final Report
Study No. 5221,08
TcoaciTY OF
IN
MBA Chemical No.; 25
Sponsor;
Sponsor
Triangle Institute
P.O. BOX 12194
Triangle
Korth Carolina 27709
Or. Derails Diets
Testing facility; Microbiological Inc* (MBA)
5221 River Bead
MD
Initiation 03,
Ion Date; January 04,
L. Thomas
Study
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REPORT DOCUMENTATION
PACE
1, REPORT NO,
EPA/530-SW-88-025
1. Recipient's Accession No.
PB88-195292
4. Title and Subtitle
Subchronic Toxicity of Para-Cresol in Sprague Dawley Rats
*. Report Date
April 4, 1988
Dr. Dennis Dietz and Dr. L, Thomas Mulligan
9. Performing Organization Name and Address
8. Performing Organization Repi- No
Microbiological Associates, Inc.
5221 Kiver Road
Bethesda, MD 20816
10. Preiect/Taik/Work tin II Na.
11. ContracHC) or Grant (G! No.
to 68-01-7075
(G)
12. Sponsoring Organization Nam« and
U.S. Environmental Protection Agency
Office of Solid Waste
401 M Street, SW
Washington, DC 20460
II. Type of Report & Period Covered
Final Report
14.
IS. Sypptemfifttary Notes
Study conducted for Research Triangle Park under EPA Contract No. 68-01-7075
IS. Abstract (Limit: 200 words)
This study was conducted to assess the tcxicity of para-cresol (p-cresol) in rats
when administered for 13 weeks by gavage.
17. Document Analytic a. Detcrlpton
b. Identlfiers/Qpen-Ended Terms
C. CO SAT I Fulc/Grouc
16- Availability Statement
RELEASE UNLIMITED
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21. No. of Pages
378
22, Price
PCS32.95/MFS6
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Sea Initmetlan* en Kertrtt
OPTIONAL FORM 272 C4-77)
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Oept rtmenl of Commerce
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Final Report
Study No. 5221.08
TABLE OF CONTENTS
Page
I. SUMMARY... 1
II. UfTSDDUCnON , 1
III. MATERIALS AND METHODS 1
A. Test Article., 1
B. Animals.. l
c. Experimental Design 2
D. Statistical Analyses... 6
IV. RESUUrS 6
A. Analyses and stability of Dosage Form Preparations 6
B. Mortality/Clinical Observations 6
C. Body Weight. 7
D. Food Consumption 8
E. Clinical Pathology 8
F. Ophthalmology 9
G. Organ Weights 9
H. Pathology... lo
V. DISCUSSION 11
VI. PERSONNEL.... . 12
VII. ARCHIVES 12
VIII. PROTOCOL 46
APPENDICES
APPENDIX A - 1WD-WEEK RANCS-FIbroiNG/EXPlJDRATORY STUDY
OF META-CRESOL IN SPRAGUE DAWL1Y RATS A-l
APPENDIX B - ANALYTICAL CHEMISTRY METHODOLOGY.... B-l
APPENDIX C - CLINICAL PATHOLOGY METHODOLOGY C-l
APPENDIX D - INDIVIDUAL ANIMAL DATA D-l
APPENDIX E - OPHTHALMOLOGY REPORT. E-l
APPENDIX F - PATHOLOGY REPORT. F-l
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ATTENTION
PORTIONS OP THIS REPORT ARE NOT
FULLY LEGIBLE. DUE TO THE IMPORTANCE
OF THE MATERIAL IT IS MADE AVAILABLE
TO THE PUBLIC. HOWEVER, IT IS THE BEST
REPRODUCTION AVAILABLE PROM THE COPY SENT
TO MIS.
DOCUMENT COMPLETE AS PAGINATED PER SOURCE.
DIRECT QUESTIONS RESULTING PROM ILLEGIBILITY
TO: U.S. EPA
OSWER - HSCD
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Final Report
Study No. 5221.08
I. '\SUMMARY;
This''study examined the oral toxicity of para-cresol (p-cresol) in
Sprague Dawley rats during 13 weeks of oral gavage administration.
Dose levels studied were 0, 50, 175 and 600 mg/kg/day. Three females
treated with the high dose of p-Cresol died during the first three
days of the study. Signs of central nervous system (CNS) depression
were apparent in high-dose males and females. Reductions in bcdy
weight gain were seen for males and females treated at the high dose
level and to a lesser extent in the mid dose males. Para-cresol was
hepatotoxic, nephrotoxic, and induced a mild anemic state. Based on
the results of the present investigation, 50 mg/kg/day appears to be
the level at which no toxic effects were observed under the conditions
of the present study. ^,:
II. INTRODUCnON:
This study was conducted to assess the toxicity of para-cresol (p-
cresol) in rats when administered for 13 weeks by gavage. All methods
and procedures were conducted in accordance with the appropriate
Quality Assurance Programs (Microbiological Associates Inc.; MEA or
Pathology Associates, Inc.; PAI) designed to conform with FDA and EPA
Good laboratory Practices Regulations.
III.
A. Test Article
Para-cresol, 4 kg, was received on 29 July 1985 and was assigned
MBA chemical number 25. The source was Eastman Kodak Company,
Rochester, NY, 14650, and was Lot No. A13A. The test article was
described as a colorless liquid and was 99.9% pure according to
information provided by the supplier. The test article was stored
in its original container, a translucent plastic bottle, at room
temperature and ambient humidity.
B. Animals
One-hundred and fifty-eight male, and 157 female Sprague Dawley
rats were obtained from Charles River Breeding Laboratores, Inc.,
Newfield, NY on 2 October, 1985. The animals were approximately
five weeks old upon arrival at the Microbiological Associates
animal facility. The animals were in quarantine/pretest for
approximately two weeks prior to the initiation of treatment.
Housing was by groups during quarantine/pretest and individual
during the treatment period. The animals were housed on Beta-Chip
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Final Report
Study No. 5221.08
hartJwood bedding in polycarbonate cages which conformed to the
upper weight range :recanmended in the Guide f or_the Care and Use
of Laboratory Animals. CHEW, (NIH) No. 78.23. All test animals
received Purina Laboratory Chow No. 5001 in block form and water
(Washington Surburban Sanitary Commission, Potomac Plant) ad
libitum except during an approximate 16-18 hour fast prior to
necropsy.
During the study period, animals were housed in a temperature-
controlled room with a 12-hour light/dark illumination cycle.
Animal room temperature and relative humidity were recorded once
daily and were noted to be outside the protocol-specified ranges
on several occasions during the study. Monthly environmental data
are summarized below:
Month/Year
10/85
11/85
12/85
1/86
Number of
Readings
16
30
31
17
Temperature ( £*}
70.3 ± 3.5
74.3 ± 2.3
70.8 ± 5.4
73.2 ± 2.2
64-76
70-82
48-80
69-78
Number (%) of Readings
Within_ Required_Bange
10 (63)
22 (73)
19 (61)
15 (88)
Month/Year
10/85
11/85
12/85
1/86
Number of
Readings
16
30
31
17
Relative
Humidity (%)a>(
46.3 ± 12.9
39.4 ± 9.8
22.6 ± 9.1
26.5 ± 6.1
2 Bange
24-63
24-64
11-50
16-38
Number (%) of Readings
Within, Required _Range
12 (75)
20 (67)
4 (13)
1 (6) -
a Protocol-required range = 69-75 °F
k Protocol-required range *= 35-65%
c Values presented as mean ± standard deviation.
C. Experimental Design
During the second week of guarantine, animals were examined by the
staff veterinarian and were found to be acceptable for use on
study. One hundred and twenty animals of each sex were selected
on the basis of body weight and were assigned permanent cage
numbers (1-120) for each sex. These numbers were then randomized
into four groups of 30 animals/sex/group. Ten male and ten
female rats were also chosen for baseline hematology and clinical
chemistry determinations. Baseline clinical pathology animals
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Final Report
Study No. 5221.08
ware chosen from animals not previously assigned to test groups
using a table of random numbers.
The following dose levels were selected by the Sponsor on the
basis of preliminary studies which included a two-week range-
finding exploratory test (Appendix A), and were administered once
daily by gavage for at least 13 consecutive weeks.
Treatment Dose l£svel Number of Animals Dosage Fonraalation
Group (mcr/kg/day) Male Percale frag/ml)
1 0 30 30 0
2 50 30 30 10
3 175 30 30 35
4 600 30 30 120
5 [Baseline Clinical Pathology] 10 10
Hie test chemical was diluted in corn oil to achieve the above
concentrations which allowed for a dosing volume of 5 ml/kg.
Dosage formulations were prepared fresh weekly throughout the
study and were stored protected from light at room temperature.
American Biogenics Corporation, Decatur, IL, tested the stability
of p-cresol dosage formulations following a 14-day holding period.
Additionally, the concentration of p~cresol in corn oil was
analyzed from formulations used during Test Weeks 1, 2, 4, 8, and
13 by ENSECD, Inc., Cambridge, MA.
All rats in the study received a unique test animal number which
appeared as an ear tag. A cage card WES displayed on the front of
each cage and contained the following information: study number,
animal number, test article name, treatment group name or number,
room number, dose level, strain, sex, receipt date, and start
date. The cage cards were color-coded as a function of treatment
group and sex.
The test article or vehicle (corn oil) was orally administered
once daily for at least 13 consecutive weeks commencing on
16 October 1985. Animals were dosed up to the day prior to
routine necropsy at either Test Week 7 (interim kill) or 14
(terminal kill). The gavage proocedure was accomplished by the
use of a rigid oral feeding needle.
Non-fasted body weights were recorded on Test Day 1 and weekly
thereafter. Individual food consumption data were collected on a
weekly basis. Moribundity/inortality checks were routinely
performed twice daily (once in the morning and once in the
afternoon), and moribund animals were killed and necropsied. The
6
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Final Report
Study No. 5221,08
test animals were given complete physical examinations on a weekly
basis.
Ophthalmology examinations were performed during the quarantine
period and In Test Week 13 by Dr. Nancy Bromberg, Diplcmate,
American College of Veterinary Ophthalmologists. This procedure
was done by indirect cphthalrooscopy, and only animals which were
free of visable lesions, or had congenital or incidental lesions
which were not considered to interfere with the study, were
considered for test animal selection.
Blood samples were collected from 10 rats/sex designated for
baseline clinical pathology determinations, 10 rats/sej^/dose
sacrificed during Test Week 7, and 10 rats/se^/dose sacrificed at
study termination (Test Week 14). Blood was obtained via orbital
sinus puncture while under 003 anesthesia. Animals were fasted
for approximately 16-18 hours prior to blood collection.
The following hematology and clinical chemistry tests were
performed;
Hematology
Hemoglobin Erythrocyte count
Hematocrit Reticulocyte count
Prothrombin time (PT)
Total and differential leukocyte count
Activated partial tbromboplastin time (APTT)
Clinical Chemistry
Sodium C02
Chloride SGFT
Potassium SCOT
Calcium Glucose
Phosphorus BUN
Direct and total bilirubin Globulin (calculated)
Alkaline Efiosphatase Total protein
Total Cholesterol Creatinine
Albumin A/G ratio (calculated)
Urine specimens were obtained from 10 rats/se^dose sacrificed
during Test Week 7 and from 10 rats/sex/dose which were sacrificed
at study termination. The urine specimens were collected from
metabolism pans into gauze-filtered urinalysis cups during the
overnight fasting period. The following parameters were assessed:
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Final Report
Study No. 5221.08
Uripalysis
Appearance Glucose
Volume Ketones
Color Bilirubin
Specific gravity Urobilinogen
pH Hemoglobin
Protein Microscopic examination
Clinical pathology methodology is contained in Appendix C.
Complete gross necropsy examinations were performed on rats found
dead during the study and those killed at the interim and terminal
sacrifice intervals. Eats assigned to the interim sacrifice
(identified at study onset) were killed in random order over a
two-day consecutive period (02-03 December 1985). At the terminal
sacrifice, all surviving rats were killed in random order over a
three-day consecutive period (15-17 January 1986). All rats were
anesthetized with OQ2 and exsanguinated by bleeding from the
posterior vena cava. Animals were fasted overnight prior to
necropsy.
The necropsy procedure included a thorough and systematic
examination and dissection of the animal viscera and carcass, and
collection of the following tissues/organs in 10% neutral buffered
formalin: ."
All gross lesions Ovaries
Brain (3 levels) Corpus and cervix uteri
Spleen Eye
Bone (with marrow) pituitary .
Skeletal inuscle Lymph node
Salivary gland Spinal cord
Mammary gland Heart
Thymus Aorta
Thyroid (with parathyroid) Sciatic nerve
Lungs (with roainstem bronchi) Pancreas
Trachea Esophagus
Liver Kidneys
Urinary bladder Small and large intestine
Testes Adrenals
Prostate - Stomach
All of the above tissues for all control and high dose animals
sacrificed at study termination as well as those that died during
the study were submitted for histopathologic evaluation.
During terminal sacrifice, in addition to terminal body weight,
the heart, liver, spleen, brain, kidneys (individually), gonads
(individually), adrenals, and toyroid/parathyroid were weighed.
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Final Report
Study No. 5221,08
D. Statistical Analyses:
Body weight, food consumption, clinical chemistry, hematology, and
organ weight data were analyzed by sex by one-way Analysis of
Variance tests with Burnett's t-test employed if a significant F
ratio was found (p < 0.05}. Individual animal data can be found
in Appendix D.
IV. RESUUTS
A. Analyses and Stability of Dosage Form Preparations
Para-cresol in corn oil was found to be stable for at least 14
days at the concentrations tested. Additionally, the analyses of
the dosage form preparations used during Test Weeks 1, 2, 4, 8 and
13 indicated that target concentrations were generally within an
acceptable range at the 10 and 35 Jng/ml dose levels. Seven of
these ten preparations were within ±10% of the intended
concentration. Of the remaining three, two were for the 35 mg/ml
dose level (mid dose), and were approximately 11% more than
target. The renaining sample (10 mg/rol dose level) was 17% over
the intended concentration. At the 120 rag/ml dose level, the
assayed values for all five samples were greater than 10% over
target. They ranged from 10.6% to 17.6% (mean = 15.6%) above the
intended concentration (Tables la and Ib). Purity confirmation
analyses performed by ENSEQO, Inc. indicated that the bulk
chemical was 99.6-99.7% pure.
B. Mortality/Clinical Observations
Three high dose females died-within the first three days of-
dosing. Animal no. 3899 demonstrated tremors and convulsions, and
was comatose prior to death. Another female (animal no. 3883) was
comatose and demonstrated tremors prior to her demise, whereas the
third female (animal no, 3910) was found dead without any clinical
signs observed.
Lethargy, excessive salivation, tremors, and occasional
convulsions and comas were observed for roost of the surviving
males and females at the high dose level. These clinical signs
were not seen at the lower dose levels. All high dose males
and/or females exhibited lethargy after dosing on days 2 and 3.
Treatment-related clinical signs of tcxicity were also observed in
the high dose rats at the weekly physical examination intervals.
The incidences of relevant clinical signs are summarized below:
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Final Report
Study No. 5221.08
Incidence of Relevant Clinical Signs In High Dose Ratsa
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
Lethargy
M F
30/30 25/30
3/30 5/27
4/30 4/27
12/30 10/27
10/30 12/27
13/30 10/27
13/20 11/18
7/20 6/18
7/20 4/18
12/20 9/18
9/20 8/18
7/20 4/18
9/20 7/18
Tremors
M F
6/30 4/30
- 2/27
2/30 2/27
3/30 6/27
5/30 5/27
4/30 2/27
7/20 3/18
2/20 2/18
4/20 2/18
5/20 5/18
4/20 2/18
5/20 2/18
2/20 3/18
Convulsions
M
-
-
-
1/30
2/20
-
-
-
"
I
1/30
-
-
-
-
"
Excess
Comatose Salivation
£J F MF
2/30 - -
_ _ _ _
11/30 8/27
4/30 3/27
_ _ 2/27
1/30 - 2/30 3/27
2/20 4/18
3/20 1/18
- - 3/18
2/20 3/18
- - 1/18
C /"^ O
D/J.O
- - - 4/18
a Number of animals exhibiting sign/number alive at beginning of week.
No other treatment-related clinical signs of toxicity were
apparent for p-eresol treated rats. Diarrhea was an infrequent
observation in the high dose animals. This finding was noted in
one high dose female during week 2 and one high dose wale during
weeks 3 and 4. Diarrhea was also noted in two control males
during week 3, one control male during week 6, one control female
during Week 4, and one low dose male during Week 6.
C. Body Weight
Dose-related reductions in body weight gains were apparent for '
p-cresol-treated males. Decreases for the high and mid dose males
were approximately 25% and 7%, respectively, throughout the
treatment period. Statistically significant (p < 0.05) reductions
in weight gain were evident for the high dose males during Weeks
1-13 and for the mid-dose males during Weeks 1-3.
Weekly body weights recorded for the high dose males showed
statistically significant reductions for all weeks throughout the
course of the study but week 1, as compared to the controls. Mid
dose males had significantly (p < 0.05) lower body weights than
controls at weeks 2-4.
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Final Report
Study No. 5221.08
The mean weight gains of the high dose females were noted to be
significantly (p < 0.05) lower than the control during weeks 1-7,
10, and 13 (approximately a 15% decrease). Slight but
statistically significant decreases in weight gain were noted for
the mid and low dose females during the first few weeks of
treatment (Tables 2-5).
High dose females had significantly (p < 0.05) reduced body
weights at weeks 2-9, and 14. The average body weight of the low
dose females was noted to be significantly (p < 0.05) lower than
the controls at weeks 1-5, and 7. Therefore, the apparent
reductions in mean body weight gain for the low dose females
during the early weeks of the study way be a reflection of the
lower initial body weights.
D. Food Consumption
Food consultation was generally decreased for high dose males
throughout most of the treatment period. The food consumption
values of the high dose males were significantly (p < 0.05) lower
than control during Weeks 1-7, and 9. This reduction was seen on
fewer occasions for high dose females, and was statistically
significant at Weeks 1, 2, and 6. Sporadic decreases were seen
for the other two dose levels which did not generally appear to be
related to treatment. Exceptions to this include statistically
significant reductions in food intake for mid-dose males during
the first and fifth test weeks. During Test Weeks 5 and 9, low
dose males showed slight, but statistically significant reductions
in food consumption.
E. Clinical Pathology
At study termination, dose-related reductions in red blood cell
count, hemoglobin concentration, and hematocrit were seen for
female but not male rats administered p-cresol at doses of
175 mg/kg/day or greater. Statistically significant reductions in
the oxygen transport parameters were evident in the mid and high
dose females; values for the low dose females were numerically
lower but not statistically significantly lower than that of the
controls. The effect was mild and physiological compensatory
responses to the anemic state, i.e., reticulocytes, macrocytosis,
and elevated numbers of RBCs, were not in evidence.
Statistically significant elevations in mean SGPT levels were
observed for high dose females at the interim sacrifice. At study
termination, high dose females showed significant elevations in
both SGPT and SCOT levels. The individual animal results showed
that the increased transaminase levels at study termination were
8
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Final Report
Study No. 5221.08
attributable to unusually high values in four high dose females
(animals 3892, 3893, 3894, and 3895); the remaining six animals In
this group had levels that were generally comparable to those of
the controls. Two of the high dose females with elevated enzyme
values (animals 3893 and 3895) had chronic hepatic inflammation,
which could explain the elevations in transaminase levels. No
correlating histopathologic findings were evident in the other two
high dose females (3892 and 3894).
No treatnnent-related effects on SGPT or SCOT levels were noted for
the high dose males. Although one high dose male (animal 3761)
showed elevated transaminase levels at study termination, the
values for all other animals in this group were generally similar
to the control values.
Significantly (p < 0.05) increased serum cholesterol levels were
observed for the high dose females at study termination but not at
the interim period. This parameter also appeared elevated for
mid-dose females and mid and high dose males at termination
although these changes were not statistically significant.
At termination, total protein was statistically significantly
increased for male but not female rats at the mid and high dose
levels in a dose-related fashion. This appeared to be primarily
due to the elevated globulin levels. Sporadic increases and
decreases for other clinical pathology parameters were seen, and'
were not considered related to p-cresol treatment (Tables 8-15).
F. Ophthalmology
The Ophthalmology Seport is contained in Appendix E.
Treatment-related ophthalmic lesions were not seen for rats
receiving para-cresol.
G. Organ Weights
Significantly (p < 0.05) elevated relative renal weights were seen
for male rats administered 175 ing/jag/day or greater. Relative
renal weights for the 50 mg/kg/day males were also numerically
elevated, although statistical significance was not noted. In the
females, increased relative kidney weights were noted at the high
dose? the mean relative right kidney weight was significantly (p <
0.05) elevated, whereas that of the left kidney was only
numerically higher than control.
A treatment-related effect on relative liver weight was also
evident in male rats administered 175 mg/kg/day or greater. The
mean relative liver weight of the 600 mg/kg/day males was
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Final Eeport
Study No. 5221.08
175 rog/>ag/day group was numerically higher but not statistically
increased. Other statistically significant increases in relative
organ weights were noted for the heart, testes, and brain (high
dose males), and for the spleen (low dose females).
Alterations in absolute organ weights, as compared to controls,
were limited to the high dose group animals. Slight but
statistically significant decreases in absolute brain weights were
apparent for high dose animals of both sexes; however, the
significant increase in relative brain weight for the high dose
male reflects that group's reduction in body weight gain.
Similarly, the slight (but statistically significant) increase in-
relative but not absolute testes weights for high dose males
probably reflects their depressed body weight gains (Tables 16-
19). In addition, significantly (p < 0.05) lower absolute liver
and spleen weights were noted for the high dose males, and
significantly lower absolute right ovary weights were noted for
the high dose females.
H. Pathology
The Pathology Report is contained in Appendix F. Gross necropsy
examinations did not detect treatment-related lesions.
Histologically, a slight increase in the incidence of chronic
... nephropathy was noted in all dosed male rat groups when compared
to the male controls. The increased incidence was significantly
(p < 0.05) greater at the low and high dose but not the middle
dose. The proportion of male rats with minimal and mild
nephropathy was generally similar for all male rats including the
controls. ,
Epithelial metaplasia of the trachea was observed to a
significantly (p < 0.05) greater extent for high dose animals than
for respective controls. The incidence of this lesion was similar
for low dose, mid dose, and control animals. This lesion was
characterized by multifccal to diffuse replacement of goblet and
secretory granular cells by squamous epithelial cells which were
flattened, had nuclei parallel to the basement membrane, and were
occasionally stratified.
No other histemorphologic lesions appeared to be related to p-
cresol treatment.
10
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Final Report
Study No. 5221.08
V. DISCUSSION
This study evaluated the oral toxicity of para-cresol in Sprague
Dawley rats when administered for 13 weeks by gavage. Three high dose
females died within the first three days of the study. Tremors and/or
convulsions were seen for two of these animals prior to their demise.
Surviving high dose males and females generally exhibited these
clinical signs throughout the trea'taient period in addition to lethargy
and excessive salivation. Additionally, statistically significant
(p < 0.05) reductions in body weight gain were seen for male and
female rats at the high dose level and to a lesser extent for mid dose
males.
Para-cresol appeared to be hepatotoxic on the basis of clinical
pathologic indices and organ weights. Histologic lesions of the
liver, however, were not in evidence. Serum transaminase levels were
significantly (p < 0.05) elevated for high dose females and
hypercholesterolemia was observed for this sex and possibly for males
at the high and possibly mid doses. Additionally, total protein and
relative liver weights were significantly (p < 0.05) increased at the
high dose for males at study termination.
Renal injury was suggested from both organ weight and light
microscopic changes. Slight increases in the incidence of chronic
nephropathy were noted in all dosed raale rat groups and were
significantly (p < 0.05) increased at the low and high dose levels.
Significantly (p < 0.05) elevated kidney weights occurred for this sex
at the mid dose or greater. High dose females also demonstrated
increased renal weights. Clinical pathologic indices of kidney
function neither clearly support nor contradict these observations.
A dose-related anemic state was seen for female but not male rats was
seen at the mid and high dose levels. This effect was slight and
compensatory physiologic mechanisms, i.e., elevated nucleated KBCs,
retulocytosis, macrocytosis, etc., were not in evidence. Bone marrow
also appeared normal. This anemic state was probably not hemolytic as
neither congestion of the spleen nor hemosiderosis of this organ or
the liver (Kupffer cells) was seen.
Ophthalmology examinations did not identify any occular lesions
attributable to p-cresol.
In summary, three females treated with the high dose of p-cresol died
during the first three days of study? lethargy, tremors, and/or coma
were observed in these animals prior to death. Lethargy, tremors,
excessive salivation, and occasional convulsions and comas were
observed in surviving high dose rats throughout the study.
Statistically significant reductions in body weight gain were observed
11
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Final Report
Study No. 5221.08
in males ana females at the high dose and, to a lesser extent, mid
dose males. Para-cresol was hepatotoxic, nephrotoxic, and induced a
mild anemic state. Based on the results of the present investigation,
50 ing/kg/day appears to be the level at which no toxic effects were
observed under the conditions of the present study.
VI. PERSONNEL
L. Tom Mulligan, Ph.D, served as Study Director, and was responsible
for the overall conduct of the study. Barry S. Levine, D.Sc.,
Diplomate, American Board of Toxicology, was Study lexicologist and
was responsible for the in-life portion of the study. Dr. Levine was
also reponsible for clinical pathology evaluations. Diana Copeland,
DVM, Diplomats, American College of Veterinary Pathologists, was
responsible for gross necropsies and histopathologic evaluations.
John Miller, DVM, was responsible for laboratory animal care. Harry
J. Paulin, M.S. served as Study Chemist, and provided dosage
formulations and analytical chemistry services. Nona S. Karten, M.A.,
was responsible for the Quality Assurance Program. Mike Schulz, B.A.,
and Brian Makle, B.S., were responsible for the collection of in-life
test animal data.
VII. ARCHIVES;'
The raw data and final report are archived at Microbiological
Associates Inc., 5221 River Road, Bethesda, MD 20816 with the
following exceptions. Pathology specimens including wet tissues,
blocks and slides and original necropsy fonts are temporarily archived
at Pathology Associates, Inc., 10075 Tyler Place, Hyatt Park II,
Ijamsville, MD 21754 and will be transferred to the MBA Archives upon
Sponsor approval of the final report.
VIII. PROGDOOOL:
The study protocol, complete with all amendments, is included
following the study tables.
12 * c;
1 O
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Study 5221,08
TABLE la
SUECHRONIC TOXieiTY OF PARA-CRESOL IN SERAGUE BAWIZY BATS
ODNCENIRATION OF PARA-CRESOL IN CORN OIL (rag/ml)
STABILITY ANALYSES3
Sairple
NurriDer
C02S7A85
C0289A85
Date
Mixed
10/15/85
10/15/35
Target
Cone. (mcr/ittL)
10
120
Concentration fiw/rnl)
Zero Day
10.42b
138.6
14-Day
11.23b
143.6
Percent
Difference*
4-7.8
+3.6
*Percent Difference = 14-Day Value minus Zero Day Value x 100
Zero Day Value
aAnalyses performed in duplicate by American Biogenics Corporation unless
noted otherwise.
^Analyses performed in triplicate.
-------
Study 5221.08
TABLE lb
SUBCHRQNIC TOXieiTY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
CONCENTRATION OF PARA-CRESOL IN CORN OIL (rag/ml)
Target
Concentration
fmcr/ml} 1
0 ND
10 9.9
35 36.8
120 140.1
FORMULATION ANALYSES3
Test Week
24 8 33
ND ND ND ND
9.2 11.7 10.3 9.6
35.1 36.1 38.8 39.0
132.7 141.1 140.1 139.2
aAnalyses performed by ENSECO Inc. (formerly ERGO), Cambridge, MA unless otherwise noted.
ND = Not detected above the minimum reporting limit of 1.0 mg/ml.
-------
Study Mo. 5221.03
TABLE 2
SUBCHROMIC TOXICm OF PARA-CRESOL IN SPRAGUE DAULIY RATS
MALE BODY WEIGHT DATA (g)
TEST
WEEK
a
i
2
3
4
5
6
7
8
9
10
11
12
13
14
0 ng/kg/day
233 ±
296 i
345 i
391 t
424 ±
452 t
460 t
501 t
525 t
547 t
555 ±
568 ±
533 i
592 ±
u<
18(
23<
25 {
2B(
32<
33 (
39 (
45<
46C
46C
46<
51(
53C
3D)
30)
30)
30)
30)
30)
30)
20)
20)
20)
20)
20}
20)
202
50 mg/ki/day
230 ±
289 i
338 i
385 i
419 i
447 t
475 t
496 t
516 i
531 ±
537 ±
549 i
562 ±
572 ±
17( 30)
21( 30)
25( 30)
28C 30)
32( 30)
33 ( 30)
36C 30)
37C 20)
4U 20)
4SC 20)
47C 20)
48( 20)
54< 20)
53( 20)
175 mg/kg/diy
227 i
282 ±
329 i
372 i
407 ±
434 i
461 ±
476 i
493 ±
516 i
526 i
535 i
550 ±
559 i
15C
21 (
24 C
29(
31 C
32C
34(
34C
35<
37(
37(
4H
4U
4H
30)
30)*
30)*
30)*
30)
30)
30)
20}
20)
20)
20)
20)
20)
20)
600 mg/kg/day
225 ±
256 t
297 ±
335 i
367 i
389 *
407 i
430 ±
447 i
463 i
469 *
483 i
495 i
507 t
17<
24(
27C
30C
34(
36(
39C
42(
47(
49(
50(
53 £
57{
59C
30)
305*
30)*
30)*
30)*
30)*
30)*
205*
20)*
20)*
20)*
20)*
20)*
20)*
Weights taken on Test Day 1 prior to dosing.
Statistically significant differtncs frem control group
using ANOVA and Ounnett's T-Test (P<=0.05).
Results presented as mean ± standard deviation CM)
IS
-------
Study Mo. 5221.08
TABLE 3
SUSCKRONIC TQXIC1TY OF PARA-CRESQt IN SPRAGUE QAWLEY RATS
KALE BODY WEIGHT GAIN DATA (i)
TEST
WEES
\
2
3
4
5 "
6
7
8
9
10
11
12
13
0 mg/kg/day
63 ±
112 t
158 t
191 4
219 ±
247 i
269 t
294 t
316 ±
324 i
337 *
352 n
360 t
7<
12C
15(
18C
22 {
24 (
30(
36(
37C
SBC
33C
43 (
45 C
30)
303
30)
30}
30)
303
20)
20)
20)
20)
20)
20)
20)
50 ing/ kg/ day
59 t
109 t
155 t
189 ±
217 ±
245 t
266 t
285 t
301 i
307 i
319 ±
331 ±
342 i
7(
13C
17C
21 C
23(
25 (
25C
28(
33 C
35(
38C
44 (
42 (
30)
30)
30)
30)
30)
30)
20)
203
20)
20)
20)
20)
20)
175 mg/kg/day
55 t
102 t
145 i
180 t
207 i
234 *
252 ±
274 t
291 ±
301 i
311 t
326 ±
335 *
7(
11C
17(
20 C
21C
24C
24 (
25 (
Z7(
29<
32C
33 C
3Z(
30)*
303-
303*
30)
30)
30)
203
20)
20!
2(3)
203
20)
20!
600 mg/kg/day
31 t
72 t
110 t
142 ±
163 i
182 ±
205 i
222 t
239 *
244 i
253 *
271 i
283 t
165 303»
17( 303*
19£ 30)*
23< 30)*
26C 30)*
28( 30)"
3H 20)*
36( 203*
38< 20)*
40C 20)*
43( 20)*
46C-20)*
48C 20)*
Statistically significant difference from control group
using AHOVA and Dunnett's T-TesC (P<=0.05).
Results presented as mean ± standard deviation ( M )
16
-------
Study No, 5221,08
TABLE 4
SUBCKRONIC TQXICm Of PARA-CRESQL IN SPRAGUi DAWLEY RATS
FEMALE BODY UEIGHT OATA (g)
TEST
UEEtC
"a
1
2
3
4
S
6
7
8
9
10
11
12
13
14
a
160
188
209
229
243
249
264
275
2B1
257
237
290
302
309
mg/kg/day
i 9<
t 12C
i 14C
t tec
t ire
t i»<
i 21(
i 21C
i 23C
s 25{
* 24 (
± 26C
± 27(
± 27C
30)
30!
30)
30)
303
30)
30)
20)
20)
20)
203
20)
20}
20}
50
152
177
195
214
230
240
251
260
265
275
279
280
290
298
nig/kg/day
i 12C 303*
t 13< 303*
s 14{ 30)*
i 17C 303*
t 17( 30)*
t 19( 30)
i 19( 30)*
i 22< 203
± 23{ 20)
t 23{ 20)
i 23< 20)
± 23 C 20)
± 25 ( 20}
± 25C 20)
175
159
182
203
224
239
247
261
269
274
281
2SS
289
299
304
mg/kg/day
± ac
± 11C
t 13(
t 14c
* 13(
± 17C
t 18C
t 19(
t 19(
± 21 (
i 22<
t 23<
± 25<
i 26(
30}
303
303
30}
30)
30)
30)
20)
20)
20)
20)
20)
20)
20)
MO
157
174
193
212
228
236
246
25S
262
269
263
274
232
285
mg/kg/day
i 10(
t 12C
s 1
-------
Study No. 5221.08
TABLE 5
SUBCHRONIC TOXICITY OF PARA-CRESQL [N SPRACUE DAWLSY RATS
FEMALE 30DY UEtGHT GAIN DATA (g)
Test
Week
1
2
3
4
5
6
7
8
9
10
11
12
13
0
28
49
69
83
89
104
113
119
125
126
129
141
147
mg/icg/day
i 6{ 30)
* 8( 30}
± 11( 30)
± 11 C 30')
± 13C 30)
t 15( 30)
t 14( 20)
± 16< 20}
t 18( 20)
i 18( 20)
± 1S( 20}
i 2Q( 20)
± 20( 20}
50
25
44
62
78
89
99
107
112
122
126
127
137
145
mg/kg/clay
t 6{ 30)
± 7( 303*
± 9( 303*
± 10( 30}
i 11( 30)
4 12( 30)
± 14( -20}
± 17( 20)
± 14( 20)
± 1S( 20}
± 16( 20}
i 17( 20}
i 17( 20)
175
23 t
44 i
65 ±
80 *
88 ±
102 4
110 t
116 i
122 i
127 t
131 ±
140 i
146 t
ntg/kg/day
5(
7(
8<
8(
12C
1*C
H(
15C
17C
19(
19C
21<
23 <
30)*
30)*
30)
30)
30)
30)
20)
20}
20)
20)
20)
20)
20}
600
16 t
35 i
54 i
70 i
78 t
as t
97 t
105 i
111 t
111 ±
116' *
125 4
123 ±
mg/kg/day
71
9C
11C
14t
15C
13C
U<
17(
17?
19C
20 (
19C
22 (
27)
27)
27)
27}
27)
27)
18)
18)
18)
18)
18)
18)
*
*
*
*
*
*
*
*
18)*
Statistically significant difference from control group
using AMOVA and Ounnett's T-Test (P<=0.05).
Results presented as mean t standard deviation C N )
18
-------
Study No. 5221.08
TABLE 6
SUBCHRQN1C TQXICITY OF PARA-CRESOL IN SPRAGUE DAULET RATS
MAtE FOOD CONSUMPTION DATA
-------
Study No. 5221.08
TA31E 7
SUBCHRQMiC TOX1C1TY OF PARA-CRESOt IN SPRAGUE DAWLEt RATS
FEMALE FOOD CONSUMPTION DATA (g/day)
TEST
WEEK 0 ms/kg/day 50 mi/kg/day 175 rag/kg/day 600 mg/kg/day
1 18.8 * 1.SC 30) 17.6 ± 1.7( 30)» 18.7 t 1.7f 30) 15.8 ± 1.7( 27}*
2 18.9 i 2.0£ 30) 17.2 t 1.9C 30}* 18.2 t 1.7< 30} 17.1 ± 1.8C 273*
3 17.8 + 3.Q( 30) 17.8 t 3.6{ 30} 17.9 ± 1.7C 30) 17.6 * 3.0C 275
4 17.2 i 2.0C 30) 16.3 ± 1.8( 30} 16.5 i 1.7{ 30) 16.1 t 1.8C 27)
5 17.7 t 2.7C 30) 16.8 t ZM 30} 17.7 ± 2.0{ 30) 16.6 * 2.0C 27)
6 18.3 * 3.0C 30) 16.9 * 2.4( 30) 17.7 ± 2.1< 30) 16,5 * 1.7C 273*
7 15.6 4 3.8C 30) 15.6 t 3.9< 30) 14.8 t 3.3< 30) ,15.2 i 4.9( 27)
8 17.5 ± 3.7< 20) 16.5 t 4.0( 20) 16.3 ± 2.0C 20) 17.1 t 2.CC 18)
9 17.0 t 2.5< 20) 16.9 ± 3.0( 20) 16.0 i 1.9( 20) IS.9 ± 1.9< 18)
10 17.5 i 2.1C 20) 17.5 t 2.1C 203 17.6 i 2.3C 20) 16.5 i 1.6< 18)
11 16.6 ± 2.7C 20) 16.3 ± 1.4C 20) 16.5 t 2.0C 20) 1S.7 s 1.9( 13}
12 17.6 i 3.0( 20) 16.4 * 2.0C 20) 16.3 ± 1.9{ 20} 15.6 t 1.3(.18)
13 15.9 ± 2.2< 20) 14.5 t 1.7C 20) 14.9 i 2.7C 20) 14.5 t 1.9C 18)
* Statistically significant difference from control group
using ftNQVA and Dunnett's T-Test (P<=0.05).
Results presented as mean - standard deviation C N )
-------
Study No. 5221.08
TABLE 3
SUBCHRONIC TQXICm OF PASA-CRgSOL IN SPRAG'JE OAULEY RATS
MALE HEHATOLOGY VALUES
[Interim Sacrifice]
Parameter 0 mg/kg/day 50 mg/kg/day 175 mg/ki/day 600 mg/kg/day
RBC 8.18 i 0.18< 10) 8.03 i 0.38( 103 8,19 ± Q.42( 10) 8.25 ± 0.30( 10)
-------
Study No. 5221.08
TABLE 8 (.continued)
SUBCHRQMIC TOX1CITT OF PARA-CRESQL !N SPRAGUE OAWLEf RATS
MALE HEMATOLQGY VALUES
[Interim Sacrifice]
Parameter 0 ing/kg/day 50 mg/kg/day 175 mg/kg/day 600 m§/kg/day
WBC 13.7 * 1.8C 10) 13.4 * 2.8C 10) 12.9 s 2.5C 105 13.7 t 3.2C 10)
-------
Paramtter
Study No. 5221.03
TABLE 9
SUBCHRONIC TOX1CITY OF PARA-CRESQL IN SPRAGUE DAULEY RATS
HALE HEHATQIOCT VALUES
[Terminal Sacrifice]
0 mg/kg/day 50 mg/kg/day 175 mg/lcg/day 600 aig/kg/day
3. 48 ± Q.38£ 10) 3.54 ± 0.55C 103 3.98 ± 0.54C 10) 8.76 i 0.33C 10)
15.2 i 0.6( 105 15.3 ± 0.7C 10) 15.* i' O.SC 10) 15.5 S Q.BC 10)
42.6 i 1.<( 10) 42.6 * 1.9< 10) 43.6 t 1.9( 10) 43.6 i 2.7C 10)
10.5 t 1.6C 10) 10.7 t 1.6£ 10) 10.2 t 1.8C 10) 10.9 * 1.3{ 10}
34.3 * 3.2C 10) 34.2 ± 1.9{ 10) 34.9 t 2.6C 10) 37.S t 2.3( 10)»
0.8 i 0.4( 10) 0.6* 0.4C 10) 1.1 i 0.7( 10) 0.9* 0.5< 10)
RBC
(x ia*6/ram*3
HG8
(9/dl)
KCT
a)
PT
(sec.)
APTT
(see. 3
RET1C
(X rbc)
* - Statistically significant difference from control group
using ANOVA and Ounnett's T-Test (P<=O.CS).
Results presented as mean s standard deviation C N )
23
26
-------
Study Ho. 5221.08
TABLE 9 (continued)
SUiCHRQNIC TOX1CITY OF PARA-CRESGL IN SPSAGUE DAULEY RATS
HALE HEMATQIOGY VALUES
[Terminal Sacrifice]
Parameter 0 mg/kg/day 50 mg/fcg/day 175 rng/kg/day 600 mg/kg/day
UBC 12.1 t 2.0( 10) 10.5 i 2.5C 10) 13.3 i 4.8C 10) 11.7 i 1.4< 10)
-------
Parameter
Study No. 5221.08
TABLE 10
SUBCHRON1C TQXIC1TY OF PARA -CRE SOU IN SPRAGUE OAULEY RATS
FEMALi HEMATOLQGf VALUES
[Interim Sacrifice]
0 mg/kg/day 50 mg/kg/day 175 mg/kg/day 600 mg/kg/day
7.99 t Q.33C 10) 7.99 t 0.22C 10) S.D2 t 0.46C 10) 8.14 ± Q.49( 9)
15.3 i 0.6C 10) 15.4 i 0.4C 10} 15.2 t 0.6C 10) 13. 2 t 0.6C 9)
43.0 ± 1.4C 10) 43.2 i 1.3( 10) 42.9 t 2.0C 10) 42.9 t 1.8C 93
SEC
(x 1Q*6/mn*3
MGB
Ci/dl)
HCT
PT 10.6 t 2.0C 10) 11.2 * 1.K 10) 10,5 i 1.4C 10) 11,9 i 1.0C 9)
Csee.)
APTT ':39.3 ± 6.7( 10) 35.9 * 7.1( 10) 36.6 s 6.2( 10) 38.5 i 4.2C 9)
(sec.)
SETIC 1.6 ± 0.7C 10) 1.6 i O.B( 105 1.4 4 O.B( 10) 1.2 t 0.6C 9}
(% rbe)
Results presented is mean 1 standard deviation < M )
25
28
-------
Study No. 5221.08
TABLE 10 (continued)
SUBCHRQNIC TOXtCITT OF PARA-CRESQL IN SPRAGUE DAULEY RATS
FEHALE HEHATOLOQY VALUES
[Interim Sacrifice]
Parameter 0 mg/kg/day 50 mg/kg/day 175 mg/kg/day 600 mg/kg/day
UBC 11.4 ± 1.7( 103 10.0 * 2. AC 10) 9.6 ± 1.9( 10} 9.7 t 2.3< 9)
(x 4.
SEGS 2.2 ± 1.5(10) 1.0s 0.4(10) 1 .8 ± 1.3C10) 1.7t 1.1( 9)
(x 10A3/mnr3)
BAKDS 0.0 ± 0.0( 10) 0.0 t O.OC 10) 0.0 t O.OC 10) 0.0 ± 0.0{ 9)
Cx 10*3/iwn*3)
LY.MPHS S.S t 1.1C 10) 8.8 t 2.2< 10) 7.5 t 1.2C 10) 7.6 * 1.S< 9)
(X 1CA3/f!TTl"3)
MONO 0.4 i 0.2C 103 0.2 i 0.1( 10) 0,2 t I). 1C 10) 0.4 4 Q.2( 9)
(x 10*3/imi*3)
EOS 0.1 i 0.1( 10) 0.1 ± 0.1C 10) 0.1 i 0.1< 10) 0.1 ± O.K 9)
(x 1
Results presented as mean t standard daviition ( M )
26
29
-------
Study No. 5221.08
TABLE 11
SU8CHRQNIC TOXIC1TY OF PARA-CRESGL IH SPRAGUE DAULEY RATS
FEMALE HEMATOLGGY VALUES
[Terminal Sacrifice]
Parameter 0 mg/kg/day 50 mg/kg/day 175 mg/kg/day 600 mg/kg/day
SBC 8.83 ± 0,48( 105 8.44 t Q.44( 10> 8,18 ± 0.50C 105* 8,09 * 0.54C 105*
(x 10A6/(twi*3)
HGS 16.3 ± 0.7( 105 15.9 t 0.7( 10) 15.3 * 0.3C 105* 15,1 t 0.7l 10)1
(g/dl)
KCT 46.4 i 2.3< 103 44.4 i 2,Q< 10) 42.9 i 2.U 10)» 42.1 ± 1.8( 10)"
PT 10.6 ± 0.5C 105 10.1 * 2.4{ 10) 10.7 * 1.5C 10) 10.7 t 0.7< 10)
(see. 5
APTT 34.9 ± 2.9C 10) 35.8 t 4.7( 105 38.2 t 5.2{ 10) 37.4 t 5.4< 105
(sec.)
RET1C 0.7 t 0.5C 10) 0.8 * 0.3{ 105 0.9 t 0.4( 10) 0.7 ± 0.3C 10)
(% rbc)
* - Statistically significant difference from control group
using ANQVA and Burnett's T-Test (P<=0.053.
Results presented as_raean t standard deviation ( N 5
27
-------
Study No. 5221.08
TABLE 11 (continued)
SUBCHRONIC TQX1CITT OF PAaA-CSESOL IN SPRAGUE DAWLEY RATS
FEMALE HEMATOLQGr VALUES
[Terminal Sacrifice] ,
Parameter 0 ing/kg/day 50 mg/kg/day 175 mg/kg/day 600 mg/kg/day
U8C 7.8 * 1.2( 10)
Cx
Results presented as mean ± standard deviation t N J
28
-------
Study do. 5221.08
TABLE 12
SUBCHRQNIC TOXICITY OF PARA-CRESOL !N SPRAGUE DAWLEY RATS
HALE CLINICAL CHEMISTRY VALUES
[Interim Sacrifice]
Parameter 0 mg/kg/day 50 mg/kg/day 175 mg/kg/day 600 mg/kg/day
GLU 310.6 ± 51. 4< 10) 207.7 i 38. 6< 10} 218.1 t 38. 7< 103 240.9 ± 43. 6( 103
Cmg/dl)
iUN 15.9 * 1.9C 103 H.7 t 2.8? 103 14.8 t 3.2( 10) 13.7 ± 1.2( 10)
(mg/dl!
