Document 3J46qEXeZxwaNYmGZmKKnB93n

NATIONAL RESEARCH COUNCIL * NATIONAL ACADEMY Or SCIENCES NATIONAL ACADEMY OF ENCINEERINC i t i eottm rviioN r t u v t wmmncto, a c t 4 it . | (A . 3 xT. itCSVTU* TOKICOtOCT u in r Ara'cHtmu Ttcanotocr 13 F e b ru a ry 1969 - # Ref: BUM D-732-pR:rmo tl, B ureau o f M edicine fc S urgery >irtmeat of the Navy ihington, D. C. 20390 1 1r S ir: 'i On 29 May 1968 you req u ested inform ation re g a rd in g the potential xards associated with the use of herbicides for weed control in Alaskan ilitary antenna Helds and tra n sm issio n lin es. We have delayed resp o n sg to your re q u e st until we could obtain detailed in fo rm atio n on se v e ra l wdevelopments which m ay affect y o u r decision on th is p ro p o sal. This eceat inform ation is included in the enclosed su m m a rie s of the to x icities f the various m a te ria ls involved, but we would like to c a ll y o u r p a rtic u la r ttention to the following a sp e c ts: i. The use of chlorinated a ro m a tic hydrocarbons a s p e stic id e s, p a r ti cularly DD^T but not lim ited to th at compound, has been under in te n fri sive attack in this country and in Europe. The state of W isconsin is currently the scene of very b itter and emotional litigation to prohibit the use of such m a te ria ls . Copies of two p ertin en t publications a re enclosed for your inform ation. We have ju st re c e n tly been g ranted confidential a c c e ss to unpublished information developed under a five year contract with the National Cancer Institute in which several pesticides, including one of the compounds included in your proposal, have been shown to be carcino genic to experim ental m ice by single subcutaneous in jectio n s. In the sam e study we have been inform ed th at a n o th e r of the h erb ic id e s proposed for your usage has been found to be highly teratogenic. The significance of the findings in item s 2 and 3 above is very difficult to asse ss scien tifically without a g reat deal of additional study. How ever, it is quite clear that when or if these data a re released they w ill result la a g reat deal of additional controversy sim ila r to that over the use of defoliants in Viet Nam, and will certainly call into the question the need for m odification of the regulations of the U. 5. D epartm en t o f A gri culture P esticides Regulation Division and the Food and Drug Admini stration's regulations on food additives. U CUefi B u r u u of M edicine It S u rg e ry 13 F e b ru a ry 1969V P ag e Zm .. We a r e retu rn in g herew ith y o u r e n d o e u re (1) Land M anagem ent P lan I lis requested. O ur com m ents on th is plan a re as fo llo w s: The p ro ce d u res suggested a re in conform ance w ith the recom m endations of the m anufacturer and when carried out under the supervision of a qualified pest control operator should resu lt in m inim al exposure of p erso nnel involved and a re not expected to produce any sig n ifican t health hazard to.the applicators. The recom m ended w eather conditions a re in accordance with standard practice for these m aterials and should resu lt in maximum effectiveness with m inim um loss o f active in g red ien ts. We a re unable to evaluate w hether o r n o t a re a s w ithin 100 fe e t of open or running w ater should be sprayed or controlled by alternate methods of weed rem oval. It is known that 2-4-D and 2 -4 -5 -T a re not highly i persistent in the soil. F o r exam ple, soils treated with 2 -4 -0 a t the rate o f 10 pounds p e r a c re showed no phytotoxicity a fte r 14 w eeks. However, there were some traces o f phytotoxicity from sim ilar tre a t t m ents with 2 -4 -5 -T a t 19 w eeks. The lite ra tu re in d ic ate s th at th ere Is little la te ra l m otion of herbicides after the agents have' in filtrated k the soil. * There are m ultiple factors affecting the