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ACUTE AND SUBACUTE TOXICITY OF DI(2-ETHYLHEXYL) PHTHALATE WITH NOTE UPON ITS METABOLISM*
C. Boyd Shafiee, Chaeizs P. Carpenter and Hknky F. Smyth, J*.1 . -*vr - , X lldlon Institute) PiUtburik, Pa. . *.
from the oral L fore we conclud is approximate^ the digestive tagh from these dost*
I(2-ethyliietyi) phthalate, available under the phthalate. It is our experience that adm^.
D the trade-mark name of "Flexol" Plasticizer DOP, if being widely used in the production
istration in this form may increase intestinal ab. sorption of water-insoluble fluids sad accordingly
of flexible films* tubing, and the like from varioreudsuce the apparent LD* town comparison vitt
synthetic resins. The commercial product a a doses given undiluted or dissolved in a digestif
light-colored fluid? of medium viscosity with a oil. However, the hugest dosage given to rap-
specific gravity of 0.985 and a vapor pressure at 79.5 gm./kg., was administered undiluted and it room temperature of less than 0.01 mm. of mercury. killed 8 of the 10 animals receiving it Tbfc
The ester is practically insoluble in water but mortality is in agreement with the curve rept*.
misdbte with most organic solvents.
renting all other results. In view of that fact **
The communication of Hodge (1) presents the believe the surface active agent used to dispel
only published observations upon the toxicity of the chemical had little if any effect upon tie
this compounds He failed to kill white rats with accuracy of the toxicity data recorded above,. oral doses of34,5 gm./kg., but did kill a small Death from oral doses waa delayed. Inasmuch
proportion of the mice given intraperitoneal injec as half of the victims survived the dose by 6 day*
tions of up to 128 gm./kg. ` Fatal doses to the or more, some injury other than narcosis ww
latter species produced enlarged livers in which obviously involved in the fatalities.. Histologic
doadyswellihff was seen. In view of the paucity examination of organa of the tats revealed marked
of information available by which one could judge generalized cloudy swelling of the.iiver and a
the health hasards involved in the use of di(2- moderate degree of cloudy sweUingof the kiduey
ethylhexyl) phthalate the study reported upon 'accompanied by granular secretion in.the tubokv
here was umj^J^n.
These changes indicsto- that liver and kidney
Bom "
injury contributed to the fatal outcome. Single intraperitoneal injections.of undihttai
Single dee^-([di(2-q|hyibexyl) phtbalate were di(2-ethylhcxyi) phthalate were made m rats oftit
administered^ strain albinos'
ttomacbtube to male Wistar same specifications. By-thidfroutMheLDH vas .weighing 90 to 120 grams and 30.7 (23J to40.6)gito/kg. Thap^eBealduig,
to m^fo
it%. weighing IS to 3.5 hSa^vjtreobserved.for M days. by Hodge (1). TU fluid gave aj
" tEbto which did not die phthalate* and is be&eftd fofl
nta BwUDitala-
lated bj-tb^afi&iihof BHn (2) was 30.6 (20i to 43.2) gn^Jkra^m rats apd 33.9 {252 to 45.7)
ester. Because the LDw fot'rata Mfowmj int#'.l peritoneal doses was identkabwitippfct from ad f
doses, it appears that abeorptiou ctfthe ester fieitj
gm./kg. fatCrafc&i*.' The slopes of the log-dosage thedigestive tractwasnomore complete thanfive |
vs. pmbibn^^rliiKS were 1.92 and 3.42 re the peritoneal caviar.. Incompleite absorption w,
spectively and these low values account for the large standard deviations indicated by the fiducial
limits shown in parentheses.' The plasticizer was actually administered as a
also inferred from the!
in ihbbits and man. -
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Using a minor modification of; the Food all
Drug Administration's cuff test (3), single fati
dispersion in a 1 per cent solution of `Tergitol^ were held upon the intact rabbit skin for 24 boos
7 penetrant,* 1 ml. of which contained 0.50 gm. of
* Received for publication February 19,1945. `With the assistance of other members of the Mul tiple Industrial Fellowship on Chemical Hygiene, Trade mark description of a surface active agent, the sodium sulfate derivative of 3,9-diethyl tndecanoI-6.
