i s cinerea. California, to use Carzol on straw berries to control the two-spotted spider mite. Fish and Wildlife Service, to use sodium-cyanide-loaded M-44 devices to control coyotes and red foxes preying on the whooping crane. Florida, to use heptachlor to control the West Indian Pesticides EPA PUBLISHES TOLERANCES. PERMITS. sugarcane rootstalk borer weevil on ornam ental plants and nonbearing citrus nursery stock. Florida, to use permethrin to control the vegetable leaf- GRANTS 13 SPECIFIC PESTICIDE EXEMPTIONS m iner on celery, lettuce, and tomatoes and to control tomato The Environmental Protection Agency March 6-18 acted on 29 pesticide petitions and received two petitions and two notices of crisis exemptions. Tolerance Amendments pinworms on tomatoes. Georgia, to use fenvalerate on cabbage to control the cabbageworm. Idaho. Oregon, and Washington, to use benomyl in fall seeded wheat acreage to control C e r c o s p o r e l la foot rot. The agency March 17 set maximum levels of acephate and its metabolite methamid'-phos on m int hay a t IS parts per million ippm) (46 FR 17020). For further information contact Clinton Fletcher, Registration Division, Office of Pesticide Programs, EPA, 1921 Jefferson Davis Highway, Arlington, Va. 22202. Tolerances for O.O-dim ethyl S- [(4-oxo-1.2,3-benzotriazin-3(4H)methyI| phosphorodithioate on birdsfoot Washington, to use Nemacur 3 EC on raspberries to con trol the lesion nematode. Washington, to use napropamide to control annual grasses in mint fields. The Texas Department of Agriculture notified EPA that it had used a crisis exemption to apply P araquat CL to mung beans and other dry beans as a harvest aid. Vermont also used a crisis exemption, for zinc phosphide to control the red trefoil and birdsfoot trefoil hay also were established March squirrel in sugar maple orchards. 17. at 2 and 5 ppm respectively (46 F R 17021). Contact: Fletcher. A proposed tolerance of 0.5 ppm for chlorthiophos on tomatoes imported from Mexico was published March 16 (46 FR 16917). Send comments by March 26 to Ja y Ellenberger at the above address. EPA March 18 proposed to set tolerances for amiben on pigeon peas and pigeon pea forage a t 0.1 ppm (46 F R 17229). Comments to Fletcher by April 17. On March 18 the agency also proposed that boiled linseed oil be exempted from tolerance requirem ents when used in a formulation of S-ethvl hexahydro-lH-azepine-l-carbothioate applied to growing rice before edible parts form (46 FR 17230). Comments to: John Shaughnessy, a t the above ad dress. by April 17. Experimental Use Permits Perm its to use pesticides in experim ents were issued to: Monsanto Co., for 8.000 pounds of glyphosate and alachlor on com and soybeans to evaluate control of weeds. Uniroyal Chemical, for 296 pounds of UBI-S734 on cot ton. peanuts, potatoes, soybeans, sugar beets, and sunflowers to evaluate control of weeds. Dow Chemical Co., for 1,000 pounds of chlorpyrifos on wheat to evaluate control of aphids, brown wheat m ites, grasshoppers, army worms, and cutworms. a- Agway. Inc., for alkanolamine salt of dinoseb on field and sweet com to evaluate use as a plant growth regulator. Sandoz Inc., for 30,000 pounds of norflurazone on soybeans to evaluate control of grass and broadleaf weeds. Tolerance Petitions Monsanto Co. filed two petitions with the agency. One re quested an increase in a proposed tolerance for glyphosate and its m etabolite aminomethylphosphonic acid on cot tonseed from 6 ppm to IS ppm. and the second proposed to set tolerances for S-2.3.3-trichloroallyl diisopropylthiocar- bamate on sunflower seed, m ustard eed, safflower seed, flax seed and buckwheat'seed at 0.02 ppm. EPA extended two perm its issued to Abbott Laboratories, each for eight pounds of gibberellic acid and 6-benzyladenine on apples to evaluate typiness and shape improvement. The agency also amended a Nor-^Am Agricultural Products Inc. perm it for use of propyl [3-(dimethyl-amino) propyl] carbam ate monohydrochloride on turf grass to evaluate con trol of pythium blight by including acreage in Nebraska and New York. Temporary Tolerances EPA issued a tem porary tolerance for norflurazon and its desmethyl metabolite on soybeans a t 0.10 part per million ippm i with an expiration date of April 20, 1982. Registration EPA approved an application submitted by Chempar Chemical Co. Inc. to register conditionally MAKI R at and Mouse Meal Bait containing 3-(3-<4-Bromo-l.i'-biphen- 3-20-81 Chemical Regulation Reporter OHS-WMI/SOOSO O * A-j: Qu 0007310 8447 IB 9 7 1 1 K.D.CROW Department of Dermatology,Princess Margaret Hospital, Okus Road,Swindon S N i JU Accepted fo r publication 7 August 1980 Itisessential to recognize that chloracne isalways a symptom ofsystemic poisoning and cot just a cutaneous affection (Goldmann, 1973). Although most cases of mild or moderate chloracne appear fit and well such a statement may seem contradictory (May, 1973), but it is not. Since chloracne appears to be the most sensitiveindicatorof poisoning in the human subject (Moore, 1978), in most cases the systemic levels of chloracneigen are insufficient to cause target organ damage either clinically,or as assessed by laboratory investigation. There are two factors which probably make up this equation; the relationship between dose and route ofabsorption on the one hand, and chloracne and systemic effects on the other. Much work remains tobe done inthisfieldbutone thingiscertain-- animal experiments demonstrate conclusively that the effects of an arbitrary amount of any chloracneigenic toxin are less severe as a single dose than ifgiven in divided doses over a longer period. The effects of the route of absorption will be discussed later. Definition Chloracne may be defined as an acneiform eruption due to poisoning by halogenated aromatic compounds having a specific molecular shape (Poland & Glover, 1977). Since brominadon renders such a compound more acneigenic than chlorinarion (Echobichon, Hansell & Safe, 1977), halogen acne may be a more specific term, but the word chloracne isnow far too well established to be abandoned. < Chloracneigens Only the following substances can unequivocally be proven to have caused chloracne inman, and some in experimental animals also: (a) Chlomaphthalenes (CXs\ (b) Polychlorinated biphenyls (PCBs). 0 3 0 7 - 6 0 3 8 8 1 -csoo-e243'0 2 . 0 0 r tqXt RIacUwclI Scientific Publication1 0011033 =43 244 KJ^.Croa (c) Polychlorinated dibenzofurans (PCDFs). (d) Polychlorinated dibenzo-dioxins (PCDDs). (e) Tetrachloroazobenzene (TCAB). (f) Tetrachloroazoxybenzene (TCAOB). Bromination ofcertainnaphthalenes, biphenyls and dibenzofurans has been achieved and their acneigenidty confirmed in experimental anim als (Kimbrough, Burse & Liddle, 1977a), but so faronlybrominated biphenyls,mainly as 2,4,5,2',4',5'hexabromobiphenyl has caused chloracne in human subjects from systemic poisoning (Selikoff, 1979), when cattle feed was accidentally contaminated with hexabromobiphenyl manufactured as a ame retardant in Michigan U S A in 1973 (Landrigan ei al., 1979). No less than four of the chloracneigens on this list are found mainly as contaminants formed accidentally during the manufacture of other materials. Thus, the dioxins occur in chlorinated phenols, the chlordibenzofurans in chlorobiphenyls and also chlorophenols (Taylor, 1979),whilst3,3',4,4' tetrachlorazoand azoxybenzenes areformed duringthe manu facture of 3,4 dichloroaniline and various end products and chemical processes involving its use or formation (Taylor, 1977). Itisessential to understand thatthe degree ofhalgenationdoes not necessarilydetermine toxicity; the position of the halogen atoms on the outside of the molecule (isomerism) is vital (McConnell et al., 1978a), and therefore a full knowledge of the nature and quantity of the various isomersin any singlechloracneigenisessentialbefore any predictionofitspossible toxicitycan be made. Great advances in analyticalchemistry by conventional and more recent radio immunoassays have made this possible (Albro et al., 1979). Cutaneous manifestations The distribution of chloracne lesions is of considerable diagnostic importance. The most sensitive areas of the human skin are below and to the outer side of the eye (the so-called malar crescent)and behind theear.They frequently may be affectedwhen the restofthe skin isperfectlynormal. Furthermore, they arethe areas most likelyto show residual lesions years after more extensive chloracne has faded. Next in frequency come the cheeks, forehead and neck but the nose isalmost invariably spared. This should cause us to reflectdeeply when we considerthesebaceous gland development ofthisregion,forthepathological basisofchloracne is squamous metaplasia of sebaceous glands into keratin-forming cysts. The genitalia, both penis and scrotum, but particularly the latter, are sensitive regions. With increasing toxicity the spread of the lesions affects the shoulders, chest and back, and eventually buttocks and abdomen. The hands, forearms, feet, legs and thighs are rarely involved and-usually only in the worst cases. One curious `quirk' of distribution is axillary lesions (Jirasek et a l., 1974) which have only commonly been seen in those patients where ingestion and/or inhalation have been known to be either the only, or a major route of absorption, as in Japan in 1968 (Yusho poisoning), or atScvcso in Italyin 1976 where axillarylesions were seen only in those few children who were actually enveloped in the toxic cloud. The basic lesion of chloracne is the comedone, and, in the mildest examples^ jhes^rj^ ^ Chloracne 245 F igure i. Chloracne: typical comedones. be the only lesions present (Fig. 1). If so, they are likelyto involve only the very sensitive areas,i.e.malar crescentsand behind the ears, and a few as a dozen lesions on each side may be diagnostic. One must, however, be most careful in older age groups ro distinguish the so-called senile comedones, so often seen in the malar areas or, in younger patients, acne vulgariswhich may exactlymimic chloracne. The distinction'infactmay beclinicallyimpossi ble, but a consideration of various other factors should decide the issue. Thus, apart from the distribution, unusual age of onset, clustering ofsimilar cases in a factory, involvement of aspecificoccupationoreven a township, thepresenceofknown chloracneigens orofchemicals with a similar molecular shape, as well as the absence of other external causes of acne such as pitch, tarand mineral oils,considered together make the diagnosis fairlystraightforward. Where doubt stillremains, histology is usually conclusive. In allbut the mildest cases small, pale yellow cysts,from pinhead to lentilsize,mingling with the comedones (Fig. 2) make up the characteristic picture of typical chloracne (Crow, 1970). As theseverityofthediseaseincreases,not only do the lesionsbecome more numerous, but, in the worst cases, comedones some no larger than pinpoints may involve every follicle givingthe appearance ofgreyishsheets.These lesionsare to be distinguished from the equally profuse but pale follicular hyperkeratoses yet to be described. --- In the most severe cases inflammatory lesions begin to appear, and with them larger cysts and even cold abscesses (Fig. 3). As ever wider areas become involved the picture may well S45Q come to resemble that of severe cystic acne but with much less inflammation than in the latter disease. Such gross lesions are most often seen on the back of the neck, mink and buttocks (Fig. 4). Widespread changes resembling solar elastosis have been described with chloracne from 2,4,5 trichlorophenol manufacture (Jirasek et a !., 1973) and the authontape 1 0 3 5 I! 1: 246 K D .C ron ! I ; ! ...... j 1 f 1I ?1 l f F ig u re 2. Chloracne: comedones and small cysts. seen such changes stillpresent in some ofover 116 cases examined in 1979 in West Virginia, U.S.A., 20-30 years after their initial severe chloracne, and some years after allcontact with I 245T had ceased. A similar case which was alsoexamined, was due presumably to hexachlordioxins from pentachlorophenol manufacture. The histology was that of chloracne. ! Scarring,absentinthemildestcases,variesfrom afinepitting,likeatrophoderma venniculata, to extensive lesions of the sort following severe cystic acne. In the worst cases, lesions exhi the > bee: Thi: hiur dire may stillbe present after 30 years but usually only in the malar region and behind the ears. Very mild cases may clear a few months after contact ceases, as at Seveso (Puccinelli, 1977), Hy. and after 2-3 years allbut a hard core of20/,, or so are likelyto have resolved. Hyi < Pigmentation * Pigmentation is largely confined to the face but may in the worst cases extend more widely, hep wh< 19: and has been known to be generalized and so severe as to cast doubt upon the patient's racial origin. Japanese victims of a mass poisoning in 1968 called Yusho due to the use of a rice- 8 4 5 Ini' based cooking oil (Kuratsunc er al., 1972) accidentally contaminated with large amounts of I'V tetrachlorobiphcnyl, itselfheavily contaminated with chlordibenzofurans (Rappc et al.,1977), sc\. 