TRL STUDY 0032-006
Conducted for:
RESEARCH TRIABLE INSTITUTE
P.O. Bex 12194
Research Triangle Park* North-Carol1na 27709
by:
TOXICITY RESEARCH LABORATORIES. LTD.
510 West Hacklcy Avenue
Nuskegon. Michigan 49444
Rat Oral Subchronle Toxlclty Study
Compound:
Normal Butanol
Start of Test (pretreatoent): August 19.. 1985
Interim Necropsy: Oct^r'7;and,8.;1985,
Final Necropsy: NB*^r;25;iiid; 26.:i985
-------
CODING FORM FOR SRG INDEXING
Microfiche No.
OTSO531O3S
'" - •""
".:," -.V-,;
,. ,'•-' ',<-.- ;"•'
-.• -i' - .'.
Submitting Organlzition
RESEflRCH TRIflNBLE INST
Contractor
TOXICITY RESEnRCH LOBORttTORIES
Document Title |
ROT ORflL SUBCHRONIC TOXJCITY STUDY (DRRFT)
Chemical* Catogory.
N-BUTONDL
-------
T8L Study 1032^006
The purpose of the study was *e evaluate the toxic Ity of normalfcutanol ,.
In • rat subchronlc toxlclty study.
f
Four groups of Mlc and finale rats (30/sex/group) were dosed orally
once dally with 6. 30. 125. or 500 ag/kg/day of compound for 6 weeks
Miit 11 the day of the Interim necropsy. After the Interim sacrifice, §11
surviving rats were dosed dally until the final sacrifice. Body weights
and food consumption were recorded weekly and the rats were observed at
least twice dally for aortal 1ty and evert .signs of toxlclty. Ophthalmo-
loglc examinations were done during the pretreataent period and again
during week 13. Blood end urine for ellhlcopathologlc valuation were
collected from a fifth group of 10 rats/sex prior to initiation of
dosing, from all surviving rats scheduled for the,1nter1m sacrifice, and.
from the first 10 rats/sex/group at the final sacrifice. The first iq
•ale and 10 female rats from each group were scheduled for necropsy on
day 43 or 44 and all remaining rats oh day 92 or; 93. -ififoss -pVstiijortem
examinations were done on all rats. Organ weights- were taken^fron rats
sacrificed on day 92 or 93. Aftar the}. filial sacriflcei. a; cdmpjete
Mstopatholcglc wamlnatlon was doiie on all rats in the Control:, .land
high-dose groups, en livers. Mdney.s, e*d hearts from: the low- and nld^
dose groups. .and en all gross lesions. In addition, a 'Mstopathoroglc
examination was done en any. rat fpund/toad: er:tacr1f1cad.r1n'ce«tce)nls;;
The .only une i|i1 vojcaj , ef f ectt; Produced 7Dy.;fH)nnaKbuttnol :wer^ ^ttx1aland;
-------
TRL Study §032-006 - « •
at the 100 ag/kg/day dose level. The aaxlBum weekly Inci-
dence was 32X end 291, respectively, but ataxla OF hyj»ac1t1v1ty were
not Been as trttatoent-related signs until the final six weeks of the
study. Wo treataent- related clinical signs were seen at the 30 or the
125 Eg/ kg/day dose level.
Sody ealght «nd food consumption values were similar for control and
all treated groups. Elo treataent- related effect was observed at the
ophthalnoscopk examinations or In gross or alcroscoplc evaluation of
the tissues.
Three rats were found dead or sacrificed In extremis, but these deaths
were wot due to administration of the noraal bwtanol .
At the Interim clinical pathologic evaluation, red blood cell count
(RBC), packed cell volume (PCV). and hsneglobln (MSB) averages of the
§00 f»B/ka/day *»« group feaales ware SS below control averages.
Although these differences were statistically significant, they were
small and no differences between the parameters were observed 1n the
sales ef the Interla evaluation or between control and treated groups
®f either sex at the final evaluation. Therefore, even 1f the lower red
blood cell parameters 1n the 500 eg/kg/day fesaales were an actual treat-
»sm> related affect, 1t was stall end transitory.