and the animals were observed for the failover j 14 days. The greatest dosage we are able to if minister reliably by this technique is 20 mL/tg' That amount killed 2 of 6 rabbits. Hence tf* LDi, by skin absorption in rabbits is in the neijk borhood of 25 ml./kg., not significantly diffue*
130
plasticizersab resins by miflfo may result ^ * formed by cpjjt from the hof& easily oridizecy present. vTo
^..
; CohvamsohowF " Basis or Bat* . Mar Fometpi
trietbyl** t ^txoateV. . riser 3-00)s
0Vycet<A.*T -Otboty'1
"fvetSoMr HO**1
,'breltl^ , groupsof 6reto'
stream 'of at 170s C. iq/s r,; The air wssJ<o metering thefeq; ' suits in inhalatk of the same; or saturated withv opportunity for process. Thee of rats were aria <'instant ratio- c ernosure isgreat Men operating r
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TOXICITY OF DI(2-ETHYLHXYL) PHTHALATE
131
f Snn the oral LD for the same species. There- light upon possible cumulative effects of repeated I fo we conclude that skin penettation in rabbits action. Table 1 shows the results of mist ex-
|J j approximately aA complete' as.abeorptionfrom posures using some plasticizers and other familiar
lifedigestive tract. Nomjurytoi the skin rtsulted fluids known to be employed with safety, for com-
|tkiromui thesedoeages.-
r parison with di(2-ethylhexyl) phthalate. .
: Alt admin,
Inhalation oy
r/
y
We recognize that the chemioris listed iuTable 1 injure the. body by diverse mechanisms and- that
intestinal ab% accordingly,
Pbstirizere are often incorporated inttfsynthetic they differmaterially in vapor pressure. The data pains by milling upon hot rpUs.V: Thi practice offer no more than a comparison of the fatal effects
ipsrisnn with
i a digestible wm .to at*,
hisy result in a mist in tbe-.heuby atmosphere imaged by condensation of plasticizer vaporized ( .hat'the hot' mixture, and' if the plasticizer is.
upon tats in an extremely severe exposure which bean qualitative similarities to a humart exposure frequent in the blending of plastic mixtures. .They
luted and it */ iay oxidized its oxidation products wilt also be show only that the health hazards.of di(2-ethyl-
njjpiuf^Thfc;
To effect arough practiati,evaluatioaof , hexyl) phthalate in this mixing process are no
cjtrve'repre- ||f?::ifrfei'
O greater than those of some other materials already
ffa^flact wev E^dbpeise
"upon the"
JX"; - . -/* - -___ -'`pWrrife,. 1 1__ ^.(WtBraoa aa Pmnazxa ffxai.-re Hexxxns on rax
Bun or iaasxAsmr n <laboia.de 6 Rare at
>Mi Fokuzd *t Coouno Am, SaTtriATXD with
used without injury to workmen, provided its
cumulative action is no greater.
* *.
,.-f L *
c... ,, .. Straacra Tojoenr^.
Mi deyr
*VS' HSH v.- a
Over a period of 90 days groups of5 male albino <re*Mxww rats weiring 120 to 150'gm. recerted'daily oral
anoM: . doses of di(2-ethyiheiyl) phthalate^; The cbemi0*1 was, administered at levels of-^O^-lJS, 0.75,
Vrateofthe^
Iphtjniajo. vW..,y
> glycol dl(2|ethyl-
Pft&ate*C^FJez^ Hastt'
Kwt>GH)&C iv. A
jy&thylene ^ytoidl(Xethyl-
^Woste);(-Tleiol,*Plastt-.
fc"*" L -
-..S'* , . i
1Anris. 3613a-
; ' - \_ \03T5, and 0.0 per cent mixed ina'diet bfground ' 'f-15 vUiS'-.Swheat, dried milk; and salt. A supplement of liver
was given twice weekly. <
; fr,
30 min.
