Document pmMmb86yeD1MER5RxjRKRnN7B
\Jotuu1*^.
hkpcw ths kousakto ch:ical caavuar tv
Cecil X Drinker, 1S.D, Dean and Profor at Physiology Harvard School of Public Health, Booton, lines ,
September 15, 1950
HONS 048123
sg*
I, Jteperinwnti to determine tbo pooaiblo toxlolty of tho following aubotaneoa: ........................................................................................................................
1, QhloroOMM ........................... .......................... ...........................
. ^lphonyl phthalato ........................... ........................
9
9. Chlorinated diphenyl #1968..................
4'
4. lqlxture of ohlorlnatad diphenyl and ohlorinotod llphenyl benneno #9460 ....................
7*
II. Soua general consideration*:
9
1. Sridaaoe for tba daatruetlon of a mixture of pente and bexaohloniQphtbaloTies (#1006) In tbo body a
9
. Tbo offoot of llioroeclng tho aodlun oh] or Ida In tbo dlot upon anisAla receiving toxlo -doson of >.'1000 .... 10
9. Too offoot of high and Ion oololun intake on enlnmla Inhaling high oonoantratlona of #1006 ................................. 10
4. 7no offoot of lnjeotlons of xanthine on onlmnla inhaling high concentrations of #1006 .................
11
HONS 046124
I* JXWKn.ra TO BBlMBIffiB WE POSSIMJS TCOCXCITT 0? TOT roi-LQ'-lrW SUHT.TAUr.rei
1. CHLQROOSJWB
On July L4, 1937, we Wn Informed by T. O. <h thnt eaoh 6 ounce bottle
of a toft drink might contain 00 to 70 mga. of ohlorooean*. Thors na no
pharmeologledl reeeoa to believe the oonipound would be Irritating or toxic In
any way, and Iherefor* It wee deolded to doee rate with It very heavily, the
argument belni; that if they tmirlved heavy dotage without any evldeneo of
damage a verdlot of no toxlolty wight be given and wuoh tine saved. If, on the
other hand, tie large doeea jrcnred poisonous It would be necessary to reduce
dotage until i non-toxic level waa reached. The firat of those alternatives
Iproved correot, kxuerlmat nt. ~ August 10, 1(37. 30 adult white rate ranging in might
from 163 to *1>
wore aoch fod 70 ncyc. of ohlorcoccne in 1 cc. of olive oil
dally by atom jb tube. Tbeee animals showed no evldenoo of danege In any way
attributable t> ohlorootane. they were examined microscopically fron the 30th
to the (2nd der. The only oonatant change observed wee e possible slight
Inornate in th> granularity of tha oolls of tht liver ocrde, but the
pathologltt in oharge felt this to bo within normal 1 Unite, Tbit finding la
doubly roattur: ,ng since many of the animal* developed o chronio tuppurotive
4
lung condition very prevalent In I'*ostor. stock rets nt tbo Uto. hut evon rlth
this added hanilieap there wot no evidence of damage
we thus ooncludo thnt
ohlorooeene *v<in in enormou* dotage Is an Inert material In the body nnd in oil
probability pnnsoa through tho intcctiue unchanged.
HONS 04B125
2. 9XFHI0KL PHTHMJO*
On Auguet 29, 1997, we were informed by Dr. R. X. Bally that diphenyl ` phthalate might be absorbed through tha akin or Bight ba inhaled and suallowad
during spraying operations. After consultation it was daeidad to feed Inorily, and if thara ara indication* of toxicity to project other axperlawnta,
2xuarlir,a>ta -- September 20, 1997 . 20 adult whita rata ranging In weight free) 242 to 9)1 pa. vara aaoh fad 0*9 npa. of diphenyl phtbalate auapandad in 1 oc. of wet#: by atoiaacb tuba daily. Tba animals ware from new atoek and with one exception ranninad olaar of tha lung condition which existed in the obloreoeane group. During tba period of experl&ent, ttoleh laatad 92 duys, practically all tba animals gained weight. Scumlnatlon of 0 animals killed at Intervals during this period of test resulted as followet
Tba orears were normal (yooely, and on microscopic exa>ainatlcn tho llvvr alone was of possible interoat. Tba changes in tha liver varied from thoea in which tho oolite of tha llvor cords wura almost normal, having only a slight awolllng and ^anularlty of thalr cytoplasm, to those in wbiob theta changes
wore pronounco 1, In tha letter there was e moderate dogree of vacuolization ami a raro hyaLlno body. Those alterations It must ba understood wore the result of very certain dosage, elnco tho compound wes given by stomach tuba end the anljwl > bad no poneible vay of avoiding it. neither th jioV.iologiat nor myself wus able to consider than of enough rnanent to cause uc to make further cxporiiwnta,
1 am oonf: dost that with the ordinary precautions .accompanying cjirny
lecouarlng no jocoihle ham could he done, even if tha concentration of
dlphony1 phtlmljbta In the leecuor uua fur nbovo the 8 nor cent figure gvcr'
uc by IS. t\ Knlly.