0011036 Chloraaie 247 exhibited a curious pigmentation affecting the nails, lips, gingival and buccal mucosae, and the conjunctive in about 70%. Such pigmentation affecting the n*il< and conjunctive has been described also in industrial PCB poisoning (Fishbein et al.y 1979), but only in 2-3%. This difference may be a dose effect,racial or both. Yusho is the only recorded instance of human poisoning where external contact and inhalation can positively be excluded, and a direct comparison made with toxicological animal feeding/intubadon experiments. Hypertrichosis Hypertrichosis,a rare finding,ismainly confined to the temples and may be secondary to the hepadc porphyria caused by T C D D , but it has undoubtedly been present also in patients whose uroporphyrins have been measured and remained consistently normal (Jirasek et a/., 1974)- Phrynoderma Follicularhyperkeratosis, to be distinguished from comedones may, in rare cases with usually severe accompanying chloracnc, be widespread and even generalized (Crow, 1978). 8 0011037 248 1 l F ig u re 4. C hloncne: resembling gross cystic aone. On the other hand, despite its usual rarity, no less than 70% of the Japanese Yusho victims developed a similar finefollicular hyperkeratosis on the upper trunk, neck and, most unusual of all, on the flexural areas (Goto & Higuchi, 1969). It is interesting to speculate whether thisisdue wholly or in pan to the exclusively gastro-intestinal route ofpoisoning in these cases. Cutaneous findings in still-born infants and neonates b o m to Yusho mothers poisoned with PCBs and PCDFs have been ofgreat interest. Instead ofchloracne, die entire skin was hyperpigmented and covered with greyish scales (Higuchi, 1976a). Several months after birth the skin became normal. The histology showed an atrophic epidermis with hyper keratosis and dilatationoffollicleswhich were filledwith keratin. These findings are clinically and histologicallysimilartothose which occurredin cattlepoisoned withpenta and hexachlor- naphthalcncs in 1947 (Olafson, 1947), and with hcxabromobiphcnyl in-TMichigan, U.S.A., in 1973. Similar change^ were again found in horses poisoned with T C D D in Missouri in 1971 (Kimbrough et al., 1977b). __ Ophthalmic changes .. \ Conjunctivitis has often been noted in severe poisoning with chlonicncigcns, but has only 1 011938 8i6fi 12 Chloracnc 249 been seen in an extreme form in Japanese Yusho victims whose meibomian glands were con verted intosquamous cysts filledwith a cheesy keratinous material (Higuchi, 1976b). Itisofsome interest thatin ingestion experiments, similar lesions are induced in Rhesus monkeys by chlordibenzodioxins, chlordibenzofurans and 3,4,3',4' tetrachlorobiphenyl (McConnell et a!., 1978b). They appear to have been an even more sensitive indicator of poisoning in the Rhesus monkey than chloracnc in the Yusho patients. Where poisoning has been mainly by external contact, however, chloracne is much more common than mei bomian gland changes, thus almost certainlyindicating the importance ofthe route ofabsorp tion in determining the clinical spectrum. Erythema The erythematous changes which may occasionally be associated with the onset of chloracne (Jiraseket al., 1974) May, 1973) have been the subjecrofconfusion in the literature. Because such erythema isconfined exclusively toexposed areas ithas wrongly been ascribed to photo sensitivity. Telegina & Bikulatuva (1970) describing an outbreak of severe chloracne and systemic poisoning during the manufacture of 2,4,5 trichlorophenol, established thattheircases had a reduced sensitivity to U.V.L. A few cases of erythem a preceding the severe chloracne resulting from massive internal exposure to probable chlomaphthalenes aregenuine, but apart from these the other recorded cases have all occurred during chlorophenol manufacture. Such erythema has never been recorded from PCBs, even in the massive Yusho poisoning, nor from T C A B or TCAOB. Exposure to chloracneigens in chlorophenol manufacture implies exposure also to sodium salts of chlorophenols (Suskind, 1978; Joint NIEHS/IARC Working Group Report, 1978) as well as to the dioxins and dibenzofurans. The corrosiveness of adequate amounts of die sodium salts on damp skin is unquestioned and there was every reason to believe that erythema was likely to have been caused by sodium chlorophenate bums. It was the Seveso accident, however, which provided abundant evidence to support this theory. Seveso The Icmesa factoryat Seveso was designed in such a way that the vent pipefrom the reactor vessel's bursting disc was extended through the factory roofinto the open air. On 10 July 1976, at around 12 noon, the full reactor began an exothermic reaction (Reggiani, 1980), terminating in an explosion which thereupon discharged its contents in a vertical jetinto the air.The cloud offinelydispersed reactor contents,mainly the potentially corrosive sodium 2,4,5*trichchlorophenate, drifted slowly downwind on a slightSouth-East breeze. The day was the hottest day of that summer so far and those who were cadght in the cloud with sweaty skins or who handled objects covered with the discharge suffered chemical burns. Seventy-six per cent of 447 'cases of adults and children examined within days of the explosion had erythema on the exposed areas ofskin. In many cases itwas severe enough to 0011039 250 KJ).Croto cause blistering. Needless to say, the small children who were contaminated suffered most. By far the most severe burns were suffered by eight children actually caught in the chemical cloud. An examination of several of the most severely burned children in Milan at die end of July revealed chemical burns which were quite typical, affecting face, neck, forearms, and arms below clothing,aswell as legsand the lower part ofthe thighs. In the burned areas were many curious, circumscribed, discoid, raised lesions,mainly confined to the hands, forearms and legs.That these were simply a pan ofthe chemical burns and nothing more esoteric was confirmed as they subsided with the rest of the lesions. A follicular hyperkeratosis affecting virtually every folliclein the burned areas heralded the firstsign of chloracne. As the bums faded leaving hyperpigmentation, so the chloracne developed. With the occasional exception of the axillae, itaffected very few covered areas. There were in all, eight severe and eleven moderately burned childrenwith a curious form ofchloracne which, in the more severe cases, formed diffuse thick hyperkeratotic sheets due to every single follicle having formed a small keratinous cyst. Four months later this diffuse crusting was already separating leaving small atrophoderma vermiculata-like scarring scattered with comedones. There were 168 othercasesofchloracne,allmild tominimal in extent. Unlike the children, lessthan 5 % oftheadults who had received caustic bums developed chloracne and even then ofa veryminor degree. Itseems likelythatthemajor contactatSevesowas externalsince there were cases where the chloracne was exactly limited to odd shaped areas of pigmented skin where bums had previouslybeen present,the intervening skin being unaffected (Crow, 1976). Some ingestion and/or inhalation could not of course be excluded. There has at no time been any dear evidence of systemic poisoning in any of the Seveso cases despite extensive and continuing investigation, again consistent with a largely external contact. Some properties of all chloracneigens The acneigenicpotentialofallchloracneigens can be equated with their overall toxidty. This issupported both by animal experiments determining the LD50 and an ingenious experimen talmethod making use ofa characteristic ofallchloracneigenic toxins-- theirability to induce various microsomal drug metabolizing enzymes of which liver cells are a particularly rich source. The most useful of these has been arylhydrocarbon hydroxylase (A.H.H.) (Poland & Kende, 1976), which is responsible for the initial rupture of the aromatic nudeus and therefore the first step in the metabolism of these compounds. The most powerful known inducer of A.H.H. is 2,3,7,8 tetrachlorodibenzo-p-dioxin, and by animal experiments it can he proved not only top z the most toxic small molecule known to man but also the most powerful to all chloracneigens. Thus we have a simple method of determining.the relative toxidtv and thereforeacneigenidtyofany given chemical and itsisomers.This same technique has, therefore, enabled the structure-activity relationships of many possible chloracneigenic isomers to be determined (Poland & Glover, 1977). All such isomers, whilst varying greatly in their overall toxidty, share the characteristic ofattacking the same target organs of various ' animal species (Moore et a 1979). The biological basis of chloracne, in particui^ \0 St dilc< r anal pr Vf'.i. m w t logi. face less It h sysi suri of l: sen* chli - His r* W h jm.. thci (Ha is <.! ine\ Th. mai Cli: Bee - dOK-. chl< det. W\ We ani wasc .*-> A W ^ H i. Li fiv in Chloracne 251 dilection for certain areas o f skin, is unknow n. Investigation is ham pered by the lack o f an analytical m ethod sufficiently sensitive to study the m aterial in comedones and cysts. . A part from the hum an subject, chloracne, or something very like it clinically and histo logically, has been produced in only three experim ental anim als; die rhesus m onkey (on the face with loss o f hair and disruption o f m eibom ian glands as in the hum an subject), the hair less mouse an d , m ost im portant o f all, the inner surface o f th e ra b b it ear (A dam s et a l., 1941). I t is n o t possible to p roduce chloracne o n any o th er p a rt o f th e ra b b it's skin. In d eed , even systemic absorption o f chloracneigens by the rabbit produces chloracne only on the inner surfaces o f the ears (Row e, 1978). T h u s , there is a clear parallel to th e curious sensitivity o f the malar crescents and eats in the hum an subject. T h e rabbit ear appears to be the most sensitive biological surface know n, reacting to as little as 1 ftg o f th e m ost potent known chloracneigen. H istology W here exposure has heen severe the histological changes may begin w ithin five days. Initially there is stim ulation o f the epithelium o f the outer root sheath and sebaceous gland ducts (H am brick, 1957). I t seems likely th a t the su b sequent disappearance o f th e sebaceous glands is due to squam ous m etaplasia o f sebaceous form ing cells. T h u s th e sebaceous gland is inevitably replaced by a keratinous cyst, which always has an attachm ent to the epiderm is. T h e exit is tiny in some lesions w hilst others are little m ore than a shallow trough. Inflam m atory changes are minim al in the majority o f lesions. C linical signs and sym ptom s in non-cutaneous system s Because o f cutaneous absorption (which has been estim ated as half the applied epidermal dose for T C D D -- Schwetz et a l., 1973), possible ingestion an d /o r inhalation, all cases o f chloracne m ust be subm itted to careful clinical and laboratory investigations designed to detect the following abnorm alities. W eight W eight loss is certainly one o f th e m ost sensitive indicators o f poisoning in experim ental anim als, especially the rhesus m onkey (M cN ulty, 1979) b u t in m ost h um an poisonings, wasting has not been carefully m onitored or, where it has, it has been found only in more severe cases (Jirasek et a l., 1974). H e p a tic change f _ L iver damage has always been heralded as one o f th m ost classic signs o f system ic poisoning from chloracneigens, but the facts do not support this. Liver damage undoubtedly docs occur. (G oldm an, 1973; Jirasek et a l., 1974) in som e severely poisoned cases, bu t apparently n o t in others (Joint N IF.H S IA R C W orking G ro u p R eport, 1978). T h is is presum ably a factor 0 4 DS 0011041 D0H2I 5 9 7 M 252 K.D.Croto ofdose and routeofabsorption. Itisimportantnottoassume thatliverenlargementnecessarily means detectable liver damage. The increase in size and weight may be due, as in the ratfor example, to a great increase in smooth endoplasmic reticulum (SER) (Higuchi, 1976c) which isthought to be an indication ofincreased enzyme induction. Lipoprotein Lipoprotein abnormalities are most important because of a possible (though as yet uncon firmed) association with cardiovascular disease. The only consistent abnormality in animals and human subjects is a raised triglyceride level. Cholesterol is variable but usually normal as are HDL/cholesterol levels where these have been done. Itis interesting that recent work with T C D D in guinea-pigs has revealed raised triglycerides and unchanged cholesterol and HDL. The cause of the raised triglycerides is much debated but two mechanisms may be involved, separately or together. The evidence for increased hepatic enzyme activity might support the suggestion of increased triglyceride synthesis. Alternatively, there may be a decreaseinremoval ofplasma triglyceridedue todecrease inplasma lipoproteinlipaseactivity as revealed in Yusho patients (Higuchi, I976d). Neurological (central) The reported symptoms of C N S involvement, being entirely subjective, are most difficult to evaluate, but a combination ofheadache, fatigue,irritability,insomnia, impotence and loss of libido have occurred so often as to be unquestionably genuine symptoms. However, it cannot be stressed too strongly that they were reported only in cases ofvery severe poisoning (Suskind, 1978; Jirasek et al.t 1974; Goldmann, 1973) before the terms