The amount of diet eaten was determined three r
times a week, sad the rets were weighed weekly
so that a calculation of dosage in terms ofgm./kg. was piosaible. These dosages were 1.9,0.9'0.4,0.2, . . . and - 0.0 respectively. Blood counfli s^re per- M
formed four times, and mkropatbologjcal examine- "
tpeWfcfiunV?
sjmm
pIu
2 tea.
tion was made of heart muade,':ilfver,ykidney, r
;^leca, and testis torn all animals.^
A'
;Ifo tatdied aa a result of the doseic Growth of
rats receiving the three greatest dosages was some- A*
' w.*iwhat retarded when compared with that of the
exposed ^control group. The blood cell county heroogiobht i
a concentrations and differential white' cell counts .
ufi maintained remained normal. The only mkropathology do- ;
fgl^g^whin^bottie. tocted was tubular atrophy and degeneration in
,
toooiti;teteperatUre- before' the testes, resembling senile changes, which be-
.! the ezposure chamber--- This method re-.- curred in ell rats eating the two higher coocen- '
inhalation of amist whoscr concentration is tiations in the diet and in none of the other
same order of magnitude as that of air
Jetoad--
Imt/kgs.: once tbr
be neigh'' different
S^-dwtthvapori at 170* C. and there is ample ..J^ntyfur oxidation products to form in the f- 3^X*a. Theexposure periods ol different groups
` --****.wearranged in a geometrical series with a
ft is obvious that such an .^pnure isgreatlyin excess of thatof human workmen
operating mixing rolls and that it throws no
In summary, a dosage of 0.4 gm./kg./day for 90 days caused no injury to rats beyond somewhat retarded growth while a dosage of 0.2 gm./kg./day caused no injury whatever. It is impossible to translate these data to. human dosages, but it is apparent that di(2-ethylhexyl) phthalate does not possess great cumulative action.
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132 JOURNAL OF INDUSTRIAL HYGIENE AND TOXICOLOGY
ii'syJWB#'
Imitation
ester vapors in air (8), its application to urine &
sodium hyrin
The irritation of di(2-ethylhexyl) phthalate is rendered impracticable by a variety of interfere^
excess of sikz
low, for 0.5 ml. of the undiluted chemical in the materials. Earlier methods for the determination eye of the rabbit produced no necrosis of the of phthalic add in urine depended upon the isofc..
10ml. to-13* Draw off
cornea detectable by fluorescein staining and only tion of the pure compound (4,5). More recently
Kjeldahl flaai
transient congestion of the lids. Upon the rabbit however, the general problem of phthalic ad|
wash water*
skin no congestion or other reaction resulted from a determination has been of interest in connect^
ca. 15 mhj
single application. The plasticizer was applied with the analysis of alkyd resins, and the metlwft,
boiling doic^
undiluted1 to 23 human subjects in the form of devised have been princqwlly gravimetric, with^.i
3 per cent fy
patch tests upon the back, left in contact 7 days . and reapplied on the same spots 10 days later. No erythema or other reaction resulted at any time during this test Accordingly we can say that the sensitising power of this ester is not great.
variety of weighingformsemployed. : Ofthelattn;
we have found the lead salt to be adequate aft^i
conversion to lead sulfate.
, : . ir
A preliminary separation of phthalic add urine is meat readily accomplished by ether extrae.-'- !
precautionSL-.'t , thesolutibtffce
' acidifyitw9b 1 add.<Bri
and; while!