SGPT 29 * 6C 10) 41 i 47C 10) 29 * 5( 103 33 i 6( 103
(lu/t)
SCOT 77 * 11E 10) 90 t 34 ( 10) 75 ± 9( 9) 78 t 9( 103
Uu/l)
T PRO 7.4 ± 0.5( 103 6.9 ± 0.4( 10) 7.4 ± 0.6C 10} ' 7.1 i 0,2( 103
(g/dl)
AL9 4.2 ± 0.3< 10) 3, 8 i 0.2( 10)* 4.2 ± 0.4C 103 4.0 t 0.2( 103
GLOS 3.3 i 0.4{ 10) 3.1 * 0.4( 10) 3.2 i" 0.4( 103 3.1 ± 0.3{ 103
(g/dl)
ALB/CLQB 1.293 ± 0.214C 10) 1,255 i 0.172< 10) 1.350 i 0.1d8< 10) 1.317 t 0.177< 10)
(ratio)
CHOL 86.3 ± 21. 4( 10) 61.5 i 11, fi< 10}* 99.5 ± 34. 4( 10} 91.3 * 14. 5( 10)
(mg/dl)
Ca 14.6 i 1.3C 10) 14.0 t 1;4C 10) 14.6 t 1.4( 10) 14.6 t 1.6( 103
(mg/dl)
* - Statistically significant diffarence from control group
using ANOVA and Dunnett's T-Test i.
-------
Study No. 5221.03
TABLE 12 (continued)
SUBCHRQKIC TOXIC1TY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
HALE CLINICAL CHEMISTRY VALUES
tlnterim Sacrifice]
Parameter 0 mg/ks/day 50 mg/kg/day 175 ng/kg/day 600 rag/kg/day
D Bil 0.01 ± O.OK 10) 0.01 t O.OH 10) 0.01 t 0.01( 10) 0.01 ± 0.01C 10)
-------
Study No. 5221.08
TABLE 13
SUSCHRONIC TOXICITY of PARA-CRESCL IH SPRAGUE OAULET SATS
MALE CLINICAL CHEMISTRT VALUES
[Terminal Sacrifice]
Parameter 0 mi/kg/day 50 ntg/kg/day 175 mg/kg/day 600 ms/kg/day
GLU 225.0 ± 52. 4( 10) 234.5 * 47. &l 10) 250.6 ± 43. 4< 10) 235.3 t 52. 5< 10)
BUN 12.9 i 1.8C 10) 11.8 s 0.9C 10) 12. 6 t 2.7( 10) 13.1 t 2.71 10)
(mg/dl)
SGPT 26 t 4( 10) 28 * 4{ 10) 32 t 5( 105 80 i 107( 10)
(lu/t)
SCOT 70 s 12C 1C) 71 ± 12< 10) 70 ± 1ZC 103 113 ± 85 ( 10)
CIu/l)
T PRO 6.8 t 0.3C 10) 7.0 t 0.3< 10) 7.3 i 0.4C 10)* 7.6 i 0.6( 10)*
(g/dt)
AL8 3.9 ± O.SC 10) 3.7 t 0.2C 10) 4.0 1 0.3C 10) 4.1 ± 0.4( 10!
(9/dl)
1
GLOB 2.9 ± 0.6( 10) 3.3 ± 0.3C 10) 3.4 t 0.4C 105 3.4 t 0.4C 10)
(g/dl)
ALB/GLOB 1.497 t 0.910C 10) 1.140 i 0.149C 10) 1.188 t 0.181J 10) t.228 t. 0.168( 10)
(ratio)
CHOI 82.8 s 9.9C 10) 76.6 1 13. DC 10) 101.6 t- 13. 5( 10) 102.9 S 42. 8( 10)
(mg/dl)
Statistically significant difference from control group
using AKOVA and Dunnett's T-Iest (P<=0,05).
Results presented as mean ± standard deviation < N )
31 34
-------
Study No. 5221.08
TABLE 13 (continued)
SUSCHRONIC TOXICITT OF PSRA-CRESQl IN SPRACUE DAUIEY SATS
HALE CLINICAL CHEMISTRY VALUES
^Terminal Sacrifice]
Parameter 0 mg/kg/day 50 ng/kg/day 173 mc/kg/day 600 mg/kg/day
0 Bit 0.01 t O.OK 10) 0.01 4 O.OK 103 0.01 * O.OU 9) 0.01 ± O.OK 105
(mg/dl)
T nil 0.13 ± Q.07C 10) Q.17 t O.Q6C 105 0.11 t O.Q6C 9) 0.14 * 0.05< 10)
(mg/dl>
Ca 14.3 * 3.0C 9) 13.3 t 1.8( 10) 17.6 i 3.4< 103* 13.8 t 1.6C 10!
Cmg/dl)
Ha 145 * 1< 45 145 * 1C 2) 146 t 0( 7) 145 ± 1( 3)
(Meq/l)
1C 7.8 ± 2.3< 4) 7.1t 1.5C 2) 6.5 ± 1.1< 7) 7.4 ± 2.5C 3)
(Meq/l)
Cl 105 ± 2C 4) 104 t K 25 104 ± 1< 7) 104 i 1( 3)
{Heq/l5
ALK PHOS 76 S 39C 10) 61 ± 1B( 10) 60 » 27( 10) 73 t 30( 10)
(lu/l)
CD2 26 ± 1< 45 27 * 3C 2) 26 t 4( 8) 26 * 4^ 3)
£Heq/l)
GREAT 0.70 4 0.07< 10) 0.64 t O.C3C 10) 0.66 * 0.06< 10) 0.68 ± 0.11C 10)
(mg/dl)
PHQS 10.0 i 2.CC 10) 8.9 S 0.9( 10) 9.9 ± 1,3( 9) 8.4 * 1.0( 10)*
(mg/dl)
LDH 266 ± 192C 10) 253 t 132< 10) 209' ± 124( 10) 339 ± 116( 10)
* -- Statistically significant difference from control group
using ANOVA and Ounnett's T-Test CP<=0.05).
Results presented as mean i standard deviation ( H )
32
Ol r^
^ 5
-------
Study Ho. 5221.08
TABLE 14
SUBCHRONIC TOXICITY OF PARA-CSES0L IN SPRAGUE DAULEY RATS
FEHALE CLINICAL CHEMISTRY VALUES
[Intel-id Sacrifice]
Parameter 0 ing/kg/day 50 isg/kg/day 175 (fj/kg/day 600 mf/kg/day
GLU 208.5 S 62.01 10} 186.7 * 59. OC 10) 194.2 i 43. 7(. 9) 204,6 t 82. 1( 93
(mg/dt)
SUN 19.8 s 4.8£ 10) 15.4 ± 2.1< 10) 17.8 t 4.3C 10) 17.9 t 3.2< 9)
£mg/dl!
SG?T 27 t 3< 10) 23 * 4( 10) 34 ± 8( 9) 35 t 10< 9)*
Clu/l)
SCOT 79 ± 8( 10} 79 t 18( 10) 85 t 19( 9) 88 ± 27( 9)
T PRO 7.4 4 0.8( 10) 7.2 t 0.3( 10) 7.2 ± 0.2( 9) 7.3 t 0.5< 9)
(g/dl)
ALS 4.3 ± 0.7( 1C) 4.3 t 0.4C 10) 4.2 i 0.3C 9) 4.4 i- 0.4{ 95
(g/dl)
GLOB 3.1 t 0.3( 10) 2.8 1 O.S< 10) 3.0 * 0.3( 9) 2.9 ± 0.4( 9}
(9/dl)
AL3/GLQB 1.424 e 0.264( 10) 1.563 i 0.372C 10) 1.445 t C.194C 9) 1.566 ± Q.254< 9)
(ratio)
CHOL 100.2 ± 26. 9( 10) 74.7 ± 11. 3( 10}* 1C8.6 ±. 13. 1( 10} 103.1 * 33.2! 9)
(mg/dl)
Ca 14.8 ± 1.QC 10) 14.6 ± 2.0C 10} 15.3 a 3.7( 9) 14.9 i 1.5( f)
* - Statistically significant difference from control group
using ANOVA and Dunnett's T-Test
-------
Study No. 5221.03
TABL1 14 (continued)
SU3CHRQN1C TOXIC1TY OF PARA-CRESQL IK SPRACUE DAWLEY RATS
FEMALE CLINICAL CHEMISTRY VALUES
[Interim Sacrifice!
Parameter 0 mg/kg/day 50 m§/ki/day 175 rag/kg/day 600 Kg/kg/day
' D BIL 0.00 ± O.OK 10) 0.01 ± O.OK 10) 0.01 i O.OH 9) 0.01 ± O.OU 93
(rng/dl)
T BIL 0.14 ± 0.03C 10) 0.15 i 0.06C 10) 0.15 i C.08( 9) 0.13 t 0.04( 9)
;
-------
Study No, 5221.08
TAIL! 15
SUBCHRONIC TOXIC1TY Of PARA-CRESQL IN SPRAGUE DAytiY IATS
FEMALE CLINICAL CHEMISTRY VALUES
[Terminal Sacrifice]
Parameter 0 mg/kg/day 50 mg/kg/day 175 mg/kg/day 600 wg/kg/day
CLU 182.6 * 56. 2( 10) 236.6 * 63. 1C 10) 240.4 i 67.2C 10) 242.9 i 49. 6( 10)
(mg/dl)
BUM 14.2 ± 2.8< 105 12.4 ± 1.8( 10} 13.4 t 2.4C 10) 12.2 ± 1.8C 105
(mg/d!3
SGPT 32 i 17< 10} 38 i 29< 10) 39 t 12C 10) 158 i 195C 10)»
Uu/t)
SOOT 79 * 16< 10) 90 t 35( 10) 79 t 17< 10) 189 ± 164< 103*
du/l)
T PRO 7.4 a 0.3C 10) 7.5 i 0.7( 10) 7.5 1 0.6C 10) 7.7 i 0.3< 103
(g/dl)
ALB 4.3 t 0.4( 10) 4.5 t 0.6( 10) 4.5 t 0.5< 10) 4.6 t 0.4< 10!
GLDB 3.1 ± 0.3C 10) 3.0 t 0.2C 10) 3.0 t 0.3( 10) 3.1 t 0.3( 103
ALB/GLOB 1.440 i Q.260C 10) 1.491 i 0.16Q( 10) 1,490 i 0.187C 10) 1.513 t 0,310( 10)
(ratio)
CHOU 96.1 t 14. 0( 10) 95.2 ± 14. 3( 10) 109.5 t 22 M 103 139.0 t 43. 4C 10)*
(mg/dl)
* - Statisticalty significant difference from control group
using ANQVA and Dunnett's T-Test (P«=O.OS).
Results presented as mean ± standard deviation ( N )
35 ; 38
-------
Study No. 5221,08
TABLE 15 (continued)
SUSCHRONIC TOXICiTY OF PARA-CRESOL IN SPRAGUE DAWLEY SATS
FEMALI CLINICAL CHEMISTRY VALUES
CTerminal Sacrifice]
Parameter 0 mg/kg/day 50 nig/kg/day 175 tn$/k$/day 600 mg/kg/day
D BIl 0.01 t 0.01< 10) 0.01 i 0.01C 10) 0.02 ± 0.01( 10) 0.01 * 0.01( 10)
(mg/dl)
T BIL 0.12 i O.Q6C 10) 0.07 ± 0.06C 10) 0.15 ± Q.Q7C 10) 0.12 * 0.07< 10)
(mg/dl)
Ca 13.8 i 4.1( 9) 16.fi i 3.1{ 10) 15.3 s 3.0( 10) 17.4 * 4.7C 10)
(mg/dl)
Ha 145 i 2< 5) 144 ± 2( 63 146 i ' 2( 4) 143 4 1( 5)
{Meq/O
K 6.8 ± 0.7C 5) 7.8 ± 1.3( 6} 9.1 t 2.3( 4) 8.2 1 3.4( 5)
(Meq/l)
, -Cl 104 t 2{ 5) 104 t 1( 6) 106 ± 1< 4) 103 i. 1C 5)
(Heq/L)
ALK PHOS 57 s 23C 10) 45 i 23C 9) 55 t 38( 10) 55 S 34( 9)
Ctu/l)
CQ2 29 t 1{ S3 25 t 2< 6) 22 ± 6( 4)* 26 * 3< 5)
CHeq/t)
CREAT 0.69 t 0.10{ 10) 0.69 i 0.04C 10) 0.69 * 0.05C 103 0.67 t 0.04< 10)
(mg/dl3
PHOS 9.6 t 1.9( 10) 8.2 t 0.7< 10) 9.9 « 2,2{ 10) 9.1 ± 1.4{ 10)
(mg/dl)
LDH 218 t 107( 103 221 t 112< 10) 209 ± S8( 10) 279 ± 2C4( 10)
Clu/O
* -- Statistically significant difference from control group
using ANOVA and Dynnett's T-Test CP<=0.05).
Results presented as mean ; standard deviation < N 3
36
-------
Study No. 5221.03
TA31E 16
SUBCHRONIC TOXICITY OF PARA-CRESOL IN SPRAGUE OAWLEY RATS
RELATIVE HALE ORGAN WEIGHT DATA (% Terminal Body Weight)
[Terminal SacrificeJ
Organ
HEART
LIVES
SPLEEN
KIDNEY-LFT
KIDNEY-RT
TESTIS-LFT
TESTIS-RT
ADRENALS
BRAIN
THY. /PARA.
0 mg/kg/day
0.313 ±
3.318 i
0.142 i
0.351 t
0.357 i
0.302 i
0.3QO t
0.010 i
0.399 *
O.OQ5 ±
0.025C 20)
0.272C 20)
0.021C 20)
0.032C 20)
Q.034C 203
0.029( 20>
0,034{ 20)
0.0025 20)
Q.Q4SC 20)
O.OOK 20)
SO mg/kg/day
0.309 i
3.232 i
0.142 ±
0.373 t
0.377 t
0.323 ±
0.323 t
0.01Q i
Q.4CS ±
0.004 t
0.020C
0.242C
0.014<
C.031C
0.034(
0.032C
0.03U
O.OQ2C
0.030C
O.OOK
20)
20)
20)
20)
20)
20)
20)
19)
20)
20)
175 mg/kg/day
0.324 ±
3. SOS ±
0.138 ±
0.382 ±
0.392 ±
0.31S ±
0.321 t
0.011 t
0.419 ±
0.005 ±
0.022C
C.228C
O.C16<
0.038C
0.033(
0.035C
O.C32C
O.OD2<
0.030(
o.cou
20)
20)
20)
20)»
2Cf>»
20)
20)
20)
20)
20)
600 nig/kg/day
. 0.345
3.530
0.140
0.407
0.419
0.351
0.350
0.012
0.445
0.005
± 0.069<
i 0.244(
± 0.02U
± 0.035(
± 0.041C
i 0.048(
t 0.048C
i 0.003<
i 0.037(
t O.OOU
20)*
20)*
20)
20)*
203*
20)*
20)*
20)
20)*
20)
Statistically significant difference from control group
using AMOVA and Dunnett's T-Test (P<=0.05).
Results presented as mean t standard deviation C N )
37
-------
Study No. 5221.08
TASLE 17
SUBCHRONIC TQXICITY OF PARA-CRESOt IN SPRAGUE DAULSY RATS
RELATIVE FEHALE ORGAN UEIGHt DATA (% Ttrminal Body Weight}
[Terminal Sacrffict]
Organ
HEART
LIVER
SPLEEN
K1DNEY-LFT
K1DNEY-RT
OVARY -LFT
OVARY-RT
ADREHALS
BRAIN
THY. /PARA.
0
0.370
3.405
0.186
0.398
0.398
0.015
0.017
0.023
0.723
0.007
mg/kg/day
i 0.032C
i 0.295C
i 0.015<
± Q.Q5QC
* 0.038C
± 0.004?
± O.OOSt
i O.CC3<
i Q.06CC
1 0.002C
20)
20)
20)
20)
20)
20)
20
20)
20)
20)
50 mg/kg/day
0.378 i
3.417 t
0.204 ±
0.413 1
0.421 i
0.016 t
0,016 t
0.023 i
0.761 t
0.009 ±
0.027{
0.19K
Q.D23C
0.04K
Q.Q47C
O.OQ4C
0,005(
0.004C
0.062C
0.006C
20)
20)
203*
20)
20)
20)
20)
20)
20)
20)
175 mg/kg/day
0.3S3 *
3.346 ±
0.179 i
0.408 *
0.408 ±
0.013 ±
0.013 t
0.022 t
0.719 i
0,003 ±
0.022(
0.282C
0.032<
Q.044(
Q.046C
0.004C
Q.004C
O.OOSC
0.06SC
0.004C
20)
20)
20)
20)
20)
20)
20)
20)
20)
20)
600 mg/kg/day
0.385
3.531
0.186
0.437
0.441
0.013
0.013
0.024
0.733
0.003
i 0.077C 18)
i 0.230C 18)
± 0.020C 18)
t 0.06K 18)
i 0.053C 18)*
s O.OOSC 13)
t O.OQ6C 18)
t Q.CQ4C 18)
± 0.072C 13)
± 0.002C 13)
* -- Statistically significant difference from control group
using ANOVA and Dunnett's T-Test (P<=0.05).
Results presented as mean ± standard deviation ( H )
38
-------
Study No. 5221.08
TABLE 18
SUSCHRQNIC TQXICITY OF PARA-CRESQL IH SPRAGUE DAULEY RATS
HALE ORGAN WEIGHT DATA
0.129C 20)
0.135C 205
O.Q1K 20)
0.117C 205*
0.005( 20)
* -- Statistically significant difference from control group
using ANQVA and Dunnett's T-Test (P
-------
Study Mo. 5221.08
TABLE 19
SUBCHRQNIC TOX1CITY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
FEMALE ORGAN WEIGHT DATA (g)
[Terminal Sacrifice]
Organ
HEART
LIVER
SPLEEN
KIDNEY-LFT
KIDNEY-RT
0 VARY- L FT
OVARY -RT
AORiMAtS
BRAIN
THY. /PARA,
0 mg/kg/day
1.059 S
9.744 i
0.533 ±
1.141 i
1.138 i
0.042 ±
0.048 i
0.066 i
2.062 t
0.021 4
0.113C
0.942C
0.052C
0.154<
0.121C
O.Q12C
0.014C
Q.Q1Q<
0.097{
0.006C
20)
20)
20)
20}
20)
20)
203
20)
20)
203
50 mg/kg/day
1.041 i
9.336 i
0.562 i
1.133 i
1.155 i
0.042 i
0.045 4
0.064 ±
2.079 i
0.024 i
0.123<
O.S35(
0.07H
0.12K
0.131(
0.009C
0-.016C
0.010(
0.079C
O.Q16C
20)
205
20)
203
20)
20)
20)
20)
20)
20)
175 mg/icg/day .
1.015 ±
9.494 t
0.507 ±
1.153 t
1.155 ±
0.036 i
0.038 t
C.061 t
2.029 t
0.022 4
O.Q76C
0.974(
0.082C
0.1Q8(
0.1 07(
0.009C
0.011C
0.01K
0.033(
0.010C
20)
20)
20)
20)
20)
20)
20)
20)
20)
20)
600 nig/kg/day
1.023 *
9.361 ±
0.494 t
1-.160 i
1.170 ±
0.034 t
0.036 s
0.064 ±
1.946 t
0.022 t
0.232C 18)
0.946{ 18)
0.067C 13)
0.188C 18)
0.170< 18)
0.014C 18)
0.016C 185*
0,010< 18)
0.107( 18>*
0.007( 18)
* - Statistically significant difference from control group
using ANQVA and Dunnett's T-Test (P<=0.05).
Results presented as mean s standard deviation ( H )
-------
Study No, 5221.08
TABLE 20
SUECHEONIC TQXZeTTY OF PARA-CRESOL IN SPRAGUE DAWLE₯ RATS
HISTOPATHOLOGY LESIONS
Dose fina/kcr/dav)
50
175
600
Kidney-Chronic Nephrooathv
Males
Present
Absent
Males
Present
Absent
Females
Present
Absent
4 11*
IS 9
Trachea-
0 0
20 20
0 1
20 19
7
13
-Epithelial Netaolasia
1
19
1
19
12*
8
10*
10
9*
10
* = Significantly different from control group using
Fishers Exact Test (p < 0.05).
1*1
-------
Table 21a
Subchrom'c Toxicity Study of
Para-Cresol in Sprague Dauley Rats
Hale Clinical Chemistry
Baseline Values
Study Ho. 5221.08
ANIHAl
TPRO
BALB
GLOB
BUM
CREA GLUC
TBIL
DBIL
AST
AIT
CHOI
AtP
PHQS
CALC
CL
C02
0 mg/kg
3781
3782
3783
3784
^ 3785
3786
37B7
3788
3789
3790
MEAN
STD
6.0
6.2
5.8
5.8
6.0
5.5
5.6
5.8
5.7
6.2
5.9
0.2
3.9
4.0
3.7
3.5
4.1
3.7
3.6
3.7
3.6
3.9
3.8
0.2
2.1
2.2
2.1
Z.3
1.9
1.8
2.0
2.1
2.1
2.3
2.1
0.2
29.6
18.5
20.9
10.2
17.4
15.6
16.4
21.8
15.1
21.5
18.7
5.2
0.81
0.65
0.63
0.63
0.60
0.61
0.49
0.54
0.57
0.60
0.61
0.08
205.8
107.1
170.0
110.1
1B0.4
189.4
124.6
202.4
108.4
190.9
158.9
41.4
0.29
0.24
0.25
0.23
0.22
0.18
0.24
0.25
0.19
0.23
0.23
0.03
0.11
0.15
0.05
0.09
0.08
0.07
0.13
0.12
0.08
0.08
0.10
0.03
82
69
71
80
66
72
86
79
74
95
77
9
52
38
46
29
28
36
41
36
37
52
40
8
50.9
65.9
65.7
56.7
64.4
47.5
75.0
71.9
47.7
48.3
59.4
10.5
370
174
138
206
251
236
191
176
323
272
234
72
13.0
13.9
13.3
12.2
13.2
12.5
13.3
12.3
12.6
13.8
13.0
0.6
10.1
11.7
11.4
10.8
11.0
11.1
11.1
12.1
11.3
11.9
11.3
0.6
9.4
9.1
8.6
7.4
9.3
8.4
10.9
9.4
9.6
10.5
9.3
1.0
143
144
149
140
142
142
141
142
141
140
142
3
102
103
108
100
103
102
100
102
101
99
102
2
31
31
30
30
30
32
26
27
24
25
29
3
-------
Study No. 5221.08
Table 21b
Subehronic Toxicity Study of
Para-Cresol in Sprague Dawley Rats
Female Clinical Chemistry
Baseline Values
ANIMAL TPRO BALB GLOB BUN CREA GLUC TB1L DBIL AST ALT CHOL ALP PHOS CALC K NA CL C02
0 mg/kg
3911
3912
3913
3914
3915
w 3'16
3917
3918
3919
3920
HEAH
STD
6.4
6.1
6.8
6.3
6.1
6.0
6.4
6,2
5.8
6.2
6.2
0.3
4.2
4.0
4.6
4,1
4,0
4.2
4.3
4.1
3.9
4.2
4.2
0.2
2.2
2.1
2.2
2.2
2.1
1.8
2.1
2.1
1.9
2.0
2.1
0.1
22.6
20.2
17.3
16.9
19.6
23.2
21.2
15.6
15.5
19.3
19.1
2.8
0.52
0.52
0.66
0.53
0.51
0.53
0.58
0.56
0.49
0.58
0.55
0.05
187.4
219.4
173.8
113.5
134.5
250.7
255.3
139.5
178.9
136.7
178.9
49.6
0.19
0.18
0.21
0.20
0.21
0.16
0.19
0.17
0.17
0.22
0.19
0.02
0.08
0.14
0.04
0.08
0.10
0.07
0.07
0.04
0.07
0.07
0.08
0.03
65
87
62
67
74
77
53
71
63
67
69
9
35
54
21
32
36
48
23
32
41
41
36
10
98.7
68.7
84.0
120.2
100.8
67.6
87.5
103.2
72.2
75.6
87.9
17.5
77
233
163
241
146
271
192
265
141
22!
195
63
11.3
12.3
11.8
11.5
11.4
11.4
11.1
11.2
11.8
12.0
11.6
0.4
11.6
11.7
11.8
11.7
11.0
11.4
12.0
11.7
12.6
11.8
11.7
0.4
9.4
7.9
a. a
8.9
10.1
a.a
9.3
9.8
7.4
7.9
8.8
0.9
140
123
142
142
136
139
141
141
102
143
135
13
101
87
100
103
99
101
101
106
66
108
97
12
26
15
24
22
19
20
21
21
18
23
21
3
-------
Study No, 5221.08
Table 22a
Subchronlc Toxlcity Study of
Para-Cresol in Sprague Oauley Rats
Hale Hematology
Baseline Values
ANSMAl UBC SEGS BANDS LYMPHS MONO EOS PT APTT
0 rog/kg
3781
3782
3783
3784
3785
3786
3787
3788
3789
3790
MEAN
STD
12.8
12.0
17.8
12.7
17.5
15.8
13.0
16.1
13.0
13.2
14.4
2.2
20
6
15
18
17
12
4
10
15
16
13
5
0
0
0
0
0
0
0
0
0
0
0
0
78
85
64
76
83
84
92
86
82
82
83
4
2
8
1
6
0
2
3
4
2
2
3
2
0
1
0
0
0
2
1
0
1
0
1
1
11.5
11.9
10.8
11.5
11.7
12.1
11.1
12.8
12.3
11.9
11.8
0.6 ,
13.2
15.2
15.4
18.4
22.4
15.8
18.1
25.1
24.2
19.4
18.7
4.1
-------
Study No. 5221.08
Table 22b
Subchronic Toxicity Study of
Para-Cresol in Sprague Dawley Rats
Female Heraatology
Saseline Values
ANIMAL
W8C
SEGS
BANDS UYHPHS
HONO
EOS
PT
APT!
0 rng/kg
3911
3912
3913
3914
3915
3916
3917
3918
3919
3920
MEAN
STD
14.4
17,7
13.1
13,8
9.5
13.9
10.5
18.1
16.4
15.6
14.3
2. S
14
22
13
11
7
13
11
10
4
8
11
5
0
0
0
0
1
0
0
a
0
0
0
0
86
73
84
84
89
87
83
87
96
92
87
5
0
0
2
4
3
0
1
1
0
0
1
1
0
0
1
1
0
0
0
2
0
0
0
1
11.5
11.7
11.2
11.1
10.9
10.8
11.2
11.0
11.4
11.6
11.3
0.3
23.4
25.4
27.4
23. 3
17.2
17.8
18.8
19.9
24.9
28.0
22.6
3.9
48
-------
Experiment Number 5221.08
SUECHRONIC TOXICTTY OF PARA.-CRSSOL IN
SFRAGUE DAWIZY RATS
I. RIRPCSS
The purpose of this study is to determine the toxic effects of
jxxesol when administered by gavage for 13 weeks to Sprague Cawley
rats.
II. SPONSOR AND TESTING FACILITY
A. Sponsor Name: Research Triangle Institute (KIT)
B. Sronsor Authorization Date: 12 July 1985
C. Protocol Approval _Date_:_ (Sea last page)
D. Testing Facility: I-Hcrcbiological Associates Inc. ,
5221 River Hoad
Bethesda, Maryland 20816
E. Principal Investigator f Study Director) : Louis T. Mulligan, Ph.D.
F. Toxicolcaist: Barry S. Levine, D.Sc., D.A.3.T.
7TT. TEST S
A. Scheduled Initiation Date: 15 October 19S5
B. Prcccsei ^Termination .Data: 15 January 19S5
-------
Experiment Number 5221.03
IV. TEST
A. Name: p-cresol
B. Source and Manufacturer
Source: Eastman Kodak Company
Rochester, NY 14650
Kanufacturer: To be supplied
Lot No. : A-13-A
Batch No. : None
Purity: 99% +
In-house Chemical No. : 25
C. Safety Precautions
1. Personnel Protection
Eye: Safety goggles
Gloves: Two pairs of gloves should be worn when
handling the neat chemical; one pair of
gloves should be worn when handling dose
preparations .
Clothing: Protective laboratory clothing will be
worn when handling dose preparations or
neat chemical.
Ventilation: Handling of open dosage containers
or chemical should be conducted in a
properly vented hood.
Respirator: A respirator fitted with an organic
vapor (or organic vapor/acid vapor)
cartridge equipped with a particulata
filter will be used at all times when
working with open containers and when
working in rooms with animals dosed
with this chemical.
-------
Exceriment Number 5221.08
Spills and Leakage
Persons not wearing' the appropriate protective
equipment and clothing should be restricted from
areas of spills or leaks until cleanup has been
completed.
If p-cresol or solutions of it are spilled the following
steps should be taken;
a. Ventilate area of spill. Eliminate all heat
and ignition sources.
b. Use vermiculite, sodium bicarbonate, sand, or
paper towels to absorb the oil.
c. Wash area with detergent and water or MiJcrc
klene and water. Rinse well with water.
d. Dispose of all .material in the cleanup as
hazardous waste.
Wasta srd. Disposal Prccadures
Securely package and label, in double bags, all
solid waste material and dispose of by
incineration or by burial at a secured landfill.
Dispose of liquid waste in liquid hazardous waste
drums.
Prsparation_of_Cpses
Doses will be prepared in the Carcinogen Handling
Boom, 3rd floor, 5221 River 3cad, Bethesda, MD 2Q31S.
-------
Experiment Number 5221.03
5. Analysis of Solutions
The stability of the test solution will be determined
after storage for the same period and under the same
condition to be used in the study.
The accuracy of formulation will be checked by analysis
of samples taken from solutions prepared for administration
durirg weeks 1, 2, 4, 8 and 13 of treatment.
V. TEST SYSTEMS
A. Animals
1. Strain/Species: Sprague Cawley Fats
2. Number/Sex: 130 males/130 females
3. Age: 5-6 weeks old at start of dosing
4. Supplier: Charles River Breeding Laboratories
Lakeview, NY
5. Justification of Test Animal: The test animal (Sprague
Dawley Eats) was specified by the sponsor and is a routine
laboratory animal utilized in small rodent subchronic toxicology
studies.
VI. HOUSING
The animals will be individually housed in polycarbonate slice boxes
marked with a test article code and held on stainless steel racks
equipped with an automatic watering system. Keat treated hardwood
chips will, be used for cage beiiirg* Backs will be periodically
repcsitioned within the rocra to minimize any effect of variation in
light intensity, temperature, etc.
VH. ANIMAL ENVIRONMENT
A. Temperature: 72° ± 3°F
B. Humidity: 50 ± 15%
C. Light Cycle: 12 hcur cycle
D. Water: Washington Suburban Sanitary Cormissicn Fotonac
Plant; untreated; ad libitum.
-------
vm.
Experiment Number 3221,08
E. Fead: Purina standard, lab chew.
?. Cage Change Schedule: Cages will be changed every other week.
G. Feeder Change Schedule: Cnce weekly.
H. Rack Changes: Every other week.
I. Air Charge: At least 12-15 per hour.
J. Bedding Changes: Twice weekly. "
K. It is not expected that there are contaminants in the feed or
water which would have any influence on the study.
A. Animals will be maintained in quarantine for 12-16 days. The
cleaning, feeding and watering procedures will be the same as
described above for the tast period. Aniarals will be group
housed during the quarantine period, but individually housed at ,
test animal selection.
B. Animals will be observed twice daily for signs of illness or
death and all unusual observations will be reported to the Principal
Investigator or Director of Veterinary Medicine.
C. Animals will be examined during quarantine and approved for use
by the Director of Veterinary Medicine prior to being placed on
tast. Health Status Evaluation form SA/QA 11 will be completed
by the Study Director and Director of Veterinary Medicine.
IX. RANDCMI2ATTCN', ANTMAL NUMBERING, STATISTICAL ANALYSTS
A. Randcmizaticn: During the quarantine period, the animals will be
randomized as follows: Starting with one sex of the species to
be rardcmized, each animal will be weighed, placed into individually
numbered cages and separated into one of a number of weight range
groups which ara based en successive intervals of 5 grains. The
weight of each is recorded en paper. After all anir?als have been
placed into their appropriate weight range groups, 130 of the
aniirals with weights closest to the median weight will be randomized.
Outliers will be used for health check evaluation and baseline
evaluations or killed.
After the appropriate number of animals per sex have been selected,
a random number table will be coirpitar generated for each sex and
used to allocate animals to a treatment group. ^ e*.
*" * i
-------
Experiment Number 5221.08
B. Numbering: Animals will be uniquely consecutively numbered using
ear tags.
C. Statistics: The data will be examined using analysis of variance
techniques followed by a multiple comparison procedure for
detecting differences between pairs of means. Some pathology and
clinical data may require nonparametric techniques to aid in
interpretation.
X. EXPERIMENTAL METHODS
A, Dosing
1. Route: Gavage (specified by sponsor)
2. Vehicle: Corn Oil
3. frequency: Daily, approximately the same time each day,
7 days a week, for a period of thirteen weeks or
until sacrifice.
4. Dosage Volume: Five (5) ml/kg calculated on animal's most
recent body weight.
5. Controls: Receive vehicle alone at the same dosage volume
as treated animals.
6. Mixing Frequency: Dosing solutions will be mixed on a weekly
basis.
THIS PAGE REVISED
Signature
Date
MICROBIOLOGICAL
ASSOCIATES INC.
-------
Experiment Number 5221.08
B. Treatment Groucs
will be randomly assigned to groups with the following
design:
Group
1
2
3
4
5
Number of Animals
Treatment
Negative control
p-cresol
p-cresol
p-cresol
Baseline clinical
pathology
Dose Level
f-mq/ka/day)
50
175
600
_
Male
30
30
30
30
10
Feruale
30
30
30
30
10
The ten male and ten female animals in group £5 will be sacrificed
prior to study initiation for collection of baseline data on
heTtiatology and serum chemistry.
Ten zala and ten female animals {selected prior to initation of
the study) from each remaining group will be sacrificed at 45-days
post-treat-nent initiation for clinical pathology and collection
of tissues for pcssbile later evaluation. The following organs
will be weighed: heart, liver, spleen, brain, kidneys (individually),
gcnads (individually) , adrenals and thyroid/parathyroid.
C. Clinical^ Observations
,
1. Animals will be observed twice daily (once in the iroming and
once in afternoon) seven days per week for Trcribundity/mcrtality.
Moribund animals unlikely to survive until the next observation
will be sacrificed and necropsied immediately.
2. Each animal will be examined weekly for clinical signs of
° toxicity .
3. Signs of toxicity noted at other times will, be recorded en
room schedules and transferred to the observation sheet if they
persist,
4. Animal Weights - Individual animal weights for test and control
groups will be recorded at initiation (day 1) and weekly
thereafter.
-------
Experiment Number 5221.08
5. Individual feed consumptions will be derived by calculating
the difference in weight of each feed jar plus contents at
the beginning and end of the feeding interval and dividing by
the number of days involved.
D. Cphthalmoscopy
Funduscopic (indirect opthalmosccpy) examination will be
performed pretreatment and at termination on all animals
designated to be terminated at 13-weeks.
E. Clinical_ Pathology
1. The following hematology (all animals fasted overnight) will
be performed on the 20 animals designated for baseline values
(day 1), on 10 males and 10 females/group designated to be
sacrificed at 45 days and on 10 males and 10 females/group
designated to be sacrificed at termination of the study:
Hemoglobin
Hematocrit
Erythrocyte count
Total and differential leukocyte count
Prothrombin time (FT)
Activated partial thromboplastin time (APTT)
Reticulocyte count
2. The following clinical chemistry will be determined on serum
samples per the hematology schedule:
Sodium
Chloride
Potassium
Calcium
Phosphorus
Blood creatinine
C02
SGPT
SCOT
Glucose
BUN
Direct and total bilirubin
SAP
Total cholesterol
THIS PAGE REVISED
Albumin
Globulin
Total protein
Study No,
Signelure Data
MICROBIOLOGICAL
ASSOCIATES INC.
-------
Experinent Number 5221.08
3. Urinalysis will be determined en days 45 and 90 as cutlinedfor
clinical chemistry. The following parameters will be measured:
Specific gravity
pH
Protein
Glucose
Ketones
Bilirubin
Urobilincgen
Microscopic examination
F. yecrqcsv and Histccatholcqv
1. A ccmplete, detailed necropsy will be performed on all animals,
2. Animals that die or are sacrificed prior to the scheduled
sacrifice will ba necrcpsied as soon as possible after death.
Animals that can not be necrcpsied irroediately will be stored
in a refrigerator until necropsy but no longer than 24 hours,
3, Fran all animals on study, except those designated for baseline
clinical chemistry the following tissues will be collected
and preserved in buffered formalin.
All gross lesions Corpus and cervix uteri
3rain (3 levels) Spleen
Eye Eone (with marrow)
Pituitary Skeletal irtuscle
Salivary gland Lynch node
Heart . Spinal cord
Thymns Mammary gland
Thyroid (with parathyroid) Aorta
lungs (with itainstem bronchi) Sciatic nerve
Trachea
Esophagus
Stomach
Small and large intestine
Adrenals
Pancreas
Liver
Kidneys
Urinary bladder
Testas
Prostate
Ovaries
-------
G.
Exserizent Number 5221. OS
Kistcpathological evaluation will be performed on all abnormal
tissues and lesions of all animals on study. All listed
tissues will be saved from all rats at the 45-day sacrifice
for possible future evaluation. All the above listed tissues
will be evaluated on all animals sacrif icad because of a moribund
condition, those that die on test, and all control and high-
dose animals sacrificed at the 13 week termination.
Histopathology in the mid and low dose groups will only fce
required for "gross lesions and apparent target organs. Target
organs will be determined frem previous studies, clinical .
data., and the histopathology in the high-dose level group.
All lesions will be rated according to their severity.
At terminal sacrifice, in addition to terminal body weight,
the heart, liver, spleen, brain, kidneys (individually) ,
gonads (individually) , adrenala and thyroid/parathroid will
be weighed to three significant figures. Organ weight to
body weight ratios will be corouted.
In general, the data will be examined using analysis of variance.^
techniques followed by a multiple ccncarison procedure for detecting
differences between pairs of means. Seine anatomical and clinical
pathology data may require nonpsrairietric techniques to aid in
interpretation.
H. Data
Abnormal observations, body weights, feed consumptions, dose
formulation documentation, and general study Garments will be
recorded in laboratory notebooks. Clinical laboratory data
will be recorded in notebooks or will be direct instrument or
ccnaputer output. Pathology data, including organ weights, will
be recorded on individual locse-leaf pathology sheets (one per
animal). At the completion of the study, all data and specimens
will be transferred to the Quality Assurance Unit for storage in
the test laboratory archives.
The following data will be collected and included in the final report:
o Sections on introduction, materials and methods, conclusions arxi
discussion
o Results of all chemical analyses
o Abnormal appearance or behavior
o Individual and loean body weights initially and weekly through
13 weeks
a Sfisults of the ciphtralmological examination .. ? c.
-------
Experiment Number 5221.08
o Individual and icean hematology, blood chemistry and urinalysis
as outlined.
o Individual and mean organ weights (heart, liver, spleen, brain,
kidneys, gcnads, adrenals, and thyroid/parathyroid) from all
animals at termination
o Individual necropsy observations of all anirrals
o Individual histcpatholcgy of tissues as outlined.
XI. RECORDS TO 35 MAINTAINED
All raw data pertaining to the conduct of this study including the
final report will be retained as the regulations require in the
archives at Microbiological Associates Inc., 5221 River Read, Eethesda,
MD 20816. If at sane time in the future any of these data are to be
discarded, the sponsor will be first notified to obtain perimission.
XII.
XIH.
All procedures not specified in this protocol will be performed in
accordance with the Microbiological Associates Inc. Standard Operating
Procedures' Manual and in compliance with the FDA's Good Laboratory -
Practice Regulations.
Alterations of the study may be made after the study has been initiated.
In the event that the sponsor verbally authorizes a change in protocol,
such change will be honored by Microbiological Associates Inc.
However, it is then the responsibility of the sponsor to produce
written verification of the verbal authorization, which will result
in the issuance of an official protocol amendment.
1. L.T. Mulligan, Fh.D: Principal Investigator/Study Director
2. Barry S. Lsvine, D.Sc. , D.A.3.T.: Tcxicologist
3. Ducas H. Erennecke, V.M.D., Ph.D.: Veterinary Pathologist
4. John Miller, DVM, ACLAM: laboratory Animal Veterinarian
5. Harold J. Paulin, M.S., demist
6. Jean L. Causer, 3.S.: Operations Supervisor
7. Nona S. Karten, M.A. : Quality Assurance
-------
Excerisent Number 5221.08
XIV. REFERENCES
1. Contract with Research Triangle Institute.
L.T. Mulligari, Ph.D. ( Sponsor
Principal Investigator
Cata Eate
.12
-------
ORIGINAL
PROTOCOL AMENDMENT
Date: October 16, 1985
Study No.: 5221.08
Title: Subchronic Toxicity of Para-Cresol in Sprague Dawley Eats
Amendment:
1. Page 7, Part X, Section B; Treatment Groups: Delete the following
sentence. "The following organs will be weighed: heart, liver, spleen,
brain, kidneys (individually) , gonads (individually) , adrenals and thyroid/
parathyroid.
Reason: Per discussion with the Sponsor, organ weights are not necessary
at the 45-day interim kill.
2. Page 3, Part X, Section E, No. 1: Add prothracbin t.jjra (PT) and activated
partial thromboplastin fri-m* (APTT) , and delete platelet count.
Reason: PT and APTT are better estimates of clotting potential than
platelet count.
Study DirectorL Date
Sponsor Approval ^"^ Date
Gi
-------
OR GiNAL
PROTOCOL AMENDMENT
Date: November 26, 1985
Study No.: 5221.08
Title: Subchronic Toxicity of Para-Cresol in Sprague Dawley Rats
Amendment:
3. Page 5, Part VII, Section E, Feed: Substitute "Purina standard lab chow*'
with "Purina Rodent Chew No. 5001."
Reason: Omitted in protocol.
4. Page 5, Part VII: Add the following: Section L. Room Number: Roam #371
Reason: Not included in protocol.
5. Page 5, Part VIII, Quarantine, Section B: Unusual observations
during the quarantine period can also be reported to the Study lexicologist.
Reason: Omitted in protocol.
6. Page 9, Part X, Section F, No.2: If necessary, .animals which die on test
are stored in a refrigerator unitl necropsy but no longer than 16 hours.
Reason: Incorrectly stated as 24 hours in protocol.
7. Page 11, Part XIII, No. 3: Change the Veterinary Pathologist to
"Dr. Diana Copeland, Diplcmate, ACVP."
Reason: This is necessary to finish all four RTI study reports on time.
Date
Sponsor Approval Date
-------
QUALITY ASSURANCE STATEMENT
Study Title: SUBCHRONIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
Study Number: 5221.08
Study Director: Louis T. Mulligan, Ph.D.
Initiation Date: October 16, 1985
Review Completed Date: September 30, 1986
This study has been divided into a series of phases. losing a
random sampling approach, Quality Assurance monitors each of
these phases over a series of studies. Procedures, documenta-
tion, equipment, etc., are examined in order to assure that the
study is performed in accordance with the U.S. FDA Good
Laboratory Practice regulations (21CFR58), the U.S. EPA GLPs
[40CFR792 and 40CFR160), and the OECD guidelines and to assure
that the study is conducted according to the protocol.
The following are the inspection dates, phases inspected, and
report dates of QA inspections of the study.
INSPECT ON 85/10/28 - 85/10/23,TO STUDY DIR 85/10/28,TO MGMT 85/10/28
PHASES: PROTOCOL REVIEW
INSPECT ON 85/12/03 - 85/12/03, TO STUDY DIR 85/12/03,TO MGMT 85/12/09
PHASES: CLINICAL CHEMISTRY
INSPECT 0« 86/04/14 - 86/04/16,TO STUDY DIR 86/04/16,TO MGMT 86/09/29
PHASES: DATA REVIEW
INSPECT ON 86/09/25 - 86/09/29,TO STUDY DIR 86/09/29,TO MGMT 86/09/30
PHASES: FINAL REPORT
This report describes the methods and procedures used in the
study and the reported results accurately reflect the raw data
of the study.
AssranceDate
R"A/QA Department
-------
-------
Study No. 5221,08
APPENDIX A
TWO-WEEK RANGE-FTNDING/EXPIJDRATORY STUDY CF FARA-CRESOL
IN SERAGUE DANLEY RATS
64
A"L MICROBIOLOGICAL
ASSOCIATES INC.
-------
>
INJ
Study Ho. 5221.08
TUO WEEK RAMGE-FIMDIHG/EXPIORATQRY STUDY Of PARA-CRESOL \ti SPRAGUE DAULEY RATS
HALE BODY HEIGHT DATA *
DAY 9 Z46.6 t B.1< 10) 253.1 t 14.4( 10) 240.8 t 20.2( 10) 233.3 t 14.1( 10) 210.7 * 12.?( 10)*
DAY 14 281.9 t 9.8( 10) 287.5 t 17.2( 10) 273.8 t 22.7< 10) 269.3 t 15.7( 9) 242.9 t 20.7( 10)*
* -- Statistically significant difference from control group
using ANOVA and Dunnett's T-Test
-------
Study No. 5221.00
TWO WEEK RANGE-F1ND1NG/EXPLORATORY STUDY OF PARA-CRESOL IN SPftAGUE DAULEY RATS
FEMALE BODY WEIGHT DATA (g)
TEST
DAY
0 mg/kg/day
100 mg/kg/day
200 rag/ kg/day
400 rog/kg/day
800 mg/kg/day
DAY 1 131.7 t 5.3C 10} 134.Z ± 5.6( 10) 133.3 ± 5.1( 10) 130.5 * 4.9( 10) 131.6 ± 5.2{ 10)
DAY 5 150.1 t 5.5< 10) 152.7 i 8.0( 10) 150.2 ± 6.0( 10) 143.6 t 7.8C 10) 130.5 ± 9.8( fl)*
DAY 9 164.6 ± 8.6{ 10) 165.5 t 7.7( 10) 165.9 t 6.7( 10) 158.5 t 9.0( 10) 150.3 * 10.4( B)*
DAY 14 179.6 ± 11.5( 10) 132.3 t B.0( 10) 179.7 t B.7( 10) 174.6 i 12.6( 10) 167.7 t 10.1( 8)
- Statistically significant difference from control group
using ANOVA and Dunnett's T-Test (P<=0.05).