chloracne, T C D D , etc.,became household words allover the world after the Seveso accident in 1976. Further more, these symptoms arose during the worst of the poisoning and not after a symptomless interval ofseveral years. Neurological {peripheral) Peripheral sensory nerves, particularly in the legs, may be affected in severe cases, almost always associated with halogenated dioxin poisoning. The neuritis may cause lower limb pains of disabling severity, together with patchy numbness. This neuropathy, may be con firmed by biopsy which shows demyelination or, more easily, by measurement ofconduction velocity which is found to be lowered. The neuropathy is remarkable in that it frequently arises relatively late in the poisoning syndrome and may appear 2 or even 3 years after the onsetoftoxicityand when othersignsand symptoms may have begun tosubsideXJIraseket al., 1974). Motor nerves are rarely affected and then only after sensory involvement. Pulmonarv Pulm onary changes are frequent, and persistent bronchitis with effort dyspnoea is well 0011042 Chloraate 253 docum ented, but the recent discovery th at there is a lowering o f the vital capacity is particu larly interesting for in PCB poisoning it may be the only sign o f toxicity (W arshaw et a l., 1979). Porphyrins Porphyria o f the hepatic ty p e rs a most interesting finding, described only twice so far in hum an poisoning, each tim e from T C D D in 245T m an u factu re (B leiberg e t a l., 1964; Jirasek t t a l., 1974). Patients exhibited, in exposed areas, hyperpigm entation, hy pertr ichosis, traum atic and actinic bullae, milia and scars. T C D D will also produce porphyria in experimental animals (Rose et a l., 1976) w hereas the very closely related 2,3 ,7,8 tetrachlorodibenzofuran appears n o t to do so (O ishi, M o rita & F ukuda, 1978). PC B s have produced porphyria in animals and also an excess o f porphyrins in the liver tissue o f Yusho victim s. U rinary uropor phyrin levels are only moderately raised in m ost cases. T h e enorm ous induction by pow erful chloracneigens o f delta-aminolaevuiinic acid synthetase in liver microsomes made it seem likely that this was the cause o f the porphyria. Recent work w ith T C D D , however, has show n that it inhibits the enzyme uroporphyrinogen decarboxylase w hich is the almost certain cause o f the hepatic porphyria (Jones & Sweeney, 1977). R apid poisoning seems to be ineffective, long term m oderate doses being apparently necessary to produce ov en porphyric changes. S w eating H yperhidrosis, m ainly o f th e palm s and soles, has b een re p o rte d by Jirasek et a l. ( 1974) an d G oto & H iguchi ( 1969), b u t it is h ard to be sure th a t it m ay n o t have been overlooked else where. C a s tro -in te s tin a l T he same is true o f nausea, vom iting and diarrhoea which seem to be confined to acute poisoning and may therefore be due to associated chlorophenols for example. On the other hand, these sym ptom s occurred in 20"; o f Yusho victim s. M u s c u lo s k e le ta l Rarer still is bursitis, usually o f the olecranon or prepatellar bursae, and oedema o f all four lim bs (K u ratsu n c ct a l., 1972; B aadcr &: B auer, 1951). f Im m unological Immunological deficiencies have been indicated in anim als o f various species b u t the wurfc'ts confusing and o f doubtful significance as Vet. In hum ans a decrease in circulating T cells has been d em onstrated ir. poisoning from hexahrom ohiphvnvl (Bekesi et a/., lyyN). 0011013 -54 K.D.Cron Teratogenicity and foetotoxicity Teratogenicity has been demonstrated in rats and mice but the far more sensitive effect of chloracneigens as foetotoxic is dearly a limiting factor. Neither of these two effects has yet been demonstrated intheonly two episodes ofpoisoningwith chloracneigensinwhich women were involved equally with men, i.e. Seveso and Yusho. Miscellaneous The actual cause of death from chloracneigens is unknown (McConnell et al., 1978b), but even when the minimum lethal dose isgreatly increased, the time to death, e.g. 14-21 days, remains unchanged. Rapid deaths ascribed to chloracneigens must, therefore, be seriously questioned and other causes sought. As in animal toxicology, so with the human subject isiteven more difficult when severe poisoning is present to distinguish lesions which are purely secondary to severe illnessfrom those which are specifically due to the toxin responsible. The symptoms and signs described so farhave occurred in a sufficientnumber of poisonings from different chloracneigens to be certainly specific Other findings which have been recorded,such as cardiac,renal,pancreatic and other changes, must await further confirmation. Carcipogenicity Numerous studiesformutagenicityhave been somewhat equivocal but carefullifetimefeeding studies on rats (Kociba et al., 1978) and mice (Holmes et al., 1978) with T C D D and the two most toxic hexachlordioxin isomers have revealed that malignant tumours can be induced, but only by doses large enough to produce a state of chronic toxicity, low doses having no effect.Skin painting(Holmes et al., 1978)suggestedthatdioxinsmay be complete carcinogens, i.e. initiators and promoters, but other experimental evidence throws doubt on this. PCBs fed to rodents throughout their lives produce liver tumours, the true malignancy ofwhich is not fully established. Against this background what are the human data? Seventy men with chloracne and very severelypoisoned with T C D D during 245T manu facture and carefullyfollowed up for 25 years, have shown an increase in stomach cancer in one age group only. Seventy-nine cases of chloracne from T C D D following the explosion of a 245T reactor in 1968 had, 10 yean later, shown no excessive evidence of malignant neoplasms. Yusho victims have shown an increased mortality from malignant neoplasms (fourofelevenautopsied),butthisisnotconsidered tobestatisticallysignificantand thesurvey must continue (lirabe, Koda & Asaki, 1979). A follow up of 121 men, allwith severechloracne and very severe poisoning from T C D D again after the explosion of a 245T reactor, has, 29 yean later, shown an incidence of nine cancer deaths againstan expected figureoT9*04 for thar area (Zack St Suskind, 19S0). The evidence,as faras itgoes,seems tosuggest that severe and lifelongtoxicityin rodents may produce excess malignancies, but so far concrete evidence of similar lesions in humans is not forthcoming. There is no reliable evidence so far of any increase in cardio-vascular 0011041 disi sug Ro Alt! of; sta: cut; less if tl I9<! SCVi chU chit evil exa: the et ing. poiblo did app. wh:- nui' nai: Ne\ indi po* Rc An An Hi Hi Chloraate 255 disease in these cases. The raised triglycerides in the apparent absence of lowered H D L suggests that allsuch data will have to be most carefully evaluated. Routes of absorption *>- Although there is no experimental evidence indicating whether or not variation of the route of absorption of a diloracneigen alters the distinctive features of poisoning, there iscircum stantial evidence which allows some speculation. It is undoubtedly in industry where the cutaneous route of absorption has been-maximal and ingestion and/or inhalation relatively less,so the tendency has always been forchloracne to be more severe than systemic changes-- ifthe latter could indeed be detected at all. Typical examples are: the Coalite explosion in 1968 involving T C D D (May, 1973) where there was little evidence of systemic changes in seventy-nine cases of chloracne, some quite severe; a personal experience of forty cases of chloracne from penta/hexachlornaphthalene from 1957-63; twenty-nine cases from hexachlordioxins and 26 from 3,4,3',4'tetrachloroazobenzene in 1978, all without obvious evidence ofsystemic disorders. Further evidence ofthe opportunities for external contact in industry are afforded by the examples ofchildren athome developing chloracne from transient contact with clothes which the worker has worn allday atwork (Kimmig & Shulz, 1957; Crow, 1970; May, 1973; Taylor et ai., 1977). Conversely, the only incident where absorption was known to be solely by ingestionled to i80/,,ofover 1,000 cases (Kuratsune et ai., 1972) developing signs ofsystemic poisoning (which could be confirmed by the highly characteristic pattern of PCBs in the blood ofvictims)without chloracne being present. Furthermore, chloracne when itdeveloped did so inmany casesseveral months afterother signs and symptoms ofpoisoning had already appeared. This one outbreak, quiteunique in the totalabsence ofskin contact,isan exception which does not disprove the otherwise almost universal rule that chloracne, in man, is the most sensitive indicator of poisoning by chloracneigens simply because cutaneous contami nation is rarely absent and, indeed, everything usually points to the skin as the major route. Nevertheless, there is the clearest indication that those who contact chloracneigens either in industry or elsewhere, must be investigated regularly, both during their exposure and, if possible, for the restof their lives. References Adams, E.M. eral.( 19 4 1) The response of rabbit skin to compounds reported to have caused acneiform dermatitis. IndustrialMedicineand Surgery,2, 1- 4. Albro, PAT. et at. ( 1 9 7 9 ) A radio-immunoassay fur chlorinated 'dibenzo-p-dioxins. Toxicology and AppliedPharmacology,50, 137-146. Baader, H.C.E. Si Bauer, H.J. (1951) Industrial intoxication due to pentachlorophenol. IndnsttWMedicineand Surgery,20, 2 8 6 - 2 9 2 . Bekesi, j.G.et al.(1 9 7 8 ) Lymphocyte function o f Michigan dairy fanners exposed to polybrominatcd__ biphenyls. Science, 1 9 9 , 1 2 0 7 - 1 2 0 9 . Bi.eirerc, ,1. cral.:1964) Industrially acquired porphyria. ArJnvesofDermatology,89, 793-799. & U 0011045 IW8SI2MOO 256 KJD.Craa Crow, K .D . (1970) Chloncne: a critical review including a comparison of two series of cases of acne from chlomaphthalcne and pitch fumes. Transactions o f the St John's Hospital Dermatological Society, 56, 79-99. CROW, K .D . (1976) Personal observations. Crow, IC D . (1978) Chloncne: the chemical disease. New Scientist, 13 April, 78-80. Echobichon, D.J., Hansell, M JA. & Safe, S. (1977) Halogen substituents at the 4 and 4 ' positions o f biphenyl; influence on hepatic function in the rat. Toxicology and Applied Pharmacology, 42, 359-366. Fischbein, .A. et al. (1979) Clinical findings among PCB-exposed capacitor manufacturing workers. Annals o f the New York Academy of Science, 320, 703-715. G oldmann, P.J. (1973) Severe acute chloncne, a mass intoxication by 2,3,6,7 tetrachlorodibenzo-diaxin. Hautarst, 24, 149-152. G oto, M . & Higuchi, K. (1969) The symptomatology of Yusho (chlorobiphenyl poisoning) in derma tology. Fukuoka Acta Medica, 6 0 ,409-431. H ambricx, G.S. (1957) The effect of substituted naphthalenes on the pilosebaceous apparatus of nbbit and man. Journal of Investigative Dermatology, 28, 89-103. H iouchi, K . (1976a) PC B Poisoning and Pollution, pp. 116-117. Academic Press, London. Hicochi, K . (1976b) PC B Poisoning and Pollution, pp. 115-116. Academic Press, London. H iouchi, K . (1976c) P C B Poisoning and Pollution, pp. 94. Academic Press, London. Higuchi, K. (i976d) PC B Poisoning and Pollution, pp. 98. Academic Press, London. Holmes, P.A. et al. (1978) Long term effects ofTC D D and HCDD in mice and rats. NewYork Academy of Sciences, 21-30 June, Abstract No. 26. Jirasex, L. et al. (1973) Acne chlorina, porphyria cutanea tarda and other manifestations of general intoxication during the manufacture of herbicides. Part 1. Ceskoslovenska Dermatologic, 48,306-317. Jirasex, L. et al. (1974) Acne chlorina, porphyria cutanea tarda and other manifestations of general intoxication during the manufacture.of herbicides. Part II. Ceskoslovenska Dermatologic, 49, 145-157. J oint K IE H S /IA R C Working G roup Report (1978) Long term hazards o f polychlorinated dibenzo- dioxins and polychlorinated dibenzofurans, p. 3 9 .1A R C , Lyon,June 1978. J ones, K.C. & S weeney, G.O. (1977) Association between induction of aryl hydrocarbon hydroxylase and depression of uroporphyrinogen decarboxylase activity. U .S. Environmental Protection Agency. Pesticides Abstracts, pp. 707, December. K imbrough, R.D., Burse, U.W . & L iddle, J.A. (1977a) Toxicity of polybrominated biphenyl. Lancet, 2,602. K imbrough, R.D. et al. ( 1977b) Epidemiology and pathology ofa tetrachlorodibenzo-p-dioxin poisoning episode. Archives o f Environmental Health, 3, 77-85. K imming, J . & S hulz, K .H . (1957) Berufliche akne (sog Chlorakne) dutch Chlorierte aromatische zyklische Ather. Dermatologica, 1 1 5 , 540-553. K ooba, R.J. et al. (1978) Results of a two year chronic toxicity and oncogenicity study of 2,3,7,8 tetrachlorodibenzo-p-dioxin in rats. Toxicology and Applied Pharmacology, 46, 279-303. K uratsune, M . et at. (1972) Epidemiologic study on Yusho, a poisoning caused by ingestion of a rice oil contaminated with a commercial brand of polychlorinated biphenyls. Environmental Health. Perspectives, 1, 119-128. Landrigan, P.J. et al. (1979) Cohort study of Michigan residents exposed to polybrominated biphenyls: epidemiologic and immunologic findings. Annals of the Netr Academy of Socieuce, 320, 284-294. M cC onnell, E.J. et al. (1978a) The comparative toxicity of chlorinated dibenn-p-dioxin isomers in mice and guinea-pigs. Toxicology and Applied Pharmacology, 44, 335-336. M cC onnell, E.E., M oore, J.A. & Dalgard, D.W. (1978b) Toxicity of 2,3,7,8 tetrachlorodibenzo-p- dioxin in Rhesus monkeys (Macaco Mulatto) following a single oral dose: Toxicology and Applied Pharmacol,<gy, 43, 175-187. 