Contract No.: DAMD17-92-C-2001 Task Order No. - DTIC

BBflR Contract No.: DAMD17-92-C-2001

Task Order No.: UIC-7N Study No.: 138

Title Page

Study Report for Task Order No. U1C-7N £ DEVELOPMENTAL TOXICITY (SEGMENT II) i

STUDY OF WR242511 IN RABBITS

Sponsor: U.S. Army Medical Materiel Development Activity

Test Article: WR242511 Tartrate

Contract No.: DAMD17-92-C-2001

j

LED

Study Director

Barry S. Levine, D.Sc, D.A.B.T.

In-Life Phase Completed On

December 02, 1994

Performing Laboratory

TOXICOLOGY RESEARCH LABORATORY (TRL) University of Illinois at Chicago (UIC)

Department of Pharmacology 1940 W. Taylor St.

Chicago, IL 60612-7353

The views, opinions, and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy, or decision, unless so designated by other documentation.

20100915171

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la. REPORT SECURITY CLASSIFICATION lb. RESTRICTIVE MARKINGS

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2b. DECLASSIFICATION/DOWNGRADING SCHEDULE

3. DISTRIBUTION/AVAILABILITY OF REPORT

Unlimited

4. PERFORMING ORGANIZATION REPORT NUMBER(S)

UIC-7N (UIC/TRL Study No. 138)

5. MONITORING ORGANIZATION REPORT NUMBER(S)

6a. NAME OF PERFORMING ORGANIZATION

Toxicology Research Laboratory .

University of Illinois at Chicago

6b. OFFICE SYMBOL (If applicable)

7a. NAME OF MONITORING ORGANIZATION

U.S. Army Medical Materiel Development Activity

6c ADDRESS (City, State, and ZIP Code) Department of Pharmacology (M/C 868) 1940 W. Taylor Street Chicago, IL 60612-7353

7b. ADDRESS (Crty, State, and ZIP Code) ATTN: MCMR-RMA-RD Fort Detrick Frederick, MD 21702-5014

8a. NAME OF FUNDING/SPONSORING ORGANIZATION U.S. Army Medical

Materiel Development Activity

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MCMR-UMP

9. PROCUREMENT INSTRUMENT IDENTIFICATION NUMBER

DAMD17-92-C-2001 8c ADDRESS (City. State, and ZIP Code)

Fort Detrick Frederick, MD 21702-5009

10. SOURCE OF FUNDING NUMBERS

PROGRAM ELEMENT NO.

63807A

PROJECT NO.

30463807

TASK NO.

QC

WORK UNIT ACCESSION NO.

073 11. TITLE (Include Security Classification)

Developmental Toxicity (Segment II) Study of WR242511 in Rabbits

12. PERSONAL AUTHOR(S) Levine, Barry S., Youssef, Ashraf F., and Mercieca, Michael

13a. TYPE OF REPORT Study

13b. TIME COVERED FROM 12/10/93 TO

14. DATE OF REPORT (Year, Month, Day) 15. PAGE COUNT

16. SUPPLEMENTARY NOTATION

17 COSATI CODES

FIELD GROUP SUB-GROUP

18. SUBJECT TERMS (Continue on reverse if necessary and identify by block number)

WR242511 Tartrate

Developmental toxicity

19, ABSTRACT (Continue on reverse if necessary and identify by block number)