. Metabolism No rise in the urinary excretion of glycuronic
tion. Before each an extraction is feasible, hsf
penriangari
ew, some pretrestment of the urine is requindi _ ` last *ojf | in order to prevent the formation of stable ea|f^ ;rsiitentpmKgp
acid, ethereal sulfate, nor conjugated amino acids sioos. The procedure described fay Folia' * tkm of oxa&bi
wss observed in rabbits and rats after feeding of Flanders (9) dhninates this difficulty withow_-,,,l : fat tbelm^ge
di(2-etby]hexyl} phthalate. These results are in' causing anydestructiorsof phthalic, ackb
Trensfentfie
accord with those of earlier investigators (4, 5). lowing this preliminary separation'the phthsfi^
the centra?tfefa
The absence of these conjugation products of add is precipitated as the lead salt, which is tfam.
the Clauaeh f}
phthalic add coincides with. Quick's theory (6) converted to leadsulfate andweighedafter-ignition.
ether for threjt
that the conjugation process is primarily a mram This latter portion of this determination fbDoag l'*vether"'
of changing- a weak add which the body cannot the method outlined byThamea (tW^ Tfae
boflofft
excrete to a strong , add which it am eliminate; ' plete procedure is as-folloiwarr'`
; ->.4
extract;!
and that strong adds are generally $xcrpted un
Pipette one hundredmLof|urui^(5tt
.toneot
combined. Phthalk add is more highly
* concentrated) into a porcelain- evaporating .
adding
than manddiq add, which is known to be excreted together with 5 mL of JO per cent" sodium 1
phthalic t
readily unconjugated.
idp, and evsporete the nrixturetitf'diyiiess <
10 mV&i]
A relatively large increase in tbe amretion of:,___.. .. ,, Transfer the iwesidueittfa 3001
taking^
fatty adds was found in the urine otrabbftere*"flaakfayme^.M^Si:
ceiving a single oral dosie of 3 gm./kg,oftheester,: foflowing the procedure described by Friedanann- of copper nitrate, a lew
tmanNdj'4 ptbc^ll
(7). From aoocsideratjoa of therab^cf
Jwuflklj
jfanae
distillations^^'iii^^'.add' conton
Ttiss'*,
that at lesst 4(k'pec. eent ismsde .......
chain, adds. than, ^ethyttankv: T8p:vt level af &tty add excretiott waa.
to a 500 mh sqiaiatoty funnel by 50 mL more of water.. The
"iMRfw
ifrcet
several days following the dose. V, ,
** ' .
Quantitative dataon the pbthalate.coirtSb of'; tion suffiae^^monnmi sulfate ^^te i
Initric.addV ' Now place
the urine was obtained on thre*spede
extrsctmacWrih 2S7
' ntahiinftl|
dog, and man, following single oral doses offi(2etbylbexyi) phthalate;. In the case of the rabbit,. at least, it is presumed that this information Is a measure of the intestinal absorption of the ester..
each of washed chloroform;' carded, as they sen's only to remove-benzoic i anda certain amount of coloring matnasL
Extract phthalic acid with four successive 50 aL
idstdutiotn
'Addseveral* f arid td tiffins
the leadphthalab
For the purpose of this investigation it was found portions of aloobd-fatee ethyl ether* The sepsia j of sulfuric add; p
necessary to devise the analytical method which tory funnel may be shaken vigorously as them k orate the nitric;
follows.
v
,i .
^ little tendency to form an emulsion. Combine tin . . tOO ml. of.one p
Estimation or PhthaxatSs in Uhnk
successive pactions of. ether in anntKi-r separatory , Allow to stand'! funnel, and wash once with 50 mL of saturstihj bcmdble, ignite:in
While the fluorescein reaction provides a con sodium chloride. Following this washing, remow lead sulfate. Tt
venient method for the estimation of phthalate the phthalic acid from the ether by extraction will 1 phthalate represei b
ZT, o. J
MiflMSI
TOXICITY OF DI(2-ETHYLHEXYL) PHTHALATE
133
arine is wdium hydroxide solution. It is essential that an lated by multiplying the weight of the precipitate
terferiug 3 eice* of alkali be present in tlii3 step; in general, by the factor 1.2873.