4^ M cN ulty, W.P. M979) Personal communication. RX 0011046 Ml 4 * 1 8 8 1ZIM Chloracne 257 M ay, G. (1973) Chloracne from the accidental production of tetrachlorodibenzodioxin. British Journal o f Industrial M ediant, 30, 276-283. M ay, G . (1978) Personal communication. M oore, J.A . (1978) Toxicity of 2,3,7,8 tetrachlordibenzo-p-diaxin. Ecological Bulletin (Stockholm), 27, 134-144. M oore, J.A. et al. (1979) Comparative toxicity of three halogenated dibeazofurans in guinea-pigs, mice and Rhesus monkeys. Annals of the Nets York Academy of Science, 320,151-163. OtSHi, S., M o rra , M . & F tn n iD A , H . (1978) Comparative toxicity of polychlorinated biphenyls and dibenzofurxns in rats. Toxicology and Applied Pharmacology, 43, 13-22. Olafsox, P. (1947) Hyperkeratosis (X-disease) of cattle. Cornell Vet, 48,135-138. Poland, A. & K ende, A. (1976) ,3,7,8 tetrachlotodibenzo-p-dioxin; environmental contaminant and molecular probe. Federation Proceedings, 35, 2404-2418. Poland, A. & G lover, E. (1977) Chlorinated biphenyl induction o f aryl hydrocarbon hydroxylase activity: a study o f the structure activity relationships. Molecular Pharmacology, 13 , 924-938. Pucqnelli, V. (1977) Personal communication. R afpe, et al. (1977) Analysis of polychlorinated dibcnzofurans in Yusho oil using high resolution gas chromatography-mass spectrometry. Chetnospere 5, 231-236. Keggxani, G. (1980) Topics in environmental health. Halogenated biphenyls terphenvls, naphthalenes, dibenzodioxinsand related compounds. In : Human Exposure. Elsevier BiomedicalPress,Amsterdam (in press). Rose, J.Q. et al. (1976) The fate of 2,3,7,8 tetrachlorodibenzo-p-dioxin following single and repeated oral doses to the rat. Toxicology and Applied Pharmacology, 36, 209-220. R owe, V.K. (1978) Personal communication. Schw eiz, B.A. et al. (1973) Toxicology of chlorinated dibenzo-p-dioxins. Einhroimtental Health Perspectives, 5,87-100. Seuxoff, J J . (1979) Personal communication. S uskind, R.R. (1978) Chloracne and associated health problems in the manufacture of 245T. Report to the Joint Conferences, National Institute o f Environmental Health Sciences, International Agency for Research on Cancer, Lyon, France, 1 1January. T elegina, ICA. St Biklolatuva (970) Affection of the follicular apparatus of the skin in workers occupied in production o f butyl ester of 245 trichlorophenoxy acetic add. Vestnih dermatologii 1 venero/ogii (Moscow), 44, 35-39. T aylor, J.S . et al. (1977) Chloracne from manufacture of a new herbidde. Archives of Dermatology, 1x3,616-619. T aylor, J.S . (1979) Environmental chloracne: update and overview. AnneUs of the Nets York Academy o f Science, 320, 295-307. Urabe, H., K oda, H. & Asaxx, M . (1979) Present state of Yusho patients. Annals of the Nets York Academy of Science, 320, 273-276. Warshaw, R. et al. (1979) Decrease in vital capadty in PCB exposed in a capadtor manufacturing fadlity. Annals o f the S e n York Academy o f Science, 320,277-283. Zacx, J. & S uskind, R.R. (1980) The mortality experience of workers exposed to tetrachlorodibenzo-pdioxin in a trichlorophenol process aeddent.Journal o f Occupational Medicine, 22, 11-14. 0011017 P7 M H O ? O620 DOVI 1 732543 K > ri O (I o 31 : 5 ^ * Q i- iU >K i /i ;ut i I I ? + *= t o I Sb 4 c c c c c I i! I C*JG B O t & L L C e i o /v x i ~> - ^ v 4 A 67.r% l * % . 7. epe. ( -- ! ' ? 1~ 2,` t o ) i u zr^C A A % ^ L f, Zo. t ^2 i (-'.S (* /^ J J v U .^ y * r< s j- i. * / r 3 * ? *7# - / ts 7 . 2 ?- q (x ^ ) Vo-#?* G Vo5 AAAa 2) 8 8 -.-A 8468 f V. v :-v"-- - V . Vv-V . ... ' . . ..' ' f : \ ~ ; . . * ' ` V . . *;.* . ...* * ;;: V*. r- >* I *.;> 31 m o M ?` t i ^ *1 o V. s r i* a > , :r> O ' . ' i V *-: r n *- S K .3...' ..' --X* ^ o > '<4 *1 ; r ; s ,::: 3 r ' S 5 '" , r ;r. -j -*i 3r - r 5 r; X* j?: ^ iri .& . . . . V ' -i * ' a r'' : .-j.a. bVb . :&.. : ' :& V .....X. V: .*'' r-4 V.:' tO -n 3 C .*% fi r;i.r.>i r-'i. * r* i.'" ' 'a ' 3 if -- 1 in V i - 'si V Cl. ** :\ r- ) ' f. .*.*-*.* .. -le ! > ` C rj C i C 1 . . . 4 1.1 t ' - r :o ' r> 5* Q *. . :i . 2 r- . $ :.> :;-r :s ii I. f- :-- iii ,.t- .?".' r-i. -? 3 : f":"5 i'3 '* ` X *rr j: ;:.,,/-1i .. ;;,-it . j .i J : J ; c. ..;r-1. ;.. r J,1 . s>'r ' . :v? r-:- -j.- i* ' .' -"i r;F .,-s "V r*-| 1.. '-i V- :' . h `r ?ri r.:>$ i r ::r ^r- ' -r*-t 'jn. V . :; *.' '> r -'J --i 'f X >-li "" ; in in V -t/t S" :-i L'.l P IV 'ff t.;/ r:r ... V -i f r- . t- % :..i *-? Si. >. .. * \ 5. i* 4 .J n V> i* cs* I 'J r*- ' ' s i ;.? r i ni :.i r x --i: v s f 3 1- i . ri*. t t C i i* * i- ;:r< :: Oc i rr. /-3 . j '- .-U si .> * h> ...V r. -il ca X O X?`/ Y * " C| 8 f cr. r~ r ; > . r ^ ; - . '4 .t-"- w ' r rC* ' .*! A s i - t < ::i -Vij- '--!s `:i i:.- i :: u ":3 r'-. s'.u r i * . re: y- e c . * . V I :n i-- i: I I ^ ^ c o cn -,j n -3i ?> CX ...' O .* ... X xs t~\ r;; -- *-- *;*V - C'*. </> V^t 0 Hi Vi >r\ .y.i. 1in.1;. V* rn ? i X.J s ci .5 :r1 ' > 3 "-`i ( 'I c:> :o H -j ;* f \ .. i Z -X S ' & --1 3v;i S r -c s :-'i O . ; i-- . 2i : P i g x g iS s r.3 > *-mt i . S' o X y fi o....>. br->i i'j H -l /-i ' *i.y H WC Lrt " f' 3t wi t * - ' n Hi <'.i 3 s . .1l.i f t *1 ,S Al > ; -i j --? s *- c: LC :;r ~s --1 i*.*.' -1 if.- c i - rn n TQOfi^RI o n V* :> ?; & :k; Mi"*.1 *1 3o o in o i i . . *.*. * r* . '* a .c O f--ft. I- y rj r : 3 r ' '*;r# .* ;* :X r ~ T ..r f* . vy:i r : r1 . j E i .*; VI >1 : :*\ .:... t: V* '.IV ' ' I-, V ." v : :.i - n 't r'r imi. , ,, r~` --ft .l~U i - f *r% . ! : -t c ; .i;.y**. .*1 vi: :i; * vi ;c . * r> j 'i :/i ? >. -S. .I. ' ... : M'5i S t ri,-.i ^*:<. Vi " -, i i...Or i . : lu r- *;0 , "-,i vi :rs `i ..`4 \ ; i'*:. .i . V-I :* U'A V `l/.l ..w iM. r,*> rf-*ri*. . O M? . .... ffii' v:'.;-i1 . ! ..H.'"-4V 'i:' r-"'. . -4 .-.Il * r *f ; "- :- * *i\ 4.7 '.' i-i '! r .: ``; v'i'` * .-v-4-vt' V ' ..-i r*C'.t'V- ":Co 'o r/i *5- 1/1 .<--<14 ::r o &* T'- 3 >u-*; i o rii. ..-X..j r~ i:.J r ,. uv -*Vcft r- "> *i . .*{`3 i < *( piH-! ..`"rHi'Ii X.V --*i i/ c i M -i i r"*i*- r.4i -v-':-ti t ; -ri - :*> r:.r.Jr .r.:i; *n n : : C.'*I5 V} V?; R 4 r. i >r.1V r:'* C.: .1-0 1lt- -...i. ;..`v r**'*.* i *..v i '-.lt4. -7t I 4' : -4 --f' . -rr.. a1.aS.'3. .`.35 ;v-'i >: 3 l,-> 3 <r.r V* .-- u * .-4 !,M P rz . - l i ' ^ 5 rn --I **j S - K*t i r :i -- !j - t Ni . -'i I*? *; ' ' O r > . r>5" ...i ``I V-+* 5.? t :l . n- - J i 'Z! .:*r -..h I ' CiV .5- -r.f in \. S iv;. I*-;-.- . !r I !'/. ' i* :-. : :. a i i ft >: oo * ; *i' .... ^ i, si i S*. f... . j.j ... -. U. '; * -- .* f ..* 'h. . V..-r, .'.*5 xi -!:j. .. ,-t4l Ui f . .- - - .'i i *.* ."'%V1. "i rV i' : rrt:; : : 4* ^ . 4' !4* ' ;k '' ,-. : -" : i -s k 1 1/1 . r v ; i *:, .? i .;:. " * . . iv.; i'- r:' * L* ili ,7r t `i ' : ; l.- v i -- S*,.l :* : vf. i;* ; - *". . ! -- ' .-.*.? .. * ..j *: * ? .! * - :>i / >.: - t ..s: :!-;l 't;:-3' ? ii-: .r rii . r ^ r ' G . : - ,! :S r ? S . ^ I . ; : J .--I i,.. i. Ct f\ :.< 1 5 3? V - istraticm." An OMB review of EPa's p ro posed RCRA rules in M ay, 1980, found that they represent "an irresponsible sys tem for public-private creation, process ing and transmission of infcrm ation.'' EPA and OMB have been jousting ever since over OMB's authority to delay, revise or reject regulations because of inade quate estimates of the economic burdens imposed on industry. EPa contends that OMB's authority extends to only a review of the cost and utility of forms, with burden defined as only the time needed to fill out the forms. OMB regards EPa's interpretations of the laws as "bizarre," "narrow" and "questionable" and recommends th at. these legal interpretations be " over turned." In addition, OMB recommends that a thorough regulatory-economic analysis of the entire RCRA program be started and suggests that "the structure of the regulations must be radically simpli fied to remove hundreds of inconsistencies that have been identified." A Potential regulatory targets O r/-A z f / C-C~y\_ * Regulations under developm ent P rojected costs Prevention of significant deterioration Radioactive waste disposal Best available technology effluent guidelines Organic chemicals in drink ing water Sewage sludge disposal Several billion over 10 years SS00 million $1.7 billion S1 billion over 3 years Unknown Superfund regulations Unknown / s to y f a ' Sectors affected ' "--1 Electric utilities Nuclear power industry Electric utilities, steel paper Public water systems w*te- systems Chemicals, petroleum Pinal regulations Review o f ambient air quality standards for NO, Review o f air quality stan dards fo r SO, Inform ation and capital- Electric utilities costs S16 bHIion annually S16 billion annually Electric utilities oQ Prevention o f significant de SB billion tor enforcement Electric utilities, tg tn y terioration others _ Air, water compliance sched S1.4 billion deferred be Steel ules for steel industry tween 1981-1984 .( ZL ^05 C onsolidated p e rm it p ro gram Hazardous waste disposal regulations S 100 million reporting cost SIS billion over 10years Marty Many cn ^05 O' CO Bixl3i faasri T he furor created in New York bv the discovery of dioxin at a refuse recycling plant on Long Islano last sum m er has died dow n'to a dull hum of confusion and resignation among federal en vironm ental officials that theyVe started flow n a Inner expensive oath toward resolv ing a problem that most hrfieve n not a prnmrmT I" W e've done it to ourselves again." savs a m eh-ranttlng E n v iro n m ental Protection Agency official. " I t's a nonis sue that has become an issue that i* going to be extremely exp c.uri .e -to lay to rest." Investigations done since trace concentrations of the most toxic m an-made chemi cal kno w n --2,3,7,8-tetrach- lorodibenzo-p-dioxin--were discoverer! in rack rm im n< T o x ic s in the stack idled H em pstead, N .Y ., p la n t. at the 2.000-ton-per-dav H em pstead. boiler problems and later at the insistence N .Y ., plant have raised the Question of nLnttm and municipal othcials because of --or. l--^e.cir)e rnmhustfon pro the ditmverv of dioxin cesses prrvliire m inute Quantities of the chlorinated com pound. in cIrnTtons a re th-ir lU.. Hn hi.f in mnrwi'rp(|<w r * . p^~- ^niiee -H fril l s range. *)T hrwe Wris health rislrs are COnsid- ered minimal, especially when compared to the environmental and economic oene- fits of resource recovery systems. Never theless-- ?i-r vion.rr.;Ti;r.n H em pstead The poliucal situation surrounding the su rt up problems at the plant ana the discovery and announcem ent of dioxin in the stack gases make Hem pstead an extreme example. *'- "-,l" p h " ' affected bv the diox in issue so far. And there are questions about wnetner the discovery of 3 to 9 parts per trillion of dioxin in the sta rt ground level around the p lan t--is th only reason the problem -plagued re source recovery plant is down. But the controversy that started o Long Island now threatens to spread t other resource recovery plants and coul eventually encompass everything fror sewage sludge incinerators to coal-fire powerplants. U nravelling the complex issues--c nonissues--and heading off problem before they arise will be a delicate task fc a num ber of reasons: Dinvin at any concentration is h arm .' ful. *n>ere is no proven lower threshold : which the chemical ceases to caus adverse health effects in laboratory ani mals. C\ re done hv D o i Chemical Co. indicate that dioxin is er t ated in a num ber of m anufacturing p re CO m tf- jr --r -,r rnm mitripn system D ow 's rest results produced as p a n of i (X ) defense of a suit brought by environmer tal groups trying to stop Dow's produi don of a herbicide, have neither bee refuted n o r duplicated. L iterature survc~. n f F n m ppan incinerator tests, howeve indicate that dioxin mav be torm ed i v irtu ally all refuse ..entires Testing.for the most toxic o f the 2 isomers of dioxin is very expensive. A analysis done for e pa in December, 198' put the cost of testing a single industri. com bustion source at 3170,000 t $700,000. Finding out if d io x in M J v i3 t-3 o O ^ 656397 through tests at specific sites--EPA is cur rently completing analyses of camples taken from an Ames, Iowa, coal and refuse-fired incinerator and a much larg er refuse incinerator in Chicago--opens the door for community and political problems such as were created at H em p stead. T h ere is currently no regulatory framework for determining the relative risk of creating minute concentrations of toxic pollutants in incinerators and the risk to groundw ater supplies of leachate from improperly designed landfill opera tions. Arm rding to the EPa official, the aeen- S_nh_a_s_c_r_e_a_t_e_d_i_t_s _o_w__n__re_g_ ulatory mess on e aioxtn issue. pr?t raicea in connctlbn with Agent U range. a detoliant used Vietnam, and again after an explosion a herbicide m anufacturing plant at Sev so, Italy, that contam inated a largrie are with dioxin. " EPA got hot on dioxin and w rit nfyrr the processes tnat create TiT' China vov/s c o m p e n s a r o n savs the official. fo r ca n ce le d p ro je c ts SneciticalTv. the agency went after Dow, attempting and failing to refute the Jap an e se lo st $ 1.57 billion chemical manuiatcturer's analytical stud ies of dioxin. " I n the p r w c we ended Chinese Deputy Prem ier G u Mu* told up finding dioxin at Hempstead and else former Japanese Foreign M inister Sabu- w here. All indications are tnat Dow" is ro Okita that his country is willing to rw : If vni look Tor H 'onn. vou ii nnd compensate Japanese corporations that i t f - l i i says, lost money when China unilaterally can A nother EPA official maintains that celed several m ultim illion-dollar con good incinerator combustion and particu struction projects, press reports from late controls can reduce dioxin emissions Beijing say. to negligible levels. " T h e whole issue of According to Japanese reports, G u M u m icropollutants is not a n issue. B ut we apologized to Okita for the troubles C hi can't ju st say it now. W e've got to prove it n a's " readjustment of the national econo and` tnat will take three years and any- my" had caused and said C h in a is willing from Sift m ilhon-to-$I8-m illion.