This study evaluated the embryo/fetal toxicity and the teratogenic potential of WR242511 taraate in time-mated New Zealand White (Pasteurella Free) female rabbits. Doses were 0, 0.5, 1.3, and 3.5 mg base/kg/day administered by gavage during gestation days (GD) 6-18 (GDO - day of observed mating). In addition, a positive control group was administered retinol palmitate, 300 mg/kg/day, on GD9 and 10 by gavage. Apparent toxicity of the test article was limited to one abortion in the mid dose (GD27) and one premature delivery (GD29) in the high dose. No other toxic effects were seen in either the pregnant females or in the fetuses. In a previous- dose range-finding study (UIC/TRL Study No. 137), early fatality of all 5 females was observed at 6 mg base/kg/day, while 2.5 mg base/kg/day showed marginal toxicity (slight decrease in female fetal weights). Accordingly, the high dose in the present study was chosen between 2.5 and 6 mg base/kg/day to induce marginal maternal toxicity. but to avoid excessive maternal fatality. Although overt maternal toxicity was not apparent in high dose animals in the present investigation, based on the results of the dose range-finding test it is believed that a dose somewhat higher than 3.5 mg base/kg/day would have resulted in excessive mortality. In the positive control group, marginal decreases in weight gain, a significant decrease in uterine weights, and significant increases in the number of early resorptions and % post-implantation loss were observed. Fetal toxicity was seen in the positive control group as a significant decrease in the number of viable fetuses and a significant increase in external and internal anomalies. Since neither overt maternal toxicity nor fetal toxicity was observed in WR242511 dose groups. 3.5 mg base/kg/day was considered at or near the no-observed effect level (NOEL) for both fetal and maternal toxicity in rabbits. In a previously conducted developmental toxicity study in rats. 2 mg base/kg/day was considered the NOEL for fetal toxicity while 0.5 mg base/kg/day was considered the NOEL for maternal toxicity (UIC/TRL Study No. 144). Taken together, rats demonstrated greater sensitivity to WR242511 than rabbits. In the rat teratology study. WR242511 did not demonstrate a developmental hazard to rat fetuses except in maternally toxic doses. Fetal body weights were reduced, but treatment-related malformations were not observed.

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BBAIFir Contract No.: DAMD17-92-C-2001


STATEMENT OF COMPLIANCE

To the best of my knowledge, Study No. 138 entitled " Developmental Toxicity (Segment II) Study of WR242511 in Rabbits" was conducted in compliance with the Good Laboratory Practices regulations as published in 21 CFR 58, 40 CFR 160 and 40 CFR 792 in all material aspects.

The protocol for this study was demonstrated by the UIC Animal Care Committee.

Signature

Study Director

Barry S. Levine, D.Sc, D.A.B.T. Date

Page

QUALITY ASSURANCE STATEMENT

STUDY TITLE: DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 IN RABBITS

STUDY NO. 138

DIRECTOR: BARRY S. LEVINE

INITIATION DATE: 11/19/93

This study has been divided into a series of phases. Using a random sampling approach, Quality Assurance personnel monitors each of these phases over a series of studies. Procedures, equipment, documentation, etc., are examined in order to assure that the study is performed in accordance with the Good Laboratory Practice regulations of the Food and Drug Administration and the Environmental Protection Agency 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 11/22/93, TO STUDY DIR 11/22/93, TO MGMT 11/22/93 PHASES: PROTOCOL REVIEW

INSPECT ON 11/4/94, TO STUDY DIR 11/4/94, TO MGMT 11/7/94 PHASES: ROOM ENVIRONMENT, QUARANTINE, LICK-IT CHECK AND TEST

ARTICLE PREPARATION

INSPECT ON 11/7/94, TO STUDY DIR 11/7/94, TO MGMT 11/8/94 PHASES: BODY WEIGHT, FOOD CONSUMPTION AND DOSING

INSPECT ON 2/8/95, TO STUDY DIR 2/8/95, TO MGMT 2/8/95 PHASES: RAW DATA AND DRAFT REPORT FROM THE ANALYTICAL LAB

INSPECT ON 3/7-8/95, TO STUDY DIR 3/8/95, TO MGMT 3/16/95 PHASES: RAW DATA

INSPECT ON 4/19-21/95, TO STUDY DIR 4/21/95, TO MGMT 4/24/95 PHASES: DRAFT REPORT

.^\oi ̂k^£vC^<W&^-^4*«<_ V/ZL *//f 6 QUALITY ASSURANCE DATE

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DMR Contract No.: DAMD17-92-C-2001


Signature Page

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 IN RABBITS

TRL Chemical No.: 1720614

Sponsor: U.S. Army Medical Materiel Development Activity

Fort Detrick Frederick, MD 21702-5009

Test Article: WR242511 Tartrate

Sponsor Representative: George J. Schieferstein, Ph.D.