nination ! fflmbtolSml.bfa'lOpercentsohitiottwillsuifice. It has recently been pointed out (11) that lead
h isola- ; i, Di*w off the alkaline phase; into a 100-mi. is unsatisfactory as a precipitant for phthalate in
ttxntly, 1 Kjddahl flask, together with 15 ml to 20 mb of aqueous solutions since the optimum pH value at
lie .add mection
; water and concentrate the entire solution to which phthalate should be determined overlaps k a. 15 mb by boiling. During this process of the pH value at which lead hydroxide forms. Ex
nethods . boiling down, add three portions of' 2 ml. each of periments performed in the course of the present
, with a ,~ 3 per cent hydrogen peroxide at intervals, taking study in which known amounts of potassium add clatter, * '. pwrantihoa to avoid excessive. foaming. When phthalate were added to control samples of rabbit
to after ab Itesehrtinn has been concentratedtosmall volume, urine showed that in the range of 50 to 75 mg. of acidify itwith a minimum amount of 20 N sulfuric phthslic add recoveries by the above method were
ufiom
add. Bring the add solution to near boiling, 2 per cent to 5 per cent high, and with quantities
crime
ind, while hot, treat it with saturated potassium of 100 mgm. the positive error was approximately
pmangsnate solution added dropwhe until the 10 per cent. Despite this uncertainty, the method
availed Stoul-
last drop is just insufficient to
a per- .was considered sufficiently accurate for biochemi
mtentpink color: This step insures the destruc cal use.
fe'Mnd ntfidut-
tion of oxalic acid which otherwise would interfere the lead precipitation.
Rxscms
#!* - Ttansfer the acidified solution quantitatively to Btmutu. Two. adult male subjects swallowed htfialk _tifceetral tube of a small continuous extractor of single doses of 10 gm. and 5 gm. respectiveiy of
iethenv | tie ansen type and extract continuously with di(2-ethylhexyi) phthalate. In the former case
etherior three hours. To the flask containing the this ingestion wu accompanied by mild gastric
tttw extract, add 25 ml. of distilled water, and disturbances and moderate catharsis, while in the
the ether on a water bath. To the aqueous latter instanon no. symptoms: whatsoever were
| C[fi**t, add
henolphthaldn and bring noted. In each instance, phthalate equivalent to
i'ti Mtzality'with 10 per cent sodium hydroxide, approximately 4.5 per cent of the done, was re
*<hfing: one drop in excess. Precipitate the covered from the urine in thesucceeding 24 hours.
PfctiaBc arid from this solution by the addition of The greater portion was excreted between 5 and
10 mtef 10 per emit lead acetate solution con- 7 hours after the dote,
^ **"^10mb of acetic add per 100 mb of solution.
Dtp. T^omalb dogs weighing U2 kgm. and
J? ^^MNS ttond ovem^htj andfilter using What- 10.56 kgm. received single oral doses of 2 gm./kg.
Nx 42 paper and washingjthroe drfour timet of the ester, and daily urine collections were made
w'thcoldwater from the flask onto thefilter. The for three subsequent days. In this period of time,
event-that lead. phthaMte.Crystals adhere "imfla*.dohot attempt to remove,
allow them toremainj^to theyhave been **leai acetate^ Addl0> mb of 1 to nitric acid to the flask, dissolving these crystals.
. * * Ptaa a. 250-ml. beaker beneath the funnel
the larger animal excreted phthalate equivalent to 4.5-per cent of the date, while 2.0 per cent was accounted forinthecaae of the smaller. In each
case, the greatest amount was excreted during the second day after dosing.