** to m ake u p for J a p a n 's financial losses says, adding, `There are couple nfuT^ " in accordance with international com- o .ought to be shot for raising the issue bierrial practices^" the first place?5 y , / / / U J O kita, as th e 'Ja p a n e se governm ent's K . i f i ' t . | -- 'V id r representative, Hew to Beijing last week to learn of China's, plans regarding a series of cancelations and postpone ments of steel and petrochemical plants whose contracted value for Japanese firms reportedly totaled almost S1.57 bil lion. Chinese trade officials p la n ' to visit Tokyo soon to discuss how to handle the situation, which Japanese industry wor ries might lead to a near-freezing of trade relations between the two countries. Japanese contractors were keeping a cautious attitude. T t is a m atter of com mon sense that China pay compensation in accordance with international custom," says one industry source. " O u r concern is to w hat degree and w ith w hat priority. C a b la s ta y e d b rid g e w ill o tier com peting con crete and steel superstructure designs. W e will ask the Chinese to m ake up for o u r loss 100%.** D e sig n le i fo r re c o rd sp a n M ajor apanese projects canceled by China inc uae a 3420-miliion hot-strip mill comp ex, a S640-million cold-strip mill and petrochemical complexes worth $32 million, $260 million and 3500 mil British C olum bia's M in istry o f T ra n s portation and Highways has retained consultants to prepare detailed alternate 'designs of a bridge that wfil have the w orld's longest cable-stayed span. T h e ment might shorten the main span slight ly or extend it to about 1,520 f t In either case, it would capture the record. T h e longest stayed girder m ain span now is 1,325 ft, p a n of a Loire River crossing in lion. U .S . re ad ie s O m a n a s troop sta g in g site agency expects to call for bias on the France completed in 1975. structure, now estimated at S64 million (U.S.), early next year. T h e total project, including approaches, will cost about 5110 million. T h e four-lane, high-level crossing is to span one channel of the Fraser River ear Vancouver, reaching from the east.m shore to Annacis Island. A low-level bridge will cross the other channel. An earlier feasibility and prelim inary engineering study prepared by CBA Engineering Ltd., - Vancouver, for the m ajor structure proposes a main span of 440 m (1,444 ft), rising 184 ft above the water. O ne engineer involved with the T he ministry has commissioned com peting concrete and steel deck superstruc ture designs. T h e former assignment went to a combine of two Vancouver firms, Bush, Bohlman & Partners and Reid, Crowther & Panners Ltd. They have retained as an adviser the Vancouv e r office of D R C C onsultants, Inc., N ew York City. Design of the steel alternative w ent to cba along w ith B uckland & Taylor, also of Vancouver. Foundation design will be carried out by C older and Associates, based in the same city. T h e crossing, touting about 9,000 ft w ith its approaches, is slated for comple- O m an is shaping up as the likeliest site for initial su g in g of U .S. troocp s and a ir units to police the Persian G ulf area. A dm inistration officials refuse to com m ent on such, a prosp e a but recent events make it increasingly credible. T h e Sultan of O m an told President Reagan last week of his " concern," says one source, about a steady buildup of Soviet naval forces in the Indian Ocean, centered on South Yemen. Sim uluneously, some 250 Army and A ir Force troops prepared to em bark for O m an to set u p i military communications center oriente, to the needs of raoid-deolovm ent U-S. air A 4o I t l Z ' i I Z 1100 STATE Of CAllfORNIA DEPARTMENT OF FOOD AND AGRICULTURE 1220 N Street, Boom A151 Sacramento 95814 January 12, 1982 -/T L - JAN 1U 1982 EDMUNO C. MOWN JR., O m w R. H. Colby, Ph.D. DOW CHEMICAL U.S.A. Route 1, Box 1313 Davis, California 95616 Dear Dr. Colby Subject: Special Local Need Registrations ESTERON BRUSH KILLER, CA-780065 ESTERON 245 HERBICIDE, CA-780066 This letter is to notify you that the subject first-party special local need registrations have been inactivated at your request. If you have any further questions, please contact me. Sincerely "1 M. D. Black Registration Specialist Pesticide Registration and Agricultural Productivity (916) 322-5130 cc Ferial Bishop, EPA Agricultural Commissioners 0008545 initiator `c. M E N T A L P R O D U C T ~C.-. !FE TO COMMERCIAL STATUS i. iN i T i A f 1; - ; . : . - T. ; i- \* --T -- _R._L.__Gantz___________ Ag Products _________ .. Midland______________ .8/25/81______ PR O O ^O C - - ' " ' ON __ESTER0N245 BE .Herbicide_______________ _ Dow Rangeland Brush KillerLX.URM-AAgs)-^ _.2,4,5-T butoxyethyl ester, emulsifiable concentrate containing 4.0 lb. ae/gal \ r C` X - Plan to sell ..in.1982_____ Subregistered under Union ______ Carbide registration ~ CO xs None (Pending) \M o o 00 ro ro iT !i \ r; ^*=VI>SC l'nor. ie.i*o n . . J I Ai5iji o i L iisrm ijiJM ii.j ..! Dow makes the technical ester for this product which is also formulated and sold by Union Carbide as "WEEDONE 2,4,5-T". Dow needs to sell this subregistered product in order to liquidate a large inventory of the technical butoxyethyl ester of 2,4,5-T. (Approved Advance to Sales is attached for reference.) w - . vv a o n o * A F r T Y C O M u '.S A N C 6 / : -, r> -.1* *: r ..iM i i n; , :' i r. ri.'.** ' k, r .;. ,i. *. r ',0*1. mt. ..... , 8473 GGQ&4.C1 s M I t 4- /A K1-? A Mty(p <91 bcc: J. Gledh111/j. Tic DOW CHEMICAL U.S.A. MICHIGAN DIVISION March 19, 1982 MJOLAXO. M ICHIG AN <44MO A. E. Schober H&E Sciences 1803 Building cc: C. H. Goodman, 2030 ESTERON 2,4,5 BE-TCDD ANALYSIS Currently our inventory of BEE 2,4,5-T technical ester is made up of one bulk tank which contains about 635,000 pounds of product and 16,500 pounds of product packaged in 55 gallon drums. The bulk tank was sampled on March 2, 1982, and was analyzed and found to contain 2 ppb of 2,3,7,8 TCDO. The analytical research method used 1s an unvalidated research method with a detection limit of 1 ppb. I have attached the raw analytical data which includes the chromatograms. All of the product in 55 gallon drums 1s from one production lot and will be sampled and analyzed next week. I will communicate the results as soon as they are available. >~v . ^ O 0. T. BuzzelH Ag Chemicals Production Environmental Services r Attachment ^ A/o *-- CO CO "X AN OPERATING UNIT OP THE DOW CHEMICAL COM PANY ''Vole 0008298 I . P ''^ T*r P R O D U C T C C ? r. : 2 6 7 5 1 f - E , ; I C A L CCMFA. ' . Y S t J l L I T Y A 5 S ^ A i C c. f p od uct i&\ s p e c i f i c a t i :;'-! QAC: 25C EFFECTIVE: 26751 FAG?: 1 MAME: E S T E K C n 1 ) 2 4 5 BE H E R B I C I D E O E S C : A r c O I L Y E ^ U L S I F I A B L E L I G U T S . ARPL G O V T /IK D STOS: EPA REG. *0. 2 5 4 - 6 5 - 4 6 4 EPA EST. NO. 4 S 4 - K I - 1 PROD* PTS u . s . : mk dept: O i-- ro VN Vj>4 ro 31 TEST TTEM : UNIT I L IM IT S : TEST METHODS 2 ,4 *5 -T R IC H L C R C P H F ':ovy ACETIC < 2.4.5-T_)k :UT0XY ETHYL (A ^ ID /T S T E R S * IM . 2 * 4 * 5 - T ACID EQUI V . M IN . 2 , 4 , 5 - T ACID E G U IV INERT INGREDIENTS 2 * 3 * 7 f fi - TE TR A C K L O R OD I ?. E N Z O P-D IC *IN X X LCS/GAL oA PPM S P E C IF IC GRAVITY s 2? E M U LS IO N CREAM RATE HR. 1 0 0 PFM HARD WATER * 5 0 0 PFM HARD WATER 1 LFS/GAL ML ML V. ------------COMPOS I T I 0 \ ( N O M I N A L ) ------- 3.9 3 .5 7 -4 .1 4+ B 3 3 J . / < 0 . 1 E A S E D ON 2 . 4 , 5 - T ACIO 1/ 1o1<8g5^" ( A P P R O X . ) 1 .0 MAX. 0.8 P .9 75 ! X < ilT i X 9 7S-1 ASTM ESS! AG 1 5 5 - 2 X97S~/ 2*4*5-TM UTOXYETHYL ESTEFS A S S O C I A T E D C O M P O N E N T S FROM. 2 4 * 5 - T F:UTO>YETHYLESTER* TOTAL* MAX. GAFtC PE .If GAFAC PE 5 1 C ris` *T i': 0* ARO M A TIC /A LIFH A TIC BLENDED OIL X X X X ** ssbbT & C - ? l.S 2.3 3.5 3 |.3 027613-72-5 REGUESTED TSC REQUESTED * & P Z E f - F t C & O U - 1J Y - 6 2-r L-fr -f------ ----------- 1 . 0 7 5 i . r r . i o * % ------------RAw V A T E P I A L S ------------ - 2 * 4 , 5 -T /-Cin EUT&XY ETHYL ESTER * G A c AS Pi . u 1' GAFAS SIC KEROSENE . N i o r*'T H A H E A V Y A R O M A T I C S O L V E N T RV. S P E C 42731-R1 56204-^1 CAS* -- 0 C 2 5 4 5 -5 5 -7 TNC TWO CG8CG8-2C-& 266233-33-0 D0H 2133681 p p c - s -; \ ; r * : r 0 R v U - A T ; r . \ I I X k *' 4 * 5 6 . (! ) 0 1 O ' - T E S A T R A AF < C F T H E l C A C ?*I c a l c o v =*a n y * D C 0 ' J I : t L T : 4 L * A : \ C T M E a 3 a c e F E L L O * S *i- o 0 0 0 8 4 2 3 io I THE DC* CHEMICAL COMPANY DUALITY ASSU^ANC PRODUCTION SPECIFICATION 28751 page: 2 PF>CO DC T CCOE: 2 5 7 5 1 CC3MI\LEO> P CDUC TI ON SPEC APPROVERS: APPROVALS :DIV-CEP T : DATE riFPROVALS :D I V - O E P T ___ .......................................... I_____ ss o *-- ro VM TE V*l ro ' 4 : l k & r i ............... :________ _______________________ ; ...................... . PRODUCTS NOT MEETING THIS SPEC IFICATICN MUST NOT dE SHIPPED UNLESS AUTHORIZED 5Y SALES AND RC?JCTION MANAGEMENT IF.) IVGI CATES A TRAOEMAP.K OF THE DO* CHEMICAL COMPANY * * * D G U C O N F I D E N T I A L * * * . LAST" PAGE DOM 2 1 3 3 6 8 2 0008424 l DOW C H E M IC A L U.S.A. March 24, 1982 MIOLAND. M ICHIGAN 48640 S I Z/ 7 I 7 Pnn < Mr. T. E. Adamczyk, Head Technical Support Section Fungicide-Herbicide Branch U.S. Environmental Protection Agency 401 M Street, S.W., Room 239 Washington, 0. C. 20460 Subject: ESTER0N 245BE EPA Reg. No. 464-574 Your letter of March 16, 1982 Dear Mr. Adamczyk: Enclosed are five copies of finished labeling for subject product. The Dow Chemical Company agrees that we will submit and/or cite all data required for registration/reregistration of this product under FIFRA Section 3(c)(5) when the Agency requires all registrants of similar products to submit such data. Also enclosed is a revised Confidential Statement of Formula declaring maximum TCDD contamination of less than 0.008 ppm (acid equivalent) for the technical ester. As described in the attached letter of D. T. Buzzelli, the majority of the technical ester (EPA Reg. No. 464-491) is in one bulk tank. The attached chromatagram and raw lab book data demonstrate the TCDD content of this quantity to be 2 parts per billion. This is the technical ester we intend to formulate and package at this time. Since it is in bulk storage and represents several "batches" of production produced according to the manufacturing process already submitted, analyses of individual batches is not possible. The single sample analysis is therefore representative. The 16,500 pounds of technical ester stored in 55 gallon drums is from one production lot and is currently being analyzed. This material will not be used until the analysis is completed to ensure that it contains less than 0.008ppm TCDD. The analysis of this production lot will be submitted as soon as it is completed. We trust that final conditional registration can be granted immediately and not be held up while this analysis is being completed. The Dow Chemical Company verifies that the amount of ESTERON 245BE to be formulated, approximating 114,000 gallons, will be from existing stocks of technical ester produced by the manufacturing process already sub mitted. We further understand that any future production of ESTERON 245BE or its active ingredient by a different manufacturing process would require an amended registration. 84S10008400 AN OA8RATING U M T OP T H 8 DOW CHKMICAL COM PANY D 011 2 I Z 7 2 I 6 -2 - Thank you for the excellent cooperation in expediting this registration. Sincerely, Arthur E. Schober Product Registration Manager Agricultural Products Department nbe Attach: bcc: C. Goodman - 2030 0. Buzzelli - 834 E. Conyers R. Laning E. Ross r i * O (y b -io c 008410 ;W A hm UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON. O f . 