Results presented as mean ± standard deviation ( N )
-------
Study No. 5221.OB
TWO WEEK RANGE-FINOING/EXPLORATORY STUDY OF PAHA-CRESQL IN SPRAGUE DAULEt RATS
MALE FOOD CONSUMPTION DATA (g/day)
TEST
DAY 0 ing/kg/day 100 nig/kg/day 200 mg/kg/day 400 mg/kg/day 800 mg/kf/day
Day 5 22.2 t 2.0( 10) 22.0 t 2.5C 105 21.8 i 2.7( 10) 19.1 ± 4.3{ 10) 14.4 t 3.2( 10)*
Day 9 Z1.5 t 1.6( 10) 19.7 ± 5.7( 10) 19.8 t 3.5C 10) 20.4 i 3.2< 10) 18.8 t 1.7( 10)
Cay 14 24.0 i 2.2( 10) 24.0 ± t.4< 10) 23.4 i 2.8{ 10) 23.7 ± 2.0( 9) 21.7 * 3.9{ 10)
Statistically significant difference from control group
using ANOVA and Ounnett's T-Test (P<=0.05).
Results presented as mean t standard deviation { H )
-------
Study Mo. 5221,08
TUO UEEK RANGE-FINDING/EXPLORATORY STUDY OF PARA-CRESOL IN SPRAGUE DAHLEY RATS
FEMALE FOOD CONSUMPTION DATA (g/day)
Test
Day
Day 5
Day 9
Day 14
0 wg/kg/day 100 mg/kg/day 200 mg/kg/day 400 ma/kg/day
16.5 * 2.4( 10) 16.6 t 2.4( 10) 16.5 t 2. 1C 10) 15.0 t 2.0(
14.1 ± 3.1< 10} 14.2 t 1.9( 10) 14.6 t 1.2C 10) 14.5 t 2.0(
17.4 i 5.9( 10) 16.2 * 1.6( 10) 16.1 t 1.5( 10) 15.5 t 1 .6(
10)
10)
9)
800 mg/kg/day
10.1 t 5.0( 10)*
14.0 t 1.1( 8)
15.4 ± 1.2C 8)
* Statistically significant difference front control group
using ANOVA and Ounnett's f-Test (P<=0.05).
Results presented as mean * standard deviation { M )
GO
-------
Study No. 5221.08
TWO WEEK RANGE-FINDtNG/EXPLQRATORY STUDY OF PARA-CRESOL IN SPRAGUE 0AULEY RATS
MALE BODY WEIGHT DATA (g)
ANIMAL NUMBER DAY 1 DAY 5 DAY 9 DAY 14
DOSE LEVEL
0 ing/kg/day
100 mg/kg/day
200 rng/kg/day
400 mg/kg/day
2401
2402
2403
2404
2405
2406
2407
2408
2409
2410
2411
2412
2413
2414
2415
2416
2417
2418
2419
2420
2421
2422
2423
2424
2425
2426
2427
2428
2429
2430
2431
2432
2433
2434
2435
2436
2437
2438
2439
2440
179.4
181.5
198.8
177.0
175.0
182.8
179.5
186.2
184.4
188.8
186.1
133.5
182.2
184.1
183.7
189.5
187.1
177.1
210.8
192. B
174.3
176.1
171.8
176.7
169.9
196.4
176.6
177.1
191.3
173.5
171.5
188.7
176.1
188.5
189.6
190.9
175.7
185,7
176.7
182.5
203,7
206.3
216.3
203.4
205.5
218.8
211.3
217.0
222.9
218.7
216.5
216.1
212.1
210.1
214.8
220.7
214.9
208.0
248.5
223.2
203.9
202.0
193.7
203.7
197.9
231.5
200.1
210. S
232.1
203.3
177.6
212.9
206.3
215.2
200.5
221.9
188.2
214.3
214.1
200.5
235.5
242.6
250.8
234.3
243.7
250.1
244.7
250.1
260.1
254.4
252. 3
249.6
248.5
247.4
240.1
249.8
251.1
233.2
283.2
266.3
229.5
230.9
218.7
235.6
233.5
273.5
223.2
243. S
279.4
239,6
209.9
246,6
234.4
241.9
226.0
250.1
217.9
243.6
243.3
219.1
264.5
281.7
283.7
270.3
284. 1
264. 3
2B5.7
277.9
301.2
285.8
290.3
286.7
283.9
288.2
-276.3
281.3
264,8
276.5
328.9
293.2
263.2
260.1
243.3
275.5
266.3
306.7
262.4
278.0
318.7
264.3
244.3
282.7
269.3
274.3
254.5
294.2
dead
278.7
270.4
254.6
A-6
6
9
-------
Study No. 5221,08
TUO WEEK RANGE-FINDING/EXPLORATORY STUDY OF PARA-CRESOL IN SPRAGU6 DAULEY RATS
MALS BODY WEIGHT DATA (g)
ANIMAL NUMBER DAY 1 DAY 5 DAY 9 DAY 14
DOSE LEVEL
800 mg/kg/day
2441
2442
2443
2444
2445
2446
2447
2443
2449
2450
167,0
182.4
179.4
172.6
187.2
1SS.2
184.4
172.2
183.1
185.6
172.8
156.4
176.2
150.6
172.8
202.9
190.6
176.6
190.1
194.4
202.6
216.3
209.7
192. a
194.1
232.5
213.0
204.5
216.7
225.2
193.1
248.2
251.6
230.1
234.2
270.5
247.4
246.0
253. 1
254.4
7 0
-------
Study Mo. 5221.08
T'WO UEEK RANGE-FIND IMG/EXPLORATORY STUDY OF PARA-CRESOL IN SPRAGUE OAWIEY RATS
FEMALE BODY UflGHT DATA (g)
AN[HAL NUMBER DAY 1 DAY 5 DAY 9 DAY 14
DOSE LEVEL
0 ng/kg/day
100 mg/kg/day
200 mg/kg/day
400 mg/kg/day
2451
2452
2453
2454
2455
2456
2457
245fl
2459
2460
2461
2462
2463
2464
2465
2466
2467
2463
2469
2470
2471
H472
2473
2474
2475
2476
2477
2478
2479
2480
2481
2432
2483
2484
2485
2486
2487
2488
2489
2490
125,3
129.0
122.4
130.2
131.4
132.7
132.6
139.8
135.8
137.6
137.9
129.1
128.1
135.3
125.4
136.7
132-7'
137.7
135.2
144.4
127.0
127.5
134.9
128,3
131.3
133.2
132.6
135.4
141.4
141.2
122.9
125.4
126.8
129.2
132.2
128.7
132.2
132,4
136.3
13B.8
141.6
153.5
145.4
149.2
150.6
146.8
U5.2
153.1
154.0
157.0
153.6
148.2
146.3
157.1
143.5
148.0
153.9
166.0
145.0
165.0
141.8
146.4
152.1
142.5
146.6
149.9
155.4
150.5
156.9
160.0
139.0
143.3
138.2
144.3
144.0
142.1
144.7
130.0
151.0
159.6
157.2
170.9
160.0
159.2
166.7
154.9
153.7
177.0
172.4
174.3
166.1
163.6
160.0
176.5
160.0
160.2
163.0
167.4
181.0
157.0
153.6
166.7
169.3
156.7
163.7
168.0
171.5
165.2
167.8
176.3
147.9
152.0
154.0
157.5
158.4
156.8
166.3
150.0
163.3
178.4
178.2
183.5
177.7
174.0
179.9
160.3
164.0
194.2
191.2
192.6
179.7
183.3
172.7
192.0
180.1
176.9
181.7
197.0
172.0
188.0
161.0
179.3
185.3
176. S
173.8
182.8
"185.9
175.4
185.1
192.1
161.4
161.1
178.5
164.2
179.8
172.5
191.2
165.3
174.1
198.1
A-8
-------
Study No. 5221.08
TUO UEEK SANGS-FiNOING/EXPLORATORY STUDY OF PARA-CRESCl IN SPRAGUE DAWLEY RATS
FEMALE BODY WEIGHT DATA
ANIMAL NUMBER DAY 1 DAY 5 DAY 9 DAY 14
DOSE LEVEL
800 mg/fcg/day
2491
2492
2493
2494
2495
2496
2497
2498
2499
2500
128.4
133.3
124.5
123.3
136.7
130.0
129.9
134.7
137.5
137.9
127.2
138.2
131.1
115.6
135.5
137.6
117.4
dead
141.8
dead
153.7
152.7
142,9
135.9
155.9
159.7
137.6
dead
164.2
dead
170.8
172.2
163.1
159.7
169.0
180.3
149.0
dead
177.2
dead
A-9 < 7 2
-------
Study No. 5231.03
TWO WEEK RANGE-FINDING/EXPLORATORY STUDY QF .PARA-CRESOL IN SPRAGUE DAWL6Y RATS
HALE FOOD CONSUMPTION DATA (g/day)
AHIHAL NUMBER Day S Oay 9 Day 14
DOSE LEVEL
0 mg/kg/day
100 mg/kg/day
200 mg/kg/day
400 mg/kg/day
2401
2402
2403
2404
2405
2406
24C7
2408
2409
2410
2411
2412
2413
2414
2415
2416
2417
2418
2419
2420
2421
2422
2423
2424
2425
2426
2427
2428
2429
2430
2431
2432
2433
2434
2435
2436
2437
2438
2439
2440
17.7
23.1
22.9
20.0
22.9
24.3
21.3
22.3
23.6
23.8
22.8
21.2
21.9
22.0
15.7
24. D
22.0
21.8
24.9
23.7
21.4
21.9
13. 2
21.9
22.1
26.8
13.5
22.1
25.4
20.2
15.7
21.7
20. 3
22.4
17.1
26.3
10.8
20.6
19.2
16,1
20.9
21.6
21.8
18-5
23,4
21.8
20.4
20.2
22.5
23,9
23.0
4.3
20.0
19,8
19,8
21.3
22.0
19.3
23.6
23.9
17.8
18.0
15.6
20.7
20.0
25. 8
15.5
19.2
25.4
19.6
17.5
19.8
20.0
18.5
18.1
25.1
18.2
23.8
25.6
17.1
22.4
24.3
23.3
20. 1
26.1
24.7
24.3
21.8
26.0
27.4
23.5
22.5
23.7
24.6
23.5
23.5
24.0
22.2
26.5
26.2
23.1
21,0
18.7
23.1
22.8
28.1
23.9
23.4
27.7
21.8
22.5
24.9
24.6
22.1
21.5
27.4
na
24.6
24.1
21.4
" 10
-------
Study No. 5221.03
TWO-U£EK RANGE-FI Mf> I HE/EXPLORATORY STUDY OF PARA-CRESOl IN SPRAGUE DAULEY RATS
KALE FOOD CONSUMPTION DATA (g/day)
ANIMAL NUMBER D'ay 5 Day 9 Day 14
OOSE LEVEL
800 mg/kg/day
2441
2442
2443
2444
2445
2446
2447
2443
2449
2450
15.6
17.9
11.2
8.5
10.3
18.0
15.6
16.7
15.4
14.4
17.0
21.9
18.1
19.2
16.7
17.3
20.0
17.8
20.7
19.8
. 11.2
24.2
21.7
23.0
21.6
23.3
22.2
24.6
23.8
21.9
A-ll
-------
Study No. 5221.08
TWO WEEK RANGE-FIND ING/EXPLORATORY STUDY OF PARA-CRESCL IK SPRAGUE DAULEY RATS
MALE FOOD CONSUMPTION DATA . 1
481.2
494.9
506.0
527.1
552.0
532.3
492.5
521.4
561.2
550.6
516.5
518.9
494.9
512.6
495.1
495.5
436.2
470.3
494.2
514.2
456.7
465.9
505.9
538.8
460.5
518.6
482.9
422.2
523.2
473.9
511.4
530.8
425.3
421.9
522.2
439.2
537.1
562.9
421.8
378.2
394.1
395.3
411.1
441.6
464.5
459.3
404. S
433.1
454.0
476.7
428.3
417.3
414.1
449.8
403.4
412.1
396,6
401.9
389.1
471.1
374.3
389.1
441.7
538.8
551.3
590.4
565.8
531.7
595.8
579.9
5B4.3
571.6
558.3
571.2
591.3
480.3
590.5
562.9
477.3
446.3
440.5
480.7
454.9
474.5
520.3
494.0
442.1
499.5
504.3
476.7
428.3
452.9
466.6 .
493.3
454.8
465.2
467.4
449.3
501.1
517.3
467.5
448.9
521.9
455.1
464.9
503.4
491.7
438.3
508.7
498.3
503.5
481.6
462.7
479.2
574.2
400.4
511.5
483.6
392.2
358.2
363.2
386.4
" 359.1
403.5
448.1
431.6
359.5
419.4
401.2
414.9
351.6
351.4
388.3
423.4
' 375.7
385.3
393.3
377.1
400.7
444.4
372.3
346.6
453,7
574.1
606.7
629.0
603.4
571.1
534.1
596.6
642.2
599.0
602.7
619.8
528.8
523.6
542.4
573.6
561.4
564.9
563.2
554.5-
512.1
639.9
493. S
508.9
538,4
517.2
553.3
579.8
534.6
553. 0
538.2
580.4
550.0
562.8
599.2
587.9
529.9
saa.2
650.3
592.1
595.5
462.2
485.2
512.4
507.8
440.7
460.5
475.2
533.1
469.1
465.7
502.2
416.2
405.0
419.3
456.2
444.0
445.1
452.2
421.8
381.1
524.5
389.0
415.3
423.0
403.2
412.9
460.4
417.7
414.5
429.2
467.9
425.7
439.6
483.9
480.3
393.1
dead
527.4
471.5
4S8.4
A-12
7
a
-------
Study No. 5221.08
TUG UEEK SANGE-FINDINS/EXPLQRATORY STUDY OF PARA-CRSSQL IK SPRAGUE DAUIEY RA1S
MALE FOOD CONSUMPTION DATA (g)
[Feeder Weights!
ANIMAL NUMBER new feeder 1 old feedtr 1 new feeder 2 old feeder 2 new feeder 3 old feeder 3
DOSE LEVEL
800 mg/kg/day
2441
2442
2443
2444
2445
2446
2447
2448
2449
4S0.7
508.7
471.6
466.7
453.3
534.8
537.5
482. 0
466.3
418.4
437.1
427.0
432.7
410.0
462.7
475. 1
415.1
404.7
475.7
480.3
506.9
467.6
512.7
531.8
522.7
448.0
477.9
407.7
393.4
434.3
391.0
446.1
462.6
442.9
376.9
395.2
601.8
680.8
695.9
623. 5
605.0
700.0
623.8
659.0
616.3
545.7
559.7
587.5
510.3
497.0
583.5
513.0
536.2
497.5
245Q 492.3 434.6 495.2 416.0 604.8 49S.5
A-13 '76
-------
Study No. 5221.08
TUO WEEK RANGE-FIND INC/EXPLORATORY STUDY Qf PARA-CRESQL IN SPRAGUE DAULEY RATS
FEMALE FOOD CONSUMPTION DATA Cg/day)
ANIMAL NUHSER Day 5 Day 9 Day 14
DOSE LEVEL
0 mg/kg/day
TOO mg/kg/day
200 rag/kg/day
400 mg/kg/day
2451
2452
24S3
2454
24S5
2456
2457
24SS
2459
2460
2461
2462
2463
2464
2465
2466
2467
2468
2469
2470
2471
2472
2473
2474
2475
2476
Z477
2478
2479
2480
2481
2482
2483
2484
2485
2486
2487
2488
2489
2490
15.2
17.1
17.2
15.3
12. 8
15.3
15.1
17.8
21.9
17.D
15.1
17.2
17.3
17.6
14.5
13.3
17.6
21 .3
K.3
17.8
14.7
16.2
18.2
16.5
16.2
16.8
21,0
15,7
16.6
13.2
14. B
15.6
14.9
14.9
18.7
13.1
15.9
9.8
13.1
19.6
13.6
15.5
14.7
6.4
15.8
12.7
12.8
16.1
17.9
15.4
12.3
14.2
13.4
17.1
15.3
11.3
13.7
17.4
13.3
14.2
12.5
14.4
14.9
13.8
16.1
14.6
16.0
12.9
15.0
15.5
11.1
15.3
13.2
14.1
14.3
13.8
,17.3
13.3
14.1
18.2
16.1
16.5
16.3
14.6
16.1
13.5
13.5
16.3
33.8
17.7
14.1
16.4
16.8
17.5
16.8
13.4
15.7
18.7
15.8
17.2
13.7
15.3
16.5
18.6
16.5
15.5
17.0
13.9
16.1
17.7
12.9
15.5
16.2
na
15.1
14.1
17.5
15.1
15.2
18.1
,
A-14 ' < *
-------
Study No. 5221.08
TWO WEEK RANGE-FINDING/EXPLORATORY STUDY OF PARA-CRESQL IN SPRAGUE OAW'LEY RATS
FEMALE FCCD CONSUMPTION DATA (g/day)
ANIMAL NUNBER Day 5 Day 9 Day 14
DOS! LEVEL
800 mg/kg/ciay
2491
2492
2493
2494
2495
2496
2497
2498
2499
' 2500
9.0
16,4
12.4
5.7
10.0
16.4
8.1
5.6
15.3
1.8
14.5
13.7
.13.0
14.2
13.2
15.3
12.4
na
15.5
na
15.5
15.1
15.8
16.9
15.3
16,4
12.8
na
15.2
na
A-15
78
-------
Study No. 5221.08
T«0 WEEK RAMGE-FINDTNG/EXPLQRATORY STUDY OF PARA-CRESOl IN 'PRAGUE DAULEY SATS
FEMALE FOOO CONSUMPTION DATA
[Feeder Weights]
ANIMAL NUMBER ntH fsedir 1 old feeder 1 nay feeder 2 old feeder 2 new feeder 3 eld feeder 3
OOSc LEVEL
100 mg/kg/day
2CC n
400 mg/kg/day
2451
2452
2453
2454
2455
2456
245?
2453
2459
2460
2461
2462
2463
2464
2465
2446
2467
2448
2469
2470
2471
2472
2473
2474
2475
2476
2477
2478
2479
2430
24B1
2482
2483
2434
2485
2436
2437
2488
2489
2490
475,5
474.4
474.6
469.7
525.8
508.9
512.2
503.5
494.7
480.4
481.4
524.2
443. S
433.9
487.6
501.9
490.4
471.1
517.2
499.5
516.9
556.8
523.1
510.4
549.3
516.6
524.9
517.2
507.5
520.8
486.3
484.7
491.3
494.3
499.8
496.9
497.0
486.0
490.7
458.6
414.9
405.9
405.9
403,4
474,6
447.7
452.0
432.1
407.1
412.4
423.9
455.6
374.2
413.7
429.7
448.5
420.0
385.1
459,9
428.1
458.1
491.8
455.5
444.5
484.4
449.6
440.8
454.3
441.2
468.0
427.0
422.5
431.8
434.6
424.9
444.7
433.5
446.6
438.2
3S0.1
502.7.
499.5
450.7
464.6
474.6
481.5
472.6
473.3
452.0
460.7
470.9
516.3
439.0
464.2
491.0
509.7
470.8
452.4
524.7
479.5
492.5
491.8
455.5
494.0
484.4
449.6
461.0
454.3
474.7
468.0
474.6
473,1
477,9
483.9
507.3
479.5
475.4
482,8
483.3
510.4
448.2
437.6
391.8
- 439.0
411.4
430.6
421.5
408.9
380.3
399.1
42T.9
459.6
38S.4
395.6
429.8
464.5
415. 9
382.8
471.7
422.7
442.6
434.1
395.8
433.6
420.0
391.1
397.0
402.7
414.9
406.2
430,1
411.3
425.0
427.7
448.2
424.5
4C6.2
429.8
427,1
437.5
608.3
636.7
578.8
506.3
462.5
547.8
512.6
517.8
471.0
474.4
515.2
668,4
694.3
630.4
597.4
672.0
640.S
620.3
741.8
594.7
613.5
630.9
535.0
593.6
600.9
585.9
543.8
538.6
493.0
537.8
621.4
528.7
607.3
607.0
590.6
627,8
558.6
593.0
607,2
539.1
527.6
554.1
497.2
433.5
332.0
430.4
445.3
436.3
302.1
385. 5
444.6
586,6
610.3
543.0
513.3
605.0
562.2
526.8
663.0
508.6
545.1
551.9
452.4
SOD. a
518.4
508.4
458.9
519.1
412.5
449.2
556.7
451.3
526.!
331.4
515.0
557.4
470.9
517.5
53T.O
448,7
A-16
-------
Study No. 5221.08
TUO WEEK SANGc-FINDINC/EXPlCRATQRY STUDY Of PARA-CRESQL IN SPRAGUE DAULEY RATS
FEMALE FOOD CONSUMPTION DATA (g)
[Feeder Weights]
ANIMAL NUMBER new feeder 1 old feeder 1 new feeder 2 old feeder 2 new feeder 3 old feeder 3
DOSE LEVEL
800 mg/kg/day
2491
2492
2493
2494
2495
2496
2497
2498
2499
502.3
519.7
500.5
480.0
494.8
519.7
521.7
545.1
572.8
466.3
'454.2
450.8
457.4
454.8
454.1
489.2
522.9
511.6
466.3
454.?.
450.8
457.4
454.8
454.1
489.2
dead
511.6
408.3
399.3
399.0
400.6
401.9
393.0
439.7
dead
449.7
558.4
573,9
541.6
534.1
546.7
602.0
629.1
dead
586.6
481.0
498.4
462.5
449.7
470.1
' 520.2
565.1
dead
510.7
2500 483.4 476.2 dead dead dead dead
A-17 , 8 0
-------
-------
Study No. 5221.08
APPENDIX B
ANALYTICAL CHEMISTRY METHODOLOGY
3-1 *~ MICROBIOLOGICAL
-------
AMERICAN BICGENIC5 CORPORATION
ANALVTICAL REPORT
PROJECT NO.:
SUBJECT: \flflrit
*/*>/*£.
PAGE
DATS
2G1000C
/ OF /
/Q
DEPARTMENT NO. 440
TEST ARTICLE HO.:
Ul^u^L.
99?,
,
TECHNICIAN
REVIEWED BY
DATE
DATE
B-2
-------
ERGO > _ c_ M_ ^ ^wji!i ^^^^..^
ENSECO
INCORPORATED
June 2, 1986
Dr. Der.nis D. Diets
Research Triangle Institute
? .0. Box 12194.
Research Triangle ?ari, NC 27709
Dear Denni3;
Inclosed please find a description of the method *e use for
analysis of compounds by direct aqueous injection ag it pertains
to Tori performed under EFA WA-35.
As 700. can see, the analysis procedure is generally the
same for all compounds differing only in the case of the cresols
ffhich use an alternate colunn and temperature program.
If you have any questions regarding the method or other
specifics, please do not hesitate to contact me.
Sincerely ,
\V . Henry Camp
Analytical Chemist
VGA Laboratory
Zncl .
cc: Dr. Barry Levine (Microbiological Associates)
Dr. Dale Mayhew (American 3iogenics Corp.)
Dr. Crosby Thotnpkins (Toxicity Research Laboratories
B-3
-r^.M'^.i .r'.l.-
T -\
-------
i . Applies" ion..
This method covers the determination of compounds by direct
aqueous injection. The following compounds can be detected
using column A and temperature program A: acetone, methyl
isobutyl ietone (MIBK), isobutyl alcohol, methyl alcohol, ethyl
acetate, n-butyl alcohol and crotonaldehyde. The following
compounds can be detected using system B and temperature
program B: p, m-; and ocresol.
2 . Summary.
A portion of a sample is injected directly onto a gas
chromatograph capillary column. The gas chromatograph is
temperature programmed to separate the constituents which are
then detected by a flame ionization detector.
3.
Instrumentation and Apparatus.
3-1. Gas chromatograph -- Hewlett-Packard 5880 with auto-
sampler and integrator. Oven temperature profile A
programmed as hold 8 min at 50*C, then to -220*C at
8'C/min and hold 5 min. Program B: hold 5 min at
50'C then to 250*C at 10'C/rain and hold 15 min.
3.2. Column A 60 m z 0.32 mm ID, 0.25 um film SUPEL-
COWAX 10 fused silica capillary column. Set linear
velocity to 25 cm/sec, He, at 100'C (flow rate = 1.2
ml/rain} .
Column B -- 30 m x 0.318 mm ID, 0.25 u^ film SE - 54
fused silica capillary column. Set linear velocity
B-A
84
-------
:o 2? era/sec, Hs, at IGCTC (flow rat* = 1.2
ml/min). ,
3.3. Injector -- configure for sample splitting and ad-
Just ratio to 100:1. Set heater temperature to
200'C.
3.A. Detector -- Hewlett-Packard flame ionizaticn de-
tector, Hydrogen flow set at 40 ml/min. Air flow
set at 4-00 ml/min. Set sensitivity at 2 + 2 and ad-
Just if necessary. Set heater temperature to
250'C.
3.5. Syringes -- 1 ml, 100 ul, and 10 ul gas-tight glass
for diluting and for sample transfer.
4-. Reagents.
4.1. Reagent Water -- prepare with Corning Mega-Pure dis-
tillation system and filter through activated
charcoal prior to use.
4.2. Methylene Chloride -- J. T. Baker "Resi-analyzed" or
equivalent,.
4.3- Standard Solution -- prepare by adding pure material
to water. Pure material should be assayed reference
liquid such as Chea Serve reagents. If not immedi-
ately available, supplied compound may be used.
4-3.1. Place about 9 ml of solvent into a stoppered 10 ml
flask. Weigh the flask. Add one or two drops of
pure material to the flask and reweigh. Dilute to
85
B-5
-------
volume, nix well, and store in a teflon-sealed
screw-cap vial at 4*C.
5. Calibration.
5.1. External Standard Calibration -- Prepare working
standards to bracket the concentration range, of the
samples of interest, Working standards are prepared
by diluting the standard solution with water or
aethylene chloride if the samples are corn oil
based. Analyze according to procedure section then
calculate response factors using this equation:
concentration of standard
HF = ^
area of standard
If the response factors are constant over the
working range (10* Relative Percent Difference), an
average response factor may be used for calcu-
lations ,
6 . Quality Control.
6.1. Interference -- a water blank must be run with each
test to check for system contamination. A blank
should also be run between samples of high concen-
tration .
6.2 Purity reagents used in the procedure should also
be analyzed with each test to determine their
purity,
8
B-6
-------
6.3 Spikes -- sample matrixes sh.ou.ia be spiked with the
compounds of Interest and a percent recovery calcu-
lated to access matrix effects and method accuracy.
6.-4. Duplicates -- Some samples should 'be analyzed in
duplicate and a relative percent difference calcu-
lated to access method precision.
7. Procedure,.
7.1, Calibration as in section 5.
7.2. Sample Preparation -- allow samples to come to room
temperature'before handling. Dilute if necessary to
bring concentrations within system working range by
adding portion of saaple to water or to methylene
chloride if corn oil based.
7.3. Analysis -- introduce sample by direct injection of
1 - 2 u 1 into the GC injection port and begin the
temperature program.
7.4 Identification -- as the compounds are analyzed
individually, there should be no coelution inter-
ferences , Retention time should still be checked
against the standard.
3 . Calculation .
8.1. Concentration -- calculate using peak area and RF
determined in section 5.1.
8-7
-------
3,2. Dilution -- take into account any dilution, performed
on the sample or the standard.
V
3.3 Report results In mg/znl without correction for
recovery percentage.
88
B-8
-------
Study No. 5221.08
APPENDIX C
CLTNICAL PMHOKX3Y MEIKDDOITXSf
cm PC
C-l
MICROBIOLOGICA
-------
HBRTOIOGY
Hemoglobin
Cyarsnethemoglobin method
Baker Cell Counter
Hematology Series 7000
Heiratocrit
Indirect method; calculated value based on erythrocyta
count and mean corpuscular volume
Baker Cell Counter
Hematology Series 7000
Erythrocyte Count
Electronic Counting Procedure
Baker Cell Counter
Kematology Series 7000
Mean Corpuscular Volume (MO/)
Electronic Sizing Procedure
Baker Cell Counter
Hematology Series 7000
Mean Corpuscular Hemoglobin fMCH)
Indirect method; calculated value based on erythrocyte
count and hemoglobin
Baker Cell Counter
Hematology Series 7000
Mean Corpuscular... Hemoglobin. Concentration fMCHCi
Indirect method? calculated value based on hematocrit
and hemoglobin
Baker Cell Counter
Hematology Series 7000
Leukocyte Count:
Electronic Counting Procedure
Baker Cell Counter
Hematology Series 7000
CFM.PC
C-2
80
-------
Leukocyte Differential Count
Neutxcphils - Iramature (bands)
Neutrophils - Mature (segs)
Mcnccytes
Basophils
Lymphocytes
Eosinophils
Wright stain procedure
Schalm, O.W. , Jain, N.C. and Carroll, E.J.
Veterinary Keraatology, Color Plates Chapter,
3rd Edition, Lee and Febiger, 1975.
Bgtigulocyte Count
New methylene blue staining procedure
Brecher, G. Am. J. Clin. Path. 19,
895, 1949.
(FT)
Pate of change in absorbance due to clot formation
Coag-A-Mate
Activated.. Partial ..ThroirbQplastm.Time (APT!)
Rate of change in absorbance due to clot formation
Coag-A-Mate
CLINICAL CHEMISTRY
Creatinine
Jaffa's alkaline picrate reaction
Centrifichem Centrifugal Analyzer System
Fabiny, D.L. and Ertingshausen, G.
Clin. Chem., 17, 696, 1971.
JnQrganic_ Hipsphorus
Phosphomolybdate reaction
Centrifichem centrifugal Analyzer System
Daly, J.A., and Ertinghausen, G,
Clin. Chem., 18, 263-, 1972.
CPN.PC
0-3 - ' 91
-------
Glucose
Eexokinase method
Centrifichem Centrifugal Analyzer System
Eondar, J.L. and Mead, D,C.
Clin. Chem. 20, 586, 1974.
Urea Nitrogen (BUN)
Modified urease tedinique
Centrifichem Centrifugal Analyzer System
TaUce, H. and Schubert/ G.E. ,
Klin. Wdinschr. 43, 174, 1965.
Total Protein.
Biuret technique'
Centrifichem Centrifugal Analyzer System
Kingsley, G.R., J. Biol. Chem. 131, 197, 1S39.
Albumin
Broroocresol Green method
Centrifichem Centrifugal Analyzer System
Douraas, B.T. snd Biggs, E.G.
standard Methods of Clinical Chemistry, 7, 175/ 1972.
Globulin
Total protein - Albumin = Globulin (Calculated value)
Calcium
Modified alizarin procedure
Centrifichem Centrifugal Analyzer System
Frings, C.S., et. al., din. Chem., 16, S16, 1970.
Aspartate. Anting Transf erase (AST/SCOT)
Mcdif ied Karmen procedure
Centrifichem Centrifugal Analyzer System
Bergmeyer, H.V., Scheibe, P., and Wahlefeld, A.W.
Clin. Chem., ,24, 58, 1973.
Alanine..J^mino Transf erase (AHT/SGPT)
Modified Henley & Pollard procedure
Centrifichem Centrifugal Analyzer System
Bergmeyer, H.V., Scheibe, P., and Wahlef eld, A.W.
din. Chem., 24, 58, 1978.
C) 9
«-' **
CPM.K:
C-4
-------
Alkaline Phosphatase
Modified Bawers-McCarrib procedure
Centrifichem Centrifugal Analyzer System
Bowers, Jr., G.N., McComb, R.B.
Clin. Chan., 12, 70, 1966.
Cholesterol
Allain enzymatic procedure
Centrifichem Centrifugal Analyzer System
Allain, C.C., et. al., Clin. Chem. 20, 470, 1974.
Total BiliruMn
Diazo colorimetric procedure
Centrifichem Centrifugal Analyzer System
Ertinghausen, G., Fabiny-Byrd, D.L., Tiffany, T.o.,
and Carey, S.J., Clin. Chea. 19, 1366, 1973.
Direct Bilirubin
Diazo colorimetric procedure
Centrifichem Centrifugal Analyzer System
Ertinghausen, G., Fabiny-Byrd, D.L., Tiffany, T.O.,
and Carey, S.J., Clin. Chem. 19, 1366, 1973.
Electrolytes (Na+, K*", Cl", C02)
Ion specific electrodes (Metpath, Inc.)
UE^IHALYSES
Qual itatiye Meagorgments
pH Ketones Urobilinogen
Protein Bilirubin
Glucose Blood
Chemstrip 7L - Chemistry Reagent Strips
Bio-Dynamics/brtic
Indianapolis, Indiana
OK. PC
C-5
-------
gpecific Gravity
Optical terperature compensated refractometer
Microscopic Evaluation
Urinary sediment stained with Sedi-stain and evaluated using the Ames
Atlas of Urine Sediment, Ames Co., Division Miles laboratories, Eikhart,
Indiana.
CM. PC
" ' . o
-------
Study No. 5221.08
APPENDIX D
INDIVIDUftL MSimL EftIA
95 . .
13-1 ~ » MICROBIOLOGICAL
ASSOCIATES INC.
-------
Study Ho. 5221.08
DISPOSITION OF AHIHALS IN 13-WEEK PARft-CRESOl STUDY 1M SPRAGUE DAWLEY RATS
O
I
Dose Level
(mg/kg/day)
0
50
175
600
-
0
50
175
6QQ
Baseline Clinical
Sex Pathology Animals3
N
H
H
H
H 3781 -3790
F
f
F
F
F 3911-3920
45-Day Sacrifice
12/2-12/3/85
3661-3670
3691-3700
3721-3730
3751-3760
-
3791-3800
3821-3830
3851-3860
38ai-3890b
90-Day Sacrifice
1/15-1/17/86
3671-3690
3701-3720
3731-3750
3761 -3780
3801 -3820
3831 -3850
3861 -3880
3891-3910°
"
a Animals selected for baseline clinical pathology were discarded without necropsy after the collection of blood
samples.
Early death, animal number 3883 on 10/18/85.
Early deaths, animal numbers 3899 and 3910 on 10/17/85.
O
-------
Study No. 5221.08
SUBCHRQNIC TOXICZK OF PABA-CKESGL
IN SPRAGUE DMCEY RATS
OQDES
Bcdv Weights 'and Food_Consumption
ISAC - interim sacrifice
na - no data available
dead - unscheduled death
Organ.. Weights
e - raw data entry error
na - no data available
dead - unscheduled death
term. wgt. - terminal body weight
Urinalvsis
thy./para. - thyroid/parathyroid
rt - right
1ft - left
tb - turbid
. c - clear
cl - cloudy
hz - hazy
y - yellow
py - pale yellow
ly - light yellow
a - amber
dy - dark yellow
s - straw color
tp - triple phosphate
co - calcium oxalate
ap - amorphous phosphate
n - none
tr - trace
m - many
f - few
ng - negative
nr - normal
nod - moderate
nura - numerous
Hematoloav & Clinical Chemistry
QNS - quantity not sufficient
dead -'unscheduled death
z - no clot was formed
sc - specimen clotted
g - greater than 110 seconds
ec
dead
vol
uro
bili
ery
RBC/HPF -
WBC/HFF
Casts/tPF -
EPI/HPF -
occasional
greater than .
unscheduled death
appearance
volume
urobilincgen
bilirubin
erythrccytes
number of red blood cells
under high power field
number of white blood cells
under high power field
number of casts under low
power field
number of epithelial cells
cells under high power
field'
D-2
-------
-------
Study Mo, 5221.08
SUBCHRONIC TOX1C1TY OF PARA-CRESCL IN SPRAGUE OAULEY SATS
MALE BODY WEIGHT DATA (g)
r.
ANIMAL NO. UEEK1 UEEK2 WEEK3 WEEK4 WEEKS WEEK6 WEEK?
OOSf LEVEL
443 473 491
438 465 496
424 458 485
465 507 545
423 447 473
374 399 427
461 492 493
434 466 493
435 467 496
410 431 463
420 443 473
377 412 443
436 462 489
467 511 540
359 379 406
431 463 491
401 426 458
462 498 541
387 419 450
424 449 483
385 406 426
414 423 460
436 454 485
442 460 493
425 442 472
430 458 499
440 484 504
428 455 479
400 421 443
452 436 512
458 489 524
448 477 503
412, 449 477
443 484 521
433 462 494
334 404 435
423 455 438
397 422 449
412 437 459
406 434 433
450 469 501
443 472 497
460 486 521
392 416 443
447 473 503
451 47! 500
D-3 88
0 mg/kg/day 3661
3662
3663
3664
3665
3666
3667
3668
3669
3670
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3681
3682 -
3683
3684
3685
3686
3687
3688
3639
3690
50 mg/kg/day 3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3701
3702
3703
3704
3705
37C6
253
233
215
255
238
207
246
234
247
224
231
221
249
259
220
233
227
237
203
236
217
214
229
236
232
226
251
239
225
248
229
236
225
237
251
206
231
232
232
211
259
254
253
215
246
256
317
296
290
325
307
260
314
303
307
277
293
282
308
333
271
292
286
313
262
298
267
273
292
300
291
296
307
302
288
311
299
297
232
305
308
261
289
290
295
26S
319
313
322
272
314
322
368
346
343
379
355
301
363
365
362
327
337
317
354
391
295
338
334
3,69
312
343
312
331
347
353
348
339
362
354
324
370
359
352
330
365
350
306
339
320
332
322
370
356
379
320
363
367
410
399
392
435
397
344
412
406
405
380
389
360
401
442
330
387
375
418
356
391
356
372
400
397
393
384
404
397
369
418
413
399
378
412
399
351
386
366
374
373
413
412
433
361
403
420
-------
Study Mo. 5221,03
SU3CHRONJC TOXICITY Of PARA-CSESQL IN SPRAGUE DAWLEY RATS
HALE BODY WEIGHT DATA C3)
ANIMAL NO. UEEK1 WEEK2 UEIK3 WEftt UEEKS WEEKS UEEK7
DOSE LEVEL
50 mg/kg/day 3707
(continued) 3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
175 mg/kg/day 3721
3722
3723
3724
3725
- 3726
3727
3728
3729
3730
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3741
3742
3743
3744
3745
3746
3747
3748
3749
3750
222
254
229
241
222
223
221
203
222
209
203
201
243
230
221
234
240
264
224
219
223
242
216
240
234
237
239
209
250
231
224
220
189
231
209
220
214
214
202
217
245
235
"231
237
274
316
266
301
268
.289
284
249
281
274
254
247
300
294
270
293
301
324
281
269
278
3Q5
262
304
293^
298-
301
259
314
279
283
270
232
286
258
274
273
262
242
271
303
289
284
284
333
369
339
364
311
339
339
286
332
335
290
289
354
344
327
342
348
376
338
301
334
350
307
358
335
346
355
304
372
318
330
312
278
334
298
320
323
305
282
324
360
339
322
324
383
412
394
419
358
382
402
327
370
390
331
329
396
355
384
382
393
434
394
330
388
397
352
400
391
391
398
341
420
363
373
350
309
371
338
363
362
340
318
375
397
387
363
364
424
443
437
452
392
415
429
360
405
436
348
354
431
381
424
421
433
471
440
352
433
423
337
442
428
423
433
388
442
391
401
380
343
412
367
397
410
373
349
411
420
420
406
392
451
466
468
487
424
446
464
387
424
466
373
373
451
427
456
446
464
511
451
375
449
453
413
471
467
452
447
413
468
426
422
412
371
440
395
432
437
395
363
436
452
432
439
419
480
494
502
517
459
469
488
409
458
492
394
396
472
466
484
473
498
533
476
395
479
485
437
501
49i
479
480
438
504
450
451
445
390
458
415
461
481
422
394
461
431
460
4S6
437
D-4
Q O
-------
Study No. 5221.08
SuaCHROHIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
MALi BODY WEIGHT DATA
-------
Study No. 5221.08
SUBCKRONIC TOXICtn OF FARA-CRESOL IM SPRAGUE DAWLEY RATS
HALE iOOY WEIGHT DATA (g)
ANIMAL NO. WEEKS WEEK9 WEEK1Q UEEK11 UEEK12 UEIK13 UEEK14
DOSE LEV!I
0 mgAg/day
50 mg/kg/day
3661
3662
3663
3664
3665
3646
3667
3668
3669
3670
3671
3672
3673
3674
3675
3676
3677
3673
3679
3680
3681
3682
3683
3684
'3685
3686
3687
3688
3689
3690
3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3701
3702
3703
3704
3705
3706
I SAC
I SAC
I SAC
I SAC
I SAC
I SAC
I SAC
1SAC
[SAC
SSAC
493
482
511
581
416
519
478
564
466
496
445
481
516
516
496
521
535
501
463
533
1SAC
1SAC
[SAC
I SAC
I SAC
I SAC
I SAC
1SAC
I SAC
I SAC
525
518
547
462
526
518
na
na
na
na
na
na
na
na
na
na
528
507
536
616
418
547
510
601
488
522
464
501
548
541
516
547
556
516
484
561
na
na
na
na
na
na
na
na
na
na
548
545
566
4 BO
544
544
na
na
na
na
na
na
na
na
'na
na
544
524
559
633
440
569
536
627
511
547
473
529
564
560
545
578
584
537
504
581
na
na
na
na
na
na
na
na
na
na
563
564
592
493
562
561
na
na
na
na
na
na
na
na
na
na
561
532
567
636
438
576
548
638
525
560
4B2
533
570
569
556
583
586
539
521
587
na
na
na
na
na
na
na
na
na
na
573
575
595
504
571
562
na
na
na
na
na
na
na
na
na
na
571
551
565
661
457
591
559
652
537
573
498
557
591
575
570
583
598
551
524
597
na
na
na
na
na
na
na
na
na
na
581
592
600
511
583
578
na
na
na
na
na
na
na
na
na
na
591
524
587
678
467
612
572
677
552
596
504
559
606
598
580
615
627
563
548
614
na
na
na
na
na
na
na
na
na
na
586
610
623
531
602
588
na
na
na
na
na
na
na
na
na
na
600
543
597
697
469
615
580
694
562
611
513
573
618
601
590
614
632
575
540
616
na
na
na
na
na
na
na
na
na
na
600
620
624
536
597
613
D-6
1
-------
Study «o, 5221.08
SU3CHRON1C TOXICITY OF PARA-CRESOL IN SP8AGUE OAWLEY RATS
MALI ICDY WEIGHT DATA (g>
ANIMAL NO. WEEKS UEEK9 UEEK10 WEEK11 UEEK12 *UEEK13 WEEK14
DOSE LEVEL
SO iflf/icg/day 3707
(continued) 3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
175 mg/kg/day 3721
3722
3723
3724
3725
3726
3727
3723
3729
3730
3731
3732
3733
3734
3735
3736
3737
3733
3739
3740
3741
3742
3743
3744
3745
3746
3747
3748
3749
3750
515
511
518
533
482
495
517
427
477
517
423
422
497
490
I SAC
I SAC
I SAC
I SAC
I SAC
I SAC
I SAC
I SAC
I SAC
I SAC
530
500
509
452
527
477
463
469
415
481
439
481
506
457
402
486
512
472
489
459
481
542
548
563
498
521
540
451
493
540
446
427
524
514
na
na
na
na
na
na
na
na
na
na
562
525
535
477
548
492
487
488
440
501
460
503
524
431
422
499
536
496
503
480
450
560
570
530
520
531
567
463
510
553
458
451
533
526
na
na
na
na
na
na
na
na
na
na
580
546
548
494
579
504
483
511
463
521
471
518
546
496
434
521
547
519
535
498
447
562
579
593
527
533
577
473
518
555
462
451
554
527
na
na
na
na
na
na
na
na
na
na
587
558-
551
508
597
508
500
521
476
528
478
543
562
506
442
533
550
534
529
506
443
570
602
601
551
553
594
482
530
565
478
470
552
546
na
na
na
na
na
na
na
na
na
na
601
569
566
511
618
515
504
531
480
537
476
556
577
516
458
542'
553
541
538
511
424
591
612
615
560
572
611
492
544
580
490
474
570
557
na
na
na
na
na
na
na
na
na
na
620
582
585
524
626
525
515
546
500
562
499
576
592
524
470
557
575
555
558
518
446
600
623
624
531
580
620
500
553
589
492
487
582
573
na
na
na
na
na
na
na
na
na
na
609
595
592
531
654
542
526
557
498
564
510
582
600
534
484
563
535
565
567
530
D-7
10
-------
Study No. 5221.08
SUBCHRONIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
MALE BODY WEIGHT DATA (g)
ANIMAL NO. WEEKS WEEK9 WEEK10 UEEK11 WEEK12 WEEK13 WEEK14
DOSE LEVEL
600 mg/kg/day
3751
3752
3753
3754
3755
3756
3757
3753
3759
3760
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
3771
3772
3773
3774
3775
3776
3777
3778
3779
3780
I SAC
I SAC
I SAC
I SAC
1SAC
I SAC
JSAC
I SAC
I SAC
I SAC
365
416
438
468
439
414
424
501
388
445
400
512
473
368
363
463
403
425
461
415
na
na
na
na
na
na
na
na
na
na
381
423
453
488
450
427
433
524
395
461
422
552
490
386
373
483
417
440
481
437
na
na
na
na
na
na
na
na
na
na
384
433
481
513
467
441
452
545
408
462
438
564
506
410
397
505
433
461
508
461
na
na
na
na
na
na
na
na
na
na
392
430
481
524
477
44S
462
555
409
471
443
577
508
418
401
501
434
464
518
462
na
na
na
na
na
na
na
na
na
na
394
436
500
542
494
473
474
567
412
486
462
600
524
436
420
510
443
473
533
482
na
na
na
na
na
na
na
na
na
na
402
452
511
563
507
490
490
576
424
496
473
631
543
443
431
524
447
469
539
439
na
na
na
na
na
na
na
na
na
na
403
472
530
575
516
497
505
596
433
501
480
640
557
460
437
544
456
432
561
500
D-8
103
-------
Study Ho. 5221.08
SUBCHRONIC TCX1C1TY OF PARA-CRESQt IN SPRAGUE DAULEY RATS
HALE BODY WEIGHT GAIN DATA (§5
AMIMAL HO, UEEK1 UEEK2 WEEK3 WEEK4 UEEK5 UEEK6 UEEK7
DOSE LEVEL
0 mg/kg/day
SO mi/kg/day
3661
3662
3663
3664
3665
3666
3667
3668
3669
3670
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
'. 3681
3682
3683
3684
3685 '
3686
3687
3688
3689
3690
3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3701
3702
3703
3704
3705
3706
64
63
75
70
69
13
68
69
60
53
62
61
59
74
51
59
59
76
59
62
50
64
63
64
59
70
56
63
63
63
70
61
57
68
57
55
58
56
63
57
60
59
69
57
68
66
115
113
128
124
117
94
117
131
115
103
1C6
56
105
132
75
105
107
132
109
107
95
117
118
117
116
113
111
115
99
122
130
116
105
123
99
100
108
88
100
111
111
102
126
105
117
111
157
166
177
180
159
137
166
172
158
156
158
139
152
183
110
154
148
181
153
155
139
158
171
161
161
158
153
158
144
170
184
163
153
175
148
145
155
134
142
162
154
158
180
146
157
164
195
205
209
210
185
167
215
200
188
186
189
156
187
208
139
198
174
225
184
188
168
200
207
206
193
204
189
189
175
204
229
212
187
211
187
178
192
165
180
195
191
194
207
177
201
195
220
232
243
252
209
192
246
232
220
207
217
191
213
252
1S9
230
199
261
216
213
189
209
225
224
210
232
233
216
196
238
260
24!