contamination of surface w aters from herbicide spraying operations which preclude an unequivocal sta te ment predicting the actual concentration which m ight develop. According ly it is suggested that tiie judgm ent of a qualified pest control o p erato r who is thoroughly fa m ilia r with th ese lo cal fa c to rs be given m a jo r con sideration. These herbicides are known to im part an unpleasant taste to drinking water at threshold levels as low as 8 jigm p e r lite r. This concentration seems to be well below that which would re su lt in any fish k ill since levels ranging from 1 to 500 ppm have been reported as safe for several species of fish. T i Chje, B ureau of M edicine & S urgery 13 F e b ru a ry 1969 Page 3 The proposed levels and conditions of treatm ent when com pared with the^enclosed toxicity data do not seem to p resen t any acute hazards to ip cal wildlife. Sincerely yours. Ralph C. Wands D irector Advisory Center on Toxicology Enclos u re s : 1, N ature 220:1098-1102, 1968. 2, Science 163:548-551. 1969. 3, Toxicity of B ro m a c il 4, Toxicity of 2 -4 -D 5, Toxicity of 2 -4 -5 -T 6.. Land Management Plan i i 16 i t) o SUMMARY O F THE TOXICITY O F BROMACIL } Brom acil is chem ically identified as 5-brom o-3-sec-butyl-6 m ethyl*1 iracil. It decom poses slowly in strong acids and is subject to m icrobial* t composition under m o is t so il conditions. It is th erm ally sta b le up feo its ' selting point and is stable in w ater9 aqueous bases and common organic Ilolvents.* It was firs t introduced under the com m ercial trad e nam e "duPont Hyvar X B ro m a c il Weed K ille r '1fo r n o n -cro p u se s. Its use was subsequently expanded to include the c o n tro l of weeds in c ro p lands and is now com m only tied fo r c itru s groves and pineapple fields. In M arch 1967 the Food and Drug Administration established a tolerance of 0.1 ppm B rom acil for residues in Ior on c itru s fru its and pineapples. i Acute Toxicity in Anim als The following data a re available on the acute toxicity of B rom acil in iBiznals. Species Route Effect C o n cen tratio n f Hat Dog rrisb (bluegill, sunfish) O ral (single dose) O ral (single dose) In water 1-D50 I-D50 8 . S. C. * 5, 200 m g/kg >5,000 m g/kg 10.1 ppm lliallard duck Inhalation LC5O >10, 000 ppm Bobwhite quail l Inhalation LC50 >10,000 ppm iI **aS. C. r e f e r s to the B iologically Safe C oncentration which is the m axim um J concentration in which the fish a re expected to survive. In com parison, the l B. S. C. fo r DDT is given as approxim ately 0,005 ppm . B ahould be noted that it was im possible to obtain a lethal o ra l doee of rB'OjnacU in dogs doe to e m e sis w h ether the dose was a d m in istere d singly o r la six divided p o rtio n s 30 m in u tes a p a rt. B7 3 L Short term feeding studies of B rom acil to ra ts at doses of 670 m g/kg .'per day w ere c a r r ie d out fo r 10 d a y s. T ra n sie n t histological changes In the sliver w ere noted, co n sistin g of fo ca l cell hypertrophy and h y p e rp la sia . t *i ) B rom acil (2^ f c ff,ronic Toxicity in Anim ala Male and fem ale ra ts w ere fed d iets containing 0, 50, 250, and s i2o5i0r-^1p m by weight B ro m acil for 2 y e a r s . T h ere was no n u tritio n al, c lin ic a l, hem atologic, t rintry or biochem ical evidence of toxicity in the test groups except among the Cfemale rats receiv in g 1250 ppm . The la tte r group showed a low er ra te of weight gain, * H fhtly d e c re a se d food intake, and a slightly low er food efficiency. All animals receiving the 1250 ppm d ie ta ry level had slig h t h y p e rp la sia o f the thyroid. Male and fem ale beagle dogs w ere also fed the sam e levels of B rom acil fria their diet fo r two y ears and showed no evidence of toxicity. At the end of these two y e a r stu d ie s, tissu e analyses showed low lev e ls 'of B ro m