CONCLUSION
Oral ©dBlnlstretlen ef woraal batanol at 500 ag/kg/day poduced ataxla
-------
TRL Study 0032-006 - 111 - DRAFT
and Hypoectlvlty at a ofixloun weekly Incidence rate of 32 and 29X,
respectively. A sUflhtly (5J) 1:-er (conparad to controls) red blood
sell eeynt (RBC), packed cell »olune (PCV). and heaoglobln (IGB) concen-
tration j^e&ent 1n the 500 eg/kB/day *se trouP Resale* at the Interim
evaluation anly isay have teen treataent^felated.
eio treatwent-related aifect nas ooserved at the 30 BB/*fl/
-------
TRL Study #032-006
Table of Contents
I Introduction [[[ *
U Methods
A Test Material [[[ J
B Animals and Husbandry «.««••«•••••••««••«*•«•••*•«••*«'•«••••••••••• Z
C Compound Administration ....••.•••.••.....•••••••.••••.•••••••••'r.« 3
D Clinical Observations .............................................. J
E Qphthal wol ogy ............................. • ....................... • *
F Clinical Pathology ................................................. *
6 fecropsy ,.«••••.••••••••••••••»••••••»••••••••••••••••••••••••••••• •
H Histology [[[ f
I Statistics [[[ f
J Data Retention ........................ . ............................ »
HI Results
A Test Material [[[ f
B Clinical Signs ...... .. ............... • ............................. »
C Body Weight* Weight Change and Food Consumption .................... 10
0 Ophthalmology ...... ••••••••••••••••••••• ..... •••••••••••• ........ •• 10
E Clinical Pathology ................................................. }*
F Observations at Necropsy .........•...•••••••••*••«••••• ........ •••• 12
6 Organ Heights [[[ \*
H Mlstopathology [[[ l3
IV D1«eyss1on [[[
V Conclusion .. ................... • ........... ».tt« ................. ••••• 15
VI References [[[ l6
VII Tables
Table 1 Incidence of Clinical Signs ....... • ......................... 17
Table 2 firoup Mean Body Height, Height Change end
Food Consumption «e«.«.»<>eoBo.«.«..«o.e»««»««««»«»«««»»«' 20
Table 3 Msnatolegy Suaaary •••••••• .............................. •••• ||
Table 4 Serua Chonlitry Susanary eo» ..... eo.e«*. ..... e« ....... • ....... 91
Table 5 Hffliatology Values ............. •••••§«• ..... «••!••••••• ...... 37
-------
TRL Study 0032-006
DRAFT
Appendix A Compound Assay Results
Appendix B Ophthalnologlc Evaluation
Appendix C Clinical Pathology Methodology
Appendix D Individual Rat Reports (Cross and H1stop»tholeg1c)
Appendix E H1stoaccountab1l1ty Report
Appendix F Protocol find Amendments.
Appendix G QAU Statement
-------
TRL Study 0032-006 • I •
DRAFT
I Introduction
The purpose of this study «* *> evaluate the toxlclty of noraal
feutanol 1n a «t subchronlc toxldty study. In order to assess the
tox1colo01c potential sifter both 6 weeks and 13 weeks of tfoslng, an
mttrta sacrifice at the 6 week Interval MS Included.8 The oral
route of administration was used because this Is the probable route of
human exposure.
This study was conducted 1n accordance with the protocol (Appendix F),
the Standard Operating Procedures of Toxklty Research Laboratories
(TRL) and 1n compliance with 6ood Laboratory Practice Regulations for
•oncllnleal Laboratory Studies.1* Procedures pertinent to this study
ere described herein.
II Methods
A. Test Material
Normal butanol (lot* 3597 KVVE) was purchased from toerlcan
Scientific Products, Romulus, Michigan. Samples of each dose concen-
tration were saved during weeks 1. 4, 6. 10. wd 13 «nd taken to the
ttoskegon County Hastewater Treatment Facility for chemical analysis at
the laboratory ywter the direction of Or. Avi Joshl, Physical Chemist.