224
247
211
198
224
190
205
223
210
218
233
201
227
215
238
263
270
290
235
220
247
259
249
239
242
222
240
281
186
258
231
304
247
247
209
246
256
257
240
273
253
240
218
264
295
267
252
284
243
229
257
217
227
227
242
243
268
228
257
244
na
na
na
na
na
na
na
na
na
na
267
261
262
322
196
286
251
327
263
260
22S
267
287
280
264
295 '
284
262
238
285
na
na
na
na
na
na
na
na
na
na
266
264
294
247
280
262
D-9
^ A
± 0
-------
Study Mo. 5221.08
SUBCHRONIC TOXICm OF PARA-CHESQL IN SPRAGUE DAULEY RATS
HALE BOO*" WEIGHT GAIN DATA
-------
Study No. 5221.08
SUSCHRQNIC TQXIC1TY Of PARA-CRESOl W SPRAGUE DAULEY RATS
MALI iODY yElGHT CAIN DATA Cg3
ANIMAL NO. WEEK! WEEK2 WEEK3 UEEK4 WEEKS UEEK6 WEEK?
DOSE LEVEL
600 mg/kg/day
3751
3752
3753
3754
3755
3756
3757
3753
3759
3760
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
3771
3772
3773
3774
3775
3776
3777
3778
3779
3780
28
47
39
24
28
33
32
35
26
41
-9
' 23
34
10
45
36
48
29
1
16
39
47
27
7
35
56
44
47
36
42
74
89
78
47
. 71
69
79
74
62
78
32
61
79
55
89
74
82
87
41
69
81
95
64
30
64
97
67
82
85
91
112
134
108
86
118
107
122
111
89
122
75
59
126
94
118
109
117
137
91
118
103
141
110
62
84
123
87
118
131
136
144
162
146
106
154
135
154
141
108
149
100
136
160
135
148
141
150
184
123
155
131
182
150
91
110
178
133
152
149
163
169
193
153
126
171
163
170
151
113
168
118
146
182
164
176
161
174
206
139
178
143
217
in
115
130
186
164
184
178
191
188
205"
183
141
182
188
192
172
131
177
131
153
198
200
195
167
196
237
160
204
165
244
198
141
138
208
183
200
208
176
na
na
na
na
na
na
na
na
na
na
148
175
222
229
219
199
214
254
179
222
187
264
221
148
162
214
197
220
217
206
D-ll
J
t
-------
Study No. 5221.08
SUSCHRONIC TQXICITY OF PARA-CRESOL IN SPRAGUE OAWIEY RATS
MALE BODY i/£!GHT GAIN DATA (g)
ANIMAL NO. yiEK3 WEEK? WEEK10 WEEK11 WEEK12 UEEK13
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3661
3662
3663
3664
3665
3666
3667
3668
3669
3670
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
363!
3682
3683
3684
3685
3666
3687
3688
3689
3690
3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3701
3702
37Q3
3704
3705
3706
na
na
na
na
na
na
na
na
na
na
297
286
237
357
198
314
283
364
285
226
247
287
319
305
284
321
305
277
259
313
na
na
na
na
na
na
na
na
na
na
289
291
313
265
298
288
na
na
na
na
na
na
na
na
na
na
313
303
310
374
220
336
309
390
308
311
256
315
335
324
313
352
333
298 .
279
333
na
na
na
na
na
na
na
na
na
na
304
310
339
278
316
305
na
na
na
na
na
na
na
na
na
na
33 D
311
313
377
218
343
321
401
322
324
26S
319
341
333
324
357
335
300
296
339
na
na
na
na
na
na
na
na
na
na
314
321
342
2S9
325
306
na
na
na
na
na
na
na
na
na
na
340
330
316
402
237
358
332
415
334
342
281
343
362
339
338
357
347
312
299
349
na
na
na
na
na
na
na
na
na
na
322
338
347
296
337
322
na
na
na
na
na
na
na
na
na
na
360
303
338
419
247
379
345
440
349
360
287
345
377
362
348
339
376
324
323
366
na
na
na
na
na
na
na
na
na
na
327
356
370
316
356
332
na
na
na
na
na
na
na
na
na
na
369
322
343
438
249
382
353
457
359
375
296
359
389
365
358
388
381
336
315
368
na
na
na
na
na
na
na
na
na
na
341
366
371
321
351
357
D-12
107
-------
Study No. 5221.C8
SUSCHRONIC TQXICITY OF PAHA-CRESQL IN SPRACU6 BAULEY RATS
MALE BQQY WEIGHT GAIN DATA CsJ
ANIMAL NO. WEEKS WEEK9 UEE<10 WEEK11 UEEK12 UEEK13
DOSE LEVEL
50 mf/kg/day 3707
(continued) 3703
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
175 nig/kg/day 3721
3722
3723
3724
3725
3726
3727
3728
3729
3730
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3741
3742
3743
3744
3745
3746
3747
3748
3749
3750
259
263
319
322
276
298
319
243
271
331
243
226
281
254
na
na
na
na
na
na
ni
na
na
na
328
288
296
268
298
261
263
268
251
270
251
283
310
267
220
282
291
261
272
243
223
306
341
339
298
308
346
265
288
344
255
250
295
296
na
na
na
na
na
na
na
na
na
na
346
309
309
285
329
273
259
291
274
290
262
293
332
282
232
304
302
284
3C4
261
225
308
350
352
305
315
356
270
296
346
259
250
311
297
na
na
na
na
na
na
na
na
na
na
353
321
312
299
347
277
276
301
287
297
269
323
348
292
240
316
305
299
298
269
221
316
373
360
329
330
373
279
303
356
275
269
309
316
na
na
na
na
na
na
na
na
na
na
367
332
327
202
368
2S4
280
311
291
306'
267
336
363
302
256
325
308
306
307
274
202
337
383
374
338
349
390
289
322
371
237
273
327
327
na
na
na
na
na
na
na
-na
na
na
386
345
346
315
376
294
291
326
311
331
290
356
378
310
268
340
" 330
320
327
281
224
346
394
383
359
357
399
297
331
380
289
286
339
343
na
na
na
na
na
na
na
na
na
na
375
358
353
322
404
311
302
337
309
333
301
362
386
320
282
346
340
330
336
293
D-13
-------
Study Mo. 5221.03
SUBCHSONIC TQXICITY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
MALE BODY WEIGHT GAIN DATA (g)
ANSKAl NO. y£EK8 UEEK9 WEEK10 WEEK11 UEEK12 UEEK13
DOSi LEVEL
600 mg/kg/day
3751
3752
3753
3754
3755
3756
3757
3753
3759
3760
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
3771
3772
3773
3774
3775
3776
3777
3778
3779
37BO
na
na
na
na
na
na
na
na
na
na
164
187
242
249
230
212
228
277
186
238
209
304
238
166
172
239
206
235
237
223
na
na
na
na
na
na
na
na
na
na
167
192
265
274
247
226
242
298
199
239
225
316
254
190
191
256
222
256
264
252
na
na
na
na
na
na
na
na
na
na
175
189
265
285
257
233
252
308
200
248
230
329
256
198
195
252
. 223
259
274
253
na
na
na
na
na
na
na
na
na
na
177
195
284
303
274
258.
264
320
203
263
249
352
272
216
214
261
232
268
289
273
na
na
na
na
na
na
na
na
na
na
185
211
295
324
287
275
280
329
215
273
260
383
296
228
225
275
236
264
295
2SQ
na
na
na
na
na
na
na
na
na
ni
191
231
314
336
296
282
295
349
224
278
267
392
305
240
231
295
245
277
317
291
D-14
10
C"
-------
Study No. 5221.08
SUBCHROMIC TQXICITY Of PARA-CRESOL IN SPRAGUE OAWLEY RATS
FEMAL1 BODY WEIGHT DATA (g)
ANIMAL HO. VJeekt WeekZ Ueek3 Ueek4 WeekS Ueek6 Week?
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3791
3792
3793
3794
3795
3796
3797
3798
3799
3800
3801
3802
3803
3804
3805
3806
3807
2808
3809
3810
3811
3812
3813
-3814
3815
3816
3817
3818
3819
3820
3821
3822
3823
3824
3825
3326
3827
3828
3829
3830
3831
3832
3833
3834
3835
3836
155
147
154
164
163
160
150
157
150
161
157
162
165
152
167
165
150
183
166
155
170
173
161
175
164
161
169
143
146
150
148
162
148
149
157
145
149
15S
135
146
162
178
162
154
147
152
185
177
172
192
178
187
175
179
182
204
182
178 .
190
180
196
194
175
215
194
183
196
209
185
212
200
187
202
173
170
178
153
136
176
182
184
167
190
185
159
171
180
198
196
175
176
177
210
196
200
217
197
207
198
201
201
229
205
204
218
207
220
209
190
231
220
201
214
234
202
235
224
207
225
193
180
200
174
2CS
190
196
200
183
211
203
176
185
201
221
216
192.
199
197
234
215
213
233
220
230
209
228
213
257
227
231
223
234
229
240
214
248
207
222
236
256
226
255
235
229
263
201
198
224
195
230
218
218
218
200
220
220
193
210
213
250
245
204
191
218
254
234
233
249
230
244
210
240
225
273.
239
248
242
246
250
249
224
264
247
237
244
263
237
2SO
255
238
264
223
209
235
205
250
222
231
232
214
241
239
211
222
231
258
258
225
236
232
255
239
233
257
.250
250
223
241
233
280
248
246
248
249
250
269
228
270
249
242
249
277
246
284
267
254
279
226
209
228
215
252
225
240
236
219
243
257
225
239
241
276
276
238
253
249
267
253
242
261
243
258
228
259
256
304
263
267
283
271
265
276
235
282
271
252
267
298
256
305
232
268
293
240
220
250
224
260
237
255
255
241
270
268
237
249
249
287
283
244
257
257
D-15
110
-------
Study No, 5221.08
SUBCHRONIC TOXIC1TY OF PARA-CRESOL JM SPRAGUE DAUIEY SATS
FEMALE BODY WEIGHT DATA CgJ
ANIMAL NO. Week! Week2 Week3 Ueek4 UeekS W*ek6 Wtek7
DOSS LEVEU
50 mg/kg/day 3837
(continued) 3838
3339
3840
3841
3842
3843
3844
'3845
3846
3847
3848
3849
3850
175 mg/kg/dey 3851
3852
3853
3854
3355
3856
3357
3858
3859
3860
3861
3862
3863
3864
3865
3866
3867
3868
3869
3870
3871
3872
3873
3874
3875
3876
3877
3878
3879
3880
165
177
134
139
147
156
159
132
153
168
148
142
143
140
154
163
149
159
160
176
156
155
157
174
157
141
165
157
153
163
140
173
153
161
169
160
166
159
164
163
160
153
155
153
190
202
156
162
170
183
180
157
179
193
179
165
169
154
174
185
168
176
178
204
186
177
174
198
172
158
182
183
183
185
163
205
176
190
195
186
189
172
194
193
182
181
176
180
202
226
174
176
196
205
202
178
198
213
194
187
190
170
189
201
184
189
205
223
210
194
196
227
199
178
203
198
195
211
173
229
197
212
220
206
208
203
220
214
201
208
193
193
217
246
186
197
221
222
222
195
217
237
216
200
212
190
211 '
221
2C8
217
207
254
237
208
225
244
207
200
229
222
218
233
197
248
220
230
244
232
236
223
240
227
224
228
217
223
237
260
203
20Z
244
233
234
205
230
256
234
222
230
199
222
242
224
229
230
262
256
226
241
254
227
224
247
236,
223
245
217
269
228
235
264
247
252
233
247
247
234
240
226
234
248
264
211
215
250
248
247
213
249
267
243
228
234
207
240
254
234
227
227
275
273
232
243
Z6S
230
236
247
246
230
256
217
283
236
248
283
262
260
255
251
249
242
244
232
242
257
280
216
225
262
257
257
217
260
273
245
246
249
217
247
265
250
234
245
291
282
249
264
282
232
246
263
267
246
269
237
299
247
268
303
285
265
263
264
263
255
255
240
2S6
D-16
ill
-------
Study Ho. 5221.03
SUBCHRONIC TOX1CITY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
FEMALE BODY WEIGHT DATA CgJ
ANIMAL NO. Weekl Week2 Ueek3 Week4 UeekS Ueek6 Week/
DOSE LEVEL
600 nig/kg/day
3881
3882
3883
3884
3385
3886
3837
3358
3389
3890
3891
3892
3393
3894
3895
3896
3397
3898
3899
3900
3901
3902
3903
3904
3905
3906
3907
3903
3909
3910
150
157
146
151
159
171
158
165
170
151
143
152
169
153
157
164
162
174
166
153
153
153
148
166
143
141
159
167
167
135
166
168
dead
173
173
195
170
180
182
163
173
159
175
170
163
173
191
201
dead
152
171
164
166
188
162
157
172
195
179
dead
181
184
dead
194
187
210
190
196
206
190
isa
160
196
195
196
200
203
231
dead
123
138
183
184
210
178
172
192
216
197
dead
197
203
dead
212
210
233
202
217
230
204
203
168
2ZO
223
222
221
223
252
dead
206
208
197
205
224
197
190
203
233
211
dead
209
214
dead
245
223
244
218
238
247
219
235
185
234
236
236
233
234
272
dead
231
231
205
223
246
206
202
218
245
236
dead
209
213
dead
252
233
246
223
241
255
229
231
193
249
249
249
242
252
277
dead
239
241
213
227
257
207
209
229
263
244
dead
222
235
dead
256
246
255
231
250
263
232
242
206
257
256
259
253
261
286
dead
251
251
228
239
263
226
215
240
272
255
dead
D-17
<>
-------
Study No. 5221.08
SUBCHRON1C TOX1C1TY DF PARA-CRESQL IM SPRAGUS DAULEY RATS
FEMALE BODY WEIGHT DATA CgJ
ANIMAL NO. UeekS Week9
Weefcll Ueek12 Ueek13 WeekU
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3791
3792
3793
3794
3795
3796
3797
3798
3799
3300
3801
3802
3803
3304
3805
3806
3307
3803
3809
3S10
3811
381 2
3813
38H
3815
3816
3817
3818
3819
3820'
3821
3822
3823
3824
3325
3826
3827
3828
3829
3830
3831
3832
3833
3834
3835
3836
I SAC
ESAC
1SAC
1SAC
ISAC
ISAC
I SAC
ISAC
ISAC
ISAC
270
261
274
285
284
283
245
292
286
266
266
306
275
311
285
277
304
24S
229
257
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
259
2S6
294
253
265
263
na
na
na
na
na
na
na
na
na
na
233
275
267
231
278
296
249
302
279
279
277
323
274
329
292
281
302
252
235
267
na
na
na
na
na
na
na
na
na
na
272
303
230
262
270
276
na
na
na
na
na
na
na
na
na
na
295
265
280
284
272
304
243
303
296
281
282
336
281
323
293
294
327
248
249
269
na
na
na
na
na
na
na
na
na
na
277
307
294
273
275
279
na
na
na
na
na
na.
na
na
na
na
290
277
286
285
272
302
248
298
302
277
286
338
281
324
295
297
224
254
250
263
na
na
na
na
na
na
na
na
na
na
279
309
298
274
284
287
na
na
na
na
na
na
na
na
na
na
300
286
273
283
278
315
251
306
306
286
286
340
282
330
293
288
332
249
250
269
na
na
na
na
na
na
na
na
na
na
275
310
311
27B
285
286
na
na
na
na
na
na
na
na
na
na
307
303
294
306
286
334
261
313
305
293
298
352
298
340
310
300
349
262
259
279
na
na
na
na
na
na
na
na
na
na
292
31S
325
298
289
296
na
na
na
na
na
na
na
na
na
na
313
304
293
309
291
332
267
327
321
294
308
365
303
346
317
312
355
270
266
291
na
na
na
na
na
na
na
na
na
na
296
319
336
307
297
306
D-18
-------
Study No. 5221.08
SUBCHRONIC TOXlCITr OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
FEMALE BODY WEIGHT DATA (g)
ANIMAL MO. UeekS Ueek9 WeeklO Week11 Week12 Week13 Week14
DOSE LEVEL
50 mg/kg/day 3837
(continued) 3838
3839
3840
3841
3842
3843
3844
3345
3846
3847
3348
3349
3850
175 mg/kg/day 3351
3352
3853
3854
3855
3556
3857
3853
3359
3860
3861
3862
3863
3864
3865
3866
3867
3868
3369
3870
3871
3872
3873
3874
3875
3876
3877
3378
3879
3380
255
291
216
234
279
265
255
220
262
290
261
260
259
227
I SAC
I SAC
ISAC
I SAC
I SAC
I SAC
I SAC
I SAC
1SAC
I SAC
244
258
278
267
246
275
245
308
258
268
313
289
272
264
275
269
262
272
250
259
271
294
226
233
287
262
266
232
259
302
272
266
27 '4
240
na
na
na
na
na
na
na
na
na
na
246
263
280
277
256
271
251
316
276
266
321
290
284
276
284
265
264
279
252
271
277
299
233
240
299
280
283
230
272
303
276
277
280
241
na
na
na
na
na
na
na
na
na
na
246
. 273
283
274
257
291
251
313
281
282
329
302
280
283
293
279
275
272
257
274
239
305
236
241 '
296
231
282
237
273
315
280
273
291
245
na
na
na
na
na
na
na
na
na
na
252
289
235
283
254
293
255
320
271
291
335
317
297
296
299
276
277
233
258
271
232
300
235
250
295
232
279
235
274
314
284
287
297
249
na
na
na
na
na
na
na
na
na
na
256
294
294
233
265
301
261
327
285
286
347
3"14
297
295
307
279
273
279
260
275
294
319
240
257
306
284
287
240
232
325
295
294
307
253
na
na
na
na
na
na
na
na
na
na
267
309
307
293
265
315
266
340
302
299
358
324
300
309
307
295
287
236
264
281
307
321
246
263
315
300
298
249
290
332
302
301
310
260
na
na
na
na
na
na
na
_ na
na
na
276
317
309
294
253
326
272
346
318
304
366
328
318
303
315
296
296
293
270
281
D-19
114
-------
Study Ho. 5221.08
SUBCHRONIC TOXlCin Of PARA-CRESOL IN SPRAGUg DAULEY RATS
FEMALE BODY WEIGHT DATA
-------
Study No. 5221.08
5USCHRCNIC TOXICITY OF PARA-CRESOL IN SPRAGU6 DAULEY RATS
FEMALE iOOY WEIGHT GAIN DATA Cg)
ANJMAL NO. Ueekl WeekZ Ueek3 Ueek4
«eek6 yeak7
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3791
2792
3793
3794
3795
3796
3797
3798
3799
3800
3801
3802
3803
3804
3805
3806
3807
3808
38D9
3810
3811
3312
3813
3814
3815
3816
3817
3318
3819
3820
3821
3822
3823
3824
' 3825
3826
3827
3828
3829
3830
3831
3832
3S33
3834
3835
3836
30
30
18
28
15
27
25
22
32
43
25
16
25
23
29
29
25
32
28
23
26
36
24
37
36
26
33
30
24
28
10
24
28
33
27
22
41
27
24
25
IS
20
34
21
29
25
55
49
46
53
34
47
43
44
51
63
48
42
53
55
53
44
40
48
54
46
44
61
41
60
£0
46
56
50
34
50
26
46
42
47
43
38
62
45
41
39
39
43
54
38
52
45
79
68
64
69
57
70
59
71
63
96
70
69
63
82
62
75
64
65
41
67
66
83
65
80
71
63
94
58
52
74
47
63
70
69
61
55
71
62
53
64
51
72
83
50
44
66
99
87
79
85
67
S4
60
83
75
112
82
86
77
94
83
84
74
81
81
82
74
95
76
105
91
77
95
80
63
85
57
as
74
62
75
69
92
81
76
76
69
80
96
71
89
80
100
92
34
93
67
90
73
84
83
119
91
84
83
97
83
104
78
87
83
87
79
104
85
109
103
93
110
83
63
78
67
90
77
91
79
74
99
99
90
93
79
98
114
84
106
97
112
106
83
97
80
98
78
102
106
143
106
105
118
119
98
111
85
99
105
97
97
125
95
130
118
107
124
97
74
100
76
98
89
106
98
96
121
110
102
103
87
109
121
90
110
105
na
Hi
na
na
na
na
na
. na
na
na
113
99
109
133
117
113
95
109
120
111
96
133
114
136
121
116
135
102
83
107
na
na
na
na
na
na
na
na
na
na
97
108
132
104
118
111
116
D-21
-------
Study No. 5221.08
SUBCHRONIC TOXICITY OF PARA-CRESQL IN SPRAGUE DAytET SATS
FEMALE BODY WEIGHT GAIN DATA
-------
Study No. 5221.08
SUBCHRQNIC TOXICITY OF PARA-CRESOL IN SPRAGUE OAULEY RATS
FEMALE BODY WEIGHT GAIN DATA (g)
ANIMAL NO. Weekl WeekZ Week3 Ueak4 UeekS Ueekfi Week?
DOSE LEVEL
600 mg/kg/day
3881
3182
3883
3884
3885
3886
3887'
3888
3889
3890
3891
3892
3893
3894
3895
3896
3897
3898
3899
3900
3901
3902
3903
3904
3905
3906
3907
3908
3909
3910
\6
11
T\»
22
14
24
12
15
12
12
25
7
6
17
11
9
29
27
na
1
18
11
18
22
14
16
13
23
12
na.
31
27
r,a
43
28
39
32
31
36
39
40
8
27
42
39
36
41
57
na
30
35
30
36
44
30
31
33
49
30
na
47
46
na
61
51
62
44
52
60
53
55
!6
51
70
65
57
61
78
na
53
55
44
57
58
49
49
49
66
44
na
59
57
na
94
64
73
60
73
77
6&
87
33
65
83
79
69
72
98
na
78
78
52
75
SO
58
61
59
78
69
na
59
56
na
101
74
75
65
76
85
78
83
41
80
96
92
73
90
103
na
86
83
60
79
91
59
68
70
96
77
na
72
78
na
105
B7
84
73
85
93
81
94
54
88
103
102
94
99
112
na
98
98
75
91
97
78
74
81
105
88
na
na
na
na
na
na
na
na
na
na
na
96
63
101
107
106
103
103
na
na
505
107
76
101
113
81
79
95
104
94
na
D-23
iis
-------
Study No. 5221.08
SUiCHRQMIC TOXICITY OF PARA-CRESOL !H SPRAGUE DAUIEY RATS
FEMALE BODY UEIGHT GAIN DATA
-------
Study Mo. 5221.08
SUSCHRONIC TCXICITY OF PARA-CBESQL IN SPRAGUE DAULEY RATS
FEMALE BODY yEIGHT CAIN DATA (g>
ANIMAL NO. WEEKS WEESC9 WEEK1Q WEES11 UEEK12 UEEK13
DOSE LEVEL
50 mg/kg/day 3837
(continutd) 3838
3339
3840
3841
3842
3843
3844
3845
3846
3847
3843
3849
3850
175 mg/kg/day 3851
3852
3853
3854
3855
3856
3857
3858
3859
3860
3861
3362
3863
3864
3865
3866
3867
3868
3869
3870
3871
3872
3873
3S74
3875
3876
3877
3878
3879
3880
106
117
92
94
140
106'
107
100
106
134
124
124
131
100
na
na
na
na
na
na
na
na
na
na
89
122
115
120
98
108
111
143
123
105
152
130
118
117
120
1Q2
104
126
97
113
112
122
99
101
132
124
124
98
119
13S
128
135
137
101
na
na
na
na
na
na
na
na
na
na
89
137
118
117
99
128
111
145
128
121
160
148
114
129
129
116
115
119
102
121
124
128
102
102
149
125
123
105
120
H7
132
131
148
105
na
na
na
na
na
na
na
na
na
na
95
148
120
126
96
130
115
147
118
130
166
157
131
137
135
113
117
130
103
118
117
123
101
111
148
126
120
103
121
146
136
145
154
109
na
na
na
na
na
na
na
na
na
na
99
153
129
126
107
138
121
154
132
125
178
154
131
136
143
116
118
126
105
122
129
142
106
118
159
128
128
108
129
157
147
152
164
118
na
na
na
na
na
na
na
na
na
na
110
168
142
136
107
152
126
167
149
135
189
164
134
ISO
143
132
127
133
109.
128
142
144
112
129
168
144
139
117
137
164
154
159
167
120
na
na
na
na
na
na
na
na
na
na
119
176
U4
137
100
163
132
173
165
143
197
168
152
144
151
133
136
140
115
128
D-25
1 9
-------
Study No. 5221.03
SUBCKRONIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
FEMALE BODY UE1GHT GAIM DATA Cg)
AM1MAL NO. UEEKS UEEK9 UEEK10 UEEK11 WEEK12 UEEK13
DOSE LEVEL
600 mg/kg/day
3881
3882
3S83
3384
3335
3886
3887
3888
3889
3890
3391
3892
3893
3894
3895
3896
3897
3393
3899
3900
3901
3902
3903
39C4
3905
3906
3907
3908
3909
3910
na
na
na
na
na
na
na
na
na
na'
109
59
112
116
117
103
111
127
na
106
111
78
103
126
92
85
104
123
99
na
na
na
na
na
na
na
na
na
na
na
108
71
108
122
116
117
117
135
na
113
125
92
110
131
97
84
111
132
117
na
na
na
na
na
na
na
na
na
na
na
103
61
115
127
117
110
115
135
na
109
129
94
115
135
96
85
107
131
113
na
na
na
na
na
na
na
na
na
na
na
110
69
122
134
124
121
129
135
na
99
125
101
126
145
88
87
118
136
121
na
na
na
na
na
na
na
na
na
na
na
115
75
131
139
123
134
134
146
na
117
135
106
132
149
122
S3
131
146
121
na
na
na
na
na
na
na
na
na
na
na
116
69
136
139
121
136
139
153
na
121
138
115
133
153
121
92
134
160
123
na
D-26
121
-------
Stydy Ho. 5221.08
SUBCHRONIC TOXICITY OF PARA-CR6SQI !M SPRAGUE DAUtEY RATS
MALE FOOD COKSUMPTSOM DATA (g)
IFeeder ueightsl
ANIMAL NO. new 1 old 1 new 2 old 2 ntw 3 old 3
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3661
3662
3663
3664
3665
3666
3667
3668
3669
3670
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3681
3682
3683 .
3684
. 3685
3686
3687
3688
36B9
3690
3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3701
3702
3703
3704
3705
3706
445.6
449. 5
450.1
448.7
45B.4
450.8
452.3
453,3
451.9
446.2
442.4
445.5
440.2
440.8
446.7
444.6
433.7
462.4
446.7
441.5
456.0
454.8
438.9
447.2
436.7
445.9
442.3
445.5
439.2
459.4
439.9
431.4
442.0
437.4
444.6
450,0
433.6
433.1
440.8
446.4
437.1
435.0
439.8
448.1
436.9
441.0
222.0
255.3
231.2
219.7
241.9
274.7
235.6
220.6
254.0
261.2
249.5
266.7
246. S
220.5
288.0
239.2
248.3
258.5
277.9
213.4
295.0
25S.4
253.3
234,9
243.6
243.7
245.5
226.7
243.3
242.2
211.6
231.2
253.4
228.3
231.5
273.5
240.6
210.6
235.9
251.7
229.0
223.8
236.3
275.7
231.1
246.2
500.6
504.3
500.2
496.4
496.1
496.6
496.6
455.7
493.5
500.7
498.9
498.4
496.8
501.5
494.3
494.5
500.4
519.6
508.8
496.6
494.0
499,6
500.4
499.8
493.3
492.1
495.8
495.6
494.5
500.4
486.4
488.6
483.2
491.1
480,5
484.4
494.7
483.1
474.0
480.5
478.8
483.5
490.4
469.6
476.5
497.3
291.5
310.0
272.3
263.4
280.5
324.0
282.9
263.1
290.4
313,4
309.2
314.2
307.0
278.5
333.9
289.9
309.7
299.3
340.6
279.5
327.0
294.9
298.9
285,5
294.0
289.0
2S6.3
269.5
315.9
2BO.O
256.0
278.0
302.0
276.1
275.2
301.8
295.5
262.1
278.9
261.5
280.7
282.6
267.0
284.8
280.4
307.5
510.2
503.5
.505.1
508.4
502.6
500.8
501.4
502.3
502.7
502.0
502.7
502.2
499.8
502.7
490.6
501 .a
493.1
525.9
492.3
501.9
497.8
501.6
501.1
502.0
500.8
498.2
503.1
500.2
494.8
498,1
502.1
501.5
500.7
501.3
501. S
494.5
502.6
500.1
500.9
499.9
501.8
495.3
502.4
506.0
497.0
514.3
317.9
318.5
272.5
287. 1
205.4
333.9
295.4
301.5
317.2
316.0
303.3
333.5
313.6
284.3
336.7
292.8
320.1
323.9
317.4
299.4
347.0
319.3
312.1
299.0
318.7
312.5
319.5
304.2
326.1
288.9
2S2.4
290.0
325.1
305.4
299.2
327.0
313.1
297.5
318.7
294.5
312.1
301.8
301.2
330.9
305.9
321.7
D-27
-------
Study No. 5221.08
SUBCHROHIC TOXICIJY OF PARA-CRESOL EN SPRACUE OAWLEY RATS
KALE FOOD CONSUMPTION DATA
[Feeder Heights]
ANIMAL NO. new 1 old 1 "«« 2 old 2 n«M 3 old 3
DOSE LEVEL
50 mg/kg/day 3707
(continued) 3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
175 mg/kg/day 3721
3722
3723
3724
3725
3726
3727
3728
3729
3730
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3741
3742
3743
3744
3745
3746
3747
3748
3749
3750
443
445
435
428
438
443
442
439
435
437
433
430
431
441
392
408
402
406
398
398
397
379
399
379
.9
.0
.5
.8
.5
.5
.1
.7
.0
.8
.3
.2
.7
.2
.6
.3
.2
,9
.2
.3
.4
.5
.6
.7
392.1
387
394
396
390
389
396
376
376
.5
.5
.2
.0
.1
.6
.2
.7
381.0
379
380
384
379
378
374
405
385
380
401
.7
.1
.4
.8
.3
.2
,4
.6
.8
.9
273
215
246
231
278
243
243
279
236
251
265
271
248
246
207
203
203
261
208
231
227
206
207
205
204
20B
206
221
208
2C8
210
208
231
213
207
212
208
213
224
211
211
208
205
230
.0
.5
.6
.2
.8
.8
.3
.2
.7
.9
.8
,4
.6
.2
.4
.1
.7
.7
.7
.7
.7
.6
.0
,4
.4
.4
.7
.2
.6
.9
.8
.7
.3
,3
.4
.9
.3
.4
,7
.4
.7
.9
.9
.3
476
475
480
477
477
,475
468
463
460
473
472
472
475
474
488
489
490
495
488
484
484
482
473
481
481
485
4S6
.4
.8
.6
.4
,7
.6
.0
.5
.6
.9
.1
.2
.6
.4
.a
.7
.2
.7
.5
.3
.0
.7
.5
.7
.3
.0
.8
479.1
478
476
483
478
479
486
474
479
475
476
476
475
474
476
479
480
.6
.7
.3
.6
.3
.6 ,
.3
.5
.1
.2
.7
.7
.9
,6
.9
.7
289
264
236
259
309
279
264
303
260
272
309
299
230
277
289
288
293
273
286'
325
295
260
270
240
267
275
253
300
248
305
288
299
322
272
267
304
255
300
314
289
281
280
293
.6
,5
.4
.7
.9
,3
.8
.4
.1
.3
.8
.9
.0
.5
.3
.0
.7
.3
.0
.8
.6
.0
.9
.9
.4
.3
.3
.9
.8
.9
.3
.7
.9
.4
.2
.1
.1
.5
.7
.4
.6
,7
.0
284.0
495.1
498.
498.
499.
491.
496.
499.
.503.
500.
498.
488.
497.
494.
505.
502.
500.
498.
505.
506.
499.
.500.
499.
494.
504.
500.
502.
502.
483.
503.
493.
498.
495.
492.
501,
497.
501.
499.
496.
481.
498.
495.
492.
499.
513.
5
5
2
5
0
1
1
5
5
6
0
8
0
3
7
6
0
3
1
6
a
6
1
3
5
9
3
2
8
1
7
1
4
7
4
4
7
7
7
3
2
1
5
312.1
300.0
314.6
292.0
320.6
315.5
299.9
350.6
308.6
297.9
331.6
340.1
312.2
338.1
292.2
315.4
307.1
290,2
299.2
247.3
311.6
307.5
295.1
287.7
293.2
322.0
302.3
320.4
297.0
323.2
322.0
332.9
339.6
291.1
308.5
335.9
305.2
328.9
324.9
327.3
321.9
317.6
320.0
340.8
» o ^
D-28 ' ~
-------
Study No. 5221.08
SUBCHRON1C TOX1C1TY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
HALE FOOD CONSUMPTION DATA (g)
[Feeder weights]
ANIMAL NO. new 1 old 1 neu 2 old 2 new 3 old 3
DOSE LEVEL
£00 mg/kg/day
3751
3752
3753
3754
3755
3756
3757
3758
3759
3760
3761
3762
3763
3764
3765,
3766
3767
3768
- 3769
3770
3771
3772
3773
3774
3775
3776
3777
3773
3779
3780
421.7
433.3
423.4
430.3
431.0
464.4
425.1
391.9
426.4
409.2
414.3
122.5
427.8
436.2
424.6
434.9
453.7
436. B
413.4
430.8
436.6
436.2
423.0
429.2
417.4
433.7
430. 2
424.3
423.0
421.7
292.0
250.9
274.8
279.6
247.6
320.6
271.7
222.7
294.0
257.9
291.3
271.8
268.4
312.3
252.2
256.0
263.5
2S9.9
318.9
308.5
2B8.1
283.6
268.2
301.3
269.5
251.9
262.2
268.7
267.9
263.1
474.5
472.1
472.1
470.2
472.9
476.4
474.4
470.3
469.1
469.2
469.6
473.2
471.5
471.4
476.8
475.0
464.6
464.4
465.9
467.3
473.6
465.1
470.1
465.3
472.2
464.0
471.1
478.0
469.3
482.3
312.1
271.1
293.2
305.3
271.3
328.7
231.1
297.4
323.7
283.9
330.5
319.8
313.1
300.4
282.3
309.6
279.3
274.9
320.5
294.5
3C4.3
283.0
268.7
296.3
320.5
271.9
315. S
310.9
279.5
312.9
491.8
506.9
500.1
503.4
501.0
512.9
511.8
503.3
501.7
505.6
514.2
513.0
513.0
520.2
-516.9
516.5
510.7
515.3
506.4
507.7
508.7
538.4
511.6
507.9
515.9
508.1
524.1
515.3
510.2
522.3
333.8
313.0
342.0
349.8
313.5
368.5
331.3
329.5
367.5
321.2
370.3
361.0
353.4
357.7
344.2
366.5
343.3
323.8
343.6
337.1
363.5
322.8
335.7
365.0
388.3
311.5
355.8
345.8
336.4
355.6
*
O
.
D-29
-------
Study No, 5221.08
SUBCHRON1C TQX1C1TT OF PARA-CRESOL IM SPRAGUE OAULET RATS
HALE FOOD CONSUMPTION DATA (g)
[Feeder weights]
ANIMAL NO. new 4 old 4 neu 5 old 5 new 6 old 6
DOSE LEVEL
0 mg/kg/day
50 mg/lcg/day
3661
3662
3663
3664
3665
3666
3667
3668
3669
3670
3671
3672
3673
3674
367S
3676
3677
3678
.3679
3680
3681
3682
3683
3684
3685
3666
3687
368S
3689
3690
3691
3652
3653
3694
3655
3696
3697
3693
3699
3700
3701
3702
37C3
3704
3705
3706
499.4
496.6
504.8
500.4
507.4
505.1
508.5
502.6
500.7
502.7
504.6
501.4
507.2
501.4
SOS. 9
508.1
502.6
509.2
504.8
500.8
500.8
502.9
503.1
501,3
501.4
500.8
501.7
501.0
502.9
500.0
510.6
500.9
502.3
501.3
503.1
504.0
501.4
500.4
502.5
501.3
501.9
504.4
500.3
501.5
501.6
503.3
309.7
309.4
.295.7
279.6
328.8
341.8
302.8
304.9
313.9
319.8
323.9
351.8
329.6
302.5
356.2
290.6
339.2
303.8
335.4
311.1
345.9
321.9
312.4
306.9
314.3
316.4
319.0
298.4
333.5
294.5
287.8
306.9
322.4
307.2
320.8
343.8
307.4
320.0
319.1
303.1
318.3
308.6
319.0
333.8
312.0
325.3
503.2
503.0
503.4
505.1
503.2
510.0
504.4
507.4
504.6
505.4
507.2
502.3
506.0
_507.3
506.4
511.1
507.3
503.8
500.1
506.0
502. 6
501.0
503.3
505.3
505.4
503.8
501.6
510.2
502.5
510.7
502.4
519.7
504.9
509.4
510.7
506.8
505.9
505.0
504.4
503.8
504.4
505.0
505.8
504-.0
522.0
502.4
306.7
310,0
308.7
271.2
319.8
333.9
305.2
301.8
308.6
312.7
323.7
322.2
324.6
288.5
353.3
278.0
339.4
295.5
324.0
297.5
340.6
329.7
315.0
316.5
323.2
310.4
296.8
308.9
330.7
295.7
283.7
317,6
321.7
323.1
323.9
341.8
310.1
330.9
328.3
306.4
320.6
317.3
332.5
340.5
339.4
329.8
498.9
492.7
494.6
498.3
498.1
494. S
498.9
498.4
494.1
493.1
495.0
495.4
494.1
499.1
499.2
.495.8
499.9
492.4
494.0
494.0
492.6
494.0
493.2
493.5
492.1
492.7
495.8
494.9
493.4
497.2
494.2
497.9
496. S
496.9
498.3
498.2
498.8
499.5
498.0
495.2
496.2
498.7
497.4
497.3
497.1
500.4
328.0
302.0
284.2
255.5
325.3
328.9
345.3
291.2
308.2
313.1
328.6
315.9
326.0
279.5
341.8
290.8
326.1
272.9
326.8
296.5
341.3
321.7
306.8
299.1
313.9
300.3
313.2
306.4
238.9
296.3
257.1
295.3
306.0
300.7
306.1
312.9
289.8
312.7
330.9
344.0
304.4
311.2
309.8
335.2
302.7
325.4
125
D-30
-------
Study No. 5221.08
SU8CHRONIC 10XICITY OF PARA-CRESCt IN SPRAGUE DAMLET SATS
HAUi FOOD CONSUMPTION DATA (g)
[Feeder weights]
AMI HAL NO. new 4 old 4 new 5 old 5 new 6 old 6
DOSE LIVEL
SO ng/kg/day 3707
(continued} 3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
175 mg/kg/diy 3721
3722
3723
3724
372S
3726
3727
3728-
3729
3730
3731
3732
3733
3734
3735
3736
3737
1738
3739
3740
3741
3742
3743
3744
3745
3746
3747
3748
3749
' 3750
500.2
501.9
502.6
. 501.2
501.0
503.3
504.1
498.4
501.3
530. 9
493.2
497.2
501.3
504.4
506.0
5C1.1
502.1
504.9
501.4
503.3
503.6
502.0
498.1
503.4
503.7
505.3
499.8
503.5
505.3
505.5
498.2
502.7
493.1
508.8
498.8
504.7
495.4
500.8
499.8
507.2
495.4
495.4
498.8
504.2
318.2
317.6
316.6
290.9
332.0
320.2
319.6
358.3
327.8
301.1
346.0
343.9
333.2
367.1
309.3
315.9
329.0
296.0
288.4
366.4
319.1
312.4
313.2
298.1 '
292.9
329.3
304.2
331.0
327,3
338.3
319.9
333.7
339.9
314. 5
324.0
343.3
300.0
339.7
346.6
343.6
331.1
331.4
314.1
338.1
504.0
503. a
506.5
508.2
5D6.2
502.4
506.1
502.1
504.1
506.0
507.1
508.6
504.5
503.5
506.6
504.6
509.3
501.2
507.2
505.6
509.0
501. 0
504.6
508.2
508.9
510.5
508.4
507.0
510,5
510.5
507.9
502.5
506.6
506.9
502.0
501.9
506.8
506.2
501.1
503.0
507.4
502.0
503.9
508.0
325.9
316.8
322.6
309.1
325.0
322.6
327.6
358.6
333.3
318.5
351.5
349.1
344.6
303.5
301.6
317.7
335.0
285.8
316.6
367.2
351. 3
317.0
322.2
303.5
299.9
333.6
321.3
338.2
324.7
336,1
341.8
330.2
351.4
310.3
310.5
329.6
313.4
342.7
342.6
341.2
331.8
343.2
318.8
335.4
498.3
497.8
498.3
500.4
499.1
497.6
499.8
498.4
504.4
498.4
495.0
498.5
500.9
495.5
498.9
498.6
500.0
500.4
499.3
499.0
497.5
497.3
.496.3
499.7
498.1
497.7
497.6
496.1
497.4
496.6
500.3
495.2
498.3
500.6
495.5
501.9
500.0
497.0
498.3
492.6
495.5
502.3
499.5
498.7
318.0
31B.7
315.7
302. 4
324.4
314.0
316.5
361.7
333.3
314.8
340,8
337.9
328.0
316.2
306.0
316.6
315.6
281.9
321.2
365.4
319.7
301.4
319.5
295.9
289.0
325.9
307.6
339.2
292.2
326.3
337.0
314.6
345.3
314.0
307.1
331.5
295.5
320.3
350.1
333.5
328.9
348.5
325.4
335.1
D-31
-------
Study No. 5221.08
SU3CHRONIC TOXICITY OF PARA-CRESOL IN SPRACUE DAULEY RATS
MALE FOOD CONSUMPTION DATA
-------
SUSCHSONIC TOXICITT OF PARA-CRESOL IN S?RAGUI BAWLED RATS
MALE FOOD CONSUMPTION DATA (g)
[Feeder Heightsl
Study Ho. 5221.08
AW1MAL NO. new 7 old 7 new 8 old & new 9 old 9
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3661
3662
3663
3664
3665
3666
3667
3663
3669
3670
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3681
3682
3683
3684
3685
3686
3687
3688
3689
3690
3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3701
3702
3703
3704
3705
3706
497.5
498.4
498.9
493.0
496.9
495.1
498.9
497.2
499.3
498.6
498.4
500.0
497.5
497.0
500.3
500.4
498.4
495.4
494.6
498.8
497.7
494.7
497.4
500.0
497.2
497.4
499.0
494.0
496.2
497.2
500.2
493.0
495.7
498.5
497.7
494.2
500.3
496.5
496.1
498.7
498.7
496.2
496.9
496.9
497.2
497.6
380.1
394.5
342.7
355.6
377.7
395.0
367.1
341.1
391.5
371.8
325.0
307.1
332.5
274.9
340.6
301.3
327.1
273.1
324.4
290. S
349.9
324.6
319.0
310.4
316.4
296.0
305.3
297.6
335.6
295.0
335.8
393.6
364.9
386.8
370.9
386.3
382.5
408.0
383.0
367.0
321.3
317.6
326.6
338.3
309.3
332.9
na
na
na
na
na
na
na
na
na
na
488.2
495.2
495.9
490.3
494.3
492.9
491.6
491.9
496.1
492.1
490.7
497.5
488.7
491.1
433.6
495.1
499.8
494.1
489.7
493.3
na
na
na
na
na
na
na
na
na
na
491.0
497.3
490.2
492.1
495.2
498.3
na
na
na
na
na
na
na
na
na
na
319.3
313.6
318.3
268.3
357.0
"313.3
309.8
285.7
339.6
301.0
344.9
330.9
292.8
305.8
314.1
305.9
312.6
321.0
329.3
315.0
na
na
na
na
na
na
na
na
na
na
316.6
316.0
312.8
338.9
320.9
333.8
na
na
na
na
na
na
na
na
na
na
494.3
488.2
488.8
485.1
484.5
497.3
495.1
486.8
481.6
489.2
494.7
484.6
492.3
490.3
487.3
491.4
490.8
484.4
485.3
492.2
na
na
na
na
na
na
na
na
na
na
494.0
486.9
486.5
484.5
493.2
493.2
na
na
na
na
na
na
na
na
na
na
329.4
310.0
318.9
276.5
335.7
301.1
309.4
282.3
326.8
314.2
365.0
318.8
314.6
311-6
306.6
294.9
315.2
306.7
326.6
302.2
_na
na
na
na
na
na
na
na
na
na
322.3
313.4
305.2
341.3
322.2
357.3
D-33
-------
SUBCHRON1C TOXICtn OF PARA-CRESQL 1H SPRAGUE OAWLEY RATS
MALE FOOD CONSUMPTION DATA (g)
EFteder weights]
Study No. 5221.08
ANIMAL NO. new 7 old 7 new 8 old 8 new 9 old 9
DOSE LEVEL
50 mg/kg/day 3707
(continued) 3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
175 mg/kg/day 3721
3722
3723
3724
3725
3726
3727
3728
3729
3730
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3741
3742
' 3743
3744
3745
3746
3747
3748
3749
3750
499.3
495.7
497.1
500.1
495.8
496.6
499.5
497.7
496.5
498.3
497.5
500. 4
498.9
495.2
549.5
508.2
517.7
495.0
499.2
499.2
507.8
497.8
499.9
102.9
433.2
516.1
522.7
509.0
510.5
520.0
501.2
514.9
498.3
515.2
502.1
504.4
508.6
492.9
512.4
505.3
514.2
530.5
513.4
517.8
305.2
323.3
321.8
312.2
328.6
325.1
317.3
362.1
324.4
316.5
333.9
344.7
323.4
320.2
443.7
384.4
390.7
352.2
385.8
406.0
409.8
365.8
372.0
352.1
278.2
343.9
333.2
351.3
328.2
346.9
329.2
349.6
356.7
332.3
320.4
340.4
392.0
307.6
373.2
339.9
342.1
373.1
341.3
353.7
498.3
494.0
490.4
492.2
490.4
497.2
498.6
493.5
499.1
493.3
494.2
493.3
493.5
498.2
na
na
na
na
na
na
na
na
na
na
459.9
482.0
452.5
451.2
517.7
592.8
471.3
482. 3
410.1
437.9
425.8
468.6
433.4
421.8
440.0
478.5
468.3
489.3
526.4
' 508.5
391.3
321.6
309.4
305.6
330.1
324.9
321.9
359.0
345.9
314.9
344.1
350.4
320.3
326.5
na
na
n
na
na
na
na
na
na
na
250.1
305.6
253.4
296.5
315.3
431.8
311.2
319.0
258.3
262.7
246.6
296.7
262.0
239.1
3C2.3
319.5
293.9
330.7
362.7
326.1
433.3
489.4
486.5
484.8
487.2
496.2
494.7
491.7
490.9
489.7
495.6
491.3
495.3
487.3
na
na
na
na
na
na
na
na
na
na
489.2
489.1
494.2
492.2
499,1
495.8
489.5
492.3
487.9
488.7
485.0
492.7
433.4
498.6
495.0
494.6
435.0
498.6
499.1
490.1
454.9
320.2
318.6
299.9
336. a
331.5
325.2
367.5
337.9
321.5
354.0
340.4
333.5
345.6
ns
na
na
na
na
na
na
na
na
na
300.4
323.3
301.6
345.3
293.7
352.8
367.0
332.4
339.4
314.2
335.0
332.1
293.5
320.2
360.4
340.6
328.9
338.6
330.4
323.5
D-34
-------
tenacity.OF PARA-CRESQL in SPRAGUE DAWIEY RATS
HALE FOOD CONSUMPTION DATA (g)
[Feeder weights]
Study Mo. 5221.08
ANIMAL NO. new 7 old 7 new 8 old 8 new 9 old 9
DOSE LEV1L
600.ms/kg/day 1751
3752
3753
3754
3755
3756
3757
3753
3759
3760
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
3771
3772
3773
3774
3775
3776
3777
3778
3779
3780
529.3
520.2
500.9
509.0
499.0
492.5
492.7
493.4
498.3
481
501
507
505
513
503
489
491
477
499
535
508
498
503
499
513
529
492
509
500
499
.7
.9
.2
.8
.7
.3
.5
.1
.3
.9-,
.6
.9
.0
.2
.5
.6
.3
.5
.1
.8
.9
414.1
419.8
407.7
408.2
422.6 -
4Q0.7
395.3
386,5
414,3
393.4
367.