a c il proportional to the daily diet. T here was no evidence of sto rag e i- or accumulation. jfotagenic and T eratogenic Studies t In view of the suggestions of h y p e rp la sia noted above, and b ecau se of the ^'structural sim ila rities between B rom acil and 5-bromou:~acil, the m utagenic teratogenic possibilities of B rom acil w ere investigated. It is known that 5-broxnouracil is incorporated into DNA by a v ariety of species and thus has tfoond some clinical use for can cer chem otherapy. When B rom acil was ev al u ated against a thym ine-requiring m utant of E. coli. it was not incorporated ^ato the DNA. When m ice w ere .given B ro m acil they did not in c o rp o ra te it joists the DNA of the liv e r o r the spleen. When te ste d ag ain st a b acterio p h ag e Ap 72), it did not produce m utations even though this is known to be a su s c e p tible strain. Bromacil was fed to pregnant New Zealand white rabbits at dietary levels J j f 50 and 250 ppm during the 8th through the 16th day of g estatio n and produced teratogenic re s u lts . B rom acil was incorporated in the diet at 250 ppm fo r tree generations of ra ts ineluding six litte r s . T h ere w ere no ad v erse effects reproduction o r lactation and there w ere no pathological changes in the reanlings of the F3B g en eratio n . .13-69 ii SUMMARY OF TOXICITY OF 2 - 4 .0 (2 ,4-DicUoropheaoxyacetic add) -V The horm onal effect of 2-4-D in stim ulating plant growth and Its subteqaent effect aa an herbicide was f ir s t reported in 1942. Since that tim e ggisctenflve lite ra tu re has collected on its effectiveness and upon its toxicity, f t l i sum m ary w ill only include those p a p ers which a p p ea r m o st germ ane to fc/proposal for weed control in antenna and transm ission y ards, . 2-4-D is a stable, nonhygroscopic compound which is a fairly strong gdd sad as a re s u lt it is corrosive and reactive with bases to form the corresponding sa lts. . Ac u te Toxicity in A nim als It has been shown that the acute toxicity of the free acid and of the sodium sit are essentially the sam e. The following Table I sum m arises the acute 250 values for se v era l species by a v ariety of routes of adm inistration. Table II p resen ts a com parison of the LD50 values for som e of th ese sp ecies the m axim um n o n -leth al o ra l dose of the sodium s a lt of 2 -4 -D . According gc the data is th ese ta b le s, 2 -4 -D would be c la sse d as m o d erately to v e ry toxic, jothe most susceptible species, dogs, initial sym ptom s were frequently noted 'within six hours a fte r a d m in istratio n of 2 -4 -D . The sym ptom s w ere d e p re ssio n gsd a flight atax ia which in c re a s e d in se v e rity e sp ecially in the hind le g s. Death as delayed for two to nine days after adm inistration and w as preceded by a decrease in body weight accompanying anorexia. H istological studies showed erne necrosis and inflam m ation of the in te stin a l m ucosa, h epatic congestion, pneumonia. In ra ts lethal doses of 2-4-D produce dem yelinization of the dorsal portion of the b rain . Subacute feeding studies in ra ts and guinea pigs w ere ra th e r inconclusive, ^vever, it appears that ra ts can tolerate as much as 0.1% 2-4-D in the diet fex two weeks without effect. Qronic Toxicity in Animals Dogs w ere fed 0, 2, 5, 10, and 20 m g /k g daily fo r 90 days. The 20 mg dose was also given as a divided dose tw ice a day. The two dogs receiv in g the 2d mg single doses died a t 18 and 25 d ay s, and one of the dogs receiv in g the 20 inf divided dose died at 49 d ay s. T he fourth dog at the 20 m g divided dose fevel survived. All surviving dogs showed n o rm al body w eight changes and Vre generally fre e of any sym ptom s. T hose anim als w hich did not su rv iv e gradually*I1* w eight and developed w eakness in the hind leg s and slig h t atax ia. 