Duplicate staples were Mrt to Mr. John Maney. ERCO, a division of
Enseco, Inc.. IBS Alwlf* Brook Parkway, Cambridge,'Massachusetts for
referee analysis.
Protocol Change 04. effective »/10/B5.
Federal Register, Vol. «3, ft. M7. Pitt II, tecember 22, 1978.
pp. S99B6-60020.
-------
TRL Study W32-006 - 2 -
DRAFT
B. Animals and Husbandry
The rat was chosen as a test system because of Us established useful-
ness 1n toxlcologlc studies end as a pharmacologle asodel. One
hundred-fifty three Bale end one hundred-forty seven female rats* (45-
55 grains) aged 22-23 days Arrived en August 12. 1985 and were housed
Individually 1n wire-bottom cagesb. Filtered oinlclpal water0 and
Purina Certified Rodent Laboratory Chow** were available ad libitum.
This feed has been tested by the ranufacturer for contaminants, none
of which were present at levels that would be expected to affect the
outcome of the study. An declination period of 7 days prior to the
pretreafenent week was si lowed. During the acclimation period, the
rats were observed with respect to general health and any rat with
evidence of disease or physical abnormality was discarded. A
clean/dirt^ corridor system was In effect. Room air was filtered and
humidity (average 47.6X. * 9.2) and temperature (average 70.2°F. t
2.2) controlled. The temperature value was calculated using the
dally high and low value. *1 standard deviation. One value per day
was used to calculate the humidity average. A 12 hour Ughf.lZ hour
dark cycle was controlled automatically.
Charles,, River Breeding Laboratories. Inc.. Portage. Michigan,
Crl: CDR(SD)BR.
Rats were housed In accordance with recommendations contained In
BHEH Publication No. 78-23 (WIH): Revised W78. B6u1de for the
Care and Use of Laboratory AnlMls." During the acclimation
period the rats ©ere boused 3/eage.
Mater used at TRL analyzed periodically for the presence of
contaminants as defined by the Snvlrwaental Protection Agency
•national Interim Prleary Drinking Mater Regulations11 Code
af Federal Regulation. Title 4C~Protect1on of Environment Part
l4i.ll (B) end 141.11. Records retained at TRL.
Let 0s §tay02-85-3E, Aug01-B5-2E. Aug07-85-lB. AuglO-B5-2D.
Aug2l-|5-$D. Purina Lab Chow-12T, Checkerboard Stpare. St.Louls.
Gn\ £31Bo.
-------
TRL Study #032-006 - 3 -
The first day of the pretreatment week was August 19. 1985. At the
Initiation of the pretreetoent week the rats were assigned randomly to
/
groups (30 rets/m/group end a fifth group of 10/sex) using a
computer printout.8 The rats were Individually Identified by toe
clipping.
£. Compound Administration
Administration of the test ooterlal began on August 26. 1985. The
rats scheduled for the Interim sacrifice were dosed dally for 42 or 43
days and the rats scheduled for the final sacrifice were dosed dally
for 91 or 92 days.
Normal Butanol Animal Numbers
Croup (e«/kq/day) Male Female
—_e interim Final Interim final
I 0 001-010 OTP530 031-040 04TB60
II 30 061-070 071-090 091-100 101-120
III 125 121-130 131-150 151-160 161-180
IV 500 181-190 191-210 211-220 221-240
V Baseline 241-250 251-260
The amounts administered were based on Individual weekly body weight
values. Fresh solutions of the compound (In delonlzed water) were
prepared weekly and dosed orally at a volume of 10 ml/kg. Controls
received delonlzed water at the sane volume. A plastic syringe and an
18 gauge ball»t1pped seta! dosing cannula ensheathed 1n a number 8
French catheter were used to administer the solution.