366.
359.
307.
301.
340.
324.
298.
356.
377.
359.
311.
336.
362.
359.
362.
331.
338.
371.
338.
.0
7
7
,5
.4
6
5
9
8
2
6
0
0
7
4
7
9
9
1
1
491
472
464
477
473
539
615
533
565
614
601
499
532
507
511
479
538
507
522
540
na
na
na
na
na
na
na
na
na
na
.1
.2
.2
.8
.4
.2
.0
.9
.4
.4
.9
.7
.0
.7
.9
.9
.a
.9
.5
.7
342
334
300
na
na
na
na
na
na
na
na
na
na
.0
.4
.1
287.8
295
360
429
330
415
437
407
285
342
344
364
304
377
339
339
371
.1
.5
.0
.8
,2
.2
.1
.3
.2
.6
.0
.7
.0
.4
.3
.8
na
na
na
na
na-
na
na
na
na
na
496.5
493.6
489.
3
491.6
493.8
497.
497.
488.
499.
489.
488.
491.
486.
484.
499.
487.
499.
496.
486.
502.
3
0
3
8
2
2
3
8
9
0
4
4
4
2
6
na
na
na
na
na
na
na
na
na
na
376.0
371.8
319.2
307.2
318.4
338.5
338.5
314.0
376.4
342.8
345.8
323.4
317.3
346.5
355.8
304.8
349.9
335.6
298.5
341.1
D-35
130
-------
Study Mo. 5221.08
SUBCKRONIC TOXIC1TY OF PARA-CRISOL 1M SPRAGUE OAULEY RATS
- HALE FOOD CONSUMPTION DATA
-------
Study Na. 5221.08
SUBCKRONIC TOXICITY OF PARA-CRESQL 1H SPRAGUE DAULEY RATS
MALE FOOD CONSUMPTION DATA
-------
Study Wo. 5221.06
SUBCHROHIC TOX1CITY OF PARA-CRESOL IN SPRAGUE OAWLEY RATS
HALE FOOD CONSUMPTION DATA (g)
[feeder weights]
ANIMAL NO. new 10 old 10 new 11 old 11 new 12 old 12 neu 13 old 13
DOSE LEVEL
600 mg/kg/day
3751
3752
3753
3754
3755
3756
3757
3753
3759
3760
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
3771
3772
3773
3774
3775
3776
3777
3778
3779
37SO
na
na
na
na
na
na
na
na
na
na
486.0
495.7
502.0
478.2
462.6
473.8
513.9
474.4
525.5
476.3
516.1
433.4
487.8
475.9
497.3
466.9
503.6
498.6
473.1
497.0
na
na
na
na
na
na
na
na
na
na
356.6
364.2
324.9
289.9
279.8
308.2
344.9
294.6
388.5
315.8
358.7
297.3
320.9
330.1
351.6
292.7
351.5
336.7
256.2
329.3
na
na
na
na
na
na
na
na
na
na
499.5
496.4
480.5
493.4
491.2
494.7
502.6
533.7
492.8
497.5
504.8
490.8
436.8
4S8.7
483.4
488.9
488.2
501.9
503.3
501.4
na
na
na
na
na
na
na
na
na
na
390.2
375.3
323.4
315.2
316.2
331.0
338.2
365.9
371.3
348.2
356.3
307.8
319.5
350.1
343.3
333.0
339.8
340.4
337.8
345.5
na
na
na
na
na
na
na
na
na
na
429.1
469.2
458.9
444.6
448.9
500.2
498.9
492.8
475.2
495.7
477.1
465.3
430.7
457.7
456.6
444.4
447.2
456.4
454.0
453.4
na
na
na
na
na
na
na
na
na
na
356.2
343.5
298.0
262.0
275.1
345.7
336.3
321.1
342.9
341.7
323,2
263.0
253.3
314.0
314.4
277.5
296:9
300.8
292.3
300.7
na
na
na
na
na
na
na
na
na
na
495.2
497.5
496.5
497.4
492.9
494.1
498.5
496.7
494.5
490.1
495.4
502.8
486.7
493.6
488.1
490.5
498.3
493.0
493.6
525.3
na
na
na
na
na
na
na
na
na
na
381.5
359.8
336.3
311.8
319.7
352.5
334.2
339.0
371.9
341.2
354.8
314.6
343.4
360.2
351.8
337.3
367.8
341.2
331.6
383.0
D-38
-------
Study No. 5221.08
SUBCHRQH1C TOXICITY OF PARA-CRESQL IM SPRAGUE DAWLEY RATS
MALE FOOD CONSUMPTION DATA (g/day)
ANIHAL NO. ueekl ueek2 week3 week4 ueekS «eek6 week?
DOSE LEVEL
0 uig/kg/day
50 mg/kf/day
366 1
3662
3663
3664
3665
3666
3667
3668
3669
3670
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3681
3682
3683
3684
3685
3686
3687
3688
3689
3690
3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3701
3702
3703
3704
3705
3706
31.9
27.8
31.3
32.7
30.9
25.2
31.0
33.2
28.3
26.4
27.6
25.5
27 .7
31.5
22.7
29.3
27.2
29.1
24.1
32.6
23.0
23.1
26.5
30.3
27.6
28.9
28.1
31.3
28.0
31.0
32.6
28.6
26.9
29.9
30.4
25.2
27.6
31.8
29.3
27.8
29.7
30.2
29.0
24.6
29.4
27.8
29.9
27.8
32.6
31.3
30.8
24.7
30.5
33.2
29.0
26.8
27.1
26.3
27.1
31.9
23.0
29.2
27,2
31.5
24.0
31.0
23.9
29.2
28.8
30.6
28.5
29.0
29.9
32.3
25.5 '
31.5
32.9
30.1
26.6
30.7
29.3
26.1
28.5
31.6
27.9
31.3
28.3
28.7
30. 5
26.4
28.0
27.1
27.5
26.4
33.2
31.6
42.5
23. 8
29.4
28.4
26.5
26.6
28.5
24.1
26.6
31.2
22.0
29.9
24.7
28.9
25.0
28.9
21.5
26.0
27.0
29.0
26.0
26.5
26.2
23.0
24.1
29.9
31.4
30.2
25.1
28.0
28.9
23.9
27.1
28.9
26.0
29.3
27.1
27.6
27.7
25.0
27.3
27.5
27.1
26.7
29.9
31.5
25.5
23.3
29.4
28.2
26.7
26.1
25.8
21.4
25.4
23.4
21.3
31.1
23.3
29.3
24.2
27.1
22.1
25.9
27.2
27.8
26.7
26.3
26.1
28.9
24.2
29.4
31.8
27.7
25.7
27.7
26.0
22.9
27.7
25.8
26.2
28.3
26.2
28.0
25.9
24.0
27.1
25.4
28.1
27.6
27.8
33.4
26.2
25.2
28.5
29,4
28.0
27.5
26.2
25.7
25.9
31.3
21.9
33.3
24.0
29.8
25.2
' 29.8
23.1
24.5-
26.9
27.0
26.0
27.6
29.3
28.8
24.5
30.7
31.2
28.9
26.2
26.6
26.7
23.6
28.0
24.9
25.2
28.2
26.3'
26.8
24.8
23.4
26.1
24.7
24.4
27.2
30.1
34.7
24.7
23.7
21.9
29.6
26.6
25.7
23.8
25.6
24.0
31.4
22.5
29.3
24.8
31.4
23.9
28.2
21.6
24.6
26.6
27.8
25.5
27.5
26.1
26.9
22.1
28.7
33.9
28.9
27.3
28.0
27.5
26.5
29.9
26.7
23.9
21.6
27.4
26. B
26.8
23.2
27.8
25.0
16.8
14.8
22.3
20.3
17.0
14.3
18.8
22.3
15.4
18.1
24.8
27.6
23.6
31.7
22.8
28.4
24.5
31.8
24.3
29.7
21.1
24.3
25.5
27.1
25.8
28 .8
27.6
28.1
22.9
23.9
23.5
14.2
18.7
16.0
18.1
15.3
16.8
12.6
16.2
18.8
25.3
25.5
24,3
22.7
26.8
23.5
D-39
«~1 /
-1 4
-------
Study No. 5221.08
SUSCHRQNIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
MALE FOOD CONSUMPTION DATA (g/day)
ANIMAL NO. weekl weekZ week3 *eek4 weeks week6 wetk7
POSE LEVEL
50 mg/kg/day 3707
(continued) 3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
175 rag/kg/day 3721
3722
3723
3724
3725
3726
3727
3728
3729
3730
3731
3732 .
3733
3734
3735
3736
3737
3738
3739
3740
3741
3742
3743
3744
3745
3746
3747
3748
3749
3750
24
32
27
28
22
28
28
22
23
26
23
.4
.8
.0
,2
.8
.5
.4
,9
.3
.6
,9
22.7
26
27
26
23
28
20
27
23
24
24
27
24
26
.2
.9
.5
.6
,4
.7
.1
.8
.2
.7
.5
.9
.8
25.6
26
25
25
25
26
23
20
24
24
23
25
23
21
23
27
25
25
24
.8
.0
.9
.7
.5
.9
,a
.0
.6
.9
.2
.a
.9
.3
.7
.2
.0
.5
26.
30.
27.
31.
24.
28.
29.
7
2
7
1
0
0
0
22.9
28.
28.
23.
24.
27,
28.
28,
28.
27.
31.
28.
22.
26.
31.
28.
34.
30.
30.
33.
25.
32.
24.
27.
25.
22.
30.
29.
25.
31.
25;
23.
26.
27.
28.
26.
25.
6
8
2
6
9
1
5
s
4
8
9
6
9
S
9
4
6
0
4
5
S
4
9
6
3
6
6
1
4
1
1
6
6
0
7
1
26.
23.
26.
29.
24.
25.
28.
21.
27.
28.
22.
22.
26.
23.
30.
26.
27.
30.
29.
36.
27.
27.
23.
30.
29.
25.
28.
24.
29.
24.
25.
23.
21.
30.
27.
23.
27.
24.
22.
24.
24.
24.
25.
24.
1
4
3
6
4
8
5
8
4
7
4
4
1
8
0
5
4
7
6
0
0
5
5
9
6
3
6
0
5
4
2
3
8
0
0
6
7
0
4
4
3
9
6
7
26.0
26.3
26.6
30.0
24.1
26.2
26.4
20.0
24.8
23.5
21.7
21.9
24.0
19.6
28.0
26.5
24.7
29.8
30.4
19.6
26.4
27.1
26.4
29.3
30.1
25.1
27.9
24.6
25.4
23.9
25.5
24.1
21.9
27.3
25.0
23.0
27.9
23.0
21.9
23.4
23.5
23.4
26.4
23.7
25.
26.
26.
28.
25.
25.
25.
20.
24.
26.
22.
22.
22.
28.
29.
26.
24.
30.
27.
19.
22.
26.
26.
29.
29.
. 25.
26.
24.
26.
24.
23.
24.
22.
28.
27.
24.
27.
23.
22.
23.
25.
22.
26.
24.
4
?
3
4
9
7
5
5
4
8
2
8
S
6
3
7
9
8
2
8
5
3
1
2
9
3
7
1
5
9
7
6
2
1
4
6
6
4
6
8
1
7
4
7
25.8
25,6
26.1
28.3
25.0
26.2
26.2
19.5
24.4
26.2
22.0
22.9
24.7
25.6
27.6
26.0
26.3
31.2
25.4
19.1
25.4
28.0
25.3
29.1
29.9
24.5
27.1
22.4
29.3
24.3
23.3
25.8
21.9
26.7
26.9
24.3
29.2
25.2
21.2
22.7
23.8
22.0
24.9
23.4
27.7
24.6
25.0
26.8
23.9
24.5
26.0
19.4
24.6
26.0
22.7
22.2
25.1
25.0
15.1
17.7
18.1
20.4
16.2
13.3
14.0
18.9
18.3
21.5
30.0
24.6
27.1
22.5
26.0
24.7
24.6
23.6
20.2
26.1
26.0
23.4
16.7
26.5
19.9
23.6
24,6
22.5
24.6
23.4
D-40
-------
Study No. 5221.03
5UBCHRONIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
MALE FOOD CONSUMPTION DATA (g/day)
ANIMAL NO. weekl week2 week3 week4 ueekS ueek6 week?
DOSE LEVEL
600 nig/kg/day
3751
3752
3753
3754
3755
3756
3757
3753
3759
3760
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
3771
3772
3773
3774
3775
3776
3777
3773
3779
3780
18.5
26.2
21.2
21.5
26. 2
20.5
21.9
24.2
18.9
21.6
17.6
21.5.
22.3
17.7
24.6
25.6
27.2
21.0
13.5
17.5
21.2
21.8
22.1
13.2
21.1
26.7
23.1
22.2
22.2
22.7
23.2
28.7
25.6
23.6
28.8
21.1
27.6
24.7
20.3
26.5
19.9
21.9
22.6
24.4
27.7
23.6
26.4
27.1
20.8
24.7
24.1
26. 0
28.8
24.2
21.7
30.3
22.2
23.9
27.1
24.2
22.6
27.7
22.6
21.9
26.8
20.6
25.8
24.8
19.2
26.3
20.6
21.7
23.5
23.2
24.7
21.4
23.9
27.4
22.5
24.4
20.0
30.8
25.1
20.4
lfl.2
28.1
24.0
24.2
24.3
23.8
22.7
26.7
23.3
20.0
25.6
22.5
24.4
24.9
19.7
24.7
20.1
20.4
23.0
26.5
22.3
21.5
23.1
27.6
22.1
23.6
21.2
25.7
26.3
19.9
18.9
25.3
22.6
23.1
22.7
21.9
23.1
25.8
22.6
22.6
24.5
21.8
22.0
23.9
18.4
24.8
20.5
21.6
23.3
27.0
25.7
22.1
24.6
27.1
23.4
23.4
22.4
26.2
25.7
23.0
22.6
24.2
22.6
24.5
32.0
22.9
23.1
23.5
21.5
20.6
21.4
22.9
21.9
24.2
22.3
16.7
21.9
18.8
19.9
20.5
27.2
25.0
22.9
26.2
19.9
23.4
21.4
27.8
26.4
22.6
18.3
24.3
21.7
24.6
27.8
12.5
16.5
14.3
13.3
14.4
10.9
13.1
13.9
15.3
12.0
12.6
19.3
20.1
20.9
29.5
28.8
21.3
23.8
25.5
20.4
22.6
21.3
26.7
23.9
19.5
22.0
23.9
22.9
24.3
18.5
23.1
D-Al
4 O
JL O
-------
SUBCHRONIC TOXICITY OF PARA-CRESQI IN SPRAGUE DAWtEY RATS
HALE FOOD CONSUMPTION DATA (g/day)
Study No. 5221.08
ANIMAL HO, ueekS week9
ueekll week12 ueek13
DOSE LEVEL
0 ng/kg/day
50 mg/kg/day
3661
3662
3663
3664
3665
3666
3667
3668
3669
3670
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3681
3682
3683
3684
3685
36S6
3687
3688
3689
3690
'3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3701
3702
3703
3704
3705
3706
na
na
na
na
na
na
na
na
na
na
24.1
25.9
25.4
31.6
19.6
25.7
26.0
29.5
22.4
27.3
20.8
23.8
28.0
26.5
24.9
27.0
26.7
24.7
22.9
26.3
na
na
na
na
na
na
na
na
na
na
24.9
25.9
25.3
21.9
24.9
23.5
na
na
na
na
na
na
na
na
na
na
23.6
25.5
24.3
29.6
21.3
23.0.
26.5
29.2
22.1
25.0
18,5
23.7
25.4
25.5
25.8
28.1
25.1
25.4
22.7
27.1
na
na
na
na
na
na
na
na
na
na
24.5
24.8
25.9
20.5
24.4
19.4
na
na
na
na
na
na
na
na
na
na
25.2
24.9
24.7
27.3
20.7
26.9
26.0
29.2
22.7
26.1
20.1
23.6
26.6
25.8
26.2
27.3
24.7
26.4
22.6
26.2
na
na
na
na
na
na
na
na
na
n»
23.4
26.5
25.9
21.6
25.1
20.9
na
na
na
na
na
na
na
na
na
na
23.0
24.7
20.9
25.2
22.5
25.5
23.3
29.0
21.9
24.0
22.7
23.5
25.1
22.8
24.3
24.4
24.2
22.7
22.0
24.1
na
na
na
na
na
na
na
na
na
na
24.3
25.7
22.7
22.6
24.5
20.7
na
na
na
na
na
na
na
na
na
. na
22.2
16.7
22.4
27.6
21.1
26.0
22.6
27.8
23.0
24,9
19.5
22.2
25.8
23.5
22.2
25.1
24.6
23.1
21.7
24.6
na
na
na
na
na
na
na
na
na
na
21.8
25. Q-
22.3
22.6
24.5
21.1
na
na
na
na
na
na
na
na
na
na
23.7
14.9
19.3
27.4
17.6
20.7
17.8
24.8
17.1
21.3
17.4
13.0
22.8
21.4
22.6
23.0
23,6
22.7
15.8
21.9
na
na
na
na
na
na
na
na
na
na
23.7
14.9
19.3
27.4
17.6
20.7
D-42
-------
SUBCWRONIC TCXIC1TY OF PARA-CRESQL IN SPRAGUE DAULEY RATS
HALI FOOD CONSUMPTION DATA Cg/day)
Ssudy No. 5221,08
ANIMAL NO. weekS week? week'O week11 week12 ueek13
DOSE LEVEL
50 mg/kg/day 3707
(continued) 3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
175 nig/kg/day 3721
3722
3723
3724
3725
3726
3727
3728
3729
3730
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3741
3742
3743
3744
3745
3746
3747
3748
3749
3750
15.3
24.6
25.9
26.7
22.9
24.6
25.2
19.2
21.9
25.5
21.4
20.5
24.7
24.5
na
na
na
na
na
na
na
na
na
na
30.0
25.2
28.4
22.1
28.9
23.0
22.9
23.3
21.7
25.0
25.6
24.6
24.5
26.1
19.7
22.7
24.9
22.7
23.4
26.1
4.1
24.2
24,0
26.4
21.5
23.5
24.2
17.7
21.9
24.0
20.2
21.6
23.1
20.2
na
na
na
na
na
na
na ,
. na
na
na
27.0
23.7
27.5
21.0
29.3
20.4
17.5
22. 8
21.2
24.9
21.4
22.9
27. S
25.5
t9.2
22.0
22.3
22.9
24.1
23.8
13.6
25.6
25.2
27.2
22.7
25.3
25.2
18.4
23.1
24.6
21.0
20.1
23.4
21.2
na
na
na
na
na
na
na
na
na
na
27.0
24.9
27.3
22.0
30.4
22.2
22.2
24.5
21.2
25.3
24.2
24.6
27.0
23.8
17.5
24.1
23.5
25.2
22.8
24.4
8.9
22.4
24.6
26.1
22.7
23.3
24.9
17.6
22.0
24.1
26.1
20.4
22.2
19.2
na
na
na
na
na
na
na
na
na
na
25.5 '
22.3
26. 5
19,2
28.6
20.9
20.1
21.2
18.0
25.1
20.8
23.3
24.9
13.9
19.0
22.4
22.2
21,1
21.0
20.7
7.7
22.7
22.6
26.1
20.6
24.8
24.4
17.2
21.5
22.2
18.8
19.1
21.7
19.3
na
na
. na
na
na
na
na
na
na
na
26.2
23.2
27.9
21.4
27.5
22.0
20.4
21.3
20.5
25.5
24.5
23.3
25 .8
23.3
20.5
21.0
22.7
21.5
22.7
21.4
17.8
24.8
17.1
21.3
17.4
18.0
22.8
21.4
22.6
23.0
23.6
22.7
15.8
21.9
na
na
na
na
na
na
na
na
na
na
17.1
20.0
21.8
19.7
25.5
20.8
17.3
17.8
14.2
20.3
21.8
21.3
22.7
22.5
20.1
20.0
20.0
19.9
19.7
20.7
D-43
i'38
-------
SUBCHRQMIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
HALE FOOD CONSUMPTION DATA
-------
Study No. 5221.08
SUBCHRONIC TOXICITY OF PARA-CRISQL IN SPRAGUE BAWLEY IATS
FEMALE FOOD CONSUMPTION DATA Cg)
{Feeder Uelghts]
ANIMAL HO. new 1 old 1 new 2 old 2 new 3 old 3
DOSE LEVEL
- 0 tug/kg/day
50 mg/kg/day
3791
3792
3793
3794
3795
3796
3797
3798
3799
3300
3301
3802
3803
3804
3305
3306
3807
3808
3809
3B10
3811
3812
3813
3814
3815
3816
3817
3S1S
3819
3820
3821
3822
3823
3824
3825
3826
3827
3828
3829
3130
3831
3832
3833
3834
3835
3836
401,6
394.3
401.3
398.6
413.9
413.7
397.0
393.3
402.8
444.8
419.4
412.0
405.5
40S.7
401.1
404.8
400.2
405.6
403.9
396.9
410.2
399.7
416.6
417.1
437.2
417.7
421.0
421.6
418.1
408.6
396.6
400.0
403.6
408.9
408.3
412.7
410.5
410. t
412.4
410.1
410.3
411.5
412.0
410.3
419.2
411.7
266.4
263.5
290.5
261.9
277.3
282.3
279.0
269.5
283.7
273.1
286.3
277.5
259.1
273.0
275.6
278.7
271.2
265.3
265.6
280.5
279.0
251.4
290.7
282.7
290.7
294.5
272.7
300.3
302.9
286.5
274.0
279.6
290.5
288.8
289.1
309.9
274.6
278.7
306.1
297.5
281.2
282.7
269.9
289.1
285.6
287.7
500.0
483.6
479.1
471.2
459.8
463.2
458.9
456.6
463.8
477.1
457.4
461.5
457.4
474.2
473.8
461.9
460.7
461.9
467.0
463.8
479.8
472.9
470.0
477.1
470.5
469.4
471.0
463.0
469.3
468.8
467.9
454.5
455.4
453.0
458.7
456.2
456.4
459.9
471.1
466.1
470.2
456.2
464.6
460.5
463.0
467.1
350.7
349.8
347.4
332.7
326.1
325.6
340.4
326.5
346.2
309.0
321.3
320.2
314.4
333.1
343.7
339.9
345.0
329.1
321.6
346.7
350.8
312.9
350.0
340.3
328.5
344.8
33S.6
343.2
363.8
347.5
364.6
331.1
346.4
342.6
349.2
351.0
315.1
332.1
369.7
351.5
330.4
324.8
322.1
355.8
336.9
347.1
446.2
444.9
445.8
438.7
443.6
443.3
440.6
442.5
442.7
453.9
442.9
442.1
443.1
462.1
461.8
445.0
446.0
443.9
466.5
446.9
470.6
459.7
469.3
461.9
461.2
459.2
463.7
462.8
-463.5
464.5
440.7
460.1
459.9
462.4
454.8
460.2
461.4
457.4
459.6
461.2
448.7
462.3
465.6
470.5
467.0
463.8
299.0
320.3
329.2
307.2
319.3
314.1
340.8
317.5
334.8
256.0
320.2
299.9
315.4
324.0
347.3
321.0
339.3
328.2
383.6
342.0
344.0
316.8
349.6
336.1
320.5
332.4
309.1
359.9
364.9
349.3
269.2
343.9
345.0
355.5
345.0
355.9
339.2
331.3
361.2
354.1
316.6
328.5
322.8
364.2
354.2
347.0
D-45 140
-------
Study No. 5221.08
SUSCHRONIC TOXIC1TY OF PARA-CRESOL IN SPRAGUE OAULEY RATS
FEMALE FOOD CONSUMPTION DATA
[Feeder Weights]
ANIMAL NO. new 1 old 1 new 2 old 2 new 3 old 3
DOSE LEVEL
50 mg/kg/day 3837
{continued) 3838
3839
3840
3841
3842
3843
3344
3845
3846
3847
3843
3849
3850
175 mg/kg/day 3851
3852
3853
3854
3855
3856
38S7
3858
3859
3360
3861
3862
3863
3864
3865
3866
3867
3868
3869
3370
3871
3S72
3873
3874
3875
3876
3877
3878
3879
3880
413.
396.
395.
415.
418.
406.
392.
409.
409.
414.
407.
411.
411.
404.
400.
397.
398.
411.
409.
399.
392.
397.
410.
410.
402.
394.
387.
400.
39S.
373.
8
0
1
3
2
0
7
3
7
9
9
5
5
3
0
9
3
3
0
0
4
5
6
7
4
3
1
3
7
6
330.5
412.
417.
409.
417.
391.
412.
413.
383.
399.
381.
386.
385.
387.
3
2
1
1
4
3
0
2
1
0
3
3
4
292.
26S.
298.
301.
298.
281.
249.
292.
282.
286.
2S7.
294.
238.
251.
272.
264.
244.
274.
280.
260.
260.
271.
280.
272.
292.
280.
256.
267.
263.
249.
264.
270.
296.
267.
266.
251.
282.
281.
229.
267.
267.
248.
278.
254.
4
3
4
5
2
7
5
4
3
4
5
1
1
2
5
0
7
1
5
2
6
5
9
8
5
0
8
a
8
4
8
7
2
9
7
5
6
9
6
5
7
0
0
6
471
461
443
452
453
460
460
454
460
457
465
465
460
475
451
448
446
461
444
450
446
. 447
442
465
444
450
448
448
440
446
447
452
462
X53
454
459
4S3
450
468
450
446
448
454
459
.1
.0
.4
.9
.8
.5
.7
.3
.8
.1
.5
.2
.9
.4
.3
.1
.8
.4
.6
.3
.8
.6
.6
.0
.7
.8
.4
.2
.6
.7
.1
.0
.0
.6
.1
.7
,7
.0
.6
.9
.3
.6
.3
.2
355
328
351
340
331
332
314
347
333
324
348
344
336
351
334
330
319
334
320
319
318
328
322
313
325
342
315
317
316
323
341
301
340
318
317
317
334
316
.9
.9
.4
.1
.3
.8
.3
.4
.4
.1
.9
.9
.2
.3
.6
.1
.5
.4
.8
.8
.2
.6
.6
.1
.0
.2
,4
.6
.0
.1
.9
.4
.2
.2
.6
.5
.3
.4
319.0
316
336
306
341
331
.9
.2
.7
.1
.9
464.
445.
455.
460.
465.
460.
447.
463.
464.
464.
462.
465.
470.
466.
448.
446.
452.
464.
446.
449.
447.
448.
469.
461.
456.
445.
450.
450.
3
2
6
1
1
3
2
1
0
8
8
7
4
9
4
3
1
3
1
6
7
1
4
2
3
6
1
5
449.7
447.
446.
467.
462.
468.
467.
2
7
4
3
3
9
-447.4
467.
462.
455.
446.
448.
447.
468.
449.
2
2
5
4
3
5
7
8
347.3
305.2
326.6
347.9
340.3
339.7
212.0
358.0
340.5
333.9
336.3
348.3
350.7
352.1
326.7
324.0
322.0
330.1
341.6
316.4
316.9
339.8
343.1
326.7
350.0
336.0
311.7
321.8
332.0
320.0
340.0
325.5
347.7
336.9
332.1
304.8
329.6
329.1
315.5
318.1
338.1
319.2
362.7
326.6
D-46
41
-------
Sturfy Mo. 5221.08
SUICHRONIC TOXICITY OF PARA-CRESQL IK SPRAGUI DAULEY RATS
FEMALE FOOD CONSUMPTION DATA (3)
[Feeder Heights]
ANIMAL NO, new 1 old 1 new 2 old 2 new 3 old 3
DOSE LEVEL
600 rng/kg/day
38B1
3682
3883
1884
3885
3886
3887
3888
3889
3890
3891
3892
3893
3894
3895
3896
3897
3898
3899
3900
3901
3902
3903
3904
3905
3906
3907
3908
3909
3910
392.6
364.9
392.2
389.7
409.1
384.5
379.2
374.6
380.8
388.9
392.6
381.4
400.9
402.3
379.5
374.9
376.5
376.1
419.2
370.6
388.7
419.1
405.6
376.1
378.4
410.5
404.0
415.2
413.7
408.8
287.6
258.8
na
237.8
299.5
260.3
271.2
264.8
270.4
275.1
285.6
277.7
293.0
292.2
272.7
260.1
259.6
253.8
na
289.4
297.5
313.9
288. S
241.3
272.9
314,1
293.2
275.2,
303.3
na
455.2
453.4
na
452.3
454.9
467.9
457.4
452.5
462.3
459.4
452.6
445.7
494.5
452.6
462.7
457.2
453.0
477.9
na
460.6
463.2
466.8
498,1
412.1
455.4
469.5
467.7
467.2
468.1
na
345.2
340.4
na
320.6
324.0
341.1
349.5
334.9
341.3
336.2
335.1
360.2
376.1
336.5
328.8
322.6
335.7
332.4
na ,
336.1
364.7
351.7
373.9
321.6
347.0
367.6
342.5
333.1
350.0
na
442.4
443.1
na
442.9
442.4
441.1
443.2
444.9
442.9
447.0
444.9
449.3
456.3
460.6
443.0
444.2
446.1
447.0
na
444.6
448.5
464.5
460.0
442.7
445.1
482.1
462.1
452.5
457.fi
na
336.2
237.5
na
304.4
305.8
311.1
341.3
321.3
310.2
327.1
339.2
361.8
332.2
341.3
319.3
306.9
334.4
315.9
na
318.2
334.6
354.0
337.7
312.7
321.7
313.8
345.1
320.8
335.7
na
D-47
4 *>
i f^l
-------
Study No. 5221.08
SUSCHRQNIC TOXICITT OF PARA-CRES.OL IN SPRAGUE DAULEY SATS
FEMALE FOOD CONSUMPTIOM DATA
[Feeder UeightsI
ANIMAL Ma. new 4 old 4 >new 5 old 5 new 6 old 6
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3791
3792
3793
3794
3795
3796
3797
3798
3799
3800
3BQ1
3802
3803
3804
3805
3806
33Q7
3808
3809
3810
3311
3812
3813
3314'
3815
3816
3817
3818
3819
3820
3321
3822
3823
3324
3825
3826
3827
3828
3829
3830
3831
3832
3833
3834
3835
3836
471.7
470.1
470. S
470.5
472.4
469.9
474.1
469.7
471.3
477.5
469.6
469.2
471.6
473.6
470.2
468.4
467.7
470.6
465.5
470.3
472.6
470.5
474.3
475.7
470.7
471.4
473.7
472.3
477.3
471.0
474.6
472.5
472.7
471.9
472.3
473.5
474.2
474.0
471.9
472.6
464.0
472.8
471.8
474.2
474.8
473.8
338.0
351.1
354.7
338.9
354.6
346.5
382.4
353.6
367.1
319.5
350-5
335.0
337.4
344.5
352.8
351.9
363.1
348. 7
330.4
364.2
355.5
338.8
353.7
350.9
340.8
351.1
339.6
367.5
388.4
353.2
365.9
355.1
370.4
368.4
367.6
376.0
357.5
343.8
373.7
366.3
337.9
348.0
344.9
368.7
354.4
357.0
D-48
476.2
476.9
478.3
476.7
474.1
477.0
474.6
480.9
479.4
475.9
479.9
478.7
470.7
473.0
476.3
477.4
478.7
476.1
470.6
481.2
486.4
478.3
472.8
482.5
478.8
473.9
472.1
475.3
481.3
470.5
467.9
467.8
461.9
462.5
464.8
466.4
465.0
465.8
469.9
468.1
466.6
469.0
463.6
483.6
482.5
479.6
345.3
348.3
356.2
347.3
341.4
351.9
373.3
366.8
379.4
275.5
354.7
347.8
345.7
332.3
364.2
363.5
371.3
355.1
331.5
369.3
367.6
338.1
353.7
360.4
342.8
345.9
333.6
367.0
388.0
355.6
300.7
357.1
366.2
354.9
355.0
363.6
336.5
342.9
363.4
356.6
338.6
344.4
327.5
373.4
345.7
359.1
465.1
468.3
469.7
468.1
-467.7
468.9
467.4
467.7
469.7
468.5
468.9
470.0
469.7
467.6
467.4
470.2
468.5
466.8
468. 6
469.8
465.4
467.7
469,5
468.1
469.7
465.5
468.3
469.0
468.4
465.9
464.0
466. B
469.4
469.3
469.2
466.3
466.4
468.2
464.7
469.7
468.7
467.7
468.2
466. S
468.2
469.4
-
336.7
343.7
356.5
345.4
347.0
345.7
373.0
350.8
349.5
283.1
345.9
324.8
281.0
332.9
349.3
337.4
370.5
344.9
322.2
352.5
338.7
320.0
345.7
340.7
332.8
328.5
324.7
361.6
368.2
347.1
341.6
352.8
360.6
367.9
354.2
356.4
339.7
338.3
357.3
359.1
336.8
340.9
333.8
365.3
343.6
352.5
A A 9>
* 4 o
-------
Study Ho. 5221.OS
SU8CHRONIC TOXICITY OF PAftA-CRESOL IN SPRAGUE DAWLEY RATS
FEMALE FOOD CONSUMPTION DATA (g)
[Feeder Weights]
ANIMAL NO. new 4 old 4 new 5 old 5 new 6 old 6
DOSE LEVEL
SO mg/kg/day 3837
(continued) 3328
3839
3340
3841
3342
3843
3344
3845
3846
3847
3845
3849
3550
175 mg/kg/day 3S51
3852
3853
3854
3855
3856
3857
3858
3859
3860
3861
3362
3863
3864
3865
3866
3867
3868
3869
3870
3871
3872
3873
3874
3875
3876
3877
3878
3879
3880
471
471
471
475
469
471
473
474
470
471
474
472
470
474
473
463
468
477
469
468
470
470
470
469
469
470
471
470
472
472
467
472
490
491
462
470
472
473
469
463
469
476
473
470
.1
.8
.4
.9
.5
.8
.3
.6
.3
.6
.0
.1
.8
.3
.0
.8
.8
.6
.2
.6
.1
.7
.8
.4
.9
.0
.2
.2
.0
.5
.3
.0
.7
.4
.9
.3
.9
.7
.0
.6
.5
.8
.9
.6
359.
347.
383.
369.
348.
360.
324.
379.
359.
344.
360.
354.
349.
360.
358.
345.
346.
361.
362.
350.
345.
367.
357.
348.
366.
367.
348.
356.
360.
360.
365.
343.
385.
378.
328.
308.
361.
355.
. 348.
349,
4
4
3
7
1
4
9
0
2
7
5
0
2
4
2
2
0
0
8
2
8
0
7
4
8
7
9
7
3
2
2
5
5
6
8
4
7
8
6
1
366.9
364.
375.
361.
1
0
0
483
477
479
482
481
479
475
484
486
479
483
472
482
479
470
471
464
472
461
466
472
465
470
464
467
471
473
463
465
467
.3
.0
.1
.5
.9
.9
.6
.6
.0
.2
.0
.1
.0
.6
.0
.9
.4
.4
.3
.3
.3
.1
.6
.8
.8
.7
.2
.5
.6
.9
463.3
466
469
464
465
465
472
466
465
473
474
476
466
471
.5
.6
.6
.8
.1
.1
.5
.3
.6
.4
.4
.0
.5
369.
349.
387.
372.
366.
362.
329.
3E4.
370.
347.
352.
354.
363.
399.
344.
316.
335.
360.
352.
332.
337.
354.
352.
326.
362.
356.
343.
317.
351.
343.
359.
325.
358.
340.
321.
325.
343.
331.
334.
362.
364.
357.
364.
354.
5
4
4
8
6
4
7
8
0
6
3
2
0
3
9
1
6
1
9
0
4
4
3
0
4
1
4
1
5
7
6
3
8
1
0
7
4
6
1
6
5
7
3
6
468.
468.
467.
467.
464.
467.
465.
468.
463.
468.
469.
465.
-468.
469.
463.
469.
466.
467.
466.
466.
466.
467.
466.
466.
464.
465.
464.
464.
470.
465.
466.
470.
468.
470.
469.
467.
467.
461.
467.
467.
466.
467.
469.
468.
4
8
1
8
3
3
9
4
8
6
6
9
4
5
3
9
2
7
7
4
6
6
1
4
1
4
6
3
3
9
5
0
2
1
0
6
9
6
3
9
2
7
4
1
356.3
339.5
379.4
356.2
343.2
354.4
284.0
374.1
3S7.1
341.7
361.5
329.0
349.9
353.3
339.4
297.9
332.6
348.7
353.3
336.9
344.6
351.5
347.7
327.2
357.3
353.6
341.9
336.5
352.2
341.4
362.9
330.3
355.1
333.5
321.1
327.9
349.0
334.9
339.3
340.0
357.0
349.0
369.9
353.0
D-49
144
-------
Study No. 5321.08
SUSCHRONIC TOXICITY OF PARA-CftESOl IH SPRAGUi DAytEf RATS
FEMAlf FOCO CONSUMPTION DATA
-------
Study Ho. 5221.08
SUBCHRONIC TOXICITY Of PARA-CRESQL IH SPRAGUE DAWLEY RATS
FEMALE FOOD CONSUMPTION DATA (g)
[Feeder Weights]
ANIMAL NO. new 7 old 7 new 8 old 8 new 9 old 9
DOSS LEVEL
0 mg/kg/day
50 mg/kg/day
3791
3792
3793
3794
3795
3796
3797
3798
3799
3800
3801
3802
3803
3804
3805
3806
3807
3803
3809
3810
3811
3312
3813
3314
3815
3816
3817
3818
3319
3S20
3821
3822
3823
3824
3825
3826
3827
3828
3829
3830
3831
3832
3833
3834
3835
3836
463.7
468.2
470. 0
465.7
460.6
464.3
467.7
468.0
468.4
471.3
471.0
462.5
469.6
465.1
471.4
466.4
471.6
469.9
464.8
468.3
468.2
468.3
470.3
468.6
476.1
466.1
471.0
462.9
469.5
469.0
467.2
463.2
463.2
466.6
468. 8
460.6
461.2
462.0
466.4
461.6
463.3
464.4
462.6
469.5
469.5
473.4
386.0
387.5
397.7
388.7
370.0
376.5
406.3
403.0
401.2
372.7
355.4
329.8
312.2
319.5
350.1
351.3
170.9
348.2
336.0
350.9
347.6
319.6
344.1
345.9
352.3
339.0
331.5
347.8
367.4
351.3
374.1
390.9
384.3
379.1
389.7
393.7
386,0
403.4
381.7
385.6
330-.3
336.5
348.3
323.3
339.8
364.2
1SAC
I SAC
I SAC
I SAC
ISAC
I SAC
ISAC
ISAC
ISAC
ISAC
451.6
454.6
452.1
457.2
456.5
454.0
455.0
456.8
455,8
494.5
487.5
540.5
540.5
479.9
444.5
433.2
476.7
450.9
481.0
468.7
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
435.6
460.3
523.6
466.8
429.1
447.2
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
331.3
313.8
338.2
342.2
362.4
340.2
358.4
328.3
341.3
337.1
381.3
330.9
429.9
358.9
320.7
306.2
342.9
345.7
384.1
343.9
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
314.0
335.8
491.9
358.1
317.9
338.3
na
na
na
na
na
na
na
na
na
na
449.1
450.1
452.6
456.8
456.7
450.1
451.9
454.9
455.8
454.0
453.6
452.3
453.8
_454.7
450.7
451.8
451.7
456.4
462.S
452.6
na
na
na
na
na
na
na
na
na
na
448.7
453.8
452.8
458.4
456.1
458.2
na
na
na
na
na
na
na
na
na
na
325.2
312.8
330.0
332.6
351.2
327.1
359.4
335.0
318.9
347.0
336.5
292.7
348.3
333.8
328.3
324.9
310.2
363.7
364.1
352.3
na
na
na
na
na
na
na
na
na
na
320.5
332.1
329.4
349.8
332.2
347.7
D-51
-------
SUICH8QNIC TOXICITY OF PARA-CRESOl IN SPRAGUI DAULEY RATS
FEHALE FOOD CONSUMPTION DATA (3)
[Feeder Weights}
Study No. 5221.03
ANIMAL NO. new 7 old 7 new 8 old 2 new 9 old 9
DOSS LEVEL
50 mg/kg/day 3837
(continued) 3838
3839
3840
3841
3842
3343
3844
3845
3846
3847
3848
3849
3850
175 mg/kg/day 3851
3852
3853
3854
385S
3856
3857
3858
3859
3860
3861
3862
3863
3864
3865
3866
3867
3868
3869
3870
3871
3872
3873
3874
3875
3876
3877
3878
3379
3880
466,0
464.0
463.9
463.4
464,3
466.8
466.9
467.1
463.4
464.7
464.1
467.4
461.5
466.4
468.5
463.3
460.1
464.7
466.9
460. 6
459.2
463.6
453.1
453.3
443.2
471.7
480.0
475.1
473.7
485.5
483.4
464.4'
471.8
460.4
475.6
453.9
466.9
496.3
460.9
453.5
473.6
473.1
508.5
489.1
351.9
325,4
371.8
336.5
341.8
345.6
334.6
367.9
343. B
336.5
328.7
294.1
337.1
348.1
389.3
371.4
387.3
404.9
390.8
383.5
386.7
404.6
374.2
369.0
334.4
363.1
355.3,
348.5
364.2
361.2
372.7
332.0
360.3
341.9
343.7
310.6
350.1
380.0
324.4
337.3
377.4
358.9
412.4
38D.9
423.7
445.2
441.7
485.7
437.4
423.5
413.1
444.1
426.1
479.2
447.?
411.2
455.2
441.3
1SAC
I SAC
I SAC
ISA:
1SAC
I SAC
IS AC
1SAC
I SAC
ISAC
383.2
425.9
436.1
431.2
437.8
429.8
450.2
438.0
451.0
461.1
442.1
415.9
467.1
473.5
458.3
464.4
476.6
463.3
462.9
475.9
309.7
324.3
349.9
374.4
314.8
310.8
221.0
346.0
313.1
348.3
322.0
291.1
329.9
319.0
I SAC
':SAC
iSAC
1SAC
ISAC
ISAC
ISAC
ISAC
ISAC
ISAC
290.7
316.4
320.0
310.6
332.1
342.2
351.1
306.9
332.5
331.7
320.4
316.2
328.9
3S4.3
326.7
347.4
371.0
345.0
364.1
356.4
453.1
455.5
456.9
450.5
457.2
457.2
456.1
461.1
456.8
454.9'
453.1
453.8
465.4
459. S
na
na
na
na
na
na
na
na
na
na
457.2
452.4
453.5
451.4
452.6
455.6
_451.6
459.0
452.4
459.3
456.3
454.2
453. S
453.2
457.7
452.8
452.8
455.2
456.0
454.2
333.9
329.1
370.3
347.4
341.0
347.6
261.5
366.1
346.8
333.3
332.9
343.3
339.4
347.4
na
na
na
na
na
na
na
na
na
na
360.0
330.3
339.7
347.2
353.7
341.6
353.8
332.3
337.7
347.7
331.7
315.2
345.0
332.0
318.5
341.2
350.8
260.6
362.3
348.8
D-52
147
-------
Study No. 5221.08
SUBCHRONJC TQX1C1TY Of PARA-C3ESQL IN SPRAGUE OAULEY RATS
FINALE FOOD CONSUMPTION DATA (g)
[Feeder Weights]
ANIMAL NO. new 10 old 10 new 11 old 11 .new -12 old 12 new 13 old 13
DOSE LEVEL
0 ing/ kg/day
50 mg/kg/day
3791
3792
3793
3794
3795
3796
3797
3798
3799
3800
3801
3802
3303
3804
3S05
3806
3807
3808
3809
3S10
3811
3812
3813
3314
3815
3816
3817
3818
3819
3820
3821
3822
3823
3S24
3B25
3826
3327
3828
3829
3830
3831
3332
3833
3834
383S
3836
na
na
na
na
na
na
na
na
na
na
448. a
448,7
450.3
453.5
453.5
449.5
448.7
447.8
458.4
462.0
450.5
450.5
450.0
450.0
447.5
451.9
449.6
465.1
457.0
459.9
na
na
na
na
na
na
na
na
na
na
443.7
452.5
449.9
449.1
446. a
449.0
na
na
na
na
na
na
na
na
na
na
324.2
293.4
325.7
332.7
340. S
327.1
353.9
326.4
308.5
343.0
324.0
309.6
336.2
333.5
326.0
322.1
316.0
350.1
357.4
342.0
na
na
na
na
na
na
na
na
na
na
318.7
327.8
310. D
340.8
305.5
333.1
na
na
na
na
na
na
na
na
na
na
499.5
495.1
491.3
468.9
477.4
491.3
472.7
471.9
500.4
495.0
469.5
482.3
487.1
486.8
488.3
485.8
478.8
452. B
498,7
482.5
na
na
na
na
na
na
na
na
na
na
460,5
476.1
486.3
484.7
475.6
465.5
na
na
na
na
na
r,a
na
na
na
na
383.3
343.6
368.3
388.8
365.7
368,1
387.0
354.0
367.5
351.0
356.0
345.5
375.3
372.4
369.0
381.1
343.4
357.5
405.2
371.6
na
na
na
na
na
na
na
na
na
na
349.1
360.6
359.4
379.4
346.1
355.4
na
na
na
na
na
na
na
na
na
na
523.3
514.7
509.1
507.5
488.2
473.2
482.0
489.2
439.5
516.1
500.4
462.4
503.4
466.8
498.5
477.8
441.3
467.1
513,0
523.3
na
na
na
na
na
na
na
na
na
na
459 ."2
570.9
550.1
497.6
492.6
470.0
na
na
na
na
na
na
na
na
na
na
406.0
344.0
377.8
367.2
373.7
346.1
393.4
374.5
359.1
345. S
384.?