35* Immediately p rio r to death th e re was difficulty in chewing o r swallowing and ireatuaUy food was refu sed . T here w ere no hem atologic changes in any of the l PTmsl in this feeding study except those th at died showed a d e c re a se in lym pho*cytei im m ediately p rio r to death. T h ere w ere no outstanding change* in organ vdghts in any of the dogs and there w ere no significant m icro scopictbhaages epos autopsy. a Female rats w ere given 2-4-D five tim es a week for a four week period doses of 0, 3 10, 30, 100, and 300 m g /k g . The doses of 30 m g /kg and less jgdwed no adverse effects as judged by g ro ss appearance and b ehavior, m o r tality growth, hem ato lo g ical v a lu e s, blood u re a n itrogen c o n cen tratio n s, organ weights, and g ro ss and m ic ro sc o p ic exam ination of the tis s u e s . Those r a t s ., receiving 100 m g /k g showed g a stro in te s tin a l irrita tio n , slig h t cloudy sw ellirg jp the liver, and a d e p re ss e d grow th r a te . The 300 m g/kg dose caused a rapid decline and death of a ll anim als w ith se v e re g a stro in te stin a l irrita tio n being &e principle effe ct o b se rv ed . A nother s e t of fem ale ra ts was given d iets conttioing up to 10, 000 ppm of 2 - 4 - 0 . D iets as high as 300 ppm fo r 113 days p ro duced no effect. 1000 ppm in the d iet fo r 113 days caused a d e c re a se d grow th T*te, increased m o rta lity and in c re a s e d liv e r w eights w ith slig h t cloudy sw elling of the liver. D ie ta ry lev e ls of 3,000 and 10, 000 ppm of 2-4-D caused a v e ry rspid decline and the anim als w ere sa c rific e d a fte r 12 days. r*atril Nervous 5ystem Effects Electroencephalogram s w ere recorded on ra ts , cats and dogs responding to electrical stim ulation and sound stim u latio n following the in tra p e rito n e a l Injection of single o r re p e a te d daily doses of 2-4-D at the le v e l of 200 m g /k g . The repeated daily d o se s la ste d as m uch as six days before the death of the miznals. In a ll e x p e rim e n ts, the 2 -4 -D produced a definite d e p re ssio n o f the leetroencephalographic activity with changes in amplitude and frequency and joii of he d esynchronization re s p o n se . In those anim als receiv in g rep e ate d goies, the c a rd ia c output.w as d e c re a se d by as m uch as 357 and th e re was a weight loss o f 23% during the six d ay s. H istology showed no changes in the grey or white m a tte r o f the b ra in s o f th ese a n im als. How ever, th e re was a gfTnyclinization of the d o rs a l p ortion of the spinal eo rd . Myotonia is read ily produced in sev eral species by injection of approxi mately 1/2 to 2 /3 of the LD50- Within 30 to 45 m inutes a fte r a d m in istra tio n , &e animal has lo s t m o st spontaneous activity and when s ta rtle d into a sudden movement lo ses a ll m u scle coordination. The anim als slow ly re c o v e r without jtrmaaent effects. ggerction and M etabolism g its w ere given single o ra l doses of 3 to 300 m g /k g o f ra d io a c tiv e - t excreted in the urine and fe c e t within 48 hour. At higher doe lev els, the ir cent excretion decreased linearly with increased dosage. At thq highest ' dost levels, the body s till retain ed som e radioactivity a fte r six dayV and the activity was found in a ll tw elve tis s u e s which w ere exam ined. *. ? IWnnalSffe eta : 2-4-D salts and e s te rs w ere applied to the skin of rab b its in w ater and ~dil and produced a lo cal in flam m ato ry rea ctio n in a ll a n im a ls. T hese effects appeared to be m o re se v ere when oil was used as the vehicle, guman Exposure to 2-4-D From a series of accidental exposures, it appears that the o ral dose required to produce sym ptom s in m an is approxim ately 3 to 4 g ram s. One ssan is re p o rte d to have consum ed 500 mg p e r day fo r 21 days w ithout ill effects. The sym ptom s observ ed in accidental exposures and suicides resem b le those observed in a n im a ls. In a suicide case the o ra l dose was at le a s t 6500 m g. patient suffering from coccidiom ycosis was given progressively increasing Intravenous doses of 2-4-D acid during sev eral weeks of tre a tm e n t without ill effects. A final dose of 3600 mg produced com a, fib rilla ry tw itching of som e Bseles, hyporeilexia, and u rin ary incontinence. Within 48 hours he had com pletely rec o v ere d fro m the effects of the 2 -4 -D . 