Testing Facility: TOXICOLOGY RESEARCH LABORATORY (TRL) University of Illinois at Chicago (UIC) Department of Pharmacology (M/C 868) 1940 W. Taylor St. Chicago, IL 60612-7353

Barry S. Levine, D.Sc, D.A.B.T. Date Study Director

Ashraf F. Youssef, M.D., Ph.D. Reproductive Toxicologist

Date

In-life Phase Initiation: October 31, 1994

Dosing Initiation: November 06, 1994

In-Life Completion: December 02, 1994

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DMH Contract No.: DAMD17-92-C-2001 Task Order No.: UIC-7N

Study No.: 138

TABLE OF CONTENTS

TITLE PAGE 1

STATEMENT OF COMPLIANCE 2

QUALITY ASSURANCE STATEMENT 3

SIGNATURE PAGE 4

TABLE OF CONTENTS 5

1. SUMMARY 7

2. INTRODUCTION 7

3. MATERIALS AND METHODS 7

3.1 Test Article 7 3.2 Animals 8 3.3 Experimental Design 9 3.4 Statistical Analyses 11

4. RESULTS 11

4.1 Dosage Formulation Analysis 11 4.2 Mortality/Clinical Signs 11 4.3 Maternal Body Weights 11 4.4 Food Consumption 12 4.5 Cesarean-Section and Maternal Gross Observations 12 4.6 Fetal Observations 12

5. DISCUSSION/CONCLUSION 12

6. PERSONNEL 13

7. ARCHIVES 13

TABLES

1 Summary of Toxic Responses 14 2 Dosage Formulation Analyses 15 3 Summary of Clinical Signs 16 4 Summary of Body Weights (Maternal) 17 5 Summary of Body Weight Gains (Maternal) 19 6 Summary of Daily Mean Food Consumption 21 7 Summary of Cesarean-Section Data and Fetal Evaluations 22

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Study No.: 138

TABLE OF CONTENTS (contd.)

APPENDICES

1 Analytical Chemistry Report 1-1 2 Individual Maternal Clinical Signs 2-1 3 Individual Maternal Body Weight and Weight Gain Data 3-1 4 Individual Maternal Food Consumption Data 4-1 5 Teratology Report 5-1 6 Protocol and Amendments 6-1 7 Study Deviations 7-1

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DBfllFir Contract No.: DAMD17-92-C-2001 Task Order No.: UIC-7N

Study No.: 138

1. SUMMARY

This study evaluated the embryo/fetal toxicity and the teratogenic potential of WR242511 tartrate in time-mated New Zealand White (Pasteurella Free) female rabbits. Doses were 0, 0.5, 1.3, and 3.5 mg base/kg/day administered by gavage during gestation days (GD) 6-18 (GDO = day of observed mating). In addition, a positive control group was administered retinol palmitate, 300 mg/kg/day, on GD9 and 10 by gavage. The results are summarized in Table 1. One female in the high dose prematurely delivered on GD29 and one female in the mid dose aborted on GD27. No other maternal toxic manifestations were observed in any WR242511 dose level. In addition, fetal toxicity was not apparent. In the positive control group, one female aborted on GD22. Other manifestations of toxicity in this group were a marginal decrease in weight gain during dosing; significant decreases in uterine weight and viable fetuses; and significant increases in post-implantation loss, early resorptions and fetuses with external, visceral and skeletal malformations.

With the exception of one abortion and one premature delivery in test article-treated animals, toxicity was not apparent in either the does or their fetuses. Based on the results of this study, the highest dose tested (3.5 mg base/kg/day) was considered at or near the no observed effect level for both maternal and fetal toxicity in rabbits. Since 6 mg base/kg/day in a previously conducted dose range-finding study was lethal to 5/5 animals, it is believed that a dose in excess of 3.5 mg base/kg/day in the present investigation would have resulted in excessive mortality.

