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ni :'. dr'r.is r . r u . > y 1' '.rays et r i e : nauta -.0-,,n, 2 ' Hy e'i ver.- do Ss; levisi 2 nere `rim in ic - v" ranging ir o n 251- mg/kg through 1 5 - 0 . IX-O, 670, l / l , 3CP, ?': , i s o , Lry. 12 t e 1 . 5 mg/kg. S u b s e ru e n tiy ivo co n firm * t o r y t e s t ? v e r
CO'';UC:t I r? first, three rsts received li mg/kg of ole CgArFC and ere killed./
XL days later, y t o sec rod, groupsrf 3 ratr r-ecsivoi 132, 61 , 26. 12, 5.1
2.5 and " ny/kr art vert tiled 11 lays later, The incidence and severity:
of lesions to-.".: at cr rsy ar--- list'. ; in Tal .c- 1- Organ weight data are
present: in Table. 2 to 5.
four rats died wit; i; one Ussy after administration of the 22$0,
150.'./, 100' ar.u 670- mg/kg doses. These deaths were due primarily to injury
to the stomach and intestine, but there war-' secondary effects on the lungs,
brain, and pancreas, post-mortem autoiysis partially obscured the. effects:
of the chemical in these four -instances.
The principle change was in the liver which shoved morphological
deviations and weight changes. The 12 mg/kg dose level appears to be the
transition d^ne for this effect.
HLAB000241
The chemical also produced changes in the kidneys down bo th;s * 0
*
12 mg/kg level, which were accompanied by an increase in weight ab
snu higher.
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U S E P A 16158
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may b--- reit-c* l : no v-rately Vf-re chrv. ic p m -jnc-r.1r.iz it it -sc rats.
Trcrv ch-r
w\ c l >arly bo":-rexa :o :, t ;.3y r*pres-or.i indirect,
effect a of c.enemies!.
Corrn--.:
: e f f e c t ' this chemical or. the liver is jr' special interest
sine:- riniitr flu or:- >.: i aiipi v.ics i ms pr.-deeni p^rs-isi-nt increases
ir. liver weight. It is of in ..'res: *,2 nets ha* the liv r weight was
increased even. a? -,v 1.1 ?.g/k level ir: rasa which had 3 relatively big:,
body veic:'.i a*. ..re start :.i tbs experiment, whereas in rats with the
sUr.-.'.srd initial body weight, liver enlargement was ret noted for A-ses
below 16 mg/kg. Th? same observation applies for the kidney. The weigh*
response of the pencres was more irregular but suggests a dose relation
ship to 2 o-.-yro-, especially in the second confirmatory test (Table 5).
A decisive weight increase tor thw pancreas was demonstrated even at the
low dose of
m y h/ n-s-r .
would seem, therefore., that the pancreas is
more respond::vc to this compound than is thv liver.
` , would be ox interest to sec if the change in liver weight,
progresses, as occurred with AHTM.
/
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"0. Schupefsi' H.DV Pathologist 2-8-62
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U S E P A 16159
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Approved By;
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0 W. Hv SchepsrsP/ M.D Pathologist
2-8-62
USEPA 16160
LSSSND FOR
1
1 Liv-'r - ectena 2. U v s r - pair or Vr - s v r j ah
1 ?. tiv . r - sore
Li';~r ~ lobular mark.;:e procdr-.'.-.:',* 3. Kidneys - to rises sp<.,*V.le<i 6. Kidneys - pals ?. fhyrus - pet.chiarad 8 Lur.gS - odfefft.3
Lu'igc - irreg\:!ar oergesti :r. 10. Lungs - local Jetalect&sia 11. Longs ~ ssnl-consoliJatxon
Ckaraieai gsu trosnteritis xnli. p-.saticni-ir Op. Advanced autolysis D'-,. Hem.,rrhaxit gastritic K*. Killed
a. D if fu s e - congestion of ung b. Hyperinflation of lur.g c. Subpleural plaques ++* (lung;; a. Adrenals: pals c. Spleen: enlarged f . Fer.crsas: pain
g., Brain: congested and sd-wstous
+ ~ Slight m.action +* ~ Moclerets reeccior. +* - Harked reaction
Preps red By:
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carl sohr:son s p.V.K,
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Approved Eyj
G. W, [, ''SchepeFs, -83157" Pathologist
2-S-62
HLAB000244
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TABLES' 3"5
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.nskell No: 3035
Kfeterial: AmMonium Periluorocaprylate ___________
&<eipisn't; .,.,
MB No: 6>0Ii Species: Male CROP Rats Test: Oral - i. do-:<: .11 mg/lcg -<eport No: P~62~I?2Experiment Period:
Procedure;____ ?.I. B.G.