Rabbits. The urinary excretion of phthalate wae studied in five adult male albino rabbits (2 to
------------------------and wash the nitric Arin *t*rt*on frm the flask onto the filter paper,
several additionai 5 mb porticos of 1 to 1 nitric
3 kg. in weight) following single oral doee* of 2 gm./kg. of di(2-thylhexyl) phthalate. Urine collections were made for three successive days
the filter in order to complete washing of after dosing, since experience showed that con
i11*0 the beaker. Then add 3 ml. siderable amounts of phthalate were excreted even ufuiic add, predpitating lead sulfate. Evap- on the last day of this period. The largest part of
jqq nitric add completely, and take up in f0 ml, of paxt alcohol and one part water. ^'*io,w I* 5tand 2 hours, filter through a Gooch !*** ignite in a muffle furnace, and weigh the
the dose accounted for in this time was 65.4 per cent in one case, while in another phthalate equiva lent to only 26 per cent of that administered was found. The remaining three animals excreted
amount of di(2-ethylhexyl) phthalate equivalent to 33.8, 43.8, and 40.5 per 7** represented by the lead sulfate is calcu cent of the dose respectively.
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134
JOURNAL-QJE4NDOSTRIAL HYGIENE AND TOXICOLOGY
W 27, it
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Rats. No quantitative data wen gathered on these dosages were fed, all of 10 rats would
this spedes, but considerable amounts of phthalic except in the unlikely case of a strong anUgo^
add wen recovered from the urine of rats fed the ester. It is probable, therefore, that the rat is similar to the rabbit in its inability to metabolize this acid.
between the injurious actions of the two. ever, no unchanged ester was found in the Therefore only pert of the doee of the ester coaty have been absorbed front the digestive tract,
(l) Hobo of 1 Pro 19*
Discussion
in fact phthalate was demonstrated qualitative
in feces.
.
<2> Buss mat
Because study of the metabolism of <(2-thyl- . Appsrnimatdy35percentnsbaorbedbecause bexyl) phthalate has revealed that the eater is only dosage of amixture q acid and alcohol in t}, saponified in the body, o-phthalic add being ex proportions hydrolysis yields, which will kill 59^ creted unchanged and none of the ester appearing cert of the'rate is 7.1 gm./kg. of alcohol taS^.\ in the urine, we have estimated the LDh of the gm./kg. of the add if the two have mdepend^ 4 alcohol and add where administered separately to, joint toxic actions- If there is some degn* $ , rats. It is true that Hodge (1) has reported the association between the toxic actions, the pfnp^i
oral LDn of 2-ethyUwxaaol to be3.2 gm./kg. for' tion of ester absorbed would be somewhat mo* rats, but he used heavy TMwh of mixed sex and The a__v__e__r-ag...e.....r.e....c...o....v. -e--ry of phthalic add isn_ tihe . /
unspecified strain. With many materials we find
tabbita receiving the ester indicated about ft
these factors cause significant differences in the ^ P* t*n* abioiption, which supports the forego^
/I (3) Cars*
%! /Wtt r>W Juvat
aew (9 Ptiax.
WA Bath OS) Qors;
vif
LD,, and therefore decided *to repeat hht work,- *rS'Bnen*' A doaage of 4.6 gm./kg. of ophtB^h
using our90 to 120 gram, maleWister strain- add would kill about 0.01 percent of the rt,,.
white T*ts.>
. , - ' ; >fe. Wng it^ according to-the dosage-mortality jj*
Phthalic; add was administered aa m solution!
the mixed sodiiutt and potaadnmisalt adjusted,!
pH 7,1 ml; equivalent to OLSOgateophthalic i
The etbyihexanol was dispersed n^t pg
"Tergitor' penetrant 7; 1 mil'containing O&Qlg
The resultasre listedbdaw;4'f'
^Our datado not justify projecting the line to *4.' ^ Vraortalitie*, but it is nevertheless apparenttte \
|thalkiadd can have little if any irduert i ' - i toddty .of di(2-ethyiheiyl> phtkfcfe |
t&lsrgdyot entirely due to theafty) ] Etheiqolecule and ft seems Kkefy that even j
4*k
o-phthalic, add, LDw,7J? (7Jto *.4) i
.sbpcLfLli di7JH 2-ethyihexanol, LDw, 7i(5A toShl) ,
- ' Slope4.09 .2.64Jf
-*
MjMoeplastiasm cad be produced by esinith ] jj-rdatwefy strongly kniaed addslike o-phtMtj
tdftoxidtylbwerthan Z^ethjdkcniid j it^nriist^be' tealized that thts aigomat ij
Zr-T-w-M*
di(2-ethylhexyl) phthalafWil.P
'5'
uts with aninuds which<
f ophtiialic add and Hath] ^With spectea which can dhet|||
Mtlcoholand d^lmiritot's
fdk thatof theaddiswii
_pf.phthalic add &om the urme i
froolthwfobner two. Thisfacti* 1
taeqod to that ofrat>abd|
darintii does metabolite the add tef
to that.af the alcohol rather than to* that off add./'fFarther indirect evidence fiat1
iad0t(5). ^v-V` ...