2 -4 -D has produced e ase s of 'contact d erm atitis and chloracne, but these a re not as sev ere n o r as frequent as might be expected fro m the anim al e x p erim en ts. The Food and Drug Adm ini stration has estab lish ed to leran ce lim its for resid u es of 2-4-D a t 5 ppm on four crops which m ake up about 6% o f the to tal d ie t, so that a lev e l of 0. 3 ppm is ttssidered acceptable in the human diet. Carcinogenicity The iso -o cty l e s te r of 2-4-D was injected subcutaneously at a single dose of 21.5 xog/kg d isso lv ed In co rn o il into two s tra in s of c a rcin o g e n ic -su sce p tib le pice. Eighteen m a les and 18 fem ales of each s tra in w ere in jected once and then fceld fr observation fo r 18 m onths, a t which tim e a ll but five anim als su rv iv ed . U but one of the 72 an im als was n ecropaied and 15 w ere found to have tu m o rs. fclf of the 16 tu m o rs w ere reticu lu m c ell sa rc o m a . Using a Chi sq u a re s ta tis >* tfcxl analysis, the p ro b ab ility of this incidence of tu m o rs o c c u rrin g by chance {the experim ental an im als is le s s than 1% for both to tal tu m o rs and fo r the gercoma. S im ila r o r a l feedings a t a m axim um to le rate d dose o f 4 6 .4 m g /k g glminlstered in the d ie t in the 18 m onth experim ent failed to produce a sig n ifi'o o t number of tum ors. Closely related compounds including the 2-4-D acid, fta isopropyl e s te r , and its butyl e s te r , w ere sim ila rly evaluated and did not Induce any significant num ber o f tu m o rs. 91 Offset on Fiah . Kour species of illh (goldfish, m innows, sunfish, and catfish) V ere ^potad for seven days to concentrations of 2*4-D ranging from 10 ppm to 19,000 ppfn and to ta l m o rta lity was o b se rv ed . The d a ta fo r the goldfish w ere tp and the unexposed co n tro ls had a high m o rta lity r a te . The re s u lts the other th ree sp eeies led to the conclusions th at the m axim um non-lethal jots of 2-4-D is 1,500 ppm for m innows, 500 ppm fo r sunfish, and 500 ppm jet. catfish. Zt w as fu rth e r concluded that since a sp ra y co n ce n tra tio n of 1000 ppm was adequate fo r h e rb ic id a l p u rp o ses, th e re would p robably be no significant fish k ill in su rfa c e w a te rs contam inated by runoff when spraying operations w ere p ro p e rly conducted, since th ere would be at le a s t a 50% Ration during runoff. % 2-13-69 ' SUMMARY OF THE TOXICITY OF 2 -4 -5 T richlorophenoxy a c e tic acid Ve have ao inform ation on the stability of this compound o r it^ c h e m ic a l TQpsrtif j except that the sa lts a re soluble in w a ter and insoluble in hydroyghoe solvents w hereas its e ste rs a re insoluble in w ater and soluble in hydro- ciiboa*. , i^nte Toxicity in A nim als The acute o ra l LD50 fo r 2 - 4 - 5 -T acid in a v ariety of sp e cie s is given Ja he following ta b le : Spe eie 3 LD50 (nig/kg) Rat louse Guinea Fig Chick Dog 300 to 500 390 380 310 100 jiM was seen w ith 2 -4 -D , the dog is the m o st su scep tib le sp e cie s to acid. It produces effects very sim ila r to those of 2-4-D and the sig - jlficaat findings in those anim als receiving lethal doses w ere irrita tio n and .jtcrosis'of the in testin al m ucosa, pneumonia, focal n ecro sis of the liver and agestin and anorexia accompanied by weight loss and