.
Prosectorsr ~'yYSr*s ~r *"*!s
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iroup Animal vival. Body Weight Age
tua <LiNo, Days Init. Final Days
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141693
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Averag 3 Hi Centre L
333 li03 30C 363 325 6.0$
319 390
390
1,02 1 ,1 8 1.83 1.02 1.96 l.li3
1.8? 1.21
2,02 1.25
2.36 1.6S 1.62
1.82
1.55
1?.<1 l!:.03 16u3
16.52
li.5i
0.63 v ?3 0.68
0.68
l.?6 1.38 1,72
1.62
1.76
0.88 3-25 3.08 .053 0 .8? i
0 .6 1 3 .2 2 . 3.68 0,,?6 3.3'? 2 .73
y.?5 3-28 3.08
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USEPA 16163
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USEPA 16167
SUBACUTE ORAL TOXICITY TESI
HASKELL NO. 3 0 E E MATERIAL
DPT, .'V>-.v<. , ANIMAL V.> ..;3
CODE HQ, c- u Q?r-.,,,..... HT.- te O J i
SEX STRAIN V
30QK.,,,0,,^,.,X...,, PAGE-.Lk-- --
Vr,, ALP
V~K
ag/Rg
Material given fey stomach tube -or
Dot- or as a
0 *>
solution
of -active-tegredrene>~ ^
" -suspension
original saraplo
C--V. .
DOSE k-'i
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NO, TREATMENTS I0
MORTALITY RATIO o l.k
WEIGHT RECORD
* ca >-1
D ate Say Tr.K o.
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Anlisa i Number
V-;ifht of- Animals {g ra tis)
FATE OF ANIMALS
i -;. D ,S
3 il ij. & t I L in a 'Eoa 303 DAS
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' Investigator
DBHtemh 11- 10-60
EST COPY AVAILABLE
000032
' ' v V V
U S E P A 16168
Clinical Signs of Toxicity
Treatment Period
First V?eeki Five oral 6.7 mg/kg coses of H# 3035 administered over a one week period produced no clinical signs of toxicity in all the treated animals.
Second Week;
7 rr/ka dm ses of H# 303? administered during; the second
.'sek produced nc clinical signs of toxicity in nil the treated animals,
Observation Period
First Week; Three of the rats were sacrificed four hours after the tenth treatment, The remaining three animals exhibited no clinical sign? of toxicity.
Second Week; T remaining three animals exhibited no clinical signs of toxicity during the second we of observation,
Summary and Conclusion
Clinical
H# 3035 produced no observable clinical signs of toxicity during the treatment or observation period. i. Conclusion: Based upon its effect upon weight gain, Ammonium, Ferfiuorocsprylate is not considered cumulatively coxic,
::
HLAB000252
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U S E P A 16169
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liinnnninis
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p<vlv `.-Jt
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303
305
Liver 't.
8fT:<... 19.9 IS.00
18.25
14 Dsvs After. 10th Tr..
364 PI.60 402 20.80 377 18.84
Livor Wt
Bouy Vt.
x
0*vf .y
e/.*/;* 5.99
100
5.93
5.52
4.69
Control Group
14 Ssvs After IQth Tr, 196 16-10 354 14,95 375 13.63
4/^7
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4.7 4.04 4,84
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*AM''M'..O...N...I...U. .M.......P~ERfLUOHOCArRYLiU'E (CoAP.F...C..)..I.. HR-c-04 - I/pOpp - P-oS-l/p
SUMMARY
Administration of ten successive doses of 6.V mg/Kg to six rats caused"moderate enlargement of the liver and slight enlargement of the kidneys, adrenals and testes. Simultaneously t-neru was slight depression of pancreatic weight and the lungs of the rats shoved slightly enhanced pneumonitis.