334.5
381 .a
351.0
380.5
367.7
307.7
364.0
423.8
406.5
na
na
na
na
na
na
na
na
na
na
335.4
448.1
423.7
377.5
367.7
362.6
na
na
na
na
na
na
na
na
na
na
470.1
471.3
471.3
478.6
472.8
470.2
473.7
474.4
472.2
471 . 1
470.2
470.5
468.1
473.0
477.0
470.0
472.4
477.0
469.5
469.7
na
na
na
na
na
na
na
na
na
na
470.1
470.8
471.7
470.7
466.8
473.3
na
na
na
na
na
na
na
na
na
na
370.9
342.5
328.9
358.4
380.0
362.4
334.3
352. a
360.4
381.2
362.8
338.9
359.0
356.9
355.9
357.5
333. S
378.5
374.6
367.3
na
na
na
na
na
na
na
na
na
na
363.9
374.7
363.4
358.4
356.7
373.8
D-54
148
-------
-------
Study No. 5221,08
SUBCHROHIC TOXICltr OF PARA-CRESOL IN SPRAGUE DAULEY RATS
FEMALE FOOD CONSUMPTION DATA
[Feeder Weights]
ANIMAL NO. new 10 old 10 new 11 old 11 new 12 old 12 new 13 old 13
DOSE LEVEL
50 mg/kg/day 3837
(continued) 3838
3839
3840
3841
3S42
3843
3844
3845
3346
3847
3848
3849
3850
175 mg/kg/day 3851
3852
3853
3854
3855
3856
3857
3858
3359
3860
3861
3862
3S63
3864
3865
3866
3867
3868
3869
3870
3871
3872
3873
3874
3875
3876
3877
3878
3879
3880
449.0
447.7
444.7
443.6
449.2
441.0
458.3
454.9
451.6
453.5
455.2
454.3
452.9
457.8
na
na
na
na
na
na
na
na
na
na
443.6
449.8
449.9
445.6
446.7
445.6
448.3
451.4
438.5
447.3
447.4
449.0
448,6
453.8
445.4
447.3
444.7
454.5
456.2
455.2
333.5
310.4
348.4
321.9
334.5
317.5
302.2
358.5
338.0
318.7
327.8
335.2
323.4
346.9
na
na
na
na
na
na
na
na
na
na
329.3
319.5
332.2
319.5
326.0
311.1
343.3
316.7
329.0
310.1
318.6
284.9
325.1
317.0
303.6
340.7
330.4
35Q.7
360.4
340.7
467.5
461.0
467.6
476. D
473.0
473.8
463.7
476.3
467.4
472.6
463.7
477.6
475.0
467.4
na
na
na
na
na
na
na
na
na
na
467.6
460.3
467.4
465.2
468.9
467.6
475.6
466.9
471.4
470.0
472.0
467.1
477.6
473.0
473.9
453.8
475.5
468.3
470.6
467.5
352.8
343.2
365.1
353.8
368.8
372.8
340.5
377.5
365.7
342.2
345.6
361.6
352.0
356.0
na
na
na
na
na
na
na
na
na
na
363.7
335.7
354.3
349,0
362.8
344.5
337.9
336.3
363.6
359,3
342.1
340.3
368.7
353.3
330.3
346.7
375.5
366.3
381.7
362.0
472.2
470.0
466.3
545.0
497.2
487.6
467.6
463.0
453.1
459.8
490.1
515.7
476. Q
432.6
na
na
na
na
na
na
na
na
na
na
457.6
469.4
457.0
450.0
458.~9
463.6
479.5
461.1
470.5
460.9
441.0
449.7
460.2
455.5
446.4
. 461.9
462.6
467.2
486,7
462.7
358.9
343.7
385.1
426.6
374.9
386.6
340.0
379.4
350.1
328.2
370.4
399.1
356.0
368.4
na
na
na
na
na
na
na
na
na
na
350.6
342.4
338.0
326.4
354. 5
331.0
388.9
331.0
342.8
327.8
313.9
319.3
344.9
338.0
312.6
345.4
356.1
358.2
393.5
356.2
472.7
467.3
469.9
470.9
465.9
469.4
475.7
474.6
477.1
475.2
464.2
496.2
466.9
465.7
na
na
na
na
na
na
na
na
na
na
472.1
479.6
476.4
475.3
474.3
480.0
466.4
474.3
466.5
464,3
469.8
470.9
473.0
469.4
466.9
471.0
468.3
462.9
471.9
468.1
377.7
359.9
400.1
369.7
361.3
369.4
353.0
392.9
386.0
362.0
349.7
395.5
357,5
370.3
na
na
na
na
na
na
na
na
na
na
375.4
361.9
373.0
365.8
411.5
363.7
380.6
324,0
366.0
361.6
360.9
359.6
342.0
370.9
340.2
365.4
371.5
377.1
389.8
376.9
D-55
149
-------
Study Ho. 5221.03
SUSCHRONIC TQXICITY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
FEMALE FOOD CONSUMPTION DATA (g)
[Feeder Weights]
ANIMAL NO. new 10 old 10 new 11 old 11 new 12 old 12 new 13 old 13
DOSE LEVEL
600 mg/kg/day
3581
3882
3883
3334
3865
3636
3387
3883
3889
3390
339 1
3892
3893
3894
3895
3896
3897
3893
3899
3900
3901
3902
3903
3904
3905
3906
3907
3908
3909
3910
na
na
na
na
na
na
na
na
na
na
441.1
444.5
442.4
443.5
450.8
450.3
445.0
445.6
na
443.9
448.0
456.8
455.9
453.3
~ 450.2
452.4
453.1
460.4
449.4
na
na
na
na
na
na
na
na
na
na
na
327.4
354.4
327.9
332.6
335.4
339.3
332.6
332.4
na
340.7
329.1
346.3
325. 5
315.3
333.6
357.4
336.3
327.8
332.0
na
na
na
na
na
na
na
na
na
na
na
4S1.6
481.7
465.1
476.3
482.0
462.4
467.8
469.1
na
465.0
462.3
477.1
461.6
474.4
472.4
477.3
468.2
486.3
470.3
na
na
na
na
na
na
na
na
na
na
na
372.6
398.0
348.4
372.3
373.6
360.9
352.0
361.7
na
365.9
349.5
366.5
345.6
343.3
374.1
393.7
345.3
353.1
349.0
na
na
na
na
na
na
na
na
na
na
na
470.9
435.9
455.8
449.2
475.1
469.2
454.9
452.8
na
482.4
455.8
469.0
450.2
453.7
482.2
496.4
468.7
476.2 .
471.1
na
na
na
na
na
ra
na
na
na
na
na
365.5
395.9
338.9
343.7
376. a
360.2
346.4
346.9
na
376.6
341.6
358.9
336.9
330.5
361.3
401.9
348. 9
364.3
356.5
na
na
na
na
na
na
na
na
na
na
na
473.2
468.2
470.5
471.4
469.8
486.8
464.6
469.3
na
473.1
476.3
470.2
470.7
467.6
460.4
466.4
489.4
476.1
460.2
na
i
na
na
na
na
na
na
na
na
na
na
362.5
390.1
353.0
375.9
382.6
405.2
361.4
363.7
na
363.4
379.9
372.5
357.7
345.0
363.8
385.3
382.5
362.0
348.9
na
D-56
-------
Study No. 5221.03
SU8CHRONIC TOXICITY OF PARA-CRESQL IN SPRAGUE OAWLET RATS
FEMALE FOOD CONSUMPTION DATA (g/day)
ANIMAL NO. weekl ueek2 week3 week4 weekS Heek6 week?
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3791
3792
3793
3794
3795
3796
3797
3798
3799
3800
3801
3802
3803
3804
3805
3806
3807
3808
3809
3810
3811
3812
3313
3814
381 S
3816
3817
3818
3819
3820
3821
3822
3823
3824
3825
3826
3827
3828
3829
3830
3831
3832
3833
3834
3835
3836
19.3
18.7
15.3
19.5
19.5
18.8
16.9
17.8
17.0
24.5
19.0
19.2
20.9
19.0
17.9
18.0
18.4
20.0
19.3
16.6
18.7
21.2
18.0
19.2
20.9
17.6
21.2
17.3
16.5
17.4
17.5
17.2
16.2
17.2
17.0
14.7
19.4
18.8
15.1
16.1
18.4
IS. 4
20.3
17.3
19.1
17.7
21.3
19.1
18.8
19.8
19.1
19.7
16.9
18.6
16.8
24.0
19.4
20.2
20.4
20.2
18.6
17.4
16.5
19.0
20.8
16.7
18.4
22.9
17.1
19.5
20.3
17.8
19.3
16.4
15.1
17.3
14.8
17.6
15.6
15.8
15.6
15.0
20.2
18.3
14.5
16.4
20.0
18.8
20.4
15.0
18.0
17.1
21.0
17.8
16.7
18.8
17.8
18.5
14.3
17.9
15.4
28.3
17.5
20.3
18.2
19.7
16.4
17.7
15.2
16.5
11.8
15.0
18.1
20.4
17.1
18.0
20.1
18.1
22.1
14.7
14.1
16.5
24.5
16.6
16.4
15.3
15.7
14.9
17.5
18.0
14.1
15.3
18.9
19.1
20.4
15.2
16.1
16.7
19.1
17.0
16.6
18.8
16.8
17.6
13.1
16.6
14.9
22.6
17.0
19.2
19.2
18.4
16.8
16.6
14.9
17.4
19.3
15.2
16.7
18.8
17.2
17.8
18.6
17.1
19.2
15.0
12.7
16.8
15.5
16.8
14.6
14.8
15.0
13.9
16.7
18.6
14.0
15.2
18.0
17.8
13.1
15.1
17.2
16.7
18.7
18.4
17.4
18.5
18.0
17.9
14.5
16.3
14.3
28.6
17.9
18.7
17.9
20.1
16.0
16.3
15.3
17.3
19.9
16.0
17.0
20.0
17.0
17.4
19.4
18.3
19.1
15.5
13.4
16.4
23.9
15.8
13.7
15.4
15.7
14.0
18.4
17.6
15.2
15.9
18.3
17.8
19.4
15.7
19.5
17.2
18.3
17.8
16.2
17.5
17.2
17.6
13.5
16.7
17.2
26.5
17.6
20.7
27.0
19.2
16.9
19.0
14.0
17.4
20.9
16.8
15.1
21.1
17.7
18.2
19.6
19.6
20.5
15.3
14.3
17.0
17.5
16.3
15.5
14.5
16.4
15.7
18.1
18.6
15.3
15.8
18.8
18.1
19.2
14.5
17.3
16.7
11.1
11.5
10.3
11.0
12.9
12.5
8.8
9.3
9.6
14.1
16.5
19.0
22.5
20.8
17.3
16.4
14.4
17.4
18.4
16.8
17.2
21.2
18.0
17.5
17.7
18.2
19.9
16.4
14.6
16.8
13.3
10.6
11.3
12.5
11.3
9.6
10.7
8.4
12.1
10.9
19.0
18.3
16.3
20.9
18.5
15.6
D-57
151
-------
Study Na. 5221.08
SU8CHRONIC TOXiCITY OF PARA-CSESCL IN SPRAGUE DAWLEY RATS
FEMALE fOOD CONSUMPTION DATA (fl/day)
ANIMAL NO. weekl week2 ueek3 week4 weekS neek6 week?
DOSE LEVEL
50 mg/kg/day 3837
(continued) 3838
3839
3340
3341
3842
3843
3844
3845
3346
3347
3348
3349
3850
175 (itg/kg/da/ 3851
38S2
3853
38S4
3855
3856
3857
3858
3859
3860
3861
3862
3863
3864
3865
3866
3867
3868
3869
3370
3871
3872
3873
3874
3875
3876
3877
3878
3879
3880
17
18
13
16
17
17
20
16
18
18
17
16
17
21
18
19
21
19
IS
19
18
18
18
19
15
16
18
18
18
.3
.2
.8
.3
.1
.8
.5
.8
.2
.4
.2
.8
.6
.9
.2
,1
.9
.6
.4
.8
.8
.0
.5
.7
.7
.4
.6
.9
.8
17.7
16
20
17
20
21
20
18
18
21
18
16
19
15
19
.5
.2
.3
.2
.5
.0
.5
.7
.9
.8
.2
.8
.3
.0
16
18
13
16
17
13
20
.5
.9
.9
,1
.5
.2
.8
15.3
13
19
16
17
17
17
16
16
18
18
17
18
18
17
17
21
17
15
19
18
17
17
15
21
17
19
19
20
17
19
21
19
16
20
16
18
.2
.0
.7
.2
.8
,7
J
.9
.2
.1
.7
.6
.4
.0
.1
.7
.1
.5
.0
.7
.8
.7
.0
.5
.4'
.3
.5
.3
.0
.1
.4
.1
,1
.3
.2
.2
16.6
20.0
18.4
16.0
17.8
17.3
33.6
15,0
17.6
18.7
18.1
16.7
17.1
16.4
17.4
17.5
18.6
19.2
14.9
19.0
18.7
15.5
18.0
19.2
15.2
15.7
19.8
18.4
16.8
18.2
15.2
20.3
16.4
18.8
19.4
20.4
19.7
19.0
20.0
18.3
15.8
18.3
15.1
17.6
16
17
12
15
17
15
21
13
15
18
16
16
17
16
16
.0
.8
.6
.2
.3
.9
.2
.7
.9
.1
.2
.9
.4
.3
.4
16.9
17
16
15
16
17
14
16
17
14
14
17
16
16
16
14
18
15
16
19
23
15
16
17
17
14
16
14
.5
.7
,2
.9
.8
.8
,2
.3
,7
.6
.5
.2
.0
.0
.6
.4
.0
.1
.2-
.1
.9
.3
.2
.1
.7
.1
.1
15.7
16.3
18.2
13.1
15.7
16.5
16.8
20.8
14.3
16.6
18.8
18.7
16.8
16.3
11.5
17.9
22.3
' 18.4
16.0
15.5.
19.2
19.3
15.8
16.9
20.1
15.1
16.5
18.5
20.9
16.3
17.7
15.5
20.2
15.8
17,8
20.7
19.9
18.4
19.3
18.7
15.9
15.7
17.0
14.5
16.7
16.
ia.
12.
15.
17.
16.
26.
13.
16.
18.
15.
19.
16.
15.
17.
24.
19.
17.
16.
18.
17.
16.
16,
19.
0
5
5
9
3
1
0
5
0
1
4
6
9
9
7
6
1
0
1
5
4
6
9
9
15.2
15.
17.
18.
16.
17.
14.
19.
16.
19.
21.
20.
17.
18.
18.
18.
15.
17.
14.
16.
3
5
3
9
3
8
9
2
5
1
0
0
1
3
3
6
0
2
4
16.3
19.8
13.2
18.1
17.6
17.3
18.9
14.2
17.1
18.3
19.3
24.8
17.8
16.9
11,3
13.1
10.4
8.5
10.9
11.0
10.4
8.4
11.3
12.0
15.5
15.5
17.8
18.1
15.6
17.8
15.8
18.9
15.9
16.9
18.8
20.5
16.7
16.6
19.5
16.6
14.5
16.3
13.7
15.5
-5 fj (
D-SS
-------
Study Ho. 5221.08
SU8CHRQNIC TOXICITY OF PARA-CRESOL IN SPRAGUE D'AWLEY RATS
FEMALE FOOD CONSUMPTION DATA (g/day)
ANIMAL NO. weekl week2 neek3 wetk4 ueekS week6 week?
"DOSE LlVit
600 mg/kg/day
3881
3S82
3883
3884
3SS5
3886
3887
3888
3889
3890
3891
2892
3893
3894
3895
3896
3897
3898
3899
3900
3901
3902
3903
3904
3905
3906
3907
3908
3909
3910
15.0
15.2
na
18.8
15.7
17.7
15.4
15.7
15.8
16.3
15.3
14.8
15.4
15.7
15.3
16.4
16.7
17.5
na
11.6
13.0
15.0
16.7
18.3
15.1
13.8
15.8
20.0
15.8
na
15.7
16.1
na
18.8
18.7
18.1
15.4
16.8
17.3
17.6
16.8
12.2
16.9
16.6
19.1
19.2
16.8
20.8
na
17.8
14.3
16.4
17.7
18.6
15.5
14.6
17.9
19.2
16.9
na
15.2
29.4
na
19.8
19.5
18.6
14.6
17.7
19.0
17.1
15.1
12.5
17.7
17.0
17.7
19.6
16.0
18.7
na
18.1
16.3
15.8
17.5
18.6
17.6
14.0
16.7
18.8
17.4
na
14. S
17.7
na
19.6
18.0
16.3
13.2
16.7
16.7
IS. 3
16.6
12.5
15.8
15.3
17.7
17.4
16.0
17.9
na
16.6
16.0
14.2
17.2
18.1
14.6
12.2
14.7
16.7
15.9
na
12.7
12.5
na
21.0
17.6
16.3
14.5
15.7
18.0
16.3
16.0
13.3
17.6
16.5
19.0
18.0
17.8
18.3
na
16.3
16.8
16.1
17.5
18.9
15.3
13.5
17.7
19.1
16.5
na
14.4
18. 0
na
19.5
20.2
16.3
13.8
15.0
15.8
15.6
15.9
12.3
15.9
16.7
17.7
17.0
17.4
17.0
na
17.2
17. Q
15.4
16.2
18.1
15.7
14.2
17.3
17.9
16.8
na
8.4
10.8
na
11.3
7.1
13.1
11.9
8.7
9.7
14.0
14.4
14.1
32.2
15.6
16.6
16.8
18.3
17.2
na
16.9
16.4
14.6
17.1
21.4
15.4
13.2
18.5
19.7
17.3
na
D-59
O
-------
SUBCHRON1C TQXICm OF PARA-CRESOL IS SPRAGUE OAULEY RATS
FEMALE FOOD CONSUMPTION DATA
-------
SUSCHRDNIC TOX1CITY Of PARA-CR6SQL IK SPSAGUE DAULE? RATS
FEMALE FOOD CONSUMPTION DATA
-------
SUBCKRONIC TOXICITY OF PARA-CRESOL IN SPRACUE DAULEY RATS
FEMALE FOOD CONSUMPTION DATA
-------
Study He. 5221.08
SUBCHRONtC TOXieiTY OF PARA-CRESQL IN SPRAGUE DAWLET RATS
MALE HEMATOLQGY VALUES
[Interim Sacrifice]
OOSE LEVEL
0 mg/kg/day
50 mg/kg/day
175 rng/kg/day
600 ng/kf/day
ANIMAL NO.
3661
3662
3663
' 3664
3665
3666
3667
3668
3669
3670
3691
3692
3693
3694
3695
3696
3697
3693
3699
3700
3721
3722 >
3723
3724
3725
3726
3727
3723
3729
3730
3751
3752
3753
3754
3755
3756
3757
3758
3759
3760
R3C
(x 10A6/mn"3)
8.22
8.21
8.60
8.00
8.20
8.18
8.10
8.05
8.28
7.96
7.63
7.74
8.26
7.94
7.88
7.93
8.93
7.71
8.28
7.95
8.17
8.88
8.86
7.65
8.09
7,75
7.89
8.29
8.37
7.95
8.15
7.80
8.38
8.07
8.51
8.11
7.91
8.78
8.31
8.48
HG3
14,7
15.8
15.4
15.4
15.2
15.1
14.9
15.5
15.3
15.3
14.5
14.6
15.6
14.2
14.2
14.5
15.7
15.0
15.4
14.7
15.1
15.4
15.8
14.7
15.4
14.4
15.3
15.2
14.6
14. S
14.9
15.1
16.0
15.0
15.6
14.8
15.0
15.3
14.5
15.3
HCT
<%)
42.0
45.9
42.1
44.6
43.3
43.2
42.7
43.7
44.6
43.7
41.4
41.6
44.5
40.1
40.5
42.2
47.0
42.0
44.6
41.1
43.0
43.7
44.1
41.6
43.9
40.9
43.2
42.5
41.9
41.5
43.3-
43.8
45.7
42.5
44.1
42.3
43.1
43.5
40.9
43.5
PT
(sec.)
11.1
14.3
7.2
12.4
12.2
13.0
11.7
11.5
14.9
11.9
10.3
13.3
11.9
8.3
11.5
12.7
15.3
11.2
11.5
11.3
11.5
11.5
13.0
11.8
11.3
12.3
14.6
6.6
10.9
11.6
12.8
9.0
11.8
12.1
13.7
15.3
15.2
12.8
11.0
12.1
APTT
(sec.)
36.1
40.1
45.3
34.8
41.6
31.2
35.8
36.0
38.0
38.6
39.2
33.1
37.3
34.8
38.1
36.4
41.8
9
29.0
43.3
31.4
33.5
48.2
39.0
32.4
46.3
40.4
46.3
34.8
37.0
37.3
32.2
37.7
31.0
35.3
37.2
33.6
58.7
36.5
35.7
RET 1C
<% rbc)
0.4
1.5
0.8
2.6
1.5
0.7
0.4
0.3
0.7
1.2
0.6
2.2
0.5
0.4
0.5
2.4
1.8
1.1
1.1
1.3
2.3
1.2
0.7
0.6
1.0
1.3
0.5
2.4
0.5
0.9
0.4
0.6
0.7
2.5
1.1
0.3
1.1
2.4
1.4
1.9
D-63
j r->
1 5
-------
Study No. 5221.03
SU3CHROMIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
KALE HEMATOLOGY VALUES
CInterim Sacrifice]
DOSE LEVEL
0 mg/kg/day
ANIMAL NO. UBC SEGS
(x 10-3/iroT3) (X USC)
BANDS LYMPHS MONO EOS
-------
Study No, 5221.08
SUBCHRCN1C TQXiCITY OF PARA-CRESOL IN SPRAGUe DAWLET RATS
MALE HEHATQLCGT VALUES
Clnttrim Sacrifice]
AHI HAL NO.
UBC
DOSE LEVEL
0 msAa/day
-------
Study No. 5221.08
SUBCHRONIC TOXIC1TY OF PARA-CRESOL IH SPRAGUE DAULEY RATS
HALE HEMATOLOGY VALUES
[Terminal Sacrifice]
DOSE LEVEL
0 rag/kg/day
50 mg/kg/day
175 mg/kg/day
600 mg/kg/day
ANIMAL NO.
3671
3672
3673
3674
3675
3676
3677
3678
3679
36BO
3701
3702
3703
3704
3705
3706
3707
3703
3709
3710
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
R8C
(x 10A6/mn'2
3.13
8.33
3.66
8.21
8.48
8.37
3.56
8.42
9.45
8.16
8.66
8.57
9.62
8.80
8.74
8.18
7.65
8.14
3.97
8.09
8.31
9.06
8.90
9.06
8.99
9.63
8.13
8.94
9.96
8.84
8.51
8.70
8.92
8.96
8.35
9.05
8.32
8.50
9.24
9.10
HG3
i) Cg/dl)
14.9
15.3
15.4
15.1
15.0
14.3
15.1
14.3
16.7
15.3
15.9
15.0
16.3
15.1
15.2
14.5
14.5
15.2
15.9
15.1
15.1
16.0
15.3
15.5
15.5
16.7
15.1
15.2
16.3
15.3
14.8
15.3
16.1
16.0
14.2
15.2
14.7
15.2
16.8
16.0
HCT
(X)
42.8
42.1
42.4
42.6
42.5
42.1
42.7
41.0
46.3
41.3
42.5
41.4
46.4
42.0
42.9 .
40.5
40.5
42.4
45.0
42.0
42.4
43.9
42.8
44.3
42.8
43.0
41.7
42.1
45.6
42.3
41.9
44.2
45.9
45.7
39.4
44.6
40.3
40.7
47.3
45.7
PT
-------
Study No. 5221.08
SU8CHROM1C TOXICITY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
HALE HEMATQLOGY VALUES
[Terminal Sacrifice]
DOSE LEVEL
0 rag/kg/day
ANIMAL MO. WBC SECS BANDS LYMPHS MONO EOS
cx io~3/mf3> (% wee) ex wee) c% ys« <% UBO cs WBO
50 mg/kg/day
175 rag/kg/day
600 ing/kg/day
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3701
3702
3703
3704
3705
3706
3707
3708
3709
3710
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3761
3762
3763
3764
376i
3766
3767
3768
3769
3770
12.3
12.2
10.5
12.9
12,3
8.2
12.2
10,6
15.9
13.7
8,9
12.3
10.7
7.8
8.2
9.9
15.3
9.9
8.5
13.7
14.2
24.8
9.2
12.1
13.0
12.1
12.0
9.5
9.1
17.4
11.7
10.0
13.7
12.5
10.4
13.4
9.4
12.5
11.5
11.6
29
17
16
9
, 22
15
22
19
10
23
23
20
13
15
15
23
17
17
18
2T
22
16
19
21
27
18
13
16
12
17
26
26
22
22
19
18
22
10
28
20
1
0
0
0
0
2
0
0
0
1
0
2
2
0
0
1
0
0
0
0
3
0
1
0
1
1
0
1
1
1
1 .
0
0
0
0
0
0
0
0
0
64
79
82
88
69
81
77
74
89
74
74
75
SO
82
83
71
76
76
77
71
'73
82
79
76
65
78
87
82
86
81
72
69
78
77
77
77
78
89
71
76
3
4
2
3
5
1
1
S
0
1
3
1
2
2
1
5
7
5
5
4
2
0
0
3
7
2
0
0
0
1
1
4
0
0
4
5
0
1
1
3
3
0
0
0
4
1
0
2
1
1
0
2
3
1
1
0
0
2
0
4
0
2
1
0
0
1
0
1
1
0
0
1
0
1
0
0
0
0
0
1
D-67
64
1
-------
Study No. 5221.08
SUSCHRdNIC TDXJCITY Of PARA-CSESOl IN SPRAGUE OAWIEY RATS
MALE HEMATOIQGY VALUES
[Terminal Sacrifice!
AM I HAL MO.
UBC
SEGS
DOSE LEVEL
0 ng/kg/day
50 mg/kg/day
175 mg/kg/day
600 mg/kg/day
(x
(x
BANDS
10*3/nnr3)
LYMPHS
MONO
EOS
(x
(x
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3701
3702
3703
3704
3705
3706
3707
3708
3709
3710
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
12.3
12.2
10.5
12.9
12.3
3,2
12.2
10.6
15.9
13.7
8.9
12.3
10.7
7.8
8.2
9.9
15.3
9.9
8,5
13.7
14. E
24.8
9.2
12,1
13.0
12.1
12.0
9.5
9.1
17.4
11.7
10.0
13.7
12.5
10.4
13.4
9.4
12.5
11.5
11.6
3,6
2.1
1.7
1.2
2.7
1.2
2.7
2.0
1,6
3.2
2.0
2.5
1.4
1.2
1.2
2.3
2.6
1.7
1.5
2.9
3.1
4.0
1.7
2.5
3.5
2.2
1.6
1.5
1.1
3.0
3.0
2.6
3.0
2,8
2.0
2.4
2.1
1.3
3.2
2.3
0.1
O'.O
0.0
0.0
0.0
0.2
0.0
0.0
0.0
0.1
0.0
0,2
0.2
0,0
0.0
0.1
0.0
0.0
0.0
0.0
0.4
0,0
0.1
0.0
0.1
0.1
fl.Q
0.1
0.1
0,2
0.1
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
7.9
9.6
8.6
11.4
8.5
6.6
9.4
7.S
14.2
',0.1
6.6
9.2
8.6
6.4
6.3
7.0
11.6
7.5
6.5
9.7
10.4
20.3
7.3
9.2
8.5
9.4
10.4
7.8
7.8
14.1
a. 4
6.9
10.7
9.6
8.0
10.3
7.3
11.1
8.2
8. a
0.4
0.5
0.2
0,4
0.6
0.1
0.1
0.5
0.0
0.1
0.3
0.1
0.2
0.2
0.1
0.5
1.1
0.5
0.4
0.5
0.3
0.0
0.0
0.4
fl.9
0.2
0.0
0.0
0.0
0.2
0.1
0.4
0.0
0.0
0.4
0.7
0.0
0.1
0.1
0.3
0.4
0.0
0.0
0.0
0.5
0.1
0.0
0.2
0.2
0.1
0.0
0.2
0.3
0.1
0.1
0.0
0.0
0.2
0.5
Q.5
0.0
0.5
0.1
0.0
0.0
0.1
0.0
0.1
0.1
0.0
0.0
0.1
0.0
0.1
0.0
0.0
0.0
0.5
0.0
0.1
D-68
162
-------
Study No. 5221.08
SUBCHRONIC TOXICITY OF PARA-CRESOL 1M SPRAGUE DAULEY RATS
FEMALE HEMATOLOGY VALUES
[Interim Sacrifice]
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
175 mg/kg/day
600 mg/kg/day
ANIMAL NO.
3791
3792
3793
3794
3795
3796
3797
3793
3799
3300
3321
3322
3323
3324
3825
3326
3827
3328
3829
3330
3351
3352
3353
3354
3355
3356
3357
3858
3859
3360
3381
3382
38S4
3885
3886
3837
3888
3889
3890
RBC
(x 10"6/im*3
7.60
7.90
7.95
8.05
8.04
8.22
7.70
8.77
7.97
7.73
8.40
7.83
8.02
8.17
8.06
7.82
7.70
8.07
7.72
8.15
7.75
8.52
3.43
8.31
7.94
8.23
7.24
8.46
7.35
7.91
8.03
7.65
8.09
8.70
8.97
7.44
8.46
3.00
7.94
HC3
i) (g/dl)
14.6
16.2
15.0
15.3
15.0
15.1
14.6
16.2
15.8
15.4
15.7
14.7
14.9
15.3
15.3
15.2
15.6
15.8
15.7
15.5
14.9
16.3
15.6
16.0
14.7
15.0
14.6
15.3
14.4
15.5
15.5
14.3
15.1
15.3
15.5
14.1
16.1
15.1
15.0
HCT
(*)
41.9
44.6
42.3
42.7
41.6
43.0
40.9
45.2
44.5
43.4
44.9
41.3
41.2
43.5
43.0
44.4
43.0
45.1
43.1
42.6
41.3
46.0
43.5
44.9
40.6
44.6
40.9
44.0
40.1
43.0
43.5
40.6
43.8
45.2
43.9
39.9
44.3
42.3
42.0
PT
(Sec.)
8.6
7.3
11.0
13.3
11.4
11.6
8.5
9.4
13.1
11.8
11.1
10.6
10.9
11.7
10.9
12.4
8.8
12.2
12.7
10.8
8.3
11.4
9.9
9.3
11.0
8.7
12.2
10.7
11.0
12.2
11.0
12.2
11.7
12.4
12.0
10. 3
14.0
11.0
11.8
APTT
(sec.)
43.8
43.5
33.8
33.3
40.9
44.9
34.6
43.4
31.6
33.7
39.0
46.8
37.3
34.9
19.5
40.3
30.7
34.5
37.7
37.8
45.6
39.5
36.3
37.4
39.9
32.4
36.5
40.2
35.9
21.9
33.4
39.7
41.2
41.2
45.3
34.0
38.8
34.6
32,7
RETIC
-------
Study No. 5221.08
SUBCHRONIC TOXICITY OF PARA-CRESOL ]M SPRAGUE DAULEY RATS
FEMALE HEMATOLOGY VALUES
[Interim Sacrifice]
DOSE LEVEL
0 ing/kg/day
ANIMAL NO. UBC SEGS . BAUDS LYMPHS MONO EOS
(x 10"3/im«*3l 4
85
76
79
76
64
87
6
5
2
2
4
3
2
7
1
1
2
1
2
3
3
2
4
3
2
1
1
2
3
2
3
3
1
4
2
0
4"
5
4
7
2
1
3
2
3
0
0
0
0
1
0
1
1
0
3
2
1
1
0
1
1
1
0
0
0
0
0
0
2
2
0
2
0
0
0
1
1
0
0
1
3
0
2
0
D-70
6
-------
Study No. 5221.08
SUSCHRON1C TOXieilY OF PARA-CRESOL 1M SPRAGUE DAWLEY RATS
FEMALE HEMATOLOCY VALUES
{Interim Sacrificel
ANIMAL NO.
use
DOSE LEVEL
0 mg/kg/day
50 fig/kg/day
175 mg/kg/day
600 mf/kg/day
(x
SEGS
{x 10*3/^3)
BANDS
LYMPHS
(x
-------
Study Ho. 5221.08
SUBCHROMIC TOXICITY OF PA3A-CRESGL SM SPHAGUE DAULEY RATS
FEMALE HEMATOLQGY VALUES
[Terminal Sacrifice]
DOSE LEVEL
50 mg/kg/day
175 ing/kg/day
600 mg/kg/day
ANIMAL NO.
3801
3802
3803
3804
3805
3806
3807
3803
3809
3810
3831
383Z
3833
3834
3835
3836
3837
3838
3839
3840
3861
3862
3863
3864
3865
3366
3867
3868
3869
3S70
3891
3892
3893
3894
3895
3896
3897
3898
3900
3901
R3C
-------
Study No, 5221.08
SUBCHRQNIC TCXIC3TY OF PARA-CRSSGL IN SPRAGUE DAULEY RATS
FEMALE HEMATCLOGY VALUES
[Terminal Sacrifice]
DOSE LEVEL
0 rag/kg/day
50 mg/kg/day
175 mg/kg/day
600 mg/kf/day
ANIMAL NO.
3801
3802
3803
3804
3805
3806
3807
3808
3809
3810
3831
3832
3833
3834
3835
3836
3837
3838
3839
3840
3861
3862
3863
3864
3865
3S66
3867
3868
3869
3870
3891
3892
3893
3894
3895
3696 -
3897
3898
39CO
3901
ysc
(x 10"3/mnA3J
7.4
8.7
8.9
6.5
9.6
6.9
5.9
8.0
8.9
6.9
8.4
10.7
8.6
8.3
8.1
9.4
10.7
9.9
6.5
8.1
7.5
7.0
11.4
3.2
11.9
11.8
11.2
7.3
8.1
9.5
7.9
6.3
8.2
7.2
10.7
6.0
7.6
12.7
7.7
5.5
SEGS
(% UBC}
22
16
21
13
3
11
10
10
23
31
25
20
20
12
14
21
16
32
9
17
11
27
36
' 17
18
12
13
11
15
15
24
12
26
11
26
31
34
10
25
9
BANDS
{X UBC)
0
1
0
1
1
0
1
0
0
0
0
0
3
0
0
3
4
1
2
0
0
0
0
0
2
0
0
a
0
1
a
0
0
1
i
a
1
0
i
0
LYMPHS
(X UBC)
75
78
73
82
89
87
84
85
77
'68
73
78
75
83
84
73
80
66
39
82
88
71
62
80
75
33
84
89
84
82
67
87
72
87
67
66
62
.88
66
89
HONO
(X UBC)
2
5
5
4
1
1
4
5
0
1
0
1
1
2
1
2
0
1
0
a
1
1
1
2
3
0
3
0
1
2
5
1
1
0
4
0
2
2
6
1
EOS
<% WBC)
1
0
1
0
1
1
1
0
0
0
2
1
1
3
1
1
0
0
0
1
0
1
1
1
2
0
0
0
0
0
. 4
0
1
1
2
1
2
0
2
1
D-73
-J . f» f;
i U «
-------
Study No. 5221.08
SU8CHRON1C TOXICITY OF PARA-CRESCL IN SPRAOUE DAMLEY RATS
FEMALE HEMATOLQGY VALUES
[Terminal Sacrifice]
ANIMAL NO.
wac
SEGS
DOS 6 LEVEL
0 mg/fcg/ciay
50 irs/kg/day
175 mg/fcg/day
600 nig/kg/day
Cx
(x
BANDS LYHPHS MONO
(X 10"3/«iT3)
-------
Study No. 5221.08
SUBCHRON1C TOXIC1TY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
KALE CLINICAL CHEMISTRY VALUES
[Interim Sacrifice]
DOSE LEVEL
0 ing/ki/dsy
ANIMAL NO. GLU BUN SGPT SGQT T PRO ALS GLOB ALB/GLOB CHQL Ca
(mg/dU CIu/l) (lu/l) (g/dl) (g/dl) {g/dl) (ratio) (,ig/dt)
50 mg/kg/day
175 rag/kg/day
600 mg/kg/day
3661
3662
3663
3664
3665
3666
3667
3668
3669
3670
3691
3692
3693
3694
3695
3696
3697
3693
3699
3700
3721
3722
3723
3724
3725
3726
3727
3728
3729
3730
3751
3752
3753
3754
3755
3756
3757
3758
3759
3760
238.7
159.7
252.4
121.8
151.7
226.5
193.0
228.7
258.7
274.8
183.7
245.3
275.1
218.9
231.8
145.5
189.1
169.6
192.9
224.8
187.7
195.4
189.4
247.8
224.0
192.3
174.0
242. S
302.0
225.8
184.2
270.9
227.7
203.3
302,5
256.2
218.3
188.0
302.8
255.4
16.4
16.0
13.6
20.5
15.3
16.4
15.6
13.3
15.7
16.0
1Z.6
13.3
20.6
17.5
14.2
14.7
16.5
13,0
11.3
13.2
13.2
13.3
18.3
12.5
17.4
13.3
21.4
11.0
14.6 ,
13.2
13.5
13.2
13.8
13.6
14.4
12.9
15.3
11.2
13.8
14.8
30
23
32
28
26
44
25
27
25
33
31
25
39
27
39
32
25
51
179
33
27
33
37
27
27
24
24
37
32
27
31
42
29
21
27
36
39
36
37
29
73
77
97
81
60
76
61
82
89
74
76
77
58
71
,72
122
68
169
107
81
91
72
62
na
81
64
77
81
77
70
66
85
82
62
77
79
90
73
83
88
6.5
7.5
7.8
7.1
7.7
7.3
8.0
7.8
6.9
7.7
6.5
7.6
6.8
6.9
6.4
6.6
7.2
7.2
7.2
7.0
6.9
6.9
7.2
8.6
7.2
6.3
7.6
7.6
7.9
7.8
7,4
7.2
7.2
7.0
7.3
6.8
7.2
7.3
7.2
6.8
3.7
4.7
4.2
4.4
4.1
3.9
4.5
3.9
3.9
4.3
3.6
3.9
3.9
3.B
3.6
4.0
4.3
3.8
3,6
3.9
3.8
4.2
3.9
5.0
4.3
3.8
4.5
4.4
4.0
4.. 4
4.1
3.9
4.5
4.1
4.1
4.1
4.0
4.0
3.7
3.9
2.8
2.8
3.6
2.7
3.6
3,4
3.5
3.9
3.0
3.4
2.9
3,7
2.9
3.1
2.8
2.6
2.9
3.4
3.6
3.1
3.1
2.7
3.3
3.6
2.9
2.5
3.1
3.2
3.9
3.4
3,3
3.3
2.7
2.9
3.2
2.7
3.2
3.3
3.5
2.9
1.321
1.679
1.167
1.630
1,139
1.147
1.286
1.000
1.3CO
1.265
1.241
1.054
1.345
1.226
1.236
1.538
1.483
1.118
1,000
1.258
1.226
1.556-
1.182
1.389
1.483
1.520
1.452
1.375
1.026
1,294
1.242
1.182
1.667
1.414
1.281
1.519
1.250
1.212
1.QS7
1.345
61.7
75.0
67.8
104.1
115.4
58.8
118.0
78.7
92.1
91.9
58.6
68.4
63.0
65.6
55.1
43.8
68.3
48.6
58.7
85.1
61.6
97.9
61.2
173.2
73.7
126.1
87.5
120.7
84.3
109.3
96.2
104.4
93.4
88.7
110.0
78.8
72.2
87.6
111.2
70.9
11.9
16.3
14.5
16.5
14.2
14.7
14.4
14.1
15.5
13.9
12.8
16.8
14.5
13.6
13.0
12.3
' 14.9
15.3
13.3
13.3
14.7
13.2
14.1
15.0
17.7
13.6
16.3
13.5
14.0
13.9
13.6
15.4
15.0
13.9
16.0
16.5
15.0
12.7
16,1
11,8
D-75
P,
U
O,
-------
Study Ha. 5221.03
SUSCHRONIC TOXICiTT OF PARA-CRESQU IN SPRACUE DAWCEY RATS
HALI CLINICAL CHfMISTRT VALUES
Clnterim Sacrifice]
DOSE LEVEL
0 nig/kg/day
50 mg/kg/day
175 mg/kg/day
600 mg/kg/day
ANIMAL HO.
3661
3662
3663
3664
3665
3666
3667
3663
3669
3670
3691
3692
3693
3694-
3695
3696
3697
3693
3699
37SQ
372T
3722 -
3723
3774
3725
3726
3727
3728
3729
3730
3751
3752
3753
3754
3755
3756
3757
3758
3759
3760
D BIL
(rag/dl)
0.00
0.00
0.01
0.01
0.01
0.00
0.01
0.01
0.01
Eh 04
0.02
0.01
0.01
0.01
a. oo
a. ao
0.00
0.01
0.01
0.01
0.01
0.03
0.01
0.01
0.00
0.01
0.02
0.01
0.01
O.Q2
0.01
0.00
0.01
0.02
0.01
0.01
0.01
0.00
0.01
0.00
T BIL
Cmg/dl)
0.14
0.13
0.06
0.18
0.05
0.19
0.06
0.09
0.13
0.16
0.13
0.16
0.14
0.09
0.11
0.15
0.12
0.22
0.11
0.12
0.16
0.10
0.12
0.18
0.15
0.06
0.15
0.14
0.14
0.08
0.13
0.14
0.15
0.11
0.16
0.12
0.15
0.17
0.12
0.09
Na
CMeq/l)
194
147
166
155
174
177
161
166
149
165
158
155
162
153
164
149
149
173
157
157
153
156
174
na
149
167
153
162
157
153
161
149
"143
162
147
153
152
156
154
179
K
10.7
6.3
7.3
5.9
7.3
7.6
7.0
8.1
6.2
6.5
7.4
5.8
8.7
9.6
7.3
7.4
6.1
10.0
6.1
6.5
6.3
5.0
12.0
na
7.7
9.3
7.1
7.0
5.8
7.S
8.9
6.2
6.7
10.9
6.9
6.9
8.5
a. 2
7.1
8.0
Cl
(Meq/U
138
99
112
99
117
120
110
114
100
111
106
96
113
108
109
103
101
111
101
104
104
104 '
118
na
102
118
98
110
107
111
112
97
102
112
98
102
98
108
102
119
ALK PHOS
CIu/13
57
59
125
86
74
83
56
125
87
63
146
94
111
72
84
123
81
80
119
62
70
63
60
46
67
35
67
69
79
53
59
113
79
120
47
82
108
86
63
164
CQ2
(Meq/l)
24
na
20
27
na
27
23
na
30
23
21
26
31
24
20
27
20
25
27
22
21
na
na
na
25
24
32
na
24
26.
25
27
na
27
25
27
25
28
25
24
CSEAT
(nti/dl}
0.62
0.80
0.78
0.76
0.62
0.61
0.66
0.72
0.65
0.66
0.71
0.67
0.67
0.72
0.95
0.78
0.63
0.58
0.75
0.72
0.61
0.70
0.68
0.64
0.65
0.60
0.82
0.59
0.75
0.70
0.67
0.70
0.64
0.59
0.56
0.73
0.76
0.85
0.69
0.60
PHOS
(rag/dl )
9.9
11.3
11.4
10.2
12.8
11.1
11.6
13.9
11.9
12.5
11.2
11.2
11.1
13.4
11.7
11.7
11.1
13.1
12.1
10.5
10.7
11.0
13.2
12.3
15.5
11.4
10.3
11.5
9.5
11.4
10.0
12.1
12.8
8.0
10.8
11.8
13.2
10.1
10.8
10.2
D-76
170
-------
Study Ho. 5221.08
SUBCHRONIC TOXJCm OF PARA-CRESQL IN SPRAGUE DAULEY RATS
HALS CLINICAL CHEMISTRY VALUES
[Terminal Sacrifice]
DOSE LEVEL
0 mg/kg/day
50 tns/kg/day
175 mg/kg/day
600 mg/kg/day
ANIMAL NO.