0460 $ IS3 cn Hr. Arthur E. Schober The Dow Chemical Company P.O* Box 1706 Midland, MI 48640 CST Dear Mr. Schober: Subject: Eateron 245 BE EPA File Symbol 464-LTU Resubmission: February 3, 1982 o We have completed review of the materials submitted on the above date. The data concerning the TCDD levels in this product are incomplete. It is our understanding, from discussions with individuals in our Office of General Counsel, and based on a February 25th conversation with Mr. Akerman, that this application applies to existing stocks of 2,4,5-T butoxyethanol ester. Please confirm this for the record. In order to reasonably assess this proposal we need to know the size of existing stocks and the dates of manufacture. For the TCDD contaminant levels reported, you must submit raw analytical data and chromatograms for at least 5 batches representative of commercial production. If the existing stocks were produced at various intervals, samples must adequately cover the different batches. Is the manufacturing process described in this submission that intended for future production? The formula statement submitted November 9, 1981 states a maximum TCDD content of 0.1 ppm. The manufacturing process for this ester as submitted specifies a typical analysis of 0.02 ppm. Since the level of TCDD contaminant is an issue in the present negotiations between yourselves and the Agency over continued registerability of 2,4,5-T pesticides you must furnish a full and accurate description of the TCDD contaminant in this ester. Sincerely, Richard F. Mountfort J Product Manager (23) Fungicide-Herbicide Branch Registration Division (TS-767) r./'Ci fi ^ fw ^ V WO 4 Q March 2, 1982 DOW CHEM ICAL U.S.A. MIDLAND, MICHIGAN 48640 Mr. James K. Akerman Chief-Herbicide-Fungicide Branch Environmental Protection Agency 401 M Street, S.W., Rm. 237 Washington, D. C. 20460 bcc: E. S. Conyers C. H. Goodman - 2030 E. R. Laning G. L. Ytzen E. R. Ross Subject: ESTER0N* 245BE EPA File Symbol 464-LTU *o Dear Mr. Akerman: On November 9, 1981, Dow applied for registration of subject formulation. The purpose of this registration is only to enable Dow to dispose of our inventory of technical ester, which was produced earlier for another formulator. This ester was manufactured by the process submitted February 3, 1982. -- The inventory of the technical 2,4,5-T butoxyethyl ester has a 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) content of less than 0.008 ppm. As you know, 2,4,5-T and silvex negotiations are presently in progress between EPA and Dow which may result 1n agreement concerning permissible levels of TCDD in higher or lower levels. Therefore, the level stated for this inventory should not be construed as a precedent for other inventories which may be a subject of the negotiations. We also assume that since no other concerns have been raised by EPA about this application, the label wording as submitted is acceptable. Accordingly, to assure meeting a very tight production schedule we have ordered containers to be printed on that basis. We trust this clarification will enable acceptance of this application. Sincerely, Arthur E. Schober Product Registration Manager Agricultural Products Department nbe cc: Edward C. Gray, Esquire Acting Associate General Counsel Environmental Protection Agency 401 M Street, S.W. Washington, DC 20460 AN OPERATING UNIT OP THE DOW CHEMICAL COM PANY 0CC834 DOW C H E M IC A L U.S.A. February 3, 1982 P. O. BOX: 1706 MIOLANO, M ICHIGAN 48640 Mr. Richard Mountfort Product Manager (23) Registration Division (TS-767C) U.S. Environmental Protection Agency 401 M Street S.W. Washington, D. C. 20460 Subject: ESTER0N 245BE EPA File Symbol 464-LTU Your Letter of January 13, 1982 m r~> .A rsj <6 -- -- cn QD Dear Mr. Mountfort: Attached are the data requested to enable completion of the processing of this application. 1. A description of the manufacturing process, Including composition and purity of starting and Intermediate materials. A theoretical discussion of impurities which may be present 1s also included. 2. Physical and chemical properties. 3. Analytical methods for active Ingredient and impurities 1n the technical product Including validation reports and raw data. 4. Analytical method for active ingredient in the formulation. We trust that these data will enable the registration to be issued. While negotiations are underway between ourselves and the Agency regarding 2,4,5-T, we hope that registration can proceed under FIFRA Section 3(c)(7)(A). If additional data of a nature similar to this request are deemed necessary for this registration under the "cite all" method, we respectfully request that a "conditional registration" be granted. This would enable us to parti cipate In this use season which begins in March. I will call in a few days to learn the status of the application. We appreciate the excellent cooperation we have received. Sincerely bcc: C. Goodman - 2030 E. R. Laning - 9008 ______ T & / C Arthur E. Schober Product Registration Manager Agricultural Products Department .G. L. Ytzen - 9008 Sherri Arnold -2030(Attachment) Duane Fairbairn - Sarnia " Eva Ross - 9008 nbe Q L> 1& 3 6 Attach: AN OPERATING UNIT OP THE DOW CHEMICAL COM PANY 0008348 t i DOW C H EM IC A L U.S.A. November 9, 1981 MIDLAND. MICHIGAN 48640 o rsj Mr. Richard Mountfort Product Manager (23) Registration Division (TS-767C) U.S. Environmental Protection Agency 401 M Street, S.W. Washington, D.C. 20460 cn 03 SUBJECT: ESTERON 245 BE APPLICATION FOR NEW REGISTRATION Dear Mr. Mountfort: Enclosed is an application for registration-of ESTERON 245 ~BE, a formulation containing the butoxyethyl ester of 2,4,5-T. The label copy is identical -to that of our ESTERON 245 (EPA Reg. No. 464-205) which contains the propylene glycol butyl -ether -sters 4>f-2,4,5-T. ESTERON 245 BE is essentially identical to a presently registered product (EPA Reg. No. 264-89). We therefore request that this appli cation proceed under Section 3(c)(7)(A) of FIFRA as amended. The Dow Chemical agrees that 1t will submit and/or .cite all data required for registration/re-registration of this product under FIFRA Section 3(c)(5) when the Agency requires all registrants of similar products to submit such data. In the event that 1t is necessary to obtain concurrence from an EPA attorney that this application may be processed, we suggest either Mr. Edward Gray or Mr. Timothy Backetrom be contacted. Sincerely, A. E. Schober Product Development Manager Development and Registration Agricultural Products Department nbe Enc. bcc: E. R. Laning C. D. Woods - 2030 (label) C. H. Goodman - 9001 (label) G. L. Ytzen 2,4,5-T BE Action File s + **-+ * * * ? J e , S t t e o A / 2 * ir 3 - ..........'' 8 4 8 7 AN OPERATING UNIT OP THE DOW CHEMICAL COMPANY 0008349 REVISED 8/16/79 CERTIFICATION STATBOENT EPA File Symbol/ Reg. No. 464Product Najne ESTERON 245 BE Date of apDlication to which n.q.ai this statement auplies Applicant's Name and Address_ Dow Chemical Company P. 0. Box 1706 Midland, MI 48640 D0H 2 1 1 5 8 7 2 I certify that I have notified in writing the companies (except those with idiom I have reached written agreement) who have submitted data upon which I have relied to support my application and offered to: 1. Pay compensation for those data in accordance with Sections 3(c) (1)(D) and 3(c) (2)(T)) of the Federal Insecticide, Fungicide and Rodenticide Act, as amended; and 2. Camnence negotiations to determine which data are subject to the compensation requirements of FIFRA, and the amount and terms of compensation, if any, due. The camoanies I have notified are: / x7 All carananies listed on the Pesticide Data Submitters List for all active ingredients contained in my Droduct (see 40 CFR 162.9*5). (Check this box only if you are using the "cite-all" method of support.) n All companies listed on the Pesticide Data Submitters List for all active ingredients contained in my nroduct which are not derived from registered and purchased products (see 40 CFR 162.9-8(f)). (Check this box only if you are using the "combined" method of support.) I~ 1 Those companies who have conducted the studies which I have submitted (or cited if conducted with an identical Droduct)(see 40 CFR 162.9-8(e)). (Check this box if you are using either the "alternate" method of suoport or the "combined" method of suoport.) Signature and Title Typed name A. E. Schober . U li i l : Product Registration Manager Date signed Nov. 9, 1981 8488 0008350 8489 not urn. wy. Do tfwr and u rs . m il any sal. 58E : In > 10 Do ank yjth r in ON m i- ik e md 100 >mt an wt jnrk. in to nd 00 re. .-ut or aN is 0 DO re nd 3E a. 9 y x AIRAPPLICATION FOR BRUSH CONTROL Consult the Agricultural Experiment Station, your local Extanaion Service Waad or Ranga apacialina for bast tim e to traat and naad for ra-traatm ant in your araa. Do not uaa front early boot to mflk ataga vyhara grass aaad production is dasirad. M asq u ita: Uaa 1 pint ESTERON 245BE plus 1 /2 to 1 gallon of oil in enough water to maka 4 gaHona of total spray par acra. Apply 40 to 90 days aftar first laavos sp Sand Shinnary O ak: Uaa 1 /2 to 1 quart of ESTERON 24SBE plus 1 gallon of oil in anough watar to maka 4 gallon* of total spray par acra. P o st and B lackjack O aks: Uaa 2 quarts of ESTERON 24SBE plus 1 gallon of oil in anough water to maka 4 to 6 gaHona of totai spray par acra. STORAGE AND DISPOSAL Oo not contaminate watar, food or feed by storage or disposal. STO RAG E: Kaep container tightly dosed whan not in uaa. This product can be stored in an unhaatad buikSng. If exposed to subfraszing temperatures, the product should be warmed to at least 40 F and mixed thoroughly before using. PE STIC ID E D IS P O S A L Pesticide, spray mixture or rinasts that cannot be used according to label instruc tions must be disposed of according to Federal. State, or local procedures under the Resource Conservation and Recovery Act. C O N TA IN ER D IS P O S A L Do not reuse containers. Dispose of them in a sanitary landfiM or by other State and local procadures. -- USE PRECAUTIONS Noto : Do not graze dairy animaia on treated areas within 8 weeks after application. Do not graze mast animaia on treated areas within 2 weeks of slaughter. A V O ID C O NTACT W IT H 2 .4 J -T SUSCEPTIBLE CRO PS A N D OTHER OESIRABLE BROADLEAF P LA N TS --ESTERON 245BE Herbicide is injurious to most broadlesf plants. Thereto, do not apply diractfy to or otherwise permit even minute amounts to contact cotton, grapes, tobacco, fruit trees, vegetables, flowers, ornamentals or other desirable plants suscepti ble to 2 .4 ,S-T. 0o not use in or near a greenhouse. DO N O T APPLY IN THE V IC IN IT Y OF CO TTO N. GRAPES. TOBACCO. TOM ATOES OR OTHER O ESIR A 8LE 2.4.5-T SUSCEPTIBLE CROPS OR OR NAM ENTAL PLANTS. OO N O T SPRAY W HEN W IN D IS BLOW ING TO W A R D S SUSCEPTIBLE CRO PS OR O R N A M EN TAL PLANTS. A V O IO SPR A Y D R IFT--Applications should be made only when th e is no hazard from spray drift ainca very smalt quantities of spray, which may not be visible, nay severely injure susceptible crops during both growing and dormant periode. Uae coarse sprays to minimize drift ainca. under adverts wsaihar conditions, fine pray droplets mey drift a mile or m o . The spray thickening agent. N A L C 0-T R 0L', may ba usad w ith this product to aid in reducing spray drift. If used follow aN use commendations and pracautionaon the product label. ' NALCO-TROL --Trademark of NALCO Chemical Com- G R O U N D E Q U IP M E N T --W ith ground equipment, spray drift can ba lessened by keeping the spray boom as low as possible; by applying 20 gallorts or mom of spray per a c ; by using no m o than 20 pounds spray ing pressum with large droplet producing nozzle tips: by spraying whan wind velocity is 8 miles par hour or lest. Oo not apply w ith hoBow cone-type insectidda or other nozzles that produce a fine-droplet spray. ( I 84900 0 G 8 3 8 8 DOW 2 1 2 2 3 0 9 DON 2 1 2 2 4 9 5 * * J ' C C r 'I L N T I A L . * * * 2E7b T - C `-:v i w A L c c n f a n y o u a l i t y a s s j r a 'j : . o p p i c i r J i C A C I S - M C I r I C A T I O - v C j ;e I F A 7 1 0 C O P * r D '- T E = r i ! i - T _ > : 1 1 -! `c c P A D D L C T : 2 c 7 i :. L A C : PAGE: 1 R E V i r v E r' : 1 1 wUL 2 P E P L A C E S : : 0 7 5 APR S 2 \ V * : E S T C -O - CR) 2A5C H E R B IC ID E :*ic: A.\` Z S L S I F I A B L E H E R S I C I C I F C R V j L A T I O N C O N T A I N I N G T*E c U T Y L ES T ER S 0- 2 * * , 3 - T P I C r l L R O P H E f c X Y A C E T I C C I C - . s c : mc\-: PRD' N PTC L - T. i S i R . : lc d e f t : ?i dates : latest: ^r io * : Fi- ; : % C. T1 J*..L b 'd rt -1 8k D a t a : T R M L RAW i-VAT'L sales: test k e u d d ----------- T E S T I m s ------------ : 2 * 5 - T F I C r> L i ? C P h E '0 X Y A CE T I C ( 2 A . - T ) I D . BUTYL ESTER u n it :vt t tv**7 : 2 *4 5 -7 EQUIVALENT M m . u n i t : wt r. : 2 a , 5 - t 40*0t CONTENT :Aftu : 2 , a , = - t AC I :a. g : 2 3 ? ? TET :o .i JE M JLS'IO 'i TEST 100 PPM : UAT R 1/1C0 :\o cpeav in i :-- t S ^ E C l F I C OR A V I 7 * * 2 0 / 2 0 :I.I.-7 ?. :-- u n it :g/ l m m9 mm u n i t : l ? / c- l ---- 6 G 0 ??'* H A R D N E S S :-- C A P P R O . :-- : -- %, . *. :` :-- :L A -mKC-82001 * o :LA-AKC-82001 :L A -A M C -82 0 0 1 to \rt Sti to - - - :LA-AHC-82G01 u n i t : p p '-i : -- :s~z note i :AG 15B -2 I T I ON ( NOMI NAL) ------------ :2iA5-T T^ * 3 "L. ': j . ACI : r U TYL ESTER :--- L* *i ; : / x UNIT:''/ :--- -- :-- : S w R r C M C v5 u n i t : m/ v % v. * L- ** : S L L F C M C ft DC *w l'\-IT:U/y % -- * u L . w- LUS E S T E 6 I SPUR U l t i i i, - (i ------ un I t : u / ) t. . M :- -- ---- -- n r. >. , TE *<I AL S ----------- V i* ; ij I ** u ~YL TSTCR *r - LCi *- - : -- -- 0008390 D0H 2 1 2 2 5 * 0 (> iI i -j _ 0*. C f i w - I C A L C O . - = H * Y t i a * ;. 