Document wDv68gyvgOKm1w6KKxLGDR4qB
REPORT AMENDMENT NO. 1
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TWO YEAR ORAL(DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FM-3924 IN RATS
Experiment No.0281CR0012
The attached
of the Summa
pages
include
revisions
in
the
first
paragraph
on
page
3
The
ry and revisions were
in the third paragraph made to clarify
of
page
22
of
the Discussion.
saldaenniofmiacsanfto,unadltihnoutghhe
that the incidence of benign
hitigwha-sdoosuetsfiedmealetshe whaisstnoorticsatlat1iismtiitc.ally
hepatic
Study Director: AnReenvdineewnetd By:
pAepnpdroevnetd By:
Se-neionoarrdToJx.oincSo4ilb,oignisskS it, B.Ak . 2 Dates
9 Jars0 T R0 iTen, Ph.D.
Diplomate, A.B.T. Research Toxicologist
(02Dva4teF
Tella 1o-ocs DSitpelvoemaVt.e,ElAro.dB,.T.Ph.D. Date
MLaanbaogreart,oPraytAhnoilmoaglyM/eTdoixciicnoelogy and
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Tow rats
iThnhaevbionotgvhercaolnltroilnciadnedncFeM-o3f92h4-etpraetaotceedllu9lraorupsadewniotmhasthaendhicgahr-cdionsoemafsemawlas
vas outside sbserved in
ahisttuomroircailncicdoenntcreol thlaitm,itsw.hileThneotmasjtoartiitsyticoafllnyeospilgansimfsicawnetr,ee
TeoPlastic
endocrine or sites for older
neoplasns was similar
endocrine-sensitive organs rats of this strain. The
which are typical incidence of these
did
not
demonstrate
a
among unique
control and tumor type.
test
article-treated
groups,
ang
Based appearance, Ho years,
on tumor malignancy
ipnactitdeernncse,of ttyupmeosrs oafndtutmhoersf,inaolnsmeotrtatliimtey
of tumor values at
the design aFnMd-3c9o2n4diwtaisonnsotofcotnhissidesrteuddy.to be carcinogenic in the rat under
003985
3.
Parameters that were Progressive over time. to be associated with
These findings wereconsidered
the progressive degenerative changes of naturally
occurring chronic renal disease commonly found in rats of this strain. The primary test article effect occurred in the liver as incre
organ weight (both absolute and ashistopathologic
and
relative),
as
gross
findings
ased at necropsy,
alterations. These changes were observed at the one
tyheear tnweocryoepasry, nebcurtopsshyo.wedThreemahrikgahb-ldyoselitmtalleesPraongdresfseimaolnesonehadyeeasrselater at
equal incidences were more marke
of hepatic
findings,
while
the
mid-
and
ntially low-dose males
dose groups. dly affected than were the females from the corresponding
year.of
Hepatomegalocytosis and hepatocellular increased metabolic activit
vacuolation
are
characteristic
Tesions
may
progress
to
y in the rat. It is recognized that these
cystoid degeneration and, ultimately,
hepatocellular necrosis. was slightly increased
The incidence of hepatic necrosis in this study
rat
rarely
repairs
only in the high-dose males. Since the parenchymal cell Toss with fibrosis or
Tiver
in
the
more typical
cellular reaction
is
scar tissue, a hepatocellular hyperplasia. In this
study, the incidence of high-dose male and fema
hyperplastic
nodules
were
increased
only
in
the
to
the
control
groups
le animals (ie., (ie. 0% and 2%,
10% and 18%, respecti
respectively)
compared
wneortee tsheaetn nion parnoylifoefratthieve hihgehp-atdiocse lersaitosnsaf(tieer. vrheeylcpyee)ir.vpilnaIgstiaFiMsn-o3r9i2m4pnoeroftpoalrnatsioant)eo
Primary liver neoplasms observed consisted of hepatocellular aden
in
this
study
after
two
years
of
these
neoplasms
was
Tow,
omas and carcinomas. The overall with carcinomas occurring in
incidence
and FM-3924 treated groups as follows:
both the control males 6% 4% 2% and 2%; and
females 0%, 6% 0% and 0% for the control, high-, mid- and Tow-dose groups,
arneyspegcrtoiuvpeleyx.cepBtentihgen hhiegpha-tdiocsenefoepmlaalsemss (wiheer.e,adenomas) were not found in
significant,
an
incidence
of
8% was
although not statistically recorded. Considering the chronic
tlhievierr slitfiemulsaptaino,n tnhoetedinciindebnocteh tohfe hheipgaht-idcosneeompallaesiaandapfpeemaarlse gtrooubpes dwuirtihning
reasonable limits group. Combined
with the possible exception of the high-dose malignant and benign incidence values are
female within
003086
2.
reasonable historical control
high-dose females appear to be
limits for the
slightly outside
high-dose
these Ti
mal
mits
e
s wh
only
ile the
becaus
there were no liver tumors seen in the control group.
e
Based on these
findinMgoss,t oFfM-t3h9e24newoapslansomts coobnsseirdveered to be a hepatic carcinogen in the rat.
or endocrine-sensitive
pituit
organs
d in this
including the
study originated
adrenal glands,
from endocrine
mammary gland,
ary, thyroid and uterus. naturally occurring oncog
These are common sites for spontaneous or
specific
fron the
enesis
tcuomnotrrolinciindceindceencien
the
for
in this strain of rat as evidenced by the
ctohnetsreolnegorpoluapsms(seweerTeabnleeit1h9e)r. Deviations
numerically meaningful nor did they
this strain of rat.
involve
a
unique
tumor
type
not
commonly
seen
in
The non-neoplastic evaluation of all of the
findings
reported
from
the histopathologic
mostly
geriatric
lesions
animals typical
scheduled for the for this stra
two year
necropsy
were
which
these
lesions
were
found
included
in of rat. The organs adrenal glands, heart, kid
in
lung, testes, ovaries, thyroid, deviations from the control
urinary bladder
and uterus.
neys, Specific
addressed
in
the
results
incidence seen in FM-3924 section of this report.
treated
groups
were
changes were
incidence of
considered equivocal
nodular hyperplasia of
test article
the adrenal
However, the following related effects. The
increased
(22%)
in
cortex was
the high-dose males compared to the same
significantly
controls (4%), incidence (2%).
while
the
high-dose
female
rats
showed
finding in the a much Tower
the
Lung changes
accumulati
were
also
sporadic
in
occurrence
with
the
incidences
of
on of alveolar macrophages increased in the high-dose males
and females. increased in
The incidence of ovarian a stat
(stromal)
tubular hyperplasia
was
interpretation of thiisstifcianldliyng siisgniufnicceratnatina,ndbudtosae pdoespseinbdleentexmpalnanneart.ion The
rtehlatateidt ewfafsectssecoinndaorlyderto the hepatic changes which may evoke endocrinies
Pghleannodmsenionn.the high-dose femraaltess. coLuilkdewbiesea, mathneifeisntcarteiaosne oifn tuhtiesbriinoelogcyisctailc
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60508;
23.
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