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3701
3702
3703
3704
3705
3706
3707
3708
3709
3710
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
OLU
220.7
230.3
195.7
194.2
204.5
336.5
275.7
253.6
155.2
183.4
277.0
192.6
235.1
176.1
279.3
259.7
295.9
209.4
261.1
159.3
272.2
220.5
235.3
343.5
229.2
271.0
278.1
223.6
183-2
244.4
213.7
285.6
219.6
201.5
233.6
198.8
349.2
164.9
220.0
265.7
SUN
Cmf/dl)
12.5
10.3
16.3
12.9
15.4
13.3
11.8
12.3
12.6
11.6
12.6
13.1
12.1
11.5
11.6
12.4
10.0
11.0
12.7
11.5
13.2
14.1
11.5
12.5
16.1
11.9
17.5
9.7
9.1
10.9
14.7
9.7
15.7
10.7
10.8
17.2
16.6
12.5
11.2
12.4
SGPT
(Iu/1)
23
27
23
26
35
20
24
27
25
32
22
28
26
21
32
28
25
29
30
34
31
32
41
32
24
36
25
27
37
33
383
59
54
27
35
52
49
34
39
67
SGCT
Uu/l)
59
68
73
57
85
64
61
62
92 -
80
57
73
74
45
86
77
68
77
68
82
94
72
74
56
62
69
51
70
79
77
352
93
106
57
82
98
74
81
83
100
T PRO
(3/dl)
7.1
7.1
6.4
7.0 '
6.6
7.0
7.0
7.1
6.7
6.4
7.0
6.9
6.5
7.0
7.2
7.5
7.1
6.3
7.3
6.5
7.2
7.2
7.0
7.4
6.6
7.5
7.8
7.2
7.9
7.6
8.6 .
7.5
8.1
7.3
7.6
8.2
7.4
7.2
6.3
7.5
ALB
(f/dl>
4.0
3.9
3.5
4.0
5.3
3.9
3.7
3.7
3.5
3.6
3.5 '
3.4
3.8
4.0
3.8
3.7
3.9
3.7
3.8
3.4
3.9
3.7
3.8
4.4
3.5
4.3
4.0
4.1
3.6
4.3
5.0
3.9
4.2
4.0
4.0
4.4
4.4
3.9
3.8
3.9
GLOB
tg/dl)
3.1
3.2
2.9
3.0
1.3
3.1
3.3
3.4
3.2
2.8
3.5
3.5
2.7
3.0
3.4
3.8
3.2
3.1
3.5
3.1
3.3
3.5
3.2
3.0
3.1
3.2
3.8
3.1
4.3
3.3
3.6
3.6
3.9
3.3
3.6
3.8
3.0
3.3
2.5
3.6
ALB/GLOB
(ratio)
1.290
1.219
1.207
1.333
4.077
1.258
1.121
1.088
1.094
1.286
1.000
0.971
1.407
1.333
1.118
0.974
1.219
1.194
1.086
1.097
1.182
1.057
1.188
1.467
1.129
1.344
1.053
1.323
0.837
1.303
1.389
1.083
1.077
1.212-
1.111
1.158
1.467
1.182
1.520
1.083
CHOL
-------
Study Ho. 5221.08
SUBCHRONIC TOXICITY OF PARA-CSESQL IN SPRAGUE DAULEY SATS
HALS CLINICAL CHEMISTRY VALUES
[Terminal Sacrifice]
DOSE LEVEL
0 mg/icg/day
50 rag/kg/day
175 mg/leg/day
600 mg/kg/day
AN [HAL NO.
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3701
3702
3703
3704
37C5
3706
3707
37C8
37C9
3710
3731
3732
3733
3734
3735
3736
3737
373B
3739
3740
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
D BIL
(mg/dl.J
0,02
0,01
0,01
C.02
0.00
0,00
o.oa
0.01
0.00
0.01
0.01
o.ao
0.01
0.01
o.co
0.01
0.01
0.01
O.C2
0.01
0.02
0.01
0.00
cms
0.02
0.02
0.02
O.OT
0.01
0.01
0.01
O.OQ
0.00
0.02
C.01
0.00
0.02
0.00
0,01
0.01
T BIL
(mg/dl)
0.05
0.05
0.23
0.05
0.22
0.07
0.14
0.15
0.22
0.16
0.22
Q.ZO
0.10 '
0.03
0.18
0.19
0.19
0.20
0.16
0.19
0.11
0.19
0.07
QMS
0.11
n.oz
0.16
0.06
0.18
0.09
0.14
0.17
0.19
0.07
0.20
0.18
0.10
O.OS
0.14
0.13
Ca
Cmg/dU
10.3
18.5
15.6
13.0
12.1
18.7
15.8
12.3
12.3
QNS
16.6
13.1
16.7
15.3
11.8
13.9
12.2
12.6
13.3
12.3
14.5
17.6
17.3
16.8
26.0
16.9
18.7
17.3
13.2
17.6
15.4
13.1
12.7
15.7
13.0
14.5
11.9
12.6
16.6
13.0
Ha
(Keq/l)
QNS
145
144
QNS
QNS
CMS
145
147
QNS
QNS
145
QNS
H6
QNS
QNS
QNS
. QNS
QNS
QNS
QNS
145
146
146
QNS
146
QNS
145
146
146
QMS
QNS
QNS
144
QNS
QNS
146
QNS
145
QNS
QNS
K
(Keq/t>
QNS
8.6
6.0
QNS
QNS
QMS
10.6
5.9
CNS
QNS
8.2
QNS
6.1
QNS
QNS
QNS
QNS
QNS
QNS
QNS
8.3
7.8
5.7
QNS
5.8
QNS
6.2
6.1
5.7
QMS
QNS
QNS
10.3
QNS
QNS
5.9
QNS
5.9
QNS
QNS
Cl
(Heq/U
QNS
106
102
QNS
QNS
cms
107
105
SNS
QNS
104
QNS
135
QNS
QNS
QNS
QNS
QNS
QNS
QNS
104
106
103
QNS
105
QMS
103
103
104
QMS
QNS
QNS
105
QNS
QNS
103
QNS
103
QNS
QMS
ALK PHOS
(!u/l)
59
46
75
43
128
56
39
61
104
154
39
72
50
47
50
53
95
51
68
83
42
84
53
125
46
32
49
53
53
61
37
62
59
52
47
56
115
94
126
83
COS
CMeq/l)
QNS
26
26
QNS
QNS
QNS
24
27
QMS
QNS
25
" QNS
29
QNS
QNS
QNS
QNS
QNS
QNS
QNS
27
23
28
17
25
QNS
27
27
29
CMS
QNS
QNS
22
QNS
QNS
25
QNS
30
QNS
QNS
CSEAT
(mg/dl)
0.65
0.70
0.69
0.66
0.77
0.63
0.72
0.58
0.86
0.68
Q.63
0.59
0.67
0.64
0.67
0.61
0.84
0.56
0.59
0.62
0.74
0.68
0.66
0.62
0.57
0.64
0.63
0.69
0.63
0.76
0.64
0.69
0.75
0.62
0.59
0.93
0.62
0.52
0.72
0.76
PHOS
(rcg/dU
7.2
10.2
12.0
3.3
7.7
11.1
12.3
12.5
6.7
10.4
10.9
8.9
10. a
8,3
8,7
8.3
9.1
7.6
8.6
8.2
10.7
12.2
9.6
8.6
11.5
S.4
G!JS
9.0
9.0
10.0
6.8
8.4
9.4
7.9
8.3
8.1
10.7
8.3
8.4
7.9
IDH
-------
Study Mo. 5221.03
SUBCHROMIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
FEMALE CLINICAL CHEMISTRY VALUES
[Interim Sacrifice]
DOSE LEVEL
0 mg/kg/day
ANIMAL HO. GLU BUN SGPT SCOT T PRO AL3 GLOB ALB/GLOB CHQL Ca
(mg/dl) (ratio) (rng/dl) (mg/dl)
SO mg/kg/day
175 mg/kg/day
600 mg/kg/day
3791
3792
3793 .
3794
3795
3796
3797
3798
3799
3800
3821
3S22
3323
3824
3825
3826
3827
3828
3S29
3830
3851
3852
3853
3854
3855
3856
3857
3858
3859
3860
3881
3882
3284
3885
3886
3887
3888
3889
3890
221.9
303.0
189.6
172.6
194.6
332.1
195.5
146.1
148.9
181.2
172.2
307.2
113.3
240. 5
177.5
180.1
196.0
113.0
147.3
219. S
172.3
231.1
na
163.7
201.1
200.9
286.0
165.3
136.1
186.7
124.4
124.1
207.8
147.3
209.8
188.5
217.9
396.6
225.0
22.3
25.9
Z4.1
21.8
14.4
18.7
12.8
25.2
14.3
17.8
17.9
12.6
14.6
11.8
14.3
17.4
16.7
15.5
16.0
17.3
16.4
18.7
14.3
24.3
22.9
19.7
16.2
14.5
20.3
10.2
14.6
25.0
18.9
18.0
17.9
17.1
19.7
14.0
16.3
22
29
25
31
27
26
25
27
27
33
33
28
29
23
29
32
30
26
19
26
34
43
35
49
na
27
32
31
29
26
28
21
37
35
28
38
55
43
29
89
83
79
80
69
66
84
89
79
75
63
75
57
63
63
103
92
85
103
73
84
67
na
122
59
96
85
101
71
79
119
64
70
74
69
77
118
135
70
3.0
a.o
9.0
7.2
6.6
6.8
7.0
7.5
7.3
6.6
6.5
7.2
7.1
7.4
7.0
7.5
7.6
7.2
7.0
7.1
7.1
6.9
na
7.5
7.2
7.2
7.2
7.5
6.9
7.4
7.2
6.9
7-8.
7.0
6.4
7.3
7.6
8.2
7.6
5.0
5.2
5.1
4.1
3.4
3.8
4.2
4.8
4.1
3.6
4.4
4.5
4.Z
4.3
3.6
4.8
4.5
4.8
4.6
3.6
3.9
4.3
"na
4.2
4.5
3.9
4.5
4.5
4.0
4.4
4.5
4.5
4.9
4.6
3.9
4.0
4.4
5.0
4.2
3.0
2.3
3.9
3.1
3.2
3.0
2.8
2.7
3.2
3.0
2.1
2.7
2.9
3.1
3.4
2.7
3.1
2.4
2.4
3.5
3.2
2.6
na
3.3
2.7
3.3
2.7
3.0
2.9
3.0
2.7
2.4
2.9
2.4
2.5
3.3
3.2
3.2
3.4
1.667
1.857
1.303
1.323
1.063
1.267
1.500
1.778
1.281
1.200
2.095
1.667
1.448
1.387
1.059
1.778
1.452
2.000
1.917
1.029
1.219
1.654
na
1.273
1.667
1.182
1.667
1.500
1.379
1.467
1.667
1.87S
1.690
1.917
1.560
1.212
1.375
1.563
1.235
121.8
116.6
157.3
91.8
81.8
104.8
64.6
77.4
83.7
102.3
66.6
82.1
75.8
79.4
73.3
95.0
SO. 2
76.2
53.3
64.8
86.5
112.2
120.7
107.4
126.1
118.0
94.7
118.5
107.2
94.4
102.4
77.6
138.3
106.1
44.7
67.8
133.2
132.0
125.6
15.1
14.5
16.2
15.8
12.8
13.8
15.1
15.5
14.5
15.1
12.3
14.0
16.4
12. Z
13.0
18.3
16.0
15.4
15.1
12.9
12.4
15.0
na
14.6
13.3
24.9
15.1
15.6
13.2
13.7
14.5
16.2
16.2
15.9
12.5
12.3
14.7
15.5
16.0
D-79
i 7
-------
Study Ko. 5221.CO
SUBCHRONIC TOXICin OF PARA-CRESOL IN SPRACUE DAULEY RATS
FEMALE CLINICAL CHEMISTRY VALUES
[Interim Sacrifice]
DOSE LEVEL
0 mgAg/day
50 mg/kg/day
175 tngAg/day
600 mg/kg/day
ANIMAL HO.
3791
3792
3793
3794
3795
3776
3797
3798
3799
3BOQ
3821
3822
3823
3824
3S25
3S26
3827
3823
3S29
3830
3851
3852
3B54
3855
3856
3857
3853
3859
3860
3381
3822
3834
3S85
3886
3887
3838
3S39
3890
D SIL
-------
Study No. 5221.08
SUBCHRON1C TOXICtTY OF PARA-CRfSOl IN SPRAGUE DAUIEY RATS
FEHALI CLINICAL CHEMISTRY VALUES
[Terminal Sacrifice]
DOSE LEVEL
0 mg/kg/day
ANIMAL NO. CLU BUN SGPT SCOT T PRO ALB GLOB ALi/GLCB CHOI
(mo/ell)
-------
Study NO. 5221.08
SUBCHROMIC TOXICITY OF PARA-CRESQL IN SPRAGUE PAUlEt RATS
FEMALE CLINICAL CHEN1STRT VALUES
[Terminal Sacrifice]
DOSE LEVEL
0 rag/kg/day
50 rng/kg/day
175
600 rng/kg/day
AN1HAL HO.
3801
3802
3803
3804
3805
3806
380 7
3808
3809
3810
3831
3332
3833
3834
3835
3336
3837
3838
3839
3840
3861
3862
3363
3864
3865
3866
3867
3868
3869
3870
3891
3892
3893
3894
3895
3S96
3897
3898
3900
3901
D 811
-------
Study No. 5221.03
SU3CHRON1C TOX1CITY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
MALE ORGAN WEIGHT DATA (g)
[Terminal Sacrifice]
ANIMAL NO. HEART LIVER SPLEEN KIDNEY-LFT KJDNEY-RT
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3671
3672
3673
3674
3675
3676
3677
3678
3679
36SO
3681
3682
3653
3684
3685
3686
3687
3688
3689
3690
3701
3702
3703
3704
3705
3706
3707
3703 .
3709
3710
3711
3712
3713
3714
3715
3716
3717
37-13
3719
3720
1.769
1.616
1.795
1.795
1.394
1.997
2.033
2.159
1.780
1.875
1.436
1.795
1.622
1.739
1.847
1.814
1.981
1.528
1.577
1.801
1.725
1.818
1.707
1.638
1.621
1.331
1.514
1.645
1.982
1.919
1.739
1.634
1.622
1.474
1.635
1.782
1,527
1.4Z7
1.776
1.553
18.773
14.427
13.673
18.934
14.543
19.589
20.627
23.882
17.941
20.082
15.795
20.271
18.904
20.706
19.445
21.399
17.351
19.122
15.947
18.924
18.061
20.030
22.055
16.692
18.195
19.106
13.780
17.448
21.948
19.913
18.355
17.457
17.699
14.750
16.921
16.840
13.102
13.986
19.619
16.594
0.832
0.773
0.366
0.633
0.594
0.753
Q. 775
0.842
0.906
0.853
0.826
0.715
0.732
0.801
0.808
0.803
0.683
' 1.077
0.810
0.818
0.715
0.975
0.896
0.758
0.692
0.839
0.551
0.762
0.854
0.955
0.801
0.649
0.765
0.692
0.687
0.858
0.729
0.61S
0.840
0.782
1.985
1.582
2.298
2.029
1.605
2.020
2.358
2.341
1.885
2.186
1.613
2.126
1,935
1.822
1.891
2.092
1.926
2.000
1.831
2.06T
2.302
2.290
1.997
2.150
2.138
2.194
1.671
2.080
2.213
2.259
1.911
1.323
2.195'
1.515
2.183
1.964
1.573
1.666
2.247
2.186
1.941
1.576
2.455
2.094
1.563
2.136
2.252
2.397
2.073
2.264
1.669
2.123
1.858
1.927
1.981
2.088
1.936
2.057
1.856
2.025
2.323
2.377
2.105
2.181
2.054
2.299
1.659
2.163
2.129
2.216
1.910
1.755
2.127
1.533
2.074
1.385
1.769
1.675
2.431
2.272
D-83
^. ( (
-------
Study No. 5221.08
SUBCHRONIC TOXICITY OF PARA-CRESOL IH SPRAGUE DAULEY RATS
MALE ORGAN WEIGHT DATA (g>
[Terminal Sacrifice]
ANIMAL HO TESTIS-LFT TESTIS-RT ADRENALS BRAIW THY./PARA. TERM.WGT.
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3671
3672
3673
3674
3675
3676
3677
3675
3679
3680
3681
3682
3683
3684
3685
3686
3687
3688
3689
3690
3701
3702
3703
3704
3705
3706
3707
3708
3709
3710
3711
3712
3713 .
37U
3715
3716
3717
3718
3719
3720
1.811
1.460
1.746
1.651
1.711
1.713
1.783
1.647
1.570
1.770
1.542
1.732
1.807
1.753
1.616
1.688
1.889
1.618
1.681
1.725
1.779
1.704
1.782
1.614
1.722
1.611
1.671
1.300
1.847
1.666
1.641
1.545
1.869
1.799
1.835
1.852
1.693
1.746
1.893
1.847
1.777
1.612
1.789
. 1.675
1.609
1.766
1.850
1.580
1.520
1.844
1.152
1.761
1.822
1.721 .
1.642
1.583
1.791
1.893
1.677
1.6S4
1.758
1.745
1.922
1.512
1.691
1.642
1.646
1.693
1.827
1.745
1.646
1.525
1.967
1.761
1.863
1.900
1.727
1.738
1.847
1.793
0.074
0,053
0.069
0.040
0.046
0.075
0.072
0.056
0.064
0.054
0.063
0.042
0.051
0.076
0.033
0.065
0.059
0.053
0.056
0.054
0.040
0.063
0.062
0.060
0.053
0.054
0.063
0.035
0.073
0.043
0.065
0.054
na
0.053
0.072
0.043
0.054
0.050
0.047
O.Q61
2.149
2.274
2.301
2.033
2.357
2.356
2.349
2.311
2.291
2.238
2.196
2.235
2.385
2.056
2.110
2.283
2.294
2.006
2.120
2.361
2.328
2.251
2.298
2.208
Z.303
2.336
2.083
2.170
2.243
2.403
2.170
2.235
2.190
2.229
2.212
2.203
2.024
1.961
2.186
2.052
0.017
0.020
0.034
0.020
0.016
0.037
0.030
0.033
0.019
0.037
0.021
0.020
0.026
0.033
0.020
0.024
0.027
0.028
0.024
0.024
0.036
0.024
0.039
0.018
0.020
0.024
0.017
0.027
0.027
0.015
0.021
0.025
0.029
0.026
0.022
0.013
0.020
0.020
0.025
0.022
587
506
566
663
43 S
582
547
657
533
595
493
536
588
583
570
595
597
550
521
600
557
582
599
504
567
578
430
576
599
533
543
544
594
486
523
566
470
463
553
548
D-84
178
-------
Study No. 5221.03
SU8CHRONIC TOXICITY OF PARA-CRESOl IN SPRAGUi DAULEY RATS
HALE ORGAN yEIGHT DATA (|)
[Terminal Sacrifice]
ANIMAL NO. HEART LIVES SPLEEN KIDNEY-LFT KtDNEY-RT
DOSE LEV1L
175 mg/kg/day
600 mg/kg/day
3731
3732
3733
3734
3735
3736
3737
3738
3739
1740
3741
3742
3743
3744
3745
, 3746
3747
3748
3749
3750
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
3771
3772
3773
3774
3775
3776
3777
3773
3779
3780
1.665
1.879
1.840
1.658
1.945
1.820
1.558
1.631
1.523
1.961
1.575
1.777
1.768
1.921
1.371
1.727
f.778
1.768
1.749
1.552
1.484
1.403
1.629
1.795
1.830
1.706
1.555
1.752
1.309
1.629
1.419
1.718
1.882
1.294
1.318
1.741
2.633
1,419
1.776
1.491
19.622
21.432
20.462
19.375
20.981
19.186
18.286
19.494
14.712
19.009
16.173
17.649
20.769
17.713
14.588
21.091
18.750
17.461
19.552
17.225
14.032
14.300
17.311
18.934
20.581
15.122
17,152
19.630
13.553
15.498
16.098
20.846
18.956
13,993
13.971
19.005
16.275
15.685
19.730
17.643
0.830
0.816
0.724
0.624
0.892
0.586
0.897
0.702
0.700
0.734
0.539
0.700
0.759
0.762
0.605
0.783
0.875
0.635
0.803
0.685
0.667
0.505
0.547
0.633
' 0.6S4
0.630
0.609
0.695
0.540
0.591
0.725
0.860
0.670
0.707
0.520
0.680
0.655
0.864
0.901
0.690
1.844
2.125
2.317
1.797
2.650
1.930
1.972
2.202
1.522
2.227
1.829
1.995
1.7S6
2.038
1.678
2.260
2.290
1.886
2.254
2.057
1.584
1.784
. 2.014
2.029
2.013
1.549
1.834
2.461
1.535
1.733
2.256
2.453
2.293
1.762
1.718
2.307
1.892
1.881
2.173
1.734
2.127
2.092
2.307
1.887
2.445
2.117
1.957
2.297
1.635
2.305
1.947
1.925
1.977
2.186
1.683
2.258
2.286
1.844
2.240
2.152
1.756
1.931
1,911
2.094
2.037
1.673
1.901
2.499
1.454
1.744
2.365
2.511
2.411
1.805
1.874
2.398
1.884
1.969
2.007
1,831
O
->J
D-85
-------
Study No. 5221.03
SUBCHRONIC TOXICITY OF PARA-CRESOL IN SPRAGUE DAWLEY RATS
MALE ORGAN WEIGHT DATA
-------
Study No. 5221.08
SUBCHRCNtC TQXICITY OF PARA-CRESOl IN SPRAGUE DAWLEY RATS
RELATIVE HALE ORGAN HEIGHT DATA (X Terminal Body Weight)
[Terminal Sacrifice]
ANIMAL NO. HEART LIVER SPLEEN KIDNEY-LFT ICIONEY-RT
DOSE LEVEL
0 mg/kg/day
50 rog/kg/day
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3681
3682
36S3
3684
3685
3686
3637
3688
3689
3690
3701
3702
3703
3704
3705
37C6
3707
3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
0.301
0.319
0.317
0.271
0.318
0.343
0.373
0.329
0.334
0.315
0.291
0.334
0.276
0.296
0.324
0,305
0.332
0.278
0.303
0.30Q
0.310
0.312
0.2SS
0.325
0.286
0.317
0.352
0.286
0.331
0.329
0.320
0.300
0.273
0.303
0.310
0.315
0.325
0.305
0,321
0.283
3.193
2.851
3.300
2,856
3.320
3.366
3.771
3.635
3.366
3.375
3.204
3.768
3.215
3.521
3.411
3.596
2.906
3.477
3.061
3.154
3.243
3.442
3.682
3.312
3.209
3.306
3.205
3.029
3.664
3.416
3.380
3.209
2.980
3.035
3.205
2.975
2.783
2.988
3.548
3.023
O.U2
0.154
0.153
0.095
0.136
0.129
0.142
0.128
0.170
0.144
0.168
0.133
0.124
0.136
0.142
0.135
0.114
0.196
0.155
0.136
0.128
0.168
0.150
0.150
0.122
0.145
0.123
0.132
0.143
0.164
0.143
0.119
0.129
0.142
0.130
0.152
0.155
0.131
0.152
.0.143
0.333
0.313
0.406
0.306
0.366
0.347
0.431
0.356
0.354
0.367
0.327
0.395
0.329
0.310
0.332
0.352
0.323
0.364
0.351
0.344
0.413
0.393
0.333
0.427
0.377
0.380
0.389
0.361
0.369
0.387
0.352
0.335
0.370
0.312
0.413
0.347
0.335
0.356
0.406
0.399
0.331
0.311
0.434
0.316
0.357
0.367
0.412
0.365
0.390
0.381
0.339
0.395
0.316
0.328
0.348
0.351
0.324
0.374
0.356
0.338
0.417
0.408
0.351
0.433
0.362
0.398
0.386
0.376
0.355
0.380
0.352
0.323
0.358
0.326
0.393
0.333
0.376
0.35B
0.440
0.415
-« O i
j. 5 i
D-87
-------
Study KQ. 5221.08
SUBCHRCNIC TOXIC1TY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
RELATIVE HALE ORGAN WEIGHT DATA {% Terminal Body Weight)
[Terminal, Sacrifice]
ANIMAL NO. TESTIS-LFT TESTIS-RT ADRENALS BRAIN THY./PARA.
DOSE LEVEL
0 mg/kg/day
50 rag/kg/day
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3681
3682
3683
3684
36S5
3686
3687
3688
3689
3690
3701
3702
3703
3704
3705
3706
3707
3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3718
3719
3720
0.309
0.239
0.3Q8
0.249
0.391
0.294
0.326
0.251
0.295
0.297
0.313
0.322
0.307
0.298
0.284
0.284
0.316
0.294
0.323
0.233
0.319
0.293
0.297
0.320
0.304
0.279
0.3S9
0.313 '
0.308
0.286
0,302
0.284
0,315
0.370
0.348
0,327
0.360
0.373
0.342
0.337
0.303
0.319
0.316
0.253
0.367
0.303
0.338
0.240
0.285
0.310
0.234
0.327
0.310
0.293
0.283
0.266
0.300
0.344
0.322
0.276
0.316
0.300
0.321
0.300
,0.298
0.284
0.383
0.294
0.305
0.299
0.303
0.280
0.331
0.362
0.353
0.336
0.367
0.371
0.334
0.327
0.013
0.011
0.012
0.006
0.011
0.013
0.013
0.009
0.012
0.009
0.013
0.003
0.009
0.013
0.007
0.011
0.010
0.010
0.011
0.009
0.007 "
0.011
0.010
0.012
0.010
0.009
0.015
0.006
0.012
0.007
0.012
0.010
na
0.012
0.014
0.008
0.011
0.011
o.cca
0.011
0.366
0.449
0.407
0.307
0.538
0.405
0.429
0.352
0.430
0.376
0.445
0.415
0.406
0.350
0.370
0.385
0.384
0.365
0.40?
0.394
0.418
0.387
0.384
0.438
0.406
0.404
0.484
0.377
0.374
0.413
0.400
0.411
0.369
0.459
0.419
0.389
0,431
0,419
" 0.395
0.374
0.003
0.004
0.006
0.003
0.004
0.006
0.005
0.005
0.004
0.006
0,004
0.004
0.004
0.006
0.004
0.004
0.005
0.005
0.005
0.004
0.006
O.OC4
0.007
0.004
0.004
0.004
0.004
0.005
0.005
0.003
0.004
0.005
0.005
Q.OQS
0.004
0.003
0.004
O.QQ4
0.005
0.004
D-88
9
-------
Study No. 5221.08
SUBCKRONIC TOXIC1TY OF PARA-CRESQL IN SPRAGUE DAULEY RATS
RELATIVE MALE ORGAN WEIGHT DATA (.% Terminal Body Weight)
[Terminal Sacrifice]
AHIMAL NO. HEART LIVER SPLEEH K10NEY-LFT KIDNEY-RT
DOSE LEVEL
171 mg/kg/day
600 mg/kg/day
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3741
3742
3743
3744
3745
3746
3747
3748
3749
3750
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
3771
3772
3773
3774
3775
3776
3777
3778
3779
3780
0.290
0.323
0.334
0.319
0.321
0.360
0.313
0.312
0.321
0.369
0.316
0.313
0.31(3
0.381
0.301
0.315
0.322
0.331
0.317
0.303
0.381
0.321
0.329
0.332
0.377
0.364
0.328
0.312
0.323
0.342
0.309
0.233
0.358
0.296
0.31S
0.338
0.618
0.311
0.336
0.316
3.413
3.740
3.714
3.726
3.462
3.792
3.679
3.727
3.104
3.573
3,249
3.157
3.637
3.514
3.199
3.849
3.397
3.270
3.548
3.35B
3.558
3.272
3.497
3.506
4.235
3.224'
3.619
3.499
3.397
3.256
3.507
3.434
3.604
3.202
3.334
3.690
3.820
3.440
3.737
3.733
0.144
0.142
0.131
0.120
0.147
0.116
0.180
0.134
0.148
0.133
0.108
0.125
0.133
0.151
0.133
0.143
0.159
0.119
0.146
0.134
0.171
0.116
0.111
0.117
0.135
0.134
0.128
0.124
0.135
0.124
0.153
0.142
0.127
0.162
0.124
0.132
0.154
0.189
0.171
0.146
0.321
0.371
0.421
0.346
0.437
0.381,
0.397
0.421
0.321
0.419
0.367
0.357
0.313
0.404
0.368
0.412
0.415
0.353
0.409
0.401 .
C.406
0.408
0.407
0.376
0.414
0.330
0.387
0.439
0.385
0.364
0.492
0.404
0.436
0.403
0.410
0.448
0.444
0.413
0.412
0.367
0.370
0.365
0.419
0.363
0.403
0.418
0.394
0.439
0.345
0.433
0.391
0.344
0.346
0.434
0.370
0.412
0.414
0.345
0.407
0.419
0.450
0.442
0.386
0.388
0.419
0.357
0.401
0.445
0.364
0.366
0.515
0.414
0.453
0.413
0.447
0.466
0.442
0.432
0.380
0.388
*! O r*
± b o
D-89
-------
Study Ho. 5221.03
SUBCHRON1C TOXIC1TY OF PARA-CRESOL IM SPRAGUE DAULEY RATS
RELATIVE HALE ORGAN HEIGHT DATA (X Terminal Body Weight)
[Terminal Sacrifice]
ANIMAL NO. TESTIS-LFT TESTIS-RT ADRENALS BRAIN THY./PARA.
DOSE LEVEL
175 mg/kg/day
600 mg/kg/day
3731
3732
3733
3734
3735
3736
3737
3733
3739
3740
3741
3742
3743
3744
3745
3746
3747
3743
3749
3750
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
3771
3772
3773
3774
3775
3776
3777
3773
3779
3780
0.236
0.295
0.293
0.322
0.273
0.311
0.314
0.359
0.367
0.336
0.340
0.233
0.235
0.302
0.325
0.331
0.233
0.349
0.303
0.383
0.451
0.442
0.275
0.306
0.322
0.341
0.356
0.276
0.387
0.332
0.357
0.295
0.351
0.3S6
0.384
0.326
0.403
0.330
0.335
0.356
0.297
0.299
0.302
0.315
0.296
0.303
0.317
C.372
0.376
0.329
0.343
0.284
0.276
0.329
0.311
0.337
0.293
0.327
0.311
0.400
0.440
0.465
0.279
0.310
0.329
0.328
0.345
0.273
0.375
0.340
0.353
0.293
0.351
0.375
0.333
0.323
0.396
0.343
0.324
0.361
0.010
0.011
0.013
0.014
0.011
0.011
0.011
0.013
0.011
0.011
0.015
0.009
0.003
0.010
0.011
o.ooa
0.009
0.003
0.011
0.011
0.013
0.013
0.010
0.007
0.011
0.013
0.009
0.010
0.014
0.007
0.014
0.014
0.011
0.012
0.017
0.009
0.013
0.014
0.010
0.011
0.387
0.368
" 0.433
0,419
0.376
0.419
0.448
0.448
0.463
0.405
0.432
0.404
0.372
0.446
0.471
0.440
0.409
0.395
0.409
0.435
0.503
0.479
0.407
0.377
0.434
0.439
0.452
0.424
0.508
0.438
0.446
0.389
0.433
0.431
0.503
0.437
0.465
0.446
0.392
0.457
0.006
0.006
0.006
0.005
0.007
0.005
0.006
0.007
O.C07
0.004
0.004
0.004
0.004
0.005
0.003
0.005
0.004
0.005
0.004
0.004
0.004
0,005
0.004
0.004
0.005
0.003
0.005
0.006
0.005
0.005
0.005
0.004
0.005
0.005
0.006
0.007
0.005
0.005
0.005
0.005
D-90
18
-------
Study Mo. 5221.03
SUBCHRCNIC TOXIC1TY Of PARA-CRESOl IN SPRAGUE DAWLEY RATS
FEMALE ORGAN WEIGHT DATA'(3)
[Terminal Sacrifice]
ANIMAL NO. HEART LIVER SPLEEM KJDMEY-LFT K1DNEY-RT
DOSE LEVEL
0 tng/kg/day
50 ing/kg/day
3801
3802
3803
3804
3805
3806
3807
3aoa
3809
3810
3311
3812
3813
3814
3815
3816
3817
3818
3819
3820
3831
3332
3833
3334
3835
3836
3837
3838
3839
3340
3841
3342
3843
3844
3845
3846
3847
3843
3849
3850
1.122
1.236
1.144
1,075
0.931
1.048
0.8S6
1.086
1.208
0.958
1.065
1.063
0.943
1.218
1.013
1.120
1.174
0.880
0.927
1.106
1.100
1.178
1,344
1.058
0.925
1.059
1.061
1.180
0.881
0,892
1.007
1.016
0.939
0.837
1.103
1.139
0.964
1,023
1,146
0.961
10.654
11.468
10.897
9.544
9.516
9.904
8.202
9.903
10.173
9.768
9.064
10.854
9.809
10.215
9.571
9.340
9.830
8.260
7.629
10.225
9.352
10.768
9.767
10.703
9.749
8.855
9.997
9.997
7.740
8.794
9.665
9.071
8.792
-7.944
8.983
9.868
9.108
9.565
10.528
8.475
0,553
0.492
0.421
0.493
0.569
0.541
0.430
0.517
0.571
0.555
0.534
Q.624
0.515
0.590
0.548
0,559
0.610
0.495
0.522
0.512
0.595
0,716
0.574
0.575
0.555
0.553
0.693
0.552
0.464
0.420
0.512
0.627
0.533
0.517
0.570
0.589
0.578
0.570
0.594
0.448
1.167
1.512
1.096-
1.035
1.091
1.108
0.866
1.228
1.379
1.216
1.207
1.236
1.111
1.278
1.148
1.027
1.081
0.882
0.970
1.180
1.473
1.220
1.166
1.147
1.011
1.055
1.277
1,198
1.020
0.959
1.151
1.105
1.114
1.047
1.131
1.149
1.232
1.148
1.134
0.918
1.174
1.330
1.178
1.000
1.155
1.172
0.875
1.235
1.347
1.182
1.190
1.206
1.154
1.210
1.203
1.008
1.117
0.971
0.970
1.091
1.362
1.245
1.216
1.196
1.019
1.128
1.296
1.296
1.132
0.977
1.121
1.093
1.076
0.948
1.440
1.156
1.194
1.081
1.168
0.960
85
D-91
-------
Study No. 5221.08
SU3CHRONJC TOXIC1TY OF PA8A-CRESOL IN SPRAGUE DAWIEY RATS
FEMALE ORGAN WEIGHT DATA (g)
[Terminal Sacrifice]
ANIHAL NO. OVARY-LFT OVARY-RT ADRENALS BRAIN THY./PARA. TERM.WGT.
DOSi LEVEL
0 rag/kg/day
50 ing/kg/day
3801
3802
3803
3804
3805
3806
3807
3808
3809
3810
3811
3812
3813
3814
3815
3816
3817
3818
3819
3820
3831
3832
3833
3834
3835
3836
3837
3833
3839
3840
3841
3842
3843
3844
3845
3846
3847
3848
3849
3850
0.043
0.032
0.035
0.042
0.055
0.044
0.041
0.027
0.039
0.045
0.054
0.056
0.025
0,044
0.062
0.048
0.060
0.035
0.03?
0.020
0.045
0.049
0.057
0.028
0.036
0.047
0.023
0.034 .
0.043
0.049
0.043
0.036
0.030
0.034
0.044
0.046
0.057
0.051
0.052
0.044
0.043
0.071
0.032
0.076
0.050
0.045
0.032
0.056
0.046
0.047
D.042
0.059
0.026
0.077
0.054
0.043
0.051
0.044
0.041
0.026
0.050
Q.Q63
0.060
0.033
0.030
0.041
0.062
0.014
0.041
0.047
0.044
0.033
0.036
0.034
0.045
0.050
0.043
0.090
0.046
0.037
O.C57
0.0S7
0.079
O.C63
O.OS9
0.054
0.054
0.067
0.083
0.064
0.071
0.070
0.068
0.070
0.054
0.064
0.074
0.051
O.OS3
0.064
0.066
0.057
0.049
0.065
0.063
0.060
0.055
0.057
0.053
0.063
0.072
O.C58
0.063
O.Q52
0.086
0.088
0.066
0.073
0.066
0.059
2.170
2.139
2.027
1.897
1.932
2.143
1.946
2.119
2.172
2.113
2.127
f.980
2.052
2.209
2.064
1.831
2.150
2. 068
2.015
2.036
2.141
2.230
2.029
2.149
2.047
2.061
2.097
2.197
2.033
1.995
2.115
2.042
2.012
1.903
2.150
2.114
2.103
2.154
2.008
1.995
0.023
0.032
0.012
0.022
0.025
0.021
0.013
0.013
0.027
0.034
0.027
0.016
0.023
0.021
0.020
0.013
0.017
0.019
0.016
0.017
0.026
0.086
0.013
0.020
0.012 .
0.022
0,026
0.030
0.032
0.012
0.022
0.011
0.021
0.015
0.034
0.022
0.017
0.026
0.014
0.014
284
283
278
284
274
316
245
302
290
264
282
331
2S5
325
297
293
331
253
250
271
271
296
312
281
276
281
282
297
227
243
296
277
277
228
265
306
281
281
297
230
D-92
o /?
o to
-------
Study Ho. 5221.08
SUBCHRONIC TCX1CITY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
FEMALE ORGAN WEIGHT DATA (g)
[Terminal Sacrifice]
ANIMAL NO. HEART LIVER SPLEEN KIDNEY-LFT KIDNEY-RT
DOSE LEVEL
175 mg/kg/day
600 mg/kg/day
3S61
3362
3363
3864
3865
3666
3867
3863
3869
3870
2871
3872
3873
3874
3875
3876
3877
3878
3879
3880
3891
3892
2893
3894
3895
3896
3897
3898
3900
3901
3902
3903
3904
3905
3906
3907
3903
3909
0.968
1.051
1.109
0.886
0.951
1,096
0.937
1.073
1.124
0.983
1.176
1.006
0.983
0.973
1.072
1.037
0.975
0.999
0.930
0.908
0.932
0.767
1.036
1.001
0.920
1.878
1.001
1.006
0.945
1.069
0.861
0.936
1.087
0.940
O.B63
0.975
1.145
1.060
9.340
10.500
10.839
10.412
3.351
8.572
3.121
10.921
10.260
9.065
10.341
9.934
9.611
8.647
10.331
8.954
8.510
10.387
7.964
8.267
8.839
7.645
10.198
9.786
9.638
8.436
10.137
9.620
8.231
10.050
7.981
9.939
9.315
9.359
8.277
9.575
11.402
9.527
0.433
0.415
0.626
0.572
0.574
0.455
0.464
0.539
0.429
0.637
0.589
0.564
0.444
0.413
0.422
0.451
0.578
0.552
0.427
0.495
0.398
0.441
0.551
0.542
0.562
0.530
0.514
0.578
0.458
0.552
0.557
0.501
0,512
0.446
0.316
0.469
0.504
. 0.454
1.212
1.063
1.191
1.150
1.179
1.094
1.007
.1.228
1.434
1.210
1.109'
1.258
1.140
1.104
1.209
1.121
1.116
1.263
1.029
0.941
1.011
0.851
1.344
1.130
1.343
1.104
1.609
1.159
0.877
1.162
1.041
1.050
1.035
1.273
1.039
1.193
1.289
1.362
1.227
1.067
1.199
1.146
1.286
1.003
0.967
1.300
1.202
1.257
1.174
1,280
1.129
1.136
1.205
1.153
1.105
1.280
1.015
0.961
1.076
0.892
1.367
1.289
1.369
1.100
1.349
1.194
0.864
1.330
1.001
1.026
1.030
1.207
1.046
1.210
1.359
1.353
*' O "!
1.8 Y
D-93
-------
Study Mo. 5221.08
SUBCHRQNIC TQXICITY OF 'PARA-CRESOL 1M SPRAGUE DAWLEY RATS
FEMALE ORGAN WEIGHT DATA (3>
[Terminal Sacrifice]
ANIMAL NO. OVARY-LFT OVARY-RT ADRENALS BRAIN THY./PARA. TERM.yCT,
DOSE LEVEL
175 mg/kg/day
600 mg/kg/day
3861
3862
3363
3864
3865
3866
3867
3868
3869
3870
3 371
3872
3873
3874
3875
3876
3877
3878
3879
3880
3891
3892
3893
3394
3895
3896
3897
3898
3900
3901
3902
3903
3904
3905
3906
3907
3908
3909
0.025
0.021
0.034
0.049
0.029
0,045
0.045
0,044
0.025
0.056
O.D38
0.039
0.035
0.027
0.028
0.030
0.041
0.041
0.040
0.032
0.022
0.034
0.021
0.045
0.036
0.045
0.036
0,064
0.024
0.060
0.039
0.017
0.017
0.041
0.023
0.037
0.023
0.034
0.025
0.016
0.052
0.047
0.027
0.044
0.050
0.043
0.031
0.057
0.042
0.046
0.036
0.026
0.029
0.039
0,040
0.045
0.037
0.029
0.029
0.019
0.029
0.073
0.050
0.056
0.045
0.046
0.014
0.029
0.033
0.020
0.025
0.052
0.023
0.045
0.022
0.025
0.074
0.054
0.026
0.052
0.065
O.C78
0.057
. 0.055
0.071
0.074
0.060
0.068
0.057
0.064
0.060
0.064
0.063
0.064
0.062
0.048
0.057
0.056
0.072
0.076
0.066
0.071
0.078
0.057
0.061
0.071
O.OS6
0.056
0.041
0.055
O.Q66
0.074
0.077
0.063
2.042
1.37&
2.111
1.961
2.191
2.035
1.988
1.983
1.968
2.094
2.056
1.987
2.076
2.141
2.083
1.949
2.121
2.062
1,931
1.919
'1.933
1.794
2.041.
1.905
2.088
1.931
2.135
1.944
1.825
2.081
1.883
1.801
1.844
1.849
2.004
1.968
2.095
1.910
0.017
0,021
0.056
0.015
0.020
0.017
0.022
0.020
0.021
0.038
0.023
0.016
0.013
0.013
0.024
0.020
0.013
0.030
0.023
0.018
0.018
0.013
0.013
0.029
0.031
0.030
0.035
0.026
0.012
0.029
0.022
0.019
0.016
0.019
0,016
0,015
0.027
0.021
257
292
287
276
245
290
255
319
296
272
346
301
302
292
295
281
272
277
255
273
249
210
279
276
260
274
282
303
249
274
249
262
300
246
218
277
304
269
18*
o
D-94
-------
Study No. 5221.03
SUBCKROWIC TQXICm OF PASA-CRESOL IN SPSAGUE DAWLEY RATS
RELATIVE FEMALE ORGAN WilGHT DATA
-------
Study No. 5221,08
SUBCHRONIC TOXICSTY OF PARA-CRISQL IN SPRACUE DAULEY RATS
RELATIVE FEMALE ORGAN WEIGHT DATA tt Terminal Body Weight)
[Terminal Sacrifice]
ANIMAL NO. QVA8Y-LFT OVARY-RT ADRENALS BSAIN THY,/PAW.
'DOSE LEVEL
0 mg/kg/day
50 mg/ks/day
3801
3802
3803
3804
3805
3806
3807
3808
3809
3810
3811
3812
3813
3814
3815
3816
3817
3818
3819
3820
3831
3832
3833
3834
3835
3836
3837
3838
3839
3840
3841
3842
3843
3844
384S
3846
3847
3843
3849
3850
0,015
0.011
0.013
0,015
0.020
0,014
0.017
0.009
0.013
0.017
0.019
0.017
0.009
0.014
0.021
0.016
0.018
0.014
0.015
0.007
0.017
0.017
0.018
0.010
0.013
0.017
O.QOS
0.011
0.019
0.020
0.015
0.013
0.011
0.015
0.017
0.015
0.020
0,013
0.018
0.019
0.015
0.025
0.014
0.027
0.018
0.014
0.013
0.019
0.016
0.01S
0.015
0.018
0.009
0.024
0.018
0.015
0.015
0.017
0,016
0.010
0.018
0.021
0.019
0.012
0.011
0.015
0.022
0.005
0.018
0.019
0.015
0.014
0.013
0.015
0.017
0.016
0.015
0.032
0.015
0.016
0.020
0.031
0.028
0.022
0.022
0.017
0.022
0.022
0.029
Q.C24
0.025
0.021
0.024
0.022
0.018
0.022
0.022
0.020
0.023
0.024
0,024
0.019
0.016
0.023
0.025
0.021
0.020
0.019
O.C23
0.026
0.024
0.021
0.023
0,023
0.032
0,029
0.023
0,026
0.022
0.026
0.764
0.756
0,729
0.668
0.705
0.678
0.794
0.702
0.749
0.800
0.754
0.598
0.720
0.680
0.695
0.642
0.650
0.817
0.80&
0.751
0.790
0.753
0.650
0.765
Q. 742
0.733
0.744
0.740
0.898
a. 821
0.715
0.737
0.726
0.337
0.311
0.691
0.743
0.767
0.676
Q.867
0.008
0.011
0.004
0,003
0.009
0.007
0.005
0.004
0.009
0.013
0.010
0.005
0.003
0.006
0.007
0.004
0.005
0.008
0.006
0.006
0.010
0.029
Q. 004
0.007
0.004
0.008
0.009
0.010
0.014
0.005
0.007
0.004
0.003
0.007
0.013
0.007
0.006
0.009
0.005
0.006
190
D-96
-------
Study Ho. 5221.08
SUBCHRONIC TOX1CITY OF PA.RA-CRESOL IN SPRAGUE DAULEY RATS
RELATIVE FEMALE ORGAN yglGHT DATA {% Terminal Body Weight}
[Terminal Sacrifice!