8 Randomization printout programed by Dr. John Quiring. Associate
Professor of Natheaatlcs end Computer Science. Department of
Hathsnatlcs and Computer Science, Brand Valley State Colleges,
Allendale. ttlchlgan.
-------
TRL Study 0032-006 - 4 -
DRAFT
D. Clinical Observations
Body mights and food consumptions were recorded weekly and the rats
were observed at least twice dally for BortaWy and clinical effects.
E. Ophthalmology
All rats received an ophthainoseoplc examination during the pretreat-
rent period and week 13 by a veterinary ophthalmologist*.
Ophthalmolealc examinations were conducted on all rats 1n a darkened
room «1th an indirect ophthalmoscope. Seven rats that had an eye
lesion during the pretreataent period were not Included In the study.
F. Clinical Pathology
1. Sampling
Blood and urine samples were collected from the 10 sale and 10 female
rats 1n group V prior to Initiation of dosing. Blood was obtained at
the time of necropsy from all surviving rats scheduled for the Interim
sacrifice and from the first ten rats/sex/group at the final sacri-
fice. Urine MS collected In eetabollsm cages 3-5 days prior to the
scheduled sacrifices. The rats were anesthetized with C02, the
thoracic cavity was opened and blood was collected by cardiac punc-
ture. A necropsy was then done on each of these rats (except those
1n group V) end the tissues preserved.
* Exams perforeed by M. F. teller. O.V.M.. M.S. end
Diplomats, taeHcan College »f Veterinary Ophthalmologists,
Hlchlgan State University. East Lansing. Michigan.
-------
TRL Study 0032-006 - 5 -
DRAFT
2. Tests Par-formed
The following tests* were performed:
.
Hemoglobin (HCH). Been cell honoglobln concentration
(MCHC). total and differential leucocyte counts (WBC),
estlnated platelet count (PIT).
ChBHstry; eUallne phosphatase (AU Jjos), Mood I urea nitrogen
(BUN), plutonate Rrruvate transaminase I»PT;.
' aOT. lucose
,
I'utiMta oxelecetate JTMHMIMM iaOT). glucose
[Glue), total protein (TP). albumin (Mb). »/6 ratio
(calculated), fllobulln (calculated). toU bll rubln
(Tot. bill.), wdlua (Ma), potassium (K), chlorldg
(Cl). calcium (Ca).11 inorganic phosphate (FJoi)i
carbon dioxide (TC02), total «enw cholesterol (Choi).
creatlnlne.
»pedf1c gravity, glucose, protein,
urobHlnogen. »1croscopy of *ed1ment.
6. Hecropsy
K necropsy was perfortneii on all wrvlvlng rats of the first 10 males
and 10 females from each dose group on day 43 or 44 of the study. On
days 92 or 93 the remaining rats were necropsled. Rats found dead
*ere also necropsled. Interim and final sacrifice rats were anesthe-
tized with 002 and exsanguinated by cardiac puncture. The cranial.
thoracic and pzrltoneal cavities were opened and the contents examined
aweroscoplcally. The organs and tissues listed 1n section H were
reaoved from each eMul and preserved. Lungs were Inflated with
foraaHn via the trachea. t>es with attached optic nerve from all
* See Appendix C for clinical pathology aethodology.
* Protocol Change II. tffectlve 8/15/85; Protocol Change «,
effective B/13/85.
e Protocol Change «4, affective 9/10/85.
-------
Tfc. Study 0032-006 - 6 - _. ^ m
DRAFT
rats Ml led at the Interim and final sacrifices were preserved In a
oodlfled Zenker'K fixative. The testes with attached ep1d1dym1des
from all rale pats were preserved 1n Bouln's fixative. All other
tissues were preserved 1n 10< neutral-buffered foraalln. Feet were
preserved vlth the tissues for positive Identification of the rat.
Prior to fixation at the final sacrifice only,8 the following organs
ttere weighed: brain, heart, liver, spleen, kidneys, testes with
ep1d1dym1des. and ovaries. After fixation, the adrenals and thyroids
01 th parathyroids were weighed.* For paired organs, the organ weight
was the combined weight of right and left cambers of the pair. Organ/
body weight ratios were determined for each tissue. No organ weights
were taken on rats found dead.