myotonia. * rkranic Toxicity in A nim als Dogs w ere fed 2 -4 -5 -T aeid in capsules five days a week fo r 13 w eeks dose levels of 0, 2, 5, 10, and 20 m g /k g . All anim als su rv iv ed the doses high as 10 xng/kg witho.ut sym ptom s, but those receiv in g 20 m g /kg e ith e r s single daily dose o r a divided daily d o se, died a t 11 through 59 days out of 90 day te s t. The sym ptom s which w ere o b serv ed in these an im als p r io r to r death included stiffness in the h in d quarters and slight ataxia, with difficulty i^llowing food and som e oozing of blood from the gum s. T here w ere no ttological changes or significant changes in organ weights except a alight case in h e a rt and kidney w eights. The autopsy findings on the dogs at the pf/kg level showed irritatio n of the gastrointestinal tra c t. One animal ed generalized ic te r u s . A variety of livestock w ere perm itted to graze on alfalfa sprayed with 5.T at two to fo u r tim e s the recom m ended h e rb ic id a l dosage with no ill ets or indications of grazin g p re fe re n c e betw een the tre a te d and untreated 2-4-5-T was incorporated in the feed of turkeys at a dose rate of |C mg/kg P*r day without a d v e rse ly affecting grow th ra te o r feed consum ption, this level.there was m inim al and rev e rsib le cum ulative action. -However, either the sym ptom s n o r duration of feeding a re rep o rte d . D iscussions w ith the sta ff of a p riv ate la b o ra to ry w orking under an NIH yHtract have produced inform ation on c u rre n t re se a rc h findings th at 2 -4 -5 -T eppesrs to be highly terato g en ic. Since this w ork is not y et com pleted, the ipificaaee of these observations cannot now be determ ined. 'Smiua Exposure As usual, the conditions of exposure o f hum ans a re not w ell docum ented ^ gj. com plicated by sim ultaneous exposure to o th er m a te ria ls . T h ere is oae report.of hallucinations following inhalation of 2 -4 -5 -T , probably in the fens of a m ist or dust. T here a re also a few rep o rts of chloraene among fofessional ap p licato rs. ` The A m erican Conference of G overnm ental In d u strial gygienists recom m ends an a tm o sp h eric concentration of 10 zng/M ^ fo r re p e a te d lily 8 hour ex p o su res, with a w arning that skin absorption m ay be sig n ifican t, has been reported that 2 -4 -5 -T has an odor resem bling that of iodoform which -5s Jast detectable a t a concentration of 2 .9 ppm in w a ter. It is also re p o rte d th at 2.3 PPa w*te r ** toxic to fish. ftunbination E xposures There are a few reports in the lite ra tu re of exposure of both men and jgimals to com binations of 2 -4 -5 -T and 2 -4 -D . A co m m ercial b ru sh k ille r cgaiisting^f 30% 2 -4 -D e s te r s and 34% 2 -4 -5 -T e s te r s was given o ra lly to Steers at 1000 m g /k g . A tin g le dose produced no effect, how ever, rep e ate d y doses w ere fatal id three days. Symptoms p rio r to death w ere general ression, d ecreased food and w ater intake and decreased rum en m otility, 'taecropsy the ru m en was d ry and sm elled strongly of the h e rb ic id e . The omasum was im pacted and the in testin al contents w ere fluid. The m esen teric itsels were congested and the spleen was d ark and shrunken. S teers receiving zsg/kg on e&ch of th re e su c c e ssiv e days showed no e ffe cts. One s te e r w as. 100 m g/kg daily fo r 15 days w ith no sym ptom * and a t autopsy th e re was only t irritation of the gastrointestinal tra c t with sm all areas of focal hem or'c necrosis in a re a s of fatty degeneration of the liv e r. T here was also v ery interstitial edem a and congestion in the kidneys. jn suicide, an adult m ale ingested one cupful of weed k ille r containing ximately 20% 2 -4 -D and 40% 2 -4 -5 -T . W ithin an hour he becam e Jed and vom ited, sh o rtly a fte r which he was found conscious but dazed.