GWKS /ah
2-9-62
V
, W. K, Scnepers, M.D. Pathologist
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U S E P A 16171
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HcPi-h It !-gftrt?jjRS k r K J '. l Z (CgAlTC) (t -U;;
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Activ.- Following fiey-.-aten Oral Adair.Iutrsoior. K -;le CBCD R at
HR-6 It - . - y . `$5 ~ f'~6?~iV3
;i'f. oherr.ical was admir.istered by inirsgarcric intubation as
:n &4U'> I >"h-.-o. Haeh of 6 rats received 10 dailycbses of .7 mg/kg
v/--.r u parivi vf -2 days. Three rat.: were killed I; hours after receiving
U.e If'.1.
ar.v the remslnder were killed lit days later. 1% ardpsed
rit" served us controls. Tr -- ir.ct-ser.ts ar.i severity t? lesions are supplied
'%#
m.
m. ;y
.r V-.
*1-
a:.- fable 1 ar:; organ weights are presented tr. fables 2 3mi 3-
As could be t'-edieted fro~. the erperirtsrs with single doses
.ihn.
(Report 2-172) -he . :ot prominent eli';ct of the chemical again wee e:> Urgenenx of the liver., which, at the e-.d of the dosage regimen* was about i5i heav.1 er than the average liver nought of the control rets. This change
r./Hr;--r-' t:
persisted -Tier c'-.sootier, of dosage, l..-, the weight discrepancy was -sems-
what less since I k days later the livers were only 20% heavier than tecs*
of control rats. The ircrcas" in liver sloe woe accompanied by slight
Piccolo ration in one rat in the- group .-.illed after the 10th dose and in one
in the group killed IJj nays Xatsr,
The renal weights were 20% heavier than those of the corresponding-
control rats, and this increase persisted after cessation of dosage, being
22% above that of the control rats l h days later. These weight changes
were not accompanied by morphological changes,
-;
The pancreatic weights we< a slightly depressed, being-j8$ and
12% lower than those of controls at the end of the test and rbc|wei|f
f -*
'
* * ',05* ^
'
nhasecIrrespectively,
The adrenals and testes were slightly* in^rsasPdh
best co py available 000036 . -. ihy'f
SEPA 16172
P-t2" ,?3
in weight after the las; doae, +lU% and +ili>, respectively, lot returned tv- normal i t y 1U days later. Coirmene
)o is not clear why a deve of 6,7 mg''kg was s-decte-l for this repeats-t ;osage exp orir.c-r.t Surre deci civ liver injury was d^x.strciLiV far feature rats after a single dose of 1.5 mg/kg How r.r, the experimen- served she purpose of shoving that cumula tit a liver., kidney and pancreatic changes can be induced in young rats by relatively low doses o f CQAPeC.
It m y be worthwhile to extend the test to include rats killed
at 30* 60, and 90 days after dosage, to detamina the remote consequence;
of the various organ chances.
CJiiofs
2-7-62
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BEST COPY AVAILABLE
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bKas }fel 3035 Materials'Aamsons Bcrfluoroc.spiylate
*Excipients.`^WwewotMetasiiji;iw--iw,,W*3
Mo s 60I4 . Test ; Oral Repeated DogagcSpdi'fes: Male CROP Rats -<k Procedure ; .Gastric
Hos P~62~l?3 Expfersiorit fetibds 11-26-61, ~ 12~226l .
T.i. ...s,*..: ;
(iroup ftos
mg/kg ...X . 10......
& n$ Ko.
rV ival Pse rf
t e s t { ,:A 'iie r Death
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.K
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50006
12
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Commentt 1 , Liver polo or brownish
2. Lungs irregular congestion 3- Langs focal detelectasia h , Lungs subplouro! plaques
5. Lungs mediastinal lymph nodes enlarged + - Slight reaction
:-+ =1 Moderate reaction
+ ;+ -. Marked reaction
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IfydronePhrosis. bilateral.+.*._ - ^V,.w ^
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2~?~62
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ORGAN HEIGHTS
:ia-iKell No;^
Material: Controls for H-.3035 & 3036
MR So: 6dt Species: Male
Rats Test: (Control) - Subacute
Report Ho: P ~62~l?l>>geriiaent Period:
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USEPA 16175
USE?A 16176
A ACUTE oral t o x i c i t y t e s t
MATERIAL
MR- U> i DEPT. \ .- ,.