H. Histology
The full tissue microscopic examination listed below was done on the
control and high-dose rats, en one rat sacrificed 1n extremis, and on
those found dead. Also, livers, hearts, and kidneys of low- end w1d-
dose rats, and all gross Isslons seen at necropsy were examined
Blcroscoplcally.
As tissues were trlensd. the presence or absence of tissues and
lesions «as noted. The tissues were placed in Tissue Tek®6 cassettes
that Mere labeled with study number, rat number and the cassette
Protocol Change #4. effective 9/10/85.
Lab Tek Division, Miles Laboratories, Inc., NipinrlUe, XL 60MO.
-------
TRL Study W32-006
- 7 -
number. Th«y were then processed on a Fisher Scientific H1stomat1c®a
or an AO TP/BOod?6 After processing, the tissues were embedded 1n
paraffin using a Tissue T«k*«snbedd1ng system. They were sectioned at
6-6 alcrons, aounted on nuabertd slides and italned with hewtoxylln
and eosln.
The following tissues were placed on sequentially numbered slides as
follows:
Slide Number
I
I
2
2
2
3
S
s
6
7
1
8
9
Tissue
heart and attached aorta (a longitudinal section)
lung* (Actions from the caudal and left lobes)
trachea (a cross-section)
t nonglandular .sofhage.l are.
through tXe area of the cardiac glands Into the area of the
f Sndll fllands end another wctlon from the duodenum throuoh
the pylorlc sphincter Into the area of the pylorlc glands)
salivary glands (sections of the subllngual and »and1bular
8MllS1ntest1nes (a separate cross-section of the duodenum.
jejunum and 1l0un)
colon (a cross-section)
liver (sections from the left and right lobes)
pancreas (a separate section 1n addition to sections
cwunonly. attached to the viscera)
spleen (a cross-section)
«•
adrenal)
ewl attached «pt1e ftsrve)
thyroids snd |«i-athyro1ds e
tlSreelc spinal eerd (a erws-sectlra)
liaabar spinal cord (a cross-section)
fisher Scientific Products. SM01 Industrial Road. Livonia. MI
68150.
fesrlcen Optical Scientific XnstnB*nts Division, lutfalo. W
14215.
-------
TRL Study #032-006
-•- DRAFT
Tissue
g tt -M. «M*MM- of
ii . E i: arAs ss
13
H
B. «tc. SMMM ... .11 othr «r»» '«"<>«
At th. Mitologle w»1».t1.n. ««« «« «r«""' «*«"
sioderate, « • 8»v«r«, ami S • txtrwt.
H. tody «1.ft. *- «««n,pt1.». .H.lcop.th.lo.fc. .m. «!••
*u «« t.»t- for »»...«ity * »i— » "rtlrtt>'
(St«! «* T.«-1.. UN). M th. 4.U «« fpund to be ho.09.Mous.
Nt—
.ttMttlcrt ,1,n1f1e.»c. by th. MM tf MMt (MMtt. 1«»). M
th. *tt «« 1M< «ot to * I-MM". «• "tl>011 " S1"
DuBiwtt't) aa npleywl (6111.
Beta Retention
HI *t. 1«1».1« .M1M,
MM.
.t t«»»c1ty IMM .. It...
. Weh1,.n «M4 for .t 1.«t . y..«. Nfore
8 Protocol enrage A. effective W16/85.
-------
HI. Results
A. Test Material
The results of the analysis of saaples analysed by the Wastewater
Treafenent Facility and by SRCO ere given *« Appendix A. Stability and
econcentration were found to to acceptable.
8. Clinical Signs
The Incidence of clinical effects Is given In Table 1.