2 F-. H. L3. DOH 2 12 25 A ) -i lY1 1 11 1 1 ** V. T- ' C-ii. ICiL. C ' 7 C 'I : TT 1 L - - ** duality assurance o r c ic s 23752 I 5 . - - CI F : c - 7 TCM Cl;*: F 1= ' AT I 0 i-` CCrY : 8 7 e z c c n t i -n u l si ;,,A**.E: ESTEwQN <c > 2 HbC h EF.EICIDE PRO >* : DAT : TER.-, *L IiAu.' HAT*L: * ** 1 * r^mf TER 1 ALS----------- (CC.\*T1 *L`EL' > ALES: P A5 ? : 2 TEST *' ETH3 3 : F 3 LY3 LY CCL - 3 1 3 * M M : s u r f 3 n : : eh n 0 * a m m TDIESEL CIL % FRwC*V -Nf* **iT REVISION 27 uI-L Hi T j CH CHANCES HADE ,,u V* CAA WITH ` i ) T- : LIVE L OF 2 i 7 . 8 2 *4 *5 - 7 r f * - w XJ AND ITS TH A*. r .1 F F v c.> > rV r THEPE I S -2 CTHE.-. SOURCE OF TCCO IN 2 " 5 * - 7 Re i c i c - E c ;R.` UL-1TI 3 \ S THE FORMULATIONS THUS Ci LESS 7 h - r.. 1 OF TCl-T. . ( 2 ) r*.C<< A-i I L* - 2 3 5 LTS SALES NOTE \ C J . E . SALES SPECI F i CATICfc! MANUFACTURED AMD SOLD I -i LATIN AMERICAN AE i A ONLY a p p r o v e r s : w. l . gold J . * F RA3 E APPROVAL CF CHANGES INDICATED ABOVE: APPRC-VT.-tS CF INDIVIDUAL SP ECS : u .*L : L Ov/ Lj SAC 1.C UUL 8 2 ? j w': *J S Uu C o C.. A 1u UUL 8 w P ? 3 ji* : o . GILCHRIST PROD 23 FED 8 2 , r H J D . \ : J . RCLDAAI REG. GAC 23 Ft.?. 82 f f s d n : c . r ;.-'i ?.e z r c d 6 f e f ea PR com: M . L . 2 . OEMUJICA LA .JAA 8 Hi R 62 PROD:.: a . CASTRO OPERATIONS 2 <* ''AS 82 F- 0 0 .-.: A* p u i z R*D 24 '-'A? 82 PR-.D7;: a . OR LAND I LAA 15AC 2 9 !*AR 2 P r ' j j N : J . k U J 3 ZNCk POHL OA DEPT 27 .JUL 92 c *. i_ r -v ; TER*!.: (,<) INDICA TES A TRADi.."APK CF THE 0 0 W CHEMICAL C0 f<3ANY . . r> CONFIDENT 1AL ANOTHER PAGE FOLLOWS 0008381 iI * *** O < C O -i T `I J : TI L ** rj * i. c : c *.u ccf r; .> .w - l i t y , A C C I ? F IF IC A7 IO L CO\ F - . * 7 1 C \ COPY c-Fi-i c c 25 75^ p'-.oci.-zr: c.7~? ( c c \ t I c: ) 5 c d o m i m i :-} * c>t i r. i 'j z page: i p F a Cv i l s : d iv - led t : date : approvala : o j v - dept : dati I F . ) I ' J D I C i r I S A TP A' JIMAP.K Cr THE DOW CHEMICAL OM A\ Y * t- r w c o ' i I N T T A L * * L A 37 p. DOW 2 1225A2 0008392 . 8494 t -e - v o u e r " 'c t ? ; ? ;r:- ic -l .'.u l i - y ASCj*ANCr v e n : . Sr-.zieici7:;:\ ?37b f'AG7: i AC: ; & C ElF F ; C T IV ' : '1 JUL -2 SPE -SEDEN : V a = r '. *LZ- S*fiO'. (Fj -Suse H r -'ri CID- : e s : : an e p u l l i f i a 3 l e h e ; i c 15 F. f p m u l a t i o m c o n t a i n : .WG T ' i t cUTYL ES TERS j ~ Z i * : TR IC HL wP. G P r i ' j 0 XYCDTI C ACI D. P F O C ' N PTS L A T . -MFR. TEST ITtM :LC : Un IT : LIMITS c e f t : 31 : T S T METHODS *24*5-TRICH.C(RPH\DxriCE:T IC ( 2 * 4 . 5 - T ) aC I 3 3 J T YL ESTE?, MI-:. WT X " 2 , 4 . - T ACID EGIVLEN7 VIN. yt ? *2 4 ? -- T -Zi~ C T _ -,T 1! O/ L *2 *4 5 - T CI*. CL *T \ T V I M. L *i / S L B TCTH' CHLLRJ d i e e l c c :>i \ , a * . CP - - r ^ J L I O i . 7 E G. T iCG PPM v b-C 3 3 V r ; r . D f : E S S WATE F I .'1 J ! * r SC IF I C C<- Y I T i 2 f / 2 C p p c >. 54.7 44.8 " SC 4. g 3.1 0 CRE*-' IM 1 HR. 1.072 LA-AMC-S2C Gl LA-1MC-S2C1 L A - A MC - S 2 t i C l LA-AMC-S2001 SCD NOTE 1 K AG 1 5 E - 2 A3 TM D8 9 1 O ** N * JJ ------------CO MFCS I TI ; ( v CMI .\L ) - 4 , 5 - T ' C I C "'UTYL ESTES y/v! S AL C A w/w S=:*;IC H-P5 w/w - S . r C\ 'l C 3fc j w/w CI E;E L CIL PLUS ESTER I P J F I 7 1 DS w/w Y *'. / r. ------ b, K A I "5 ! L3------- *2*-:-T ACID r-U7YL IS TD F *S ALC A * D F F J M 0 p:.Y3i.YC3L 5=15 GU ? F E M C 3S:r. *D IE ; EL >.IL 5 4 . 2 .0 5.0 0 36.4 -RM SPC"? CAS- -- DOH 2122543 ? "03 *S M* /T **. -- * i c& J c 7 wCL H2 TC Ch AMGE -"ETh O: LUMCEP A(4L ADU METHOD ITE r .r.- v 7AA W ' Ti-iCuT .tW CI GMA7UKES. /4*li 7 - r. L ~V E L -7-F 2 2.7 S TET? ACHLf- ?2:-TEL*/c-?-cicxi\ (Ter:.) i - s c - t ci:. AND ITS '5.TEFS r FOC JC LD 5Y C EL E JCK * IS Tl A Y ,1 ~r*f< SINCE THESE IS NO OTHER SOURCE OF TCDC I.N r *4.L.-T J V sic i:E F CK/ULAT IC':S THE FG R*JL'ATE0M G ThUS CO f;/ i . SS r <C Tr A . c. 1 ?P;V. cr TCD w i . 1 - 2 5 l t : S Ti rL DR i,: '1* ` ----- - - wt j . . . j S CV ;P 1 - i:.1 >* ^ 1C JJ L c ? 0008393 4%" 1 * i *," I C 1 ' . ' T - - S E AF r\ f. u H v: : r I * ThT ^ c c^'if i c a l J. 1 * * - . . - - r- - T- j j ; l c^ ifany c u a l i ^ y assurance -- : :j c t i -;. . s p e c i f i c a t :j\; ? ' 0 : l :T r ; 7 -2 tC j:7 I*'L ->) J iL"H-.r,T -90.: 12. P: F? J OLE -N *EG. :;;c 2 < FrP S? AItEZ RC FE-> S >1 r. DEM UJIC LA JAA F >*AR A ;stfj -=e--TI " S '- ' P a . -fui? ; :* M RL - i-1 -j- U i!*r w6F *tL 4 * r2 2 7 JfL ?<r APPRuVA : " I v - 'T P T AT- :a f p r o v a l s :div pept 2 15? a t -: p r o d u c t s '!o t ^e e t t n c t h i s s p e c i f i c a t i o n h u s t -:c t b z s h i p p UNLESS AUTHORIZED r. Y SALES AND PRODUCTION MANAGEMENT (RI I NDI CATES A TF.AOiMARrt. OF Tm 30.' CHEMICAL COMPANY * * * D C W C O N F I E :i T I A L * * * LAST PAGE DOH I 2 25 A A 00SS54 8496 Q U A LIFIE D PRODUCING POINTS anaoa EUROPE PACIFIC LATIN AM. u.s>. LC be* TEST ITEM 2,4,5, T ACID CONTENT 2,3,7,8 TETRACHLORO DIBENZ0P-DI0XIN SPECIFIC GRAVITY, 20/20C, APR0X. EMULSION TEST, 100 ppm AND 600 ppm HARDNESS WATER 1/100 i n t u u w in t/n iiA i. c u m r'A N i RESTRICTED LtUfTEO INTERNAL USE PRODUCTION SPECIFICATION FOR ESTERON pC5 C NUMICt p ^g>7 OATS SUPER SEDES DATE 3c A P PL. GOVT./INO. STDL UNIT gn ppm LIMITS 480 MIN 0.1 MAX 1.072 TEST METHODS LA-ALC-82017 See Note 1 ASTM D891 NO CREAM IN 1 HOUR AG 15b-2 r*o N3 ro cn COMPOSITION W < 2,4,5, T ACID BUTYL ESTER SALCAJ^^"^ RFONIC N-95 SULFONIC 3800 *^56 L j/b X e y ij% .^^PACKAGING: 205 I ts STEEL DRUMS '- 54.6 3.0 3.0 3.0 36.4 Sa l JC5. AtoT-n. i V ,. L^TSn. S amA y **> .a a s a la . * - p^NOTE l:THE LEVEL OF 2,3,7,&-TETRACHL0R0DIBENZ0 -p- DIOXIN (TCDD) IN 2,4,5,T ACID AND ITS ESTERS AS PRODUCED BY THE CELAMERCK, IS LESS THAN 0.1 ppm. SINCE THERE IS NO OTHER SOURCE OF TCDD IN 2,4,5,-T HERBICIDE FORMULATIONS, THE FORMULATIONS THUS CONTAIN LESS THAN 0.1 ppr OF TCDD. ------------------ DENOTES OUNCE LIMITED TO DISTRIBUTION INDICATI ITEMS MARKED WITH AN ASTERISK * ARE NOT TO BE INCLUOEO IN THE SALES SPECIFICATION APPROVED (SIGNATURE) / d iv is io n or o e p t. DATE COPIES APPROVED (SIGNATURE) DIVISION OR DEPT. DATE COPIE J. * Xr>- ! <ikv >7 Production Reg. QAC Cv.Vvi. + *-*** O AA bEF*r SArttSt. )___ 1 R&O North Foi mre b ib * L.. 0AA Operations j/Z t/b " ________________ R&D Area ... Qo / 9 7 ___*__1/.__ L__ .____ LAA !! OAC 1/r A n a tr tf a iz z & t'r r w m t t z n m m-- m PRODUCTS NOT MEETING THIS SPECIFICATION MUST NOT BE SHIPPED UNLESS AUTHORIZED BY SALES AND PRODUCTION MGMT. f o r m c*teoao PRINTED R-4-71 SALES SPECIFICATIONS FOR THIS PRODUCT APPROVED FOR OUTSIDE DISTRIBUnONj AVAILABLE SALES OFFICES OR FROM QUALITY STANDARDS OFFICES. UU J O J J J DOH 2122629 T H E D O ",- C H E M I C A L C O M P A N Y G U A L I T Y A S S U R A N C E R-W MATERIAL S P E C IF IC A T IO N INTERNAL COY SUPPLIER CONFIDENTIAL 28751-01 S U P P L I E R : DOW C H E M I C A L COMPANY SPEC N O .: 28 751-R 1 E F F E C T IV E DATE: 5 APR 83 page: 1 GAC CODE: 2 9 0 N A M E : E S T E R O ! "; ( R ) 2 4 5 BE H E R B I C I D E d e s c r ip t io n : amber* o il y , em u ls ifia b le l iq u id . MSQS: 1580 PRCDf N PTS U .S . MM C L A S S - C O M M O D I T Y C O D E : PURCh S U P P L Y MGR CO DE: TEST ITEM : UNIT : L IM IT S : TEST METHODS 2.4,5-TRICHLOROPHENOXY ACETIC <2*4* 5 - T ) 3UT0XYETHYL ACID* ESTER* M IN . 2 . 4 . 5 - T ACID ECU I V Y I N . 2 , 4 , 5 -T ACID CONTENT INERT INGREDIENTS 2*3*7,8-TETRACHL0R0DIDEN2C P-DIOX IN X X LBS/GAL + PPM G O .9 43.8 4 39.1 28751 28751 28751 28751 < 0 . 0 0 8 BAS E D ON 2 * 4 , 5 -T ACID * ae o- IV VM r\3 APPROVED SOURCE DOW C H E M I C A L COMPANY SOURCE REFERENCE SALES GRADE 28751 PURCHASED AS ES TE [RON 2 4 5 BE END USE DOW 2 * 2 B R U S H K I L L E R ( P . C . 2 2 C 3 0 ) BLDG LOCATION MH USER 290 GAC a p p r o v e r : u . l . g o l d / n . g . d e l i s l e d e p t : q a c 5 APR 8 3 a p p r o v e r : j . w. d r e n c k p o h l d e p t : ca D E P T . 5 APR 83 APPROVALS :D IV -D E P T : DATE lAPPROVALS :d iv - dept : date IN F O R M A T IO N l'K C I S T S I V U T I O M R E S T R IC T E D TO T n I S S U P P L IE R AND T'*E DOW C H E M I C A L COMPANY * { R ) I N D I C A T E S A TRADEMARK OF THE DOW C H E M I C A L C O M -A N Y * COW CONFIDENTIAL * * * * LAST PAGE 0008396 8498 <7 T H E O OU C H E M I C A L C O M P A N Y Q U A L I T Y A S S U R A N C E { ^ j /v U r 2 !.`H . ' * a fe e ,s S P E C I F I C A T I O N P R O D U C T C C O E : 2 8 7 5 1 Q AC I 2 9 0 E F F E C T I V E : 2 MAY Qg 28751 _ .\ page: 1 n a m e : e s t e r o n <r > 245 be h e r b i c i d e DESC: AMBER* O ILY* EMULSIFIABLE L IQ U ID . APPL G O V T /IN D STDS: EPA REG. NO. 2 6 4 - 8 9 - 4 6 4 : EPA E S T . NO. 4 6 4 - M I - 1 PROD * V P TS u . s . : mm d e p t : 31 D0H 2122630 TEST item : UNIT : L IM IT S : TEST m ethods 2 *4 5 -T R ICKLOROPHENOXY ACETIC C2 . 4 5 -T ) 3UT3XYETHYL ACID t ESTERS* MIN. 2 , 4 * 5 - T ACID E O U IV .. M IN . 2 * 4 * 5 -T ACID CONTENT INERT INGREDIENTS 2.3*7*8-TETRACHLORODIBENZC P-21CXIN X *m lb s/ gal X PPM 6 0 .9 43.8 4 39.1 28751 28751 28751 -2 8 7 5 1 < 0 . 0 0 8 BASED ON 2 * 4 * 5 - T ACID X SALES SPEC APPROVERS: W. L . SwLD QAC 2 8 APR 8 2 j J G . C p N T I I ^ d l P S C / 1 3 A 2 ^ g / Y T Z / E N /P S lM 2 & / MfAR 21 /I j / . l i . D f R E N C K R C H lV A 5 OA 25 V&R 8 2 j / s . 4cj*CS vAt /Q A h / 2 8 \ ? i( 82 / / j / . - . DRENCKPOHL QA DEPT 2 4 Ma V-^52 to V4 approvals . t :d iv - dept : date approvals :d iv -dept : date __ Si3L-j_-?c.?=L___-_____ i___ _. T .j S A _______ ________________ :_________i_____ <R ) I N D I C A T E S A TRADEMARK OF THE DOW C H E M I C A L COMPANY LAST PAGE 'XtO CUWu.cui -. SOJAS ty T ltk X l s t T I t L U n t e k d k r (PC 2203) --UU~t \ u _ i CtV cvA 2 4 S 6 ? ? iO 0008397 8499 J . `H lo V 8500 2 .4 .5 - TR ICHLORCPHFNOYY ACETIC ( 2 . ^ " T A GUT0XY- E T H Y L (CcJ C j T T s T E F S v I\ ! . X 2 .4 .5 - T ACID E Q U IV .* H IM . J& S S u C - 9 0 > ' * ^ * 0 = 5 4/ 3 . 8 2 .4 .5 - T ACID ECU U T . CO -TEut L D S / & ' 3 . 5 7 - 4 . 1 INERT INGREDIENTS X * & s * 39m/ 2 3 ,7 ,8 -T E T R .\C H L 0 R 0 D ItE ? :7 0 - - d io #in C rc ii^ PPM <0*053 <-8nr4 B A S E D C'i S P E C IF IC GRAVITY 2 0 c -E M U L S IO N CREAM RATE 2 1 2 , 4 , 5 - T ACIO L^s/iiSG- L i H i ( A P P R O X . ) o r? HR. * 1 0 0 PPM HARD WATER ML 1 . 0 M A X . 5 0 0 PFM HARD WATER ML 0.8 COMPOSITION (NOMINAL)- *2,4, 5 - T . h U T C X Y E T H Y L E S T E R S X -A S S O C IA T E D COMPONENTS FROM 2 4 *5-T F - U T O X Y E T H Y L E S T E . R TOT AL MAX. X GAFAC : fir- X -G AP AC RE 5 1 C X 1.8 2.3 3.5 A RO M ATIC/ALIPHATIC BLENDED OIL 3|. 5 p e u a /A f a P e n o t /V AST*< D 8 S 1 ro VH VH IO AG 1 5 B - 2 C 2 7 1 3 -7 2 -5 REQUESTED TNO REQUESTED O O * HO CO CO .CO CO CO ------------V I C EL L A N E G U S ----------- S-aO C o Pfri> g a *A-f>Tu W*1< t r t * >- i f Z o rtri t - iH i* ------------5 AH M A T E R I A L S - j ; ------- 2 , 4 , - - T 'C IO E U T D X y3 t h y l E S T E R * C- Ac AC P tir GAFAC 51 S ` KEROSENE NABr-THA , HEAVY AROMATIC SOLVENT (Z>fx J jZ s iy L - z f r c e tto ..4 1' i L MTrtUW^ -RV SPECR 42 731-R1 5 6 2 C 4 - ! A t" CAST* -- 002545-55-7 INC T NO C 0 8 C 0 ft-2 Q -6 056333-93-C p R0 D* n n ' r - : % ?fo^ _ ; . t ; : n i s xs- a. bs. fe for P - b Jr ,\l^Uihu^kS.d ti-hivY l' u W M fc tk A ( ) I N D I C A T E S A TRAD*?- AC< THE ZZ' C H E M I C A L CG'-^a N Y & ttfcr.-UO'vtfu; * * D ' * C i. : s I : t r.- T I A L f . - l P I ' ' ! . - ' p i : ' - ^ C L L O V S ^ f ^ r 0008425 'f tU tu u jt c Ts?? j G I i V3 1 J I 3 3 n j .\0 1 1 3 0 3 0 S a i3Nt-nS?r A i.iTV n G : j r d. t ' ?3 17 3 I-Of 3 v a c s h l O0 0 S 4 2 G goss ihr Ihif E S /"/a a/ 2 V jT 13 S o - G r "L. tc . C c f< s # / Please review the attached specification and send to the next person listed. (P /Z o J c j& r o A S . a. P.eview specification as listed. ?. Note approval with signature, location and date. 3. I f not approved, note necessary changes and i n i t i a l . *n n av T .a . M r / * / * , t When distribution has been completed: ( Return to: ' Ag. Chem. Prod'n. ' 83^ Building 0-- uuh ZI 33686 i 8504 1 0008428 UNO 1 2 3 32 s> v>> .'S'- N. S 2133687 000842 ' ,,OUALIFIID PROOUCINC points CANa Oa EUROPE PACIFIC LATIN AM. U.S.A. M /s ' RE5 TRICTIO LIMITED INTERNAL USE NUMBER P OATe U }ifu ,4 r C^1^1production SPECIFICATION supersedes NUMBER bate ^XpRl.rotvt^ho.tmr ? h s / DCPT 3 / ST refg1 ^ ^r-^r/ ^ , r ^ z i \ A/ff O / C i O f i : ^ A W T * n ) E ffi-gqn D E s c : ? , W * 5 - T 8 u r o x y 7 * V L e s r + t t C r t v A 3 j f i t A a c Cc^ cSaj 7VC4 TX Av^-ffAy o )cv t i u i o . ro V*J V*l Te s r T.Ti~is UM TS U tfH iT 7 /" /W TV f e e r i e r*e e * ( 1 , 4 . 5 `- T j /qci, u r o A y ^ ir T>vy E T T f f t i . #, U " ' ,2 l ` . ` -jr f t c i D e ^ u f v / ^ i s v T , > L A U ^ w B 8/* (o O W -- ^ 3 .3 - t l rS -. M 7-V . / -g 6 - i P & n O V 'F Q ( d & d s. * * T/Vm" $ - n w v i/ /y ftA T 8* | H A - |a o P P w H A A D iA 4 TffA 5 a p 0 *-i H A -O U A r f f / t V *\c J . **? < ^ A G / S - u HO CO CO 0C3D ------------------ DENOTES OUNCE LIMITED TO DISTRIBUTION INDICATE: ITEMS MARKED WITH AN ASTERISK * ARE NOT TO BE INCLUDED IN THE SALES SPECIFICATION APPROVED (SIGNATURE) DIVISION OR DEPT. DATE PW APPROVED (SIGNATURE) DIVISION OR DEPT. DATE C^jPtEs >< -----. . . ... i H fi f fl PRODUCTS NOT MEETING THIS SPECIFICATION MUST NOT BE SHIPPED UNLESS AUTHORIZED BY SALES AND PRODUCTION xGMT. po n m C -I.C20 PRINTED R-4-73 SALES S PEC IFIC A TIO N S FOR THIS PRODUCT A PPRO VED FOR O U TSIDE D ISTR IB U TIO N SALES OFFICES O R F R O M Q U A L IT Y S TA N D A R D S OFFICES. . Q U A U D IO PTO O U dH C POINTS CANAOA EUROPE pa cific LATIN AM. U.S.A. THE DOW CHEMICAL COMPANY RESTRICTED LIMITEO INTERNAL USE PRODUCTION SPECIFICATION FOR J E S T S tto A / 2 .