, * .
action lies in the fact that dphthatfehrirfi
Striskan
recovered from the urine of dosed rata and
while more than half of this fatty'add.
,
was of lower molecular weight than 2-cthylheroic
f-fJ experiment of limited scope kss J**! di(2-ethylhexyi). phthalate is a chtjnk*l|
add.
low toxidty and that the health hazards inw
The LD of the ester will produce upon saponiS-** ` in its use at aplastidzer are slight. Suchh
cation 13.0 gm./kg. of phthalic add and 20.4 giro/- 'action as it does exert within the body appws*
kg. of 2-ethylhexanol. The figures listed, above.' be dun to the alkyl part of the molecule nt*
show that if a mixture of the add and aJcohojjij|^than to the phthalate portion.
mm fm
'-K'hr; - VS '
#.1 ucc
041243
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i
TOXICITY OF PK2-ETHYLHEXYL) PHTHALATE
135
would die ratagonisra to,- How-
the1 mine, ester could tract, and alitatively
REFERENCES
(1) Hodck, H. C.: Acute toxicity, for;rata and mice oi lethrihstid end 2-ethyflrexyl phthalate. Proc. Soc. Exper. Biol. & Med, S3: 20-23, 1943.
(2) Buss, C I.: The determination of the dosage. mortality curve from small numbers. Quart.
structure end physiological response. J. BioL Chem, 97V403-419,1932. (7) FUxOfoOuiW, R. E.: The identification and
, quantitative determination of volatile ajoobob and add*. J. Bird Chem, 123:161-183, 1938.
(8) Jacobs, M. B.: Analytical chemistry of industrial'
1
J. Fharm. & PharmacoL, 111 192-216, 1938.
poisons, hszsrds, sod solvents. New York,
because the
(3) Cai.vXX1, H. O.: Safe guarding foods and drugs
518-519, 1941.
oholin the
in wartime. American Scientist, 32: 103-119, (9) Fuux, O, and Fiandus, F. F.i A new method
SO per
19M, and personal communication.
for the determination of hipporic acid in urine.
aland 4.6 dtjpoKknt degree of h^pxopor^
hgt more, i the urine
< >.
.
(4) Jdvaixa, N.: 1st der Bamlkm im ThierkStper zeratarbar. Z. pbytioL chn, 13: 26-31,1889.
<5) Pubkam, E.: Zur Lehre von dm physiologixchen Wirknngen carbocyriischer SSuran. Arch. f. Path . Pham, 51: 372-382,1903L
(6) Qpkx, A. J.: The relationship betwemi chemical
J. BioL Chem., 11: 257-263, 12i (10) Tbakbs, F. C.i Determination ol phthaUe
plastidaenk' Ind. Eng. Chem, Anal Ed, Si 418-419,1936.
(11) Sens, S. B, and Snum, J. F.: Deterarinatioa of phthalate. Ind. Eng. Chem., Ansi. Ed, 10: 416,1944.
4$oUt 42
Sww ct-phthalic
Mfciats re-
AfityJine.
ufentthat
hthaJate. the alkyl that even 'estenfyKphthalic Iheranol. Went is
(Bidi-are ifcthat it h&ctits sdtiJow
4jjjuidr if 9ndtab-
< , win %
s, shown ideal of n-roh'ed
qjttriou* pears to rather
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