ANIMAL NO. HEART LIVER SPLEEM KIDNET-LFT KIDNEY-RT
DOSE LEVEL
175 mg/kg/day
600 mg/kg/diy
3861
3862
3S63
3864
3865
3866
3867
3868
3869
3870
3871
3872
3873
3874
3875
3876
3877
3878
3379
3880
3891
3892
3893
3894
3895
3896
3897
3893
3900
3901
3902
3903
3904
3905
3906
3907
3908
3909
0.377
0.360
0.386
0.321
0.388
0.37B
0.387
0.338
C.380
0.361
0.340
0.334
0.325
0.333
0.363
0.369
0.353
0.361
0.365
0.333
0.374
0.36S
0.371
0.363
0.354
0.685
0.355
0.332
0.380
0.390
0.346
0.357
0.362
0.382
0.396
0.352
0.377
0.394
3.634
3.596
3.794
3.772
3.613
2.956
3,185
3.424
3.466
3.333
2.989
3.300
3.182
2.961
3.502
3.186
3.129
3.750
3.123
3.028
3.550
3.640
3.655
3.546
3.707
3.079
3.595
3.175
3.326
3.668
3.205
3.794
3.272
3.804
3.797
3.457
3.751
3.542
0.170
0.142
0.218
0.207
0.234
0.157
0.182
0.169
0.145
0.253
O.T70
0.187
0.147
0.141
0.143
0.160
0.213
0.199
0.167
0.181
0.160
0.210
0.197
0.196
0.216
0.193
0.182
0.191
0.184
0.201
0.224
0.191
0.171
0.181
0.145
0.169
0.166
0.169
0.472
0.364
0.415
0.417
0.481
0.377
0.395
0.335
0.484
0.445
0.321
0.418
0.377
0.378
0.410
0.399
0,410
0.458
0.404
0.345'
0.406
0.405
0.4S2
0.409
0.517
0.403
0.571
0.383
0.352
0.424
0.418
0.401
0.345 '
0.517
0.477
0.431
0.424
0.506
0.477
0.365
0.418
0.415
0.525
0.346
0.379
0.403
0.406
0.462
0.339
0.425
0.374
0.389
0.408
0.410
0.406
0.462
0.398
0.352
0.432
0.425
0.490
0.467
0.527
0.401
0.478
0,394
0.347
0.485
0.402
0.392
0.343
0.491
0.480
0.437
0.447
0.505
1 Cl 1
.j- \J JL
D-97
-------
Study No. 5221.08
SUBCHRONIC TOX1CITY OF PARA-CRESOL IN SPRAOJE DAULEY RATS
RELATIVE FEMALE ORGAN WEIGHT DATA (X Terminal Body Weight)
[Terminal Sacrifice]
ANIMAL NO. CVARY-LFT OVARY-RT ADRENALS BRAIN THY./PARA.
DOSE LEVEL
175 mg/kg/day
f
600 mg/kg/day
3861
3862
3863
3364
3865
3866
3867
3868
3869
3870
3871
3872
3873
3874
3875
3876
3877
3878
3879
3880
3891
3892
3893
3894
3895
2896
3897
3898
3900
3901
3902
3903
3904
3905
3906
3907
3908
3909
0.010
0.007
0.012
0.018
0.012
0.016
0.018
C.014
0.008
0.021
0.011
0.013
0.012
0.009
0.009
0.011
0.015
0.015
0.016
0.012
0.009
0.016
0.008
0.016
0.014
0.016
0.013
0.021
0.010
0.022
0.016
0.006
0.006
0.017
0.011
0.013
0.008
0.013
0.010
0.005
0.018
0.017
0.011
0.015
0.020
0.013
0.010
0.021
0.012
0.015
0.012
0.009
0.010
0.014
0.015
0.016
0.015
0.011
0.012
0.009
0.010
0.026
0.019
0.020
0.016
0.015
0.006
0.011
o.ois
0.003
0.008
0.021
0.011
0.016
0.007
0.009
0.029
0.018
0.009
0.019
0.027
0.027
0.022
0.017
0.024
0.027
0.017
0.023
0.019
0.022
0.020
0.023
0.025
0.023
0.024
0.018
0.023
0.027
0.026
0.028
0.025
0.026
0.028
0.019
0.024
0.026
0.022
0.021
0.014
0.022
0.030
0.027
0.025
0.023
0.795
0.642
0.736
0.711
0.894
0.702
0.780
0.622
0.665
0.770
0.594
0.660
0.687
0.733
0.706
0.694
0.780
0.744
0.757
0.703
0.776
0.854
0.732
0.690
O.B03
0.70S
0.757
0.642
0.733
0.759
0.756
0.687
0.615
0.752
0.919
0,710
0.689
0.710
0.007
0.007
0.020
0.005
0.008
0.006
0.009
0.006
0.007
0.014
0.007
0.005
0.004
0.004
0.008
0.007
0.005
0.011
0.009
0.007
0.007
0.009
0.005
0.011
0.012
0.011
0.012
0.009
0.005
0.011
0.009
0.007
0.005
0.008
0.007
0.005
0.009
0.008
J
D-98
-------
Study No. 5221.08
SUBCHROM1C TOXIC1TY OF PftRA-CRESOL IN SPRAGUE DAULEY RATS
MALE URINALYS1S DATA
[Interim Sacrifice]
Animal no. App. Vol. (ml) Sp, Gr. Color pH Protein Clucose Ketones Uro. Bill. Blood Hgb.
DOSE LEVEL
0 mg/kg/day
50 mg/ki/day
175 mg/kg/day
600 mg/kg/day
3661
3662
3663
3664
3665
3666
3667
3668
3669
3670
3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
3721
3722
3723
3724
3725
3726
3727
3728
3729
3730
3751
3752
3753
3754
3755
3756
3757
3758
3759
3760
hi
cl
hz
ct
hz
ct
cl
cl
cl
hz
cl
cl
hz
hz
cl
cl
cl
cl
el
hz
Cl
hi
hz
cl
cl
hz
cl
cl
cl
cl
hz
cl
cl
hz
hz
cl
cl
hz
hz
hz
10
15
15
15
13
15
13
15
15
4
15
15
15
9
7
13
15
15
15
15
15
14
13
9
15
14
15
12
12
14
15
15
15
15
15
15
15
15
15
8
10.340
1.029
1.030
1.021
1.020
1.030
1.033
1.030
1.031
>1.Q35
>1.035
1.021
1.023
>1.035
s-1.035
>1.035
1.016
1.027
1.026
1.029
1.018
1.012
1.026
1.025
1.027
1.017
1.030
>1.035
>1.035
>1.035
1.033
1.026
1.033
1.020
1.025
1.033
1.034
1.024
1.035
>1 .035
y
y
y
ly
y
a
y
y
y
Y
y
ly
y
y
y
y
s
y
y
y
ly
s
y
s
y
s
s
y
y
s
y
s
y
y
ly
s
y
y
s
y
6.5
9.0
6.5
9.0
7.0
8.0
7.0
6.5
7.5
5.5
5.5
9.0
6.5
5.5
6.5
7.5
6.5
9.0
6.5
5.5
8.0
7.5
6.5
8.0
6.5
7.5
7.0
6.5
7.0
6.5
6.5
7.5
6.0
6.0
6.0
6.0
6.5
5.6
6.0
6.5
1*
tr
2+
1 +
2+
2+
2*
2+
2*
2*
3+
1*
1+
2+
1+
2+
1 +
Z+
1*
2*
1+
2+
1+
3+
1*
1+
2*
2+
3+
2+
1+
1*
1+
tr
tr
tr
tr
tr
1 +
2+
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
1+
ng
1+
ng
ng
1 +
ng
H
ng
2+
1*
ng
1*
ng
1*
1 +
ng
ng
ng
1*
1+
"3
"3
1 +
1 +
ng
1+
1+
1+
1+
1 +
1+
1 +
ng
ng
1*
1+
ng
ng
ng
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
1+
1+
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
-f
ng
1 +
ng
ng
ng
ns
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
"9
ng
ng
ng
ng
ng
ng
ng
ng ,
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
90
0
ng
ng
50ery\ul
ng
"3
ng
50ery\ul
SQeryAuV
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
10ery\ul
ng
ng
ng
10ery\ui
ng
ng
ng
10ery\ul
10ery\ul
r.9
10ery\ul
ng
ng
ng
ng
ng
ng
50ery\ul
ng
ng
D-99
-------
Study No. 5221.08
SUBCHRON1C TQXICITY OF PARA-CRESOL IN SPRAGUE DAytSY RATS
HALS URINALYSIS DATA
[Interim Sacrifice]
Animal no. RBC/HPF WBC/HPF EPI/HPF CASTS/IFF CRYSTALS YEAST BACTERIA
DOSE LEVEL
0 nig/kg/day
50 mg/kg/day
175 mg/kg/day
600 mg/kg/day
3661
3662
3663
3664
3665
3666
3667
3678
3669
3670
3691
3692
3693
3694
3695
3696
3697
3698
3699
3700
' 3721
3722
3723
3724
3725
3726
3727
3728
3729
3730
3751
3752
3753
3754
3755
3756
3757
3758
3759
3760
0
0
3-4
0
0
0
2-3
2-3
0
0
0
0
0
0
0
0
0
0
0
0-1
0
0
0
0-1
0
0
0-1
0-1
0-1
0
1-2
0
3
0
0
0
0
2-4
0
0
0
0
2-3
0
0
0
0-1
0-1
0
0
0
0
0
0
0
0
0
0
0
1-2
0
0
0
0
0
0
0
0
0
0
0-1
0
c
0
0
0
0
0-2
0
0
0
0
2-3
0
0
0
0-1
2-3
0
0
0
0
0
0
0
0
0
0
0
0-1
0
0
0
0
0
0
0
0 <
2-3
0
0-1
0
0
0
0
0
0
0-1
0
0
0
o-
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
. 0
0
0
0
0
0
0
0
0
0
0
0
0
Q
0
0
0
0
0
0
0
0
tp
tp
co\tp
tp
CO
' tp
tp
co\tp
tp
CO
CO
tp
co\tp
CO
co\tp
»P
tp\co
tp
tp
CO
tp
tp
tp
tp
co\tp
tp
tp\co
tp
tp
tp
eo\tp
tp
eo\tp
CO
CO
tp\co
tp
CO
CO
tp
f
m
m
occ
n
f
f
f
f
f
f
occ
n
n
f
n
f
f
f
occ
f
f
ra
n
in
n
m
m
m
n
n
n
f
n
f
n
f
f
oce
f
num
num
num
ra
m
num
nun
num
m
ra
num
Rl
m
m
num
num
num
nun
ra
num
num
num
m
m
mm
m
num
nuni
num
num
tn
m
nun
m
m
m
num
f
m
num
D-100
-------
Study Ho. 5221.08
SU3CHRONIC TOXIC1TY Of PARA-CRESOL IN SPRAGUE DAUiEY RATS
MALE URINALYSIS DATA
[Terminal Sacrifice]
Animal no. App. Vol. (ml5 Sp. Gr. Color pH Protein Glucose Ketones Uro. Bili. Blood Hgb.
COSE LEVEL
0 mg/kg/day
50 mg/kg/day
175 mg/kg/day
600 mg/kg/day
3671
3672
3673
3674
3675
3676
3677
3673
3679
3680
3701
3702
3703
3704
3705
3706,
3707
3708
3709
3710
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3761
3762
3763
3764
3765
3766
3767
3768
3769
3770
hz
cl
cl
hi
hz
cl
cl
cl
hi
cl
cl
hi
cl
hz
hi
hi
hz
hz
hz
hz
hz
cl
cl
hz
cl
hz
cl
cl
cl
cl
hz
hz
hi
hz
hz
hz
hz
hi
hz
hz
5
5
5
5
3
5
5
5
2
5
5
5
5
5
4
5
1
4
4
4
5
5
5
5
5
5
5
5
5
5
3
5
4
5
4
4
4
5
4
4
1.021.
1.020
1.028
1.023
1.023
1.023
1.015
1.026
>1.035
>1.035
1.020
1.033
>1.035
> 1.035
1.021
1.030
>1.035
>1.035
1.030
1.027
>1.035
1 .021
1.016
1.021
1.016
1.026
>1.03S
1.024
1.024
>1.035
>1.035
1.023
>1.035
>1.035
1.013
>1.035
1.026
» 1.035
>1.035
1.023
y
y
y
y
y
y
y
y
y
y
y
y
a
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
7.0
7.0
6.5
7.0
7.0
7.0
7.0
6.5
6.5
6.5
8.0
6.5
6.5
9.0
7.5
7.0
9.0
9.0
9.0
9.0
6.5
6.5
5.1
6.5
. 6.0
6.5
8.0
6.5
6.5
6.5
5.0
6.0
5.5
6.5
8.0
5.0
5.5
6.0
5.5
7.5
tr
2*
2+
2+
1+
tr
3+
tr
U
2*
2+
2*
2*
2*
2*
2+
3+
3-f
2+
2*
2+
1*
3*
1*
2+
ng
1+
2*
2+
2+
2*
2*
2*
2+
2*
1+
1+
3*
2*
1+
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
ng
ng
ng
ng
ng
ng
ng
ng
3+
ng
ng
1*
1+
ng
ng
ng
2+
ng
nfl
ng
ng
ng
1+
. ng
1+
ng
ng
1+
1*
1+
1+
ng
1+
ng
ng
ng
ns
ng
1 +
ng
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ns
ns
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
"9
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
10ery\ul
10ery\ul
ng
ng
10ery\ul
ng
ng
ng
ng
ng
ng
ng
ns
ng
ng
ng
ng
ng
ng
ng
ng
ns
ng
50ery\ul
ng
ng
ng
ng
na
ng
ng
ns
ng
ng
"S
10ery\ul
ng
ng
D-101
o
-------
Study No, 5221.08
SUBCHRQNIC TOXIC3TY OF PARA-CRESOL IN SPRAGUE DAULEY RATS
HALi MICROSCOPIC URINALYSIS DATA
[Terminal Sacrifice]
Animal no. RBC/HPF WBC/HPF EPI/HPF CASTS/IPF CRYSTALS YEAST BACTERIA
DOSE LIVEL
0 mg/kg/day
50 mg/kg/day
175 mg/kg/day
600 mg/kg/day
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3701
3702
37Q3
3704
3705
3706
3707
3708
3709
3710
3731
3732
3733
3734
3735
3736
3737
3738
3739
3740
3761
3762
3763
3764
3765
3766
3767
3768 '
3769
3770
0-1
0
0
0
0
0
0-1
0
0
0
0
0
0
0-1
0-1
a
0-1
0
0-1
0-1
0
0
a
0
0
0
0
0
0
0
0
0-1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0-1
0
0-1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
a
0
0
0
a
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
a
0
0
0
0
0
0
a
0
0
0-1
0
0
0
0
0
a
3-4
0
1-2
0
0-1
0
0
0
0
0
0
0
0
0
a
0
0
0
a
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
a
0
a
0
0
0-1
0
0
0
0
0
0
0
0
0
eo\tp
co\tp
tP
tp
tp
tp\co
tp
tP
tp
CO
tp
co\tp
CO
tp
tp
tp
tp
tp
tp
tp
CO
tp
CO
tp\eo
tp\co
co\tp
tp
tp
tp
n
CO
co\tp
CO
co\tp
tp
CO
tp\co
tp
CO
co\tp
n
n
n
n
n
n
n
n
n
n
f
f
n
n
n
f
m
m
f
f
n
f
n
n
n
f
f
n
n.
n
n
n
n
n
f
f
n
n
n
n
f
tn
n
m
f
m
f
m
f
f
nun
nuin
n
m
nun
nun
nun
nun
num
nun
f
m
m
1
m
m
m
f
f
n
m
num
num
f
num
n
m
f
num
num
D-102
196
-------
Study No. 5221.08
SUBCNRONIC TOXIC1TY Of PARA-CRESOl IN SPRAGUE DAWLEY RATS
FEMALE UR1NALYSIS DATA
(Interim Sacrifice]
Animal no. App. Vol. (ml) Sp. Gr. Color pH Protein Glucose Katones Uro. IHi. Blood Hgb.
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
175 mg/kg/day
600 mg/kg/day
3791
3792
3793
3794
3795
3796
37?7
3798
3799
3800
3821
3822
3823
3824
3825
3826
3827
3828
3829
3830
3851
3852
3853
3854
3855
3856
3857
3858
3859
3860
3681
3882
38S3
3884
3885
3886
3887
3888
3889
3890
cl
hz
cl
cl
cl
hz
hz
cl
cl
hz
hz
cl
hx
cl
hz
hz
cl
cl
cl
hz
cl
cl
hz
cl
hz
cl
cl
cl
cl
hz
hz
el
dead
cl
cl
hz
hz
cl
cl
c
9
15
15
15
8
15
9
12
15
12
15
13
5
6
8
15
5
15
10
15
13
15
13
15
8
15
15
15
15
15
9
K
dead
12
7
14
11
15
15 .
12
1.025
1.016
1.021
1.028
1.028
1.013
>1.035
1.019
1.023
1.C35
1,006
1.018
> 1.035
>1.035
1.020
1.007
1.031
1.018
1.023
1.016
t.019
1.013
1.025
1.021
1.018
1.021
1.023
1,020
1.021
1.010
1.023
1.021
dead
1.030
>1.035
1.027
1.028
1.031
1.027
>1.035
iy
s
y
y
y
y
y
Y
f
y
S '
s
y
y
y
s
y
iy
y
y
s
s
y
y
s
y
y
s
s
s
y
s
dead
y
y
s
y
y
iy
y
9.0
8.0
9.0
7.5
7.0
7.0
7.5
7.0
7.0
7.0
7.0
7.0
6.0
6.0
6.5
7.5
9.0
8.5
9.0
7.0
7.0
7.0
5.6
7.0
8.0
7.0
6.5
6.5
6.5
7.0
6.0
9.0
dead
6.5
8.0
6.5
6.5
6.0
6.0
6.0
2+
tr
1+
1+
1+
tr
tr
U
1+
1+
tr
1*
tr
1+
tr
tr
: tr
1+
2+
2*
1+
ng
1*
tr
tr
tr
tr
tr
tr
tr
2*
1+
dead
1 +
1 +
tr
1+
tr
1*
tr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
dead
nr
nr
nr
nr
nr
nr
nr
ng
ng
ng
ns
ns
1+
ng
ng
ng
1+
ng
ng
ng
1+
ng
ng
ng
"9
ng
ng
"3
ng
ng
1+
ng
ng
1+
ns
ng
ng
ng
1+
dead
ng
1+
ng
ng
1+
1+
1+
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
dead
nr
nr
nr
nr
nr
nr
nr
ng
ng
ng
ng
ng
ng
ng
1+
ng
ng
ng
ng
"9 ,
ng
ng
ng
ng
1*
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
dead
ng
ng
ng
ng
ng
ng
ng
10ery\ul
ng
ng
1Cery\ul
5ery\ul"
ng
ng
ng
ng
50ery\ul
ng
ng
tr
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
10ery\ul
ns
ng
ng
ng
ng
"S
dead
ng
ng
ng
ng
ng
50ery\ul
ns
D-103
-------
Study Mo. 5221.08
SUBCHRONIC TQXtCm OF PARA-CRESQL IN SPRAGUE DAWLEY RATS
FEMALE HICROSCOP1C URINALYSIS DATA
Clnterim SaerificsJ
Animal no. RBC/HPF WBC/HPF EPI/HPF CASTS/LPF CRYSTALS YEAST BACTERIA
DOS! LEVEL
0 mi/kg/day
50 Bi§/kg/day
175 mg/kg/day
600 mg/ki/day
3791
3792
3793
3794
3795
3796
3797
3798
3799
3800
3321
3822
3823
3824
3825
3826
3827
3328
3829
3830
3851
3852
3353
3854
3855
3856
3857
385S
3859
3860
3881
3882
3883
3884
3885
3886
3887
3888
3889
3890
0
0
0
0
0
0
0
0
0
2-3
0
0
0
0
0
0
0
Q
0
0
0
0
0
0
0
0
0
a
0
0
0
0
dead
0
0
0
0
0-1
2«3
Q
0
0
0
0
0
0
0
0
0
0-1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Q
0
0
0
dead
0
D
0
0
0
1-2
0
0
0
0
0
0
0
0
0
Q
0
Q
0
0
0
0
0
0
Q
0
0
0-1
0
0
0
0
Q
0
0
' 0
Q
0
0
dead
0
0
0
0
0
1-2
0-1
0
0 .
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
dead
0
0
0
0
0
0
0
tp
tp
tp
tp
co\tp
tp
tp
co
tp
tp
tp
tp
CO
tp\co
tp
tp
tp
tp
tp
tp\eo
tp
eo\tp
CO
tp.
tp
tp
tp
tp
CO
tp
CO
tp
dead
co\tp
tp
C<5\tp
tp
tP
tp\eo
CO
f
f
f
f
m
n
m
m
n
f
n
m
n
f
f
n
f
m
tn
n
oce
m
m
f
n
n
ra
f
f
n
f
oee
dead_
m
f
f
f
n
f
n
num
m
m
nun
nun
num
num
m
num
n
nm
m
m
f
m
m
m
m
nun
m
ra
m
m
nun
f
ft!
m
num
m
m
num
num
dead
nun
nun
nun
n
m
m
f
D-104
-------
Study No. 5221.08
SUBCHSONIC TOXICITY of PARA-CRESGL IN SPRAGUE DAWLIY RATS
FEMALE URINALYSES DATA
[Terminal Sacrifice]
Animal no. App. Vol. (ml) Sp. Gr. Color pH Protein Glucose Ketones Uro. Bill. Blood Wgfa.
OOSE LEVEL
0 mg/kg/day
50 mg/lcg/day
175 mg/kg/day
600 nig/kg/day
380 1
3802
3803
3804
3805
3806
3807
3803
3809
3810
3831
3832
3333
3834
3835
3836
3837
3838
3839
3840
3861
3862
3863
3864
3865
3866
3867
3863
3369
3870
3891
3892
3893
3894
3895
3896
3897
3898
3899
3900
3901
cl
cl
hz
hz
cl
hz
hz
hz
cl
cl
cl
cl
cl
hz
hz
hz
cl
cl
cl
hz
hz
hz
cl
hz
cl
hz
hz
hz
cl
cl
hz
hz
hz
cl
cl
cl
cl
hz
dead
hz
cl
5
2
4
4
5
4
5
4
4
5
5
5
5
5
5
4
5
5
5
5
5
5
5
4
4
3
5
5
4
5
3
4
5
5
5
5
4
4
dead
4
5
1.010
>1.03S
1.012
1.017
1.025
1.022
1.018
1.011
1.034
1.016
1.009
1.030
1.017
>1.035
1.016
1.025
1.027
1.026
1.029
1.020
1.030
>1.035
>1.035
1.022
1.009
>1.035
1.017
1.016
>1.035
1.030
>1.035
1.014
1.013
1.018
>1.035
>1.035
1.023
1.031
dead
1.023
1.029
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
dead
y
y
7.0
6.0
7.0
6.5
6.0
9.0
9.0
6.5
6.0
6.5
7.0
6.5
6.0
6.5
6.5
6.5
6.5
6.5
6.5
6.5
7.0
6.5
5.0
9.0
6.5
6.5
8.0
9.0
5.5
6.0
6.5
6.0
7.0
6.5
6.0
5.5
6.0
7.0
dead
7.5
6.0
tr
U
tr
tr
ng
1+
tr
2+
1+
tr
ng
tr
ng
2+
tr
2+
1 +
tr
ng
tr
tr
2
1+
tr
ng
tr
tr
tr
1 +
tr
2+
1+
tr
tr
1+
1+
tr
2+
dead
1+
tr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
dead
nr
nr
ng
1*
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
. ng
ng
ng
ng
ng
ng
dead
ng
ng
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
nr
dead
nr
nr
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
dead
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
10ery\ul
ng
50ery\ul
250ery\ul
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
ng
dead
ng
ng
D-105
4 C> f-l
1 b «J
-------
Study Wo, 5221.08
SUBCHROH1C TOXICITY CF PARA-CRESOL IN SPRAGUE DAWLEY RATS
FEMALE'MICROSCOPIC URINALYSIS DATA
[Terminal Sacrifice!
Animal no. RBC/HPF VJ9C/HPF EPI/HPF CASTS/LPF CRYSTALS YEAST BACTERIA
DOSE LEVEL
0 ing/kg/day
50 mg/kg/day
175 mg/kg/day
£00 mg/kg/day
3801
3302
3803
3804
3805
3806
3807
3803
3809
3810
3831
3832
3833
3834
3835
3336
3837
3838
3839
3840
3861
3362
3863
3864
3865
3866
3867
3863
386?
3870
3891
3892
3393
3894
3895
3896
3897
3898
3899
3900
3901
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0-1
0
0
2-3
0
0
0
0
0
0
0
2-3
0
0
0
0
0
0
0
dead
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
dead
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1-2
dead
0
0
0
0
0
0
0
, 0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0 .
0
0
dead
0
0
tp
CO
tP
CO
tp
tp
tp
tp
tp
CO
tp\co
tp
CO
ccAtp
tp
tp\co
n
co\tp
tp\co
co\cp
tp\co
co\rp
coUp
tP
n
CO
tp
tp
n
tp
co\tp
eo
tp
n
CO
CO
CO
tp\co
dead
"UP
CO
n
n
n
n
n.
f
n
n
f
n
n
n
n
n
n
m
n
n
n
n
f
f
f
f
n
n
n
n
n
f
m
n
n
n
f
n
n
n
dead
n
n
n
f
m
f
1
m
m
num
n
f
f
m
n
m
i
nun
f
m
f
f
m
f
f
m
n
nun
f
m
f
n
nun
m
m
f
m
f
f
m
dead
nun
n
D-106
-------
Study No. 5221.08
APPENDIX E
OPHTHAIMOIDGY REPORT
*t! A 1
,- V? 4-
MICROBIOLOGICAL
ASSOCIATES INC.
-------
-------
Study No. 5221,08
SUBCHRDNIC TOXZCTTY OF PARA-CRESOL
IN SPE&OJE DAWLEY RATS
ABBREVIATION CODES
Eye Examinations
nvl = no visible lesions
dead = unscheduled death
ph = persistent hyaloid
e = conjunctivitis
f = small amount of hyphens.
g = cornea! opacity, vitreal clot
h = vitreal hemorrhage
E-2
-------
-------
Nancy M. Bromberg, V.M.D., M.S.
Diplomate, American College of Veterinary Ophthalmologists
4105 Brandywine Street, Northwest
Washington, D.C. 20016
202^363-7303
£ Y E C I
t Q B A N I M A I S
Barry S. Levine, D.Sc., DABT
Microbiological Associates, Inc.
5221 River Road
Bethesda, MD 20816
September 25, 1986
SUBJECT: Ophthalmoscopic Evaluations
Study 5221 .08
PRETEST EXAMINATION October 10, 1985
All animals examined were found to have no visible lesions except
the following:
Male 3672 - persistent hyaloid remnant left eye
Male 3748 - persistent hyaloid remnant right eye
Male 3766 - small amount of hyphema secondary to persistent hyaloid right eye
Female 3871 - persistent hyaloid remnant left eye
Persistent hyaloid remnant is a common developmenatal finding in
young rats.
TERMINAL EXAMINATION January 10, 1986
All animals examined had no visible lesions except the following;
Male 3707 (50 mg/kg/day) - bilateral conjunctivitis with brick red serous
discharge (consistent with problems associated
with bad teeth!
Female 3809 (o rag/kg/day) - vitreal hemorrhage right eye
Female 3865 (175 mg/kg/day) - corneal opacity and small vitreal clot in
left eye
Based on the distribution of the above abnormalities identified at
terminal examination, they were not considered treatment related.
Naflcy M.flromlierg, V.M.D.,
DiplomatW, A/C.V.O'.
E-3
-------
Study No. 5221.08
5UBCHRCNIC TOXICITY OF PARA-CRE.SQL IN SPRAGUE DAULEY RATS
HALE EYE EXAMINATIONS
Animal no. PRETEST-Right Eye PRETEST-left Eye TERMINAL-Right Eye TERHINAL-Lef t Eye
DOSE LEVEL
0 mg/kg/day
50 mg/kg/day
3671
3672
3673
3674
3675
3676
3677
3678
3679
3680
3681
3682
3683
3684
3685
3686
3687
3688
3689
3690
3701
3702
3703
3704
3705
3706
3707
3708
3709
3710
3711
3712
3713
3714
3715
3716
3717
3713
3719
3720
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
ph
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvt
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl .
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
e
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvt
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
e
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
E-4
204
-------
Study No. 5221.03
SUBCHRONIC TOXICITY OF PARA-CRESQL IN SPRAGUE DAULEY RATS
MALE EYE EXAMINATIONS
Animal no. PRETEST-Right Eye PRETEST-Left Eye TERHINAL-Right Eye TERMlNAL-Left Eye
DOSE LEVEL
175 mg/kg/day
fiOO mg/kg/day
3731
3732
3733
3734
373S
3736
3737
3733
3739
3740
3741
3742
3743
3744
3745
3746
3747
374S
3749
3750
3761
3762
3763
3764
3765
3766
3767
3768
3769'
3770
3771
3772
3773
3774
3775
3776
3777
3778
3779
3780
nvL
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
ph
nvl
nvl
nvl
nvl
nvl
nvl
nvl
f
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
. nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl '
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvt
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
-------
Study No. 5221,08
SU8CHROK1C TOX1CITY OF PARA-CRSSQl IN SPHAGUE DAUIEY RATS
FIKALE EYE EXAMINATIONS
Animal no. PREIEST-Right Eye PRETEST-left Eye TERMINAL-Right Eye TERMlNAL-teft Eye
DOSE LEVEL
0 rng/kg/day
50 mg/kg/day
3801
3802
3803
3804
3805
3BC6
3807
3808
3809
3310
3811
3812
3S13
3814
3815
3816
3817
3818
3819
3820
3831
3832
3833
3834
3835
3336
3537
3333
3839
3340
3841
3842
3843
3344
3845
3846
3847
3848
3849
3850
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvt
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
'nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
h
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
nvl
E-6
-------
Study No. 5221.08
SUBCKRONIC TCXJCITY OF PARA-CRESQl IN SPRAGUE DAUIEY RATS
FEMALE EYE EXAMINATIONS
Animal no. PRETEST-Right Eye PRETEST-Left Eye TERMIMAL-Right £ya TERMlNAl-Left Eye
DOSE LEVEL
175 mg/kg/day
600 mg/kg/day
3861
3862
3863
3864
3865
3866
3867
3868
3869
3B7Q
3371
3872
3873
3374
3375
3376
3877
3873
3879
3880
3891
3892
3893
3S94
3895
3896
3897
3898
3899
3900
3901
3902
3903
3904
3905
3906
3907
3908
3909
3910
nvl
nvl
nvl
nvl
nvl
nvl
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ph
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nvt
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dead
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dead
nvl
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9
nvl
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nvt
nvl
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nvt
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dead
nvt
nvt
nvl
nvl
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nvl
nvl
nvl
nvl
nvl
dead
S-7
-------
Page Intentionally
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APPENDIX F
PATHOLOGY REPORT
Study No. 5221,08
208
F-1 ^ MICROBIOLOGICAL
ASSOCIATES INC.
-------
Page Intentionally Blank
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SUBCHRONIC TOXICITY OF PARA-CRESOL
IN 5PRAGUE DAWLEY RATS
PREPARED FOR
MICROBIOLOGICAL ASSOCIATES, INC.
>i v *-
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TABLE OF CONTENTS
PAGE
(. PATHOLOGY NARRATIVE
II. PROJECT SUMMARY TABLE
III. TABULATED ANIMAL DATA
IV. GROSS VS. MICROSCOPIC FINDINGS
Terminal Sacrifice
Interim Sacrifice
V. INTERIM SACRIFICE-EARLY DEATH
VI. QUALITY ASSURANCE STATEMENT
APPENDIX 1 REPORTS CODE TABLE
APPENDIX 2 ABBREVIATION LIST
IV-1
IV-44
V-l
Vl-l
*? 1
r-v .X
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Page Intentionally Blank
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FINAL REPORT AMENDMENT
STUDY MAMS Subchrom'c Toxicitv of Para-Cresol in SoramiP Oawlgv Rats
STUD? NUMBER 5221.08 ._ ^_
INITIATION DATS October 16, 1985 pATE OP FINAL REPORT June 5, 1986
PART OF FINAL REPORT TO BE AMENDED (EXACT LOCATION)Table of Contents.
Pages 1-2. 1-3, 1-4 and V-l, Divider pages for sections V and VI.
REASON FOR THE AMENDMENT The Table of Contents was changed to reflect the
proper title of Quality Assurance Statement, not Quality Assurance Report.
A paragraph was added on p. 1-2 to address three early death animals. The
other pages were changed due to format requirements resulting from the add-
ition of the new paragraph. Page V-I was inadvertantly omitted from the final
See attached page.
AMENDMENT (Attach additional sheets as necessary)
TABLE OF CONTENTS should read Quality Assurance Statement.
P.1-2 The last sentence in the first paragraph is deleted. A new second
paragraph beginning with "Three high-dose female rats..." is added.
P. 1-3 and 1-4 reformated due to additional paragraph.
Section V Divider Page should read "V. INTERIM SACRIFICE- EARLY DEATH"
Page V-l. (See attachment) is added.
Section VI [Divider Page should read VI. QUALITY ASSURANCE STATEMENT.
APPROVALS
SKTODY DIRECTOR /
A o n i I
0/4*14 o. C/Avv/
DATS / ""T-
_ In-lM
DATE QUALITY ASSURANCE
? 1 1
* JL J.
-------
Page Intentionally
-------
REASON FOR THE AMENDMENT (cont.)
report. Divider pages for Section V and VI accompany the previously
omitted Section V and the Quality Assurance Statement.
-------
Page Intentionally Blank
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I. PATHOLOGY NARRATIVE
61
-\ O
1 O
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Page Intentionally Blank
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SUBCHRONIC TOXIC1TY OF PARA-CRE50L
IN 5PRAGUE DAY/LEY RATS
Experiment No. 5221.08
PATHOLOGY REPORT
INTRODUCTION AND METHODS
A 13 week gavage study was conducted on Sprague Dawley rats to
determine the toxicity of p-cresol. Male and female rats were divided into 5
groups at study initiation:
Dose Level Huiftbenpf, Animals
Group Treatment fmg/kq/day) Mate Female
1 Negative Control Vehicle only 30* 30*
2 p-cresol 50 30* 30*
3 p-cresol 175 30* 30*
4 p-cresol 600 30* 30*
5 Baseline clinical 10** 10**
pathology
*10 animals sacrificed during study week seven (interim sacrifice); 20 sacrificed after 13
weeks for histopatholcg/ (terminal sacrifice)
"Sacrificed prior to study initiation
Animals were gavaged daily, 7 days a week;, for 13 weeks. Dosed
animals received p-cresol in a corn-oil vehicle at 5 ml/kg body weight.
Negative control animals received corn-oil vehicle only, At the interim
sacrifice, all scheduled rats were killed using carbon dioxide gas and were
necropsied. All required tissues (see below) were fixed in formalin for
possible future evaluation. At the terminal sacrifice, all surviving rats were
killed using carbon dioxide gas and were necropsied. Body and organ weights
(heart, liver, spleen, brain, kidneys [individually], gonads [individually],
adrenals, and thyroids/parathyroids), were recorded for all rats at terminal
sacrifice. All tissues specified by the protocol were fixed in 10% neutral
buffered formalin. Protocol specified tissues included all gross lesions,
brain, eyes, pituitary, salivary glands, heart, thymus, thyroids (with
parathyroids), lungs (with mainstem bronchi), trachea, esophagus, stomach,
small and large intestines, adrenals, pancreas, liver, kidneys, urinary bladder,
testes, prostate, ovaries, corpus and cervix uteri, spleen, bone (with
marrow), skeletal muscle, lymph node, spinal cord, mammary gland/skin,
aorta, sciatic nerve.
214-
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Page Intentionally Blank
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TilB i'AOE SE'/lSSD
Fixed tissues were trimmed, dehydrated, embedded in paraffin,
sectioned at 5jim and stained with hematoxylin and eosin. Representative
sections were examined from all control, and high (600 rng/kg) dose rats of
both sexes. All gross lesions from terminal sacrifice rats and from interim
sacrifice rats were evaluated and are listed in table form in Chapter IV.
Potential target organs (kidney in male; trachea .in male and female) were
evaluated for all low (50 mg/kg) and mid dose (175 mg/kg) terminal sacrifice
rats.
Three high-dose female rats were found dead during the course of the
study. In each case the cause of death was uncertain. Animal No. 3899 and
Animal No. 3910 were from the terminal sacrifice group. The microscopic
findings and the gross-microscopic correlations are included with their
respective group. The gross and microscopic for Animal No. 3883, originally
scheduled for interim sacrifice, are reported in Chapter V.
Results from all complete histopathologic examinations as well as all
target organs in low and mid dose terminal sacrifice rats were recorded into
a computer which required an accounting for every organ listed in the
protocol. Computer generated tables are included in the following sections of
this report. Where appropriate, incidences of lesions between treated and
control animals were compared using Fishers Exact Test.
RESULTS
Tracheal epithelial metaplasia was noted in high dose male and female
rats but not in control rats of either sex (statistically significant, at P<0.05).
This lesion was characterized by multifocal to diffuse replacement of goblet
and secretory granular cells by squamous epithelial cells which were
flattened, had nuclei parallel to the basement membrane and were
occasionally stratified. Trachea, therefore, was considered a target organ
and was examined in all low and mid dose male rats. The lesion was
predominately restricted to the high dos9 rats and occurred in the upper
trachea. Bronchi and lower airways did not exhibit this change. Three cases
noted in the mid and low dose animals were associated with focai underlying
areas of chronic inflammation:
,: i 5
1-2
-------
K
UlSd
/' /
{£,,(
INCIDENCE OF TRACHEAL EPITHELIA! MFTAP1 ASIA
SOmq/kq
0/20(02)
0/20(0-*)
0/20(02)
1/20(52)
1/20(52)
1/20(5*)
10/20(502)
9/19*(47*)
Trachea
Epith. Metaplasia
Incidence- Male
Incidence-Female
* Trachea of one female rat was too autolytic for evaluation.
Kidney was also considered a potential target organ in the male since a
slight increase in incidence of minimal nep'hropathy was noted in all dosed
male rat groups when compared to the control male rat group. (Dosed female
rats showed no increase in nephropathy over control female rats.) Increase in
incidence in the dosed males was significantly greater CP< 0.05) at the low
and high dose but not at the middle dose. No increase in percentage of
severity was noted in the dosed male rats when compared to the control male
rats (see following table).
INCIDENCE AND SEVERITY OF CHRONIC NEPHPQPATHY
Kidney (Male)
Nephropathy, chronic
Incidence
Severity-minimal
-mild
Qmg/kg
SQmg/kg
I75mg/kij 6QOmg/icg
4/20(202) 11/20(55*) 7/20(352) 12/20(601)
3/4(75*) 9/11(82*) 7/7(100?) 9/12(752)
1/4(25*) 2/11(18*) 0/7(0*) 3/12(252)
Certain lesions noted in the lung of both control and dosed male and
female rats were suggestive of infection with an adventitious agent. These
lesions consisted of perivascular lymphocytic infiltrate and scattered foci of
chronic interstitial inflammation. No specific etiological agent was noted.
Statistically significant (P< 0.05) increase in the incidence of interstitial
inflammation of the lung occurred in high dose male rats when compared to
control male rats, however a decrease in incidence was noted in the female
rats (see following table). Although minimal potentiation of interstitial
inflammation in high dose male rats can not be ruled out, clinical significance
is questionable.
o
1-3
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INCIDENCE AND SEVERITY OF PULMONARY INTFRSTIT1AI IMF! AMMAT|OM
Lung
Inflam.. IS-
Incidence
Severity'
minimal
mild
MALE
Qmg/kg 60Qmg/kg
9/20(45Z) 16/20(808}
8/9(89*) 10/16(62*)
1/9(112) 6/16(38*)
FEMALE
6QQmg/lcg
1/20(552) 8/20(408)
5/11(452) 2/8(25£)
6/1K55X) 6/8(75;?)
Additional lesions were of low incidence and/or equally distributed
between control and dosed animals and were considered incidental lesions
commonly seen in this age and strain of rat.
SUMMARY AND CONCLUSIONS
Sprague Dawley rats of both sexes were gavaged once a day, 7 days a
week for 13 weeks with 0, 50, 175, or 600 mg/kg of p-cresol in a corn-oil
vehicle.
A statistically significant (P < 0.05) increase in the incidence of
trachea! epithelial metaplasia was noted in the high dosed rats of both sexes
when compared to the control rats. Incidence was 50% in the high dose males
and 47% in the high dose females. Similar, focal lesions in 3 lower dosed rats
were associated with underlying inflammation.
Statistically significant (P < 0.05) increases in incidence of minimal to
mild chronic nephropathy occurred in low and high dosed male rats when
compared to control male rats. No statistically significant increase however
was noted for the middle dosed male rats. Clinical significance is equivocal.
In conclusion, trachea (epithelial metaplasia) in males and females, and
possibly kidney (nephropathy) in males are considered target organs in rats
under conditions of this study. ^
Diana 5. Copeland, D.V.M.
Diplomate, A.C.V.P.
September 22 , 1986
1-4
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-------
PROJECT SUMMARY TABLE
-------
-------
PATHOLOGY ASSOCIATES, INC,
STUDY NO. 5221.08
SPRA8UE-MULEY RATS
Project Summary Table
Sim«Y: InctdsRCS ci NON-NEOPIASTIC Microscopic Findings
PROJECT 10. NO: P.CRESOL
MYS: «LL
GSflUP:
NOTES OF W3MAIS:
BMIN
SCIATIC NEWS
SPIWL CORD
BCNE
80JE fWRROU
SM.MWY Sl/TO
ATROPHY
fWOIIULAR LYHPH NQEE
HEHflfiRWGE, CUTE
LYMPHOID HYPERPWS1A
THWUS
H&WRRHASc, ACUTE
HBWSIOERCSIS
B18WOIAL RBtWfT
PWCREAS
ACIfttR ATROPHY
LWHOCTTIC INFILTRATE
PITUITARY
CfST
FATES:
SEX: FEJW.E
O.D MS
20
1 I
a Ex 20
1 It £j 23
S Ex 20
t Ex 20
» Ex 20
I Ex 20
0 <03
» Ex 28
0 <0>
9 <«)
its 20
14 (70)
1 (S)
0 (0)
» £* 23
1 (51
1 <5)
K Ex 1?
4 <2t!
Il-i
All
50 HG
20
i 7,
0
0
0
a
0
0
0
5
D
i!
o-
0
0
0
0
3
0
0
0
175MB
20
1 X
0
D
0
B
0
0
0
0
D
0
0
0
g
0
0
0
0
I
j (05
600 MS
20
I X
20
20
23
23
25
20
1 (5)
20
1 (5)
7 (35)
21
13 C»5)
fl (0)
i (5)
20
i (5)
0 CO)
20
3 US
218
(Resort Cantir.ued)
-------
PATHOLOOY
ASSOCIATES,
WW-CSES3L
STUDY NO, 522 S. 08
RAT3
IMC
Project Summary Table
SltflARY; Incidence ol NON-ftEDPWST'C Microscopic Findings
PROJECT ID. NO: P.CREEQL
DAYS; ALL
6ROUP:
NUMBER OF tfHMALS;
THTIOIO
EPITHELIAL CYST
IWHBCmC INFILTRATE
tmimm
TRACHEA
LWHOCrriC INFILTRATE
1NFLAW1AT3CN, CHRCNIC-AC7IVI
EPITHELIAL METAPLAilA
INFLATION, CHRCNIC
MINERALIZATION
ESQPWiUS
AOREWL iLAND
ECTASIA, HEOULIA
LUN6
LYMPHOCTTIC INF1L,,PERWASC.
INFLfll., INTERSTITIAL .CHRONIC
CTCESTIW
HJSTIQCYTOSIS
OIL MOPLETS
EDBtt
HEART
INFLAM^TION, CHRONIC
FATES: All
SEX: FE»LE
0
«
1 Ex 20
13
0
I Ex ;;
1 Ex 20
3
I
0
0
0
i £s 23
» Ex 20
I
K E: ID
20
11
0
0
0
a
» Ex 23
0
,0 MS
29
y.
«5)
(0)
<15)
(53
(03
(0)
«fl)
(5)
UflO)
(55)
(0)
(tt)
(Q)
(0)
(0)
5(3 H6
2(3
It Y.
D
3
0
0
20
D (0)
8 (0)
I (5)
C «J)
i CO)
II
a
0
0
0
0
9
0
0
(1
0
3
175 ME
20
* y.
0
0
0
Q
20
3 (15)
0 (0)
1 <5>
3 (15)
i (5)
a
Q
3
3
3
3
0
J
a
8
0.
0
403 KS
1
20
1!
I
1(5
15
!
2
9
D
0
23
20
1
20
1?
8
2
3
2
1
23
1
20
X
(55)
(5)
(5)
<5)
AORTA
* EJ 20
C3LCN
» EJ 20
20
11-2
(Riuart Continued)
9
-------
PATHOLOGY ASSOCIATES, INC.
WRA-CHE30L
STUDY NO, 5221.38
SATS
Pr oj ec
SUWARY: Incidtnce
PROJECT ID. NO; P.CSESQL '
MYS; ALL
GROUP:
NUniEi OF miWLS',
DUODENUM i
FDRESTOHACH i
SbWULAft STCWCK »
SKIN *
fWtfcSY 6WW t
SKELETAL HUSCLE 1
LIVER X
iNFiAwr, mmt
NECROSIS
LIP01DOSIS
SPLEEN *
KIDNEY ' I
NECROSIS, TUBULES
LYMPfflCYTIC INFILTOTE
(1MMLIZA7ICN
NEPKRffiWWf , CKRWIC
CYST
HYORCNEPHROSiS
mmm BLAOCES *
7ESTES »
t Summary
of NCN-NEQPLASTIC
FATES; All
SEX: FBW.E
0.0 HG
20
K '/. i
EJ 21 e
Ex 20 0
Ex 20 3
Ex 20 0
Ex S9 0
Ex 20 a
Ex 20 0
13 (45) 0
II i
cs 20 0
Ex 0 .0
n-3
'^ejort Continued)
Tab! e
dicroscopic Findings
53 ME 175 HG ^DO MG
20 20 2tl
X » X t X
0 20
o a
0 28
0. 2
0 1?
0 20
0 20
0 1C (503
0 2 (10)
0 0 <03
. 0 20
i 20
(0) 0 (0) 1 (S3
<0) S (0) 4 (201
(SO) 0 (0) i (51
(0) 0 (0) 1 (5)
<0> a (0) 0 !8)
(EC) I
-------
PATHOLOGY ASSOCIATES, INC.
Wltt-CSESGt
STUDt NO. 5221,01
SPRAGUE-WULEY RATS
Project Summary Table
: Incidence of NON-NEOPLASTIC Hicroscopic Findings
PROJECT ID. NO; P.CSESQL WTES: All
DAYS: ALL SEX:
SfiOUP; 0,0 MG 50 HS [75 MG 4GO MS
NiJHBES 0? W1WLS: 20 20 20 20
IX * X I X
PSOSTATE - I Ex 0 0 0
EYES » Es 20 0 0 20
RETIWL ATROPKT 1 (5) 0 0 2 (U)
LWH.INFH... mKMtt 51. 0
-------
PATHOLOGY ASSOCIATES. INC.
PAfW-CSESOL
STUDY NO. 5221.08
RATS
Project Summary Table
i Incidence |