* i M e & tc t . PZ HUMER p date SUPERSEDES NUMftEJt DATE A P P L . CO VT./W O . STO. ----- C oMi f l S / T / a W ------- At r "2 4t? S.o_Zj*y Z T H V t -S T S_-__^____ % A SSO C I A T C D Ca * * .P o k / K n T S F K o r - t f l^ r o x y JTP^VC CSTC* -T a7/< .,/***, ^4 /3 i - T * f c f c < * f c 5 u r o *y Twyc f s r e / z , A u ? a * y ^ Tpy a t S tS T C fi, t 2 . 9 - r v E T t - f x y --y^S-- < o-ii-o o P H S ajo* y / e r r ' - A tisi ,s - r e - <t , v . ^ . . H *wSTHflxy *Z i V " BI L.4A4 P * i t A J G * . y / ? < . . AC.S, tO T S T K ./*.*. - *. ~ <3 0 '^ c .,o ,a e t - , ' ------------------------- -- GRPAC. R e (pio G a =a c P e /o > v - ^ *v < 3 ^3*2.3 % -5 r s - 3 ' r C.RS /V-j: -- _ __ Mr o o z s 'y .S '- s - ? - y iJN ^ V j> \ 0 0 / 9 A .? - 7 3 - 3, I >I ^ f U C 5 - F t * / ? > { fe _'/^eauesr-o ro '*'*'"^(3 /i e u's^ VN y? IW Tn o T/VO ^ g . r . f j , ^ T i Q . a - a ^ e n o c e s e . %/ A .av<A Ti / A U PPM T fC IZLCN&Jc &** '* ra ia ^ c ^ . cc cc OCC cc DENOTES CHANGE LIMITED TO DISTRIBUTION INDICATE ITEMS MARKED WITH AN ASTERISK * ARE NOT TO BE INCLUDEO IN THE SALES SPECIFICATION APPROVED (SIGNATURE) DIVISION OR DEPT. DATE COPIES APPROVED (SIGNATURE) DIVISION OR DEPT. DATE COPTE: JX " --------- -------------------------------------- oUuT i){ r>8 ' ] i PRODUCTS N--OT-----MEETI.N..G.....T..H..I.S...S..P..E..C..I.F.I.C...A..T..I.O..N....M..U..S.T....N..O..T.....B..E....S.H...I.P.P..E..D....U...N..L..E.S..S....A..U..T..H..O...R..I.Z.E..D.....B..Y....S..A..LES AND PRODUCTION mGmT. ponm c-i #029 PRINTED Ra7) SALES SALES SPEC OFFI IF IC CES ATI OR ONS FRO FO M R Q T H IS UA LIT PR Y ODUCT STAND APPR ARDS OOVFFEIDCEFSO R O U TSID E D ISTRIB U TIO N A V A ILA BLE CUALIFICO PROOUCING POINTS CANADA EUROPE PACIFIC LATIN AM. U.S.A. THE DOW CHEMICAL COMPANY RESTRICTED LIMrTED in t e r n a l u se PRODUCTION SPECIFICATION FOR % 7 & > a/ A V Z & tf A 4 /C i NUMUR P Oa t s SUPRSqes tu te A R R L. COV*TyiMD. JT D J. --------- -- -- m A TH iO LS 2 1 S " - T /&C.I O o T P X y C 7 V E S 7 S V 2 inora i + z ) R .m Sfic-- -- c ^ s .-- -- e o z s ^ jr-r* G a f a c RE C*i o G a FAC PC-SlO A M P H T N A j W S A V y A R i h a t c 3W-T/vfr D i e r e L o u . -*c*o , e s s o 5 "<*t . o v - i R i z ro VN N>4 0 L & f$ -? P n . o D / v A /a TIT ' T U * . Z j i + . S ' - T ' A c- i o u ^ f o / a i P H B P A t w t / o a Z W T 2 , V y i * - T 3 u / i * y E t* vl U ili.L C o m T A t*t A f S S 7W 4/ V O . / Pf>r*l **4r 2, "i,T,2 - T < oJ >/ 4 * t Z. o -* 2. f v * * o o r t j Is Z,HtS - r 9<-J7oxy c t h y u s ra < s* / * s> /**oa4 7 7 PE<.e*JT Ci6!. 7 V* oa*via^uih f l u CQ.\Ji \JAu &aJT)* 3. T H I S P E C ! n o * rta AJ /A & S K i v t o /eve>M *>CA//*irAJ7H, fiSA.ateiJ~ Xs*t P<2<lu.d-fe $u0Hr?^i$fa*cl (Ium trWfc co co co ----------------- DENOTES CHANGE LIMITED TO DISTRIBUTION INDICATE ITEMS m a r k e d w it h AN ASTERISK * ARE NOT TO BE INCLUOEO IN THE SALES SPECIFICATION APPROVED (SIGNATURE) DIVISION OR DEPT. DATE COPIES APPROVED (SIGNATURE) DIVISION OR DEPT. DATE C O P IE /k l.S t L & r IU I.S 1 / ,4W lu lU T iW W tt* / ! J fc lA.il r > ` f V Z Z ~ J*& 0 t "7 % ' P ^ - L i h -s?l ( GT t - ... ... n rn o o U Ci w LZ l p^o p K a .* : *\* 1/ t<' I 7 _ Jr 1 A U C 0 f4 3 \ ') ' JL~Jia+wl ' W S o a -Z f-e t 7 'PRODUCES NOT MEETING TfllS SPECIFICATION MUST NOT BE SHIPPED UNLESS AUTHORIZED BY SALES AND PRODUCTION MGMT. FORM C-IR020 R R IN T C 3 -B.73 SALES S PEC IFIC A TIO N S FOR THIS PRODUCT A P P R O V E D FOR O U TSIDE D IS TR IB U TIO N A VA ILA B LE SALES O FFICES O R F R O M Q U A LITY S TA N D A R D S OFFICES. 8509 00822 MATERIAL SAFETY DATA SHEET PAGE: 1 OW C H E M I C A L U . S . A . M I D L A N D M I C H I G A N 4 8 6 4 0 E M E R G E N C Y P H O N E : 5 1 7 - 6 3 6 - 4 4 0 0 F F E C T I V E D A T E : 19 MAY 8 2 PRODUCT CODE: 28751 RODUCT NAME: ESTERON (R ) 2 4 5 BE M E R fejciE m so: 1530 NGREDIENTS (TYPICAL VALUES-NCT SPECIFICATIONS) D0W2113014 2 * 4 * 5 - TR I C H L OR OP H E N O X Y EST ER E MU L S I F I ER S P L U S PE TRO .VENT : 59.1 : 40.9 SEC T I ON 1 PHYSIC A L DATA O I L IN G PO IN t : i b p > 3 0 0 AP PRES s : < 6 MMhS 3 2 0 C AP DENS IT Y ( 4 I R = 1 ) : NOT : so l. in w ater: e m u l s if ia b l e : SP. G R A V ITY : 1.129 ( 6 8 / 6 8 F ) P P E A R A N C E A N'D O D D r : A MB SE C T I ON 2 F L A S H P O I N t : 1 7 5 F , 7 9 rw* ET H OD U s e d : TCC : FLAMMABLE L IM IT S : l f l : not d eter , u f l : not deter. XT I N G U I S H I N G M E D I a : WAT PEC I AL F I RE F I G H T I N G EQ CD N D I T 1 0 NS USE P O S I T S E C T I ON 3 R E A C T IV IT Y DATA TAB I L I T y : AV O ID TEMP ERA NCOMp A T I B I L IT Y : ACID* BASE* O X ID IZ IN G M A TERIAL. CONSULT MANUFACTURER FOR S P E C IF IC CASES. AZARDOUS DECOMPOSITION PRODUCTS: NOXIOUS FUMES UNDER F IR E CONDITIONS HYDROGEN C H L O R ID E AND OTHERS. AZARDOUS POLYM ERIZATIO N: WILL NOT CCCUR. SECTION 4 S P IL L * LEAK* AND DISPOSAL PROCEDURES 1 8510 CTIO N TO TAKE FOR S P IL L S (USE APPROPRIATE SAFETY E Q U IP M E N T ): ABSORB S P IL L S W I T H I N E R T DRY M A T E R I A L S U C H AS SA N D OR S A W D U S T . D I K E A R E A I N IN CASE OF LARGE S P I L L S . DO NOT USE WATER FOR C L E A N U P . C O NTINU ED ON PAGE 2 > R) I N D I C A T E S A TRADEMARK OF THE DOW C H E M IC A L COMPANY 0003997 * MATERIAL SAFETY DATA SHEET PAGE*. 2 OW C H E M I C A L U . S . A . M I D L A N D M I C H I G A N 4 8 6 4 0 E M E R G E N C Y P H O N E : 5 1 7 - 6 3 6 - 4 4 0 0 F F E C T I V E D A T E ! 19 MAY 8 2 ROOUCT (CDNT^DAC ESTERON' ( R ) ' 2 4 5 -9E H E R B I C I D E PRODUCT CODE : 2 3 7 51 MSD: 1580 SECTION A S P I L L * LEAK* AND D IS P O S A L PROCEDURES (C O N T IN U E D ) . I S P O S A L M E T H O D : D I S P O S E I N A C C O R D A N C E W I T H L O C A L * S T A T E OR F E D E R A L REGULATIONS. D0W2 I ( 3 0 5 SECTION 5 HEALTH HAZARD DATA N G E S T I O M m o d e r a t e TO LOW S I N G L E DOSE ORAL T O X I C I T Y . lYE CONTACT: S LIG H T TR A N SIEN T CORNEAL INJURY AND I R R I T A T I O N . KIN CONTACT: PROLONGED CONTACT: SLIGHT IR R IT A T IO N ? REPEATED CONTACT: MODERATE I R R I T A T I O N * D R Y IN G * AND EVEN A EURN. K IN A B S O R P T IO N : NOT L I K E L Y TO BE ABSORBED IN T O X IC AMOUNTS. I N H A L A T I O N : NO G U I D E FOR C O N T R O L OF M I X T U R E E S T A B L I S H E D . DOW I N D U S T R I A L HYGIENE GUIDE 10 MG/M3 AEROSOL* 3 5 0 MG/M3 VAPOR NAPHTHA. - F F E C T S OF O V E R E X P O S U R E : NAUS EA I F S W A LLO W E D * A N E S T H E S I A . SECTION 6 FIRST AID 'YE S: I R R I G A T I O N IM M E D IA T E L Y W ITH WATER FOR 5 M IN U T E S I S GOOD SAFETY PRACTICE. K I N : C O N TA C T W I L L PROBABLY CAUSE NO MORE THAN I R R I T A T I O N . WASH O F F I N F L O W I N G WA T E R OR S H O W E R . WASH C L O T H I N G B E F O R E R E U S E . IN H A L A T IO N : REMOVE TO FRESH A IR I F EF F EC T S OCCUR. I F R E S P IR A T IO N STOPS GIVE MOUTH-TO-MOUTH RESUSCITATION. N G E S T I O N : DO NOT IN D U C E V O M I T I N G . to em ergency f a c i l i t y , CALL A PH YSIC IA N AND/OR TRANSPORT ote to p h y s ic ia n : e y e s : MAY c a u s e i r r i t a t i o n , i n j u r y i s u n l i k e l y , s t a i n f o r e v id e n c e of corneal in j u r y . s k i n : may cause i r r it a t io n , not l ik e l y to be abso rbed in acutely TO XIC a m o u n t s , e f f e c t s may be c u m u l a t iv e , r e s p i r a t o r y : a n e s t h e t ic or n a r c o t ic e f f e c t s may o c c u r , o r a l : may c a u s e r e a c t i o n s i m i l a r to p e t r o l e u m or p e t r o l e u m - l i k e s o l v e n t , danger of c h e m ic a l p n e u m o n ia m ust be w e ig h e d a g a in s t t o x ic it y when c o n s id e r in g e m p t y in g th e s to m a c h , i f la va g e is p e r f o r m e d s u g g e s t e n d o t r a c h e a l a n d / or e s o p h a g o s c o p ic c o n t r o l , s y s t e m i c : a n e s t h e t i c or n a r c o t i c e f f e c t m a y o c c u r , m a y i n c r e a s e m y o c a r d ia l i r r i t a b i l i t y , a v o id EPINEPHR IN E or s i m i l a r a c t in g drugs i f at all p o s s ib l e , no s p e c if ic a n t id o t e , t r e a t m e n t based ON T h e s o u n d j u d g m e n t o f p h y s i c i a n a n d t h e i n d i v i d u a l r e a c t i o n s o f THE PA TIE N T. CONTINUED ON PAGE 3 > R) I N O I C A T E S A TRAOEMARK OF THE DOW C H E M I C A L COMPANY 0003998 8511 D0W2113016 1 I M A T E R I A L S A F E T Y O A T A S H E E T PAGE: 3 GW CHEMICAL U .S .A . MIDLAND MICHIGAN H86H0 EMERGENCY PHONE: 517-636-M O O : f f e c t i v c d a t e : 19 m a y 82 RODUCT . .CCONT' D S : S T R D N t R } 2 4 5 -6E H E R B IC ID E . p r o d u c t c o d e .: 2 3 7 5 1 MSD: 1580 SECTION 7 SPECIAL HANDLING INFORMATION E N T I L A T I O N : R E C O M M E N D C O N T R O L OF N A P H T H A V A P O R S OR A E R O S A L S TO SUGGESTED GUIDE- E S P I R A T C R Y P R O T E C T I O N : NONE L I K E L Y TO BE NEEDED I N A N T I C I P A T E D O P E R A T IO N S - FOR EM ER G EN C IES* A P O S IT IV E -P R E S S U R E BREATHING A P P A R A T U S OR A F U L L - F A C E R E S P I R A T O R W I T H AN A P P R O V E D O R G A N I C V A O R CANISTER IS RECOMMENDED. -ROTECTIVE c l o t h in g : clean BODY-COVERING CLOTHING- : ye p r o t e c t io n : safety glasses w itho ut s id e s h ie l d s . S E C T IO N 8 S P E C I A L P R E C A U T IO N S AND A D D IT IO N A L IN F O R M A T IO N R E C A J T I O N S TO BE T A K E N I N H A N D L I N G AND S T O R A G E : SEE L A B E L . K E E P OUT OF REACH OF C H IL D R E N . A V O ID CONTACT WITH S K IN AND E Y E S . PR O V ID E W A S H I N G F A C I L I T I E S NEAR WORK A R E A . DO NOT STORE NEAR F E R T I L I Z E R * S E E D S * I N S E C T I C I D E S * AND F U N G I C I D E S . KEEP AWAY FROM OPEN F L A M E . - D O I T I O N A L I N F O R M A T I O N : NEW MSDS 1 9 MAY 8 2 . .AST PAGE R ) I N D I C A T E S A TR A D E M A R K OF THE DOW C H E M I C A L COMPANY O N S U L T TH E COW C H E M I C A L CO MPANY FOR F U R T H E R I N F O R M A T I O N . HE IN F O R M A T IO N H E R E IN I S G IV E N IN GOOD F A I T H * BUT NO WARRANTY* . X P R E 3 S E 0 OR I M P L I E D * I S M A D E . 8512 0003999 8513 DOW C H E M IC A L U.S.A. XLA (A - 9001 BUILDING May 21, 1982 MIOLANO. MICHIGAN 48S40 o n e * * i ?Mfin R. L. Eischer, 9008 R. G. Holzschu, 9008 E. R. Laning, 9008 J. A. Schultz, 9001 M. J. Skurski, 489 J. Woods, 834. cc: D. W. Osborne, 9001 J. M. Tichon, 489 G. L. Ytzen, 9008 MEETING REGARDING ESTERON* 245BE QUALITY AND OPTIONS 3 Meeting was held to discuss possible responses to the appearance of a crystalline sludge (as much as 3/4 -inch in some gallon cans) in ESTERON* 245BE formulated and manufactured in 1982. All cans do not contain precipitate, even within the same lot. Background: -- Technical ester was produced in 1976-77. -- The formulation and registration package for the material was obtained from Union Carbide. -- 55M Gallons of product were formulated and packaged; 35M in one gallon cans and 20M in 55 gallon drums. The one gallon cans have all been shipped except for a recent lot of 3.2M gallons; 19.4M gallons of the drummed material is still at 489 Building. Technical Considerations: -- The crystalline precipitate has been identified as the bis (2,4,5-T) ester of ethylene glycol. -- The liquid above the solid material in one can of lot 82041467 has an assay of 42.0% T acid (label says 42.5%). -- In general, the precipitate appears when the material is cooled to 45?F. -- The limited data available indicates the tech ester is continuously degrading. Without a major change in formu lation, the tech ester will be totally unusable by 1984 or 85. Trademark of The Dow Chemical Company. .4p r AN OPERATING UNIT OP THE OOW CHEMICAL COMPANY 0006547 60H U M O O I /t . R. L. Eischer et.al. May 21, 1982 Page 2 Technical Considerations: Continued -- Both the liquid supernatant above the precipitate and also the formulation containing redissolved solids give accept able emulsion properties upon dilution. -- T h ere s no M a y to b u rn n r d is p o s e o f th e te c h ^ s t e r . _ It m ist b e s o ld . Options: -- For drums: Redissolve solid; then, ship all material to Texas/Oklahoma with adequate notification to customer that material should not over-winter. -- For 1 gal. cans: Distribute through dealers a tie-on-tag telling the user to heat the can in a bucket of water and shake before using. This would require the appropriate fire-sale rebates. There appears to be a comfortable mar gin here for rebates, given the difference between the standard cost in 1977 dollars and the selling price in 1982 dollars. -- The alternative is recall of 1 gallon cans. This would in volve loss of the cans, can disposal costs, shipping, and reprocessing costs. Rework technology would have to be developed. Waste solids that couldn't be burned would probably be made in the product rework. To Do: -- Determine if drums can be heated and rolled to redissolve solids (Skurski). -- Depending on business considerations, consider the possi bility of developing a new formulation for the 300M lbs. of tech ester remaining in storage. This could not be ready in time for any 1982 sales. Marketing will make the recall vs. "fire-sale" rebate decision in the near future. Agricultural Products Department psk 0008548 P) S O o S O