Treetmsnt-related Jtajc1a-f4rst-««p»aped -4«-tbeJdgh=dose .group dur1.n$
<*sek S_. At&x1a and hypoactlvlty occurred 1nf recently during weeks 9
Qnd jo. These signs Increased to a weekly Incidence of 32 and 29S for
ataxla end hypoactlvlty. respectively, at ueek 11 and continued at
epproxlmately the same freqiency during weeks 12 and 13. Onset of
ataxla and hypoeetlvlty was about 2-3 alnutes after dosing and dura-
tlon was less than one hour.
Other clinical signs observed did not appear to be directly related to
treatment. Three rats died during the study. Two of these deaths
were the result of the rubber catheter slipping off the wtal dosing
eannula. During week 4. a catheter lodged 1n the esophagus of a high-
dose female and the rat died of apparent asphyxiation before the
catheter could te raaovcd. During roek 7. a high-dose oale swallowed
© catheter. It was sacrlf 1c«d too days later often It teeam apparent
that the situation was tdvarsely affecting the haalth §f the rat.
This accident and the occurrence of ^activity, salivation, labored
respiration, and/or retching over a S day period 1n another high-dose
-------
TW. Study 0032-006 - 10 -
rat account for- the clinical effect* observed 1n the high-dose group
during »««** 6 «i»d *• * aid-dose sale died during week 1. It began
exhibiting hypo»et1v1ty. mac tot ton, and labored respiration on day 4
and uas found dead en day 6. H1stopatholog1c evaluation of this rat
i be dUcussed later 1n the report.
Dark yrlne and rales occurred 1n a high-dose sale during week 8
following a eage related accident. This rat was normal In appearance
»1th1n three days. During week 7. a 2 en diameter tissue mss
appeared 1n the left axillary area of one low-dose female and a 3 on
diameter oass appeared 1n the right axillary area of another low-dose
female. WeUher aass Increased In tlze and both disappeared before
study termination.
C. Body Height. Height Change and Food Consumption
The body weight, weight change and food consumption values are given
1n Table 2.
No treatment- related effect was present on body weight, weight
or food consumption. Statistically significant differences between
control and treated group seen might change and food consumption
would eeeur sporadically, but no trend was @b served and total body
weight averages for control and treated groups were stellar throughout
the study.
Ophthalmology
The results ef the ophthalraloglc evaluations are given In Appendix B.
-------
TRL Study 0032-006 - XI
An ophthalmoscoplc examination uas performed prior to 1n1t8t1on of
dosing and all animals with eeular abnormalities were Identified and
discarded. Another ophthalmoscoplc examination teas performed during
»»ek i3. The pathology observed was considered to fee within normal
Halts for the age, sex, and strain of th« animal.
E. Clinical Pathology
Results of the el1n1cop«tho1eg1c evaluation are given In Tables 3
through 7.
Only one alteration In clinical pathologic parameters occurred that was
suggestive of a treatment- related effect. At the Interim sacrifice.
SBC (p«S 0.05). PCV (p* 0.01), «nd KGB (p« 0.01) averages In the
high-dose females were IX less than the corresponding control aver-
ages. The RBC and PCV (p <0.05) averages for the middle-dose females
were also slightly (4X and 31. respectively) below those of the con-
trols. However, RBC. PCV, and K5B averages were similar for control
and treated groups of Bales st the Interim evaluation And for control
and treated groups of both sexes at the final evaluation.
Other §mist1cally slgnUNeant differences between control and
treated f?rw»P averages wcurved fcut they were satl!. occurred In one
eex and at ene evaluation enly, and there was w> dose response rela-
tionship. ?tesB ttey «ere aot eensldepad to fee treeteant^related.
They eere: ft lower (p
-------
TRL Study 0032-006 - 12 - DRAFT
higher (p< 0.05) relative segmented wsutrophll count and a lower
(p €0.05) relative lymphocyte count 1n the low-dose females at the
final evaluation, and higher (p«0.05) urine pH values 1n the low-
dose Bales at the Interim end low-dose females et the final evalu-
ations.
F. Observations at Hecropsy
Observations made at necropsy ere given 1n Table 8.