INTRODUCTION

This study was conducted to evaluate the embryo/fetal toxicity and the teratogenic potential of the test article in New Zealand white rabbits. The test article was administered by daily gavage to time-mated females during gestation days 6-18. The fetuses were delivered by Cesarean section on gestation day 29. All fetuses were examined for external anomalies and by Staples' technique for visceral anomalies and then fixed in ethyl alcohol (95%) for subsequent skeletal examinations. All methods and procedures in this study were conducted in accordance with the Toxicology Research Laboratory, University of Illinois at Chicago and Pathology Associates Inc. Quality Assurance Programs designed to conform with FDA Good Laboratory Practices Regulations. No unforeseen circumstances affected the integrity of the study. This study was stagger-started over four days and was initiated on October 31, 1994 (observation of mating). Dosing was initiated (stagger-started) on November 06, 1994 (GD6) and the in-life portion was terminated on December 02, 1994 (GD29).

MATERIALS AND METHODS

3.1 Test Article

WR242511 tartrate (Bottle Lot No. BM 05816), a fine, yellow powder, was received on June 16, 1993 from Herner & Co. and was previously assigned an in-house chemical number (1720614). The chemical name of the test article is 8-[(4-amino-l- methylbutyl)amino]-5-(l-hexyloxy)-6-methoxy-4-methylquinoline DL-tartrate and the mole fraction of the base is 0.71. It was stored at -20 to -15°C and ambient humidity

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Study No.: 138

in the freezer, and was protected from light (the container was wrapped in aluminum foil). The chemical structure follows.

(CH2)5CH3

H3CO

NHCH(CH2)3NH2

C02H

CHOH

CHOH

C02H

CH,

3.2

The test article was initially identified by GC-MS and the purity was determined to be greater than 99.6%. The purity was re-determined following the completion of the in-life portion of the study. At that time, the purity was greater than 99.5%. Thus, the test article was stable under storage conditions.

Animals

A total of one-hundred and twenty female New Zealand White (Pasteurella Free) rabbits were obtained from HRP, Inc., Denver, PA, on November 1 & 4, 1994 (30 and 90 animals, respectively). The animals were ~ 6 months old upon arrival at the UIC AAALAC-accredited animal facility (date of birth 04/30/94). Each animal was given an ear tag number by the supplier, and a separate study-unique number (ear-tag) upon arrival. This number appeared on a cage card visible on the front of each cage. The cage card additionally contained the study number, test article identification, treatment group number, dose level, and the assigned date of necropsy. Cage cards were color-coded as a function of treatment group. Animals were singly housed in stainless steel cages in a temperature (61-69°F) and humidity (approx. 30-70 %) controlled room with a 14 hour light/10 hour dark cycle. The cage size, 0.32 m2 area and 38 cm height, was adequate to house rabbits at the upper weight range as described in the Guide for the Care and Use of Laboratory Animals, DHHS (NTH) No. 86.23. All animals were routinely transferred to clean cages every other week with weekly pan changes.

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DtMin Contract No.: DAMD17-92-C-2001


The animals were fasted on the day of arrival. They received approximately 25 g of High Fiber Certified Rabbit Chow #5325 (PMI Feeds, Inc., St. Louis, MO) on the second day, which was gradually increased over a few days to approximately 100-130 g/day. This regimen was recommended by the animal supplier (HRP, Inc.) to reduce the incidence of intestinal problems. On the days of measured food consumption, an exact amount of 130 g was provided. Tap water from an automatic watering system in which the room distribution lines were flushed daily was provided ad libitum from arrival until termination. The water was not treated with additional chlorine or HC1. There are no known contaminants in the feed or water which were expected to influence the study. The results of the most current comprehensive chemical analyses of Chicago water