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Solid
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HASH. NO, g?,". DENSITY
Solution C } g r a s /lO ml C }
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{ 5 gma/100 p is ( ) In
Powder { ) ml/100 ml { )
>S V'S^j utv!
Material fivers by stomach tube -er-- by^
tO/r* O: -Ln -origdriefeL
-orm~on- as a &.\ '~ solution of -aot-ivo-I'ngred'ien-to- in
miseon-s-l-oer
original sarvpie
,,
TnTnaT D ate Number
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ilt Dose D ose
i eight Cnange
{TT;i }
(xng/kg ) S o l
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U S E P A 161'
cis'
m i S C T STOPIBS OP ?HK5Rft3A%aOM SaSpgag.M AQgffgS Hc^c^ %,*refr Project fea gtrgg ad 10-0-1
<vj\'&i>j>r-&A/-~ '>^
Amoni'aa ^rfluorosaprylate {C^FS)# tmmxwm '5?dfto&eyadBcafltis*o~
nonaheate (CjFDA) and ewoiua~3#^^ox^2jfS^{tapiriu<awaBtfcyl>~undscafluoy~
donanosto (AB?) ars diapcrsing agente usai in tho polynsrlasiinn uf
tatrafluoroethyls. In acut toxicity studies with these etmp&xmdat ih most
striking abnormality in asinai surviving a stagi subisti! dosa m s gross
snlsrgemnt of the liver. A stallar but lese nsrkad effect ras observed in
rabbits that had absorbed AHI through the skin,
The preliriosry espsrtasnta reported hers era designed to m asure -som of the biochunieal ebsngns that accm pm ^ the aeeelsrated growth of ret
J
liver? to dsiersnins uhethsr functional istf&iraeut oi the liver occurs ss mil?
l3 hatiier there is a species differ in rcaceptibility, ihe liver function
studies isesy undertaken to find suns sitatesi laboratory procedure timi night be
useful to dica! supervision ta detecting f^uoroesrben liver injury. The
latter phase of the work m s supported by the Plastics BepartEsesrt under Hsdlcai
Research Project Ho. MR*63?
1 D035
Procedure Three Rale beagles fron the stock &otot%? were given a single oral
dead-of AHT,.,equivalent te h 6* or 9 ag/kg* Staples of blood -vero taken at
^request- tabenvals fcr thro m s k s and then eee&ly thereafter untii th timls
i^j^feerifined or given is additional does of the cebspound* Four ether seals
$.- .,
a*jtei*,iira s single ersi dose of either OgPDA or CfPDA* er
qUiv.
jTisttitb ]$Q 8,4 asd-e- tastier erta of aasesardenata ade>
.i'V'bfj ^l^fcsSyf
m % 'V-s
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. . ' . ' W ' beaart# 4te^qnc4wmb * rspeited Idl^jsithr.a it#??-
t<V*-*~</-;*>
03ag$&g) nf this dispsetaing- *$i, The isd* de|S that
Sv.
!&
m pm rn ia the C ^ A w give an additional oral dose*
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changea hepta to ecear
one fiar -se dose iss administered
0819 i VVI3SO
HLAB00263
normal range. The depression of the plasma cholesterol occurred, more
slowly# hut there ras no evidence of a return to normal after three weeks.
Bilirubinaria wee also observed.
With the lower dose of the CgFBA (30f> of ret lethal dose) the
transaminases were elevated in both dogs within k& hours and continued to
rise daring the first week after the exposure, Thereafter there was e
return to normal, The dog that appeared to have retained the largest
portion of the dose showed the greatest effect. The .Fase was also elevated
in this dog and paralleled the OPT. The cholesterol was normal or only
slightly elevated within on week after the treatment. There was no effect
on tha blood sugar and a decrease in any!age activity. lh..n a higher dose
of this compound was administered (2/3 of the rat lethal dse) ail of the
ensymes measured were markedly elevated within 2h to h8 hours. The greatest
changes occurred in the QFT and ICBH. There was no change in the plasma
cnolesterol. Both animals expired within IS hours after dosing.
With a doss of the CoFBA equivalent to 30^ of the rat lethal dose#
elevated values of all enaymas measured occurred within hS hours in one of the
two dogs exposed. These returned to the normal range within seven to tan
days The plasma cholesterol m s normal or only slightly elevated after after
one week. The other dog showed ho effect from the treatment. At the higher-
dose (2j$ of the rat lethal dose) of this compound,tha more snsnsptible-dog
again shewed a rise in GOT and OPT during the first k & hours and a Saturn'to.
normal within two weeks. There wn& a slight rise in APa-sa end. d^ithe^piafe:
cholesterol. Similar# but less marked changes occurred In the nih^-4pjg. '
The -amylase activity wss lower than aarmai daring the
&8'aHMyrora1**?**-',
rise did occur during the week following the esposer*.
in the blood sugarci this tinse Within
maaurements were normal.
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rat aara eoaasted with only &m of the
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rats ware still quite large* sithough thj wsre app&restlj m longer growing
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months thsre was less difference feetwsm control end AET~trsated rats* suggesting either a decrease in the sise of the cells or m lacrosse is saltests.
The results reported seem to indicate that the liver of rats stimulated by a single oral dose of AKT undergo alteration Is their bio
chemical behavior and metabolim durimg the period of rapid growth. Later*
when the accelerated growth has slowed down or ceased* the biochemical
aberrations also rnd to disappear. The greatest changes occur during the first few weeks or month after the expomir%> By the end of t m months sees evidence of a reversal of these effects Is already apparent? between five and six months recovery of the organ is virtually complete. 2. Regenerating end Degenerating Liver
Procedure; Regenerating liver tissue was induced by partial
hepetectpmy C<O~?0$) in six male rats from the stock colony. Forty-eight
hours after the operation a single oral dose of AHT* equivalent to 12 mg/kg
body weight was administered by intubation. Fourteen days later ths animals
were sacrificed, the livers removed* weighed and analysed. The experiment
was repeated a second tine* reversing the procedure by performing the partial
hepateciomy forty-eight hours after ths dose of AKT had been administered.
Degenerating liver tissue was induced chemically by administering*
intraperitooeally* A,1 ml of carbon tetrachloride per 100 gm of body weight
to rats h 8 hours after intubating them with 12 mg/kg of 1HT, Abimale-which
received only carbon tetrachloride served as controls.
Results i The results are sastasfieed in fable 3i*
produced m accelerated growth of the liver tissue far s&fchiib
:,
A- or marly sll of ths tissue-wee restored. The OTA* WjkxA
than in normal tissue.
rr AHf daiiaed :n accelerated growth -of*^he Myef
than twice normal
K,
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USEPA 6185
seelrat>ed growth that occurred b nomai tissue after treatment uith AHT.
HLB000269
USEPA 16186
-10dogs. Liver enlargernant occurs In rats but. In dogs, hypocboleateroleicie is the rest unusual fh ding, it would be useful to investigate these in several other species -- mice, guinea pigs, rabbits, The cesdslned effect of carbon tetrachloride end Ah! rtoy be of practical significance since such mliiple exposures could conceivably be experienced by personnel handling AB'f. Further study of this problem is recommended,
USE? A 16187
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EXPCBRE TO FLDOBOCHBOM D3H8B3im ASSETS'
C holestrol
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133 66 69 6? 86
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2cedure?
S in g le o r a l 12 mg/kg doses o f H# 3035 were given to th reo { 3 ) r a t s , which observed f o r 14 d 3;.?s and s a c r if ic e d .- T his procedure was sp ie le d sc s to en ab le in v e s tis & te rs t o compare r e s u l t s w ith e t h e r d is p e r s in g ag en ts ad m in istered in a s im ila r r&nner*. :
3jgig&l H# 3035 given in single oral 12 mg/k^ doses produced no clinical signs of toxicity,
gonciusion
H# 3035 may be considered relatively harmless when administered to rats in ninftle oral doses of 12 mg/kg, having produced no clinical signs of toxicity.
Hat No,
49685 49686' 49693
Table of Liver Weights
Body Wt,
sr..
Liver Wt,
m.
403 17.51 363 14,03 05 18,03
Liver Wt. x : _..Body Wt.......
4,343.86 4.45
HLAB00274
USEPA 16191