No treateent-relattf lesion was observed In gross necropsy at the
Interim §r final sacrifices or ef the rats found dead or sacrificed
1n extras. The lesions present were those commonly observed 1n
laboratory rats end they were present 1n control and treated groups
at similar f regency or war* one tlae occurrences. The enlarged
uterine horns are related to the stage of the estrus cycle.
Three pats died during the study. Wo gross lesions were seen 1n rat
d 224. aat $ 202 (which had a catheter 1ri Its stomach) had dark areas
®n the glandular oucosa of the stomach. In rat 0 133 (alddle-dose),
the left lobe of the lung was red and the cranial and nlddle lobes
Here shriveled.
Heights
Relative and absolute group Bean organ might values are given 1n
Table 9.
-------
TRL Study 0032-006 - " - foR A PT
•^ ix f^\ i B
There was no apparent treatment-related effect on organ might values.
The only statistically significant difference between control and
treated group averages was a slightly (p« 0.05) higher thyroid
*e1ght average 1n the hlgh-dose sales. Ho dose response relationship
«ros present, as toe ebfolute thyroid weight* were stellar for all
three treated groups ef Bales. Moreover, they were only W above
the control average. Thyroid weight averages of the treated femiles
were not above those of the controls. Thus, this difference appears
to be e chance occurrence rather than a treatment-related effect.
N. Histo pathology
The results of the Mstopathologlc examination ere given In Table
10 and Appendix 0. The MstoaccountablHty report U given In
Appendix E.
No treotsnent-related lesion was observed at the hlstopathologlc
evaluation. Tne lesions that were observed were one time occurrences
or were present In the control end treated groups at A similar fre-
«8iency. The diffuse subacute lyaphadenltls ef the aandlbular lymph
node was vUable grossly as red or enlarged lymph nodes. This 1s a
eoswonly ebserved lesion In laboratory rats. The cause ef death of
the Bid-dose ret («33) that died during the study was determined to
fee a savaging accident since e perforated esophagus was found at the
hlstopathologlc exenlnatlon.
IV Discussion
At tba littrfai evaluation. f®C, PCV. and KB averages 1n the hlgh-dose
-------
TRL Study «32-006 - 1« • DRAFT
females were 58 below control averages. The differences were statis-
tically significant but the biological significance 1s Questionable.
All three parameters arc closely related, so a decrease 1n the RBC
count »oul(! be eRpected to result 1n a decrease 1« «V and MSB
values also. Moreover, the observed differences were wall and no
difference between these parwwters was *««n In Bales at the Interim
evaluation or between control and treated groups of either sex at the
fine! evaluation. Thus, even 1f the decrease 1n RBC count (and hence.
PCV and MSB) was a true treatnent-related effect, 1t was swell and
transitory.
One Bid-dose and too high-dose rats died during the study, but none of
these deaths was due to administration of noraal butanol. The two
high-dose rats died because the rubber catheter slipped off of the
dosing cannula during dosing. In one case (ret « 224). the catheter
lodged In the throat and esophagus, thus cutting off air flow Into the
lungs. The rat died of apparent asphyxiation before the cannula could
t* removed. Ko gross or Mstologlc lesion relating to the
-------
TRL Study #032-006 •«- DRAFT
result tf esophagi towge at dosing.
V Conclusion
« . ».«» •'« "*
. A
Mil »1« (PCV). Md
tki MO vyttf
-------
YRL Study 0032-006 - W -
VI References
Dunnett, C.M. (WM). filsetrlcs 20.482-491
•111. J.u. (W77). f
.
Wew York.
-------
CERTIFICATE OF AUTHENTICITY
THIS IS TO CERTIFY that the microimages appearing on this mlcrollcho are accurate
and complete reproductions of the records of U.S. Environmental Protection Agency
documents as delivered In the regular course of business for microfilming.
Data produced
(Month) (Day) (Year) Camera Operator
Place Syracuse New York
(City) (State)
ASVSTEK
corp
------- |