HONS 0%8126
8* OHlflHlKATZD DIKL2JYL -- OOUPOUHD #1868
Ibis mete: 1*1 ni furnished by the Monsanto Chemloul Co*fany. it wu*
eld to hot* ohlorls* eontsnt of 68 pr osnt, th* hlghset ohlorlns figure
of any oompoxmi teeted by u* during tho paat thraa yaara. It bad bcon our
ltqpresalon that tootle ity a&d ohlorln* eentont followed obo another closely,
but thie he* nojt turned out to b* the ease for #1868.axdxiaxsaiuiscilaAc*ith
nkawn|:
Turther dlaoueclon of thl* point will follow the description
of the experimental obeervations end their result*.
txperlment im, -- august 8, 1937. The ooopouad #1868 was administered by
Inhalation, tbe teohnlque be me thet described in the popes' entitled The Problem
of Possible Syetotalo gffoot* from Certain Chlorlnotod Hydroc:irbon. Journal of
Industrial Hygiene, 1937, 19, 883. Tor the first observation* 80 adult wblto
ret* were used. They were exposed co follows:
Oroup 1. -- 80 anlnmle. T:rport\ire to which tho compound v:ns hontod to
Introduce fume Into eir line 140-1PO* C. Average concentration in air brecthod
by rate 0,53 . per oublc meter. Average daily exposure 1G hours. Tho
experiment vea o ontinued for 119 days, cni-nl* being occrlflood ct intervale for
pathological exu-.lnatlon and for tho c.-xbon tetrachloride nnd eloohol test
]viper previously cited). Tito conditions Cj:;jribod nbovu eswred swelling and lucroure of crunnlurity
of ths llvsr cclIs. Hyalin* lnclucloua were rare. Tbess phengss wen; rulte
uniform in ell ailnsls cxeninad alter the Slat lay, but vern not csrteinly
progressiva. Tht rats wars very healthy throughout the period and tharo wee aJt
alnoet uniforw g'.in inwoight. Tho c;;rl>oa totrachlorlle-ulcohol teat was
positive after D 5 dtye, v.hich indicates tlmt though liver dutnu^ wo* uppurently
r.iigkt toirj do(0'<>e of
had been tkmo tho organ. Tharo v.-aa no evidence of
HONS 048127
damage in any part of the body except the liver*
At tho <|nd of OS day* 10 rata, qjjtarently In exeellert condition, wore
removed fron the experiment and oet aelde for observations upon liver roeovary.
Thao# rocoTcrr animals showed no ellnloal change# of any eort. Vhen eacrlfleod
72 and 141 dare after removal from exposure It wee observed that the swellleg of the liver sail# had dleappoarod, but the granular and hyalin* material
remained In tpe liver cell* and bad apparently bei
porMinent. There was
absolutely no progreseion of damage after moral from exposure, These chuiinga# may becoi(>ared with those produced in rats by inhalation
of chlorinated diphenyl #4468, administered In a similar manner In concontre-
Ilona of 0.87 to 0.93 $a. par cnblo meter over elnllor porloda of time. Zn the ease of tliia eorpound the eonaplouou* differonea woo the fur greoter
incidence of byallniaation of tho liver cell*, which in our opinion woe the
charhcterlet 1< laalon otniecd by
end mixtures containing It. Ono can
therefore ooiujluda that #1260 in low concentretIons 1c definitely lose toxic
tlum -- After 119 day*, the low concentration of #1260 having proved
but slightly joloonous, It was decided to increase the concentration In the air breathed by VI* 84 rats thsn remaining. Tomparaturo and other conditions \rc n/iintcir.ed no during tho first 119 doye, but by the utu of < vcporln'o-/. .Instead or 1 tho itverdk'.o oorccr troll on of j?12G0 in tho dir wiin brought to 6.23 wcj. por cubic, rmter of air. Brjtoeure to tbir. very high concentration v.ua continued for
07 days. Under thejs# extreme conditions the onlmls agoin rewainod in pwfcct
health. The c rbon trirf.cUorlOc '-ri uleoV^l tcr.t. vnr. ponltive but thoro i.nr. t.
ebnolutely no >th#r Indlcution of llvor during* and no evt-lnncc of diottiubur.co
to olhor orgur.i.
MONS 048128
titan eiaminad it autopay at tta ond of 6? day* -- tha anlBmla tad
*xj>*rl*nc*d a total expoaur# of 206 day* -- ttar* war* no groaa evidences of
abnormality In any part. On microscopic examination no organ showed changes
except tta liver. Tta number of oella oontainlhg hyaline and tli* mount of
hyalin* in tt* o*llc Involved increased during this period of axposuro to tta
higher concentration of #1258. Tta hyalin* we* moat abundant is tta portal rone
of tta lobula with very littl* in the central ar*a. Aftor 42 day* of exposure 10 rata war* **t aside and war* aorifla*d 75 day* lat*r. Ttay wore in *xc*llent
condition whan removed and did not change. Grossly, at autopay, ttay *botie0
nothing obnoraal, end on mieroaeopie examination tta liver cella tad loat their swelling but retained inor*a**d granularity and hyaline inclusion*.
Tb* axpo: rimanta on inhalation* of high concentration* of #1250 raanforco
the eorielualoii that this cosqiovmd ic of low toxicity ot> compared with #4*65 or with chlorinated napbtlialcno* r.bova triehloruopbthaloho, Tho quartion as to why
#1268, tta moat highly chlorinated compound tested, proved but slightly harmful
cannot bo ansvirad with any daflnitenoas. It haa boon suggested that tta toxicity of alL theso chlorinated confound*, even though of variod composition,
may depend on the ability of tbe animal to decocipoae them efter lodgment in the tlaauoc, and t mt thin decomposition mlc>r be shown by an increase in the cblorlno
in the urine In *uitrbly conducted foedin,- taperinmnin. In experis'on to upon this point we have ihor.ti a daflnlto increase in the urlnrory chi or ido o when dogn a-.d
rots were fed a mixture of penta and .ViXaci'.lomophtfc'-l'wn'C (}"100C), e compound highly injurlouk to tho liver end containing 0E.6 per cent of chlorine, but similar
obsorvctlonc huro not been made with any of tta chlorineted diphenyl* or allied
compound*. It nmy, however, bo Vtat titan about Cb per cent clilorinntlou is nsi-ctad tho aut'Stcncus formed arc <;uJto atr.blo in the body and t;o cau?:o n minimum of
dnmtigo.
HONS 0<|8129
(
-7-
la concl iiIon, #1968, If handled with ordinary precautions ae to vent He-
tion should hi i ntlrely harmless to worknsn. Vhlls it cannot bs given on
absolutely el(>an hill aa to haalth. It la preferable to #4463 and #m>.
4. ISPCIURR OF CHLORINATED DtPHWfYI AND OHLQROiATdD Dll'HB.TL HNZBflt -- OOUKM #9460
Ibis subs tone* wus furnished by the Uoneanto Chemical Cottony end vee eeld to have a ohlo'tne eontent of 60 per cent, being in this reaped bolou #4469 und far below #1860.
txpcrlraen'a. -- The Inhalation toclinlque wee used an In tbo cane of flhi-0 and #4469.
August Z, 1937. 80 adult white rats wore the subjects. Temperature to which the oompojuaA wee hostod to Introduoe fusa Into the air Mm 1<0-I.f$# C. Average oonoent ration in elr breathed by rata 0*009 mgm. Pr cubic meter. Average dally etpoturo 16 hours. The experiment lasted 119 days, a eoru-iii number of animats ware sacrificed for pathological examinetion, others wore used for tbo oa-bon totracblorlda end alcohol tost, and still otl.rf wl ecit'o for observation i aa to recovery from possible damage.
In spits os' the foot that tho coneentmtion In tho rtr brruthed 1.;- tho r .i? evoreged about :/$ that obtained nt comporeble temper:::'' < i'rw.. "l'-'OC1, c n>u r of thsso snlmoli became aielc and lont weight towards thr end of the r.ocw-d wah of exposure. Wen hilled, sueb lndlvlduelr ohowed ctobb uotllin/r of the livtr but no changes la other organs. On nicroeooplo exaaijiotion e-vcllinf, of tho liver colls, liiurenncd granularity ut;d hyaline inclusion:' \.>tu notul ii! ; ii Filled as early is tho 16th duy of exj<osi>re. Thuso changei; obviously eccurnu) rapidly. Hyalini dopocite wore never us numerous us with *li;60. Ar.iirula
HONS 048130
-0-
removed for re every after 81 and 119 day* of expoeuro Aid not gain amrkedly ls weight, and On* died for no obvious causs. tJben oxamined at autopsy tba
mUUe of tho lifer cell* had subaided, but ebnonaal jjronulerity and hyalinlsatlon remained. Nee&lees t aay the carbon tetrachloride and alcohol teat was positive whenever used*
In vleu of the foot that #8460 In such low concentration proved so definitely toxl), no higher concentrations wore tested. It seem Imperative that whenever t ils compound Is used in Industry, great care bo taken to keop concentrations in the air at an cxtrerooly low level. Ko llhortiM ecu be td:sn tlth it, ns with r6*.
KONS 040131
XX. eS0aI3a(iTnJiaCaa/Ut. TCOnNnSX:sDtnRAuT;X3O3lS
Xa eddlt Lon to these teste of confounds, cartaIn experiments war* done whleb ora of .attract to tboao manufacturing or using ohlorlnatad hydrocarbons. Petalla at to tbaeo experiments ora of couraa available but ara not Included in this report since they are not of dlroet industrial Interest*
1. znna<C3 rat tks ksuiuction or a udourx or piwta and
HSCAO!SUOroiAP!mUUr33 (/1006) IN TIBS HOST
It bao alueya bean a quoDtion as to whether the chlorlnatad hydrocarbons which hsTO boon oxibIimA by ouraolvoo end by otbara do buna per ao or whether toxlolty deport la on their broahdoun in tho body with tbo liberation of ootnotla Inc hurjiful .0 the liver, A partial answer bcc boon obtclnod b7 feeding 1006 to rate and does idilch were os a low chloride diot with unifora excretion of chlorides In the urine, Vlion these cninals reeolvud tho chior Instad hyi roottrbon (1006) the urinary chlorides rose. This lhdlcaius that tha body < ertalniy hue poucr to detach chlorine from this euupouad, eua it la probublo that the tone condition in true for allied toxic coiqtounds. It would be rsoct interesting to geo vbethcr inco*tloa of fI860 results In sii-.Jlor findings or l.hatbor in tho cane of this rolutively nun-toxic cu.^khuiO. there ic practloally no splitting off of oblerlne. Jloithor tine nor our ilnenclal reeouroee permitted ouch teste.
HONS 046132
-10-
4* IMS XFTBCT OP XHCRSAsm 71!B SODTU.: C)001(21* I* nu OZBT WCH JHIMAI3 *CSIYD TOXIC ICSES OF #1001
.
On lb* ground thut eliloridea night bo fundamentally uieauut elth toxioity, a proup of 15 rats ana fad a lot' toxic doao of #1006 and tortured elth a alnllur grouj. on tha aama doaapo of #1006 plua a narkad lncrar.no In ohlorlda Inti he aaourad by elTlng 5 co. par kilogram of body aalght of 4 per eant XaCl eolution dally*
No dlffranoaa warn found boteeen the teo group*, and It nay ba oonoludad tbot ehlorlna lneraaao aacurad through tha dlat doao not enhance toxicity. Thin azparlm-nt ana dona In order to find out tbather Increase In chloride intake during hot weather algbt be harnful.
A partlcilar phoao of the problen, tha pottlbla anhoncer.ent of typloel akin lealona by lncrcbelttf. chloride Intake^ oannot be decldud by ezperi&onts on fur-baorlnc nnlaatla with no aabuceoua Glenda. All Dint can be cold at tho aerjant la that lnoraoaad eblorldo Intake doaa not Increnso ayatomlc toxicity.
9. ims jffi'arr o? way /uni w.; c/jcjitj LiV.jrj cn aj.'B'alp
ujiauks nio:: ccij.c.'iinvncw cr v'iooo
It la eel! i knora tbot a diet rich in calcluir. lc r-urfcedly effective In
prorantliic the aeuta yallot atrophy of tha liver produced by carbon tetra
chloride (Ti>e ITeventlon and IVesti-out of Crnbon To trueliToil da Intor.lcct ion.
By P. 1). luisoi,
a. S. I'.lTiot, rn.B., end B. 11. Hobblne, 1..S., Journul
of tha AaiHoar 1-edJcc.l AswociotJon, 2920, volvu.e S*0, fu^.w 945).
To die cover whnliur e e.lcivr in the diov uoult! product Lj.iv.xl )iv*.-r
,;i`
HONS 0 6 8 1 3 3
-H-
from toil i eblerlnetsd hydrocm-bon, 90 adult white rata were placed upon a dlat of loan horeemeat, atarch and. lard, a eoablnatlos adequate for maintenance but very lw la oaloluo. Another gtovp waa given a dlat aonalstlng of doe eboo, milk, lattuoa end eggs, with added ealclw laetata -- a ration very high In ealeium.
Both gr >ups vara exposed simultaneously to Inhalation of high concentretlona of /lO>6, an average of 11*21 mg*, par eub'le aatar far Id hour/i a day.
Aftar 11 days, 12 high oalelun dlat rata vara alive and 7 of lha loo aalalum grcu;>. At intervals an lamia vara klllad for axaniaatlon. In both groups the liver oaa abnormal groaaly and microscopically, and In both groups animals died frcv* Hear danags. It oaa lmpoaalbla to consider that the high cslolun dlat aaa In tlia lauat degree protective. It may, therefore, be concluded thajt adding calelum to the dlat of worker* either in tho fora of extra Milk or of ealeliM laetata will not prevent liver damage*
4,| us Ermrr or vexenots or x/omwiz ost anu^als MiAULi'.o men ccsjc^riK/iHois or liooe
in 1037, 0. Meala published a brief paper (Tbe rrotective Actloo of Certain Purl no i agulnot Liver necrosis Productid by Curium Tctruchlovlde and Cblorofom. folenee, 1037, volui 66, ptef- 03). Ha cluinod thnt rata lnjeotcd with iodlun xanthine becw. mnrkedly rni*tant to enrboM tetrachloride.
Thin uce*ated that xanthine might hove similar protective power over liver
damage from the chlorinated hydrocarbons on examination In this laboratory, itccordlngly SO adult vrhlto rntc r.orn coueed to lnh'ilo y 1006 In ocncentri.-
tlona cvcrop.Jnrt 15 nyya. por cubic notcr for 16 hours dally. Ono p*w*p of 80 rets wee nJvpn 80 wr-. of xenthin* oubcutonoouely ovory other day and <0 '"
HONS 0V8134
of xaatbla# 1? atoenab tub*'mi tha altarnata day*. lba MOOBd croup of 18 rota ted tba am* npoavr* to 1008 *1 ttowt xanthine traatnaat. Jb ilffaraaota *ara BOtad and ona aanaot axpaat any offleaay from xanthine ilthv In tha prcreation or treatment >t llrar diaaaaa u to thl* chlorinated hydrocarbon, and In all probability t to aaan negative ra cult ould bo onoouatorod in oomoetlon with allied toxic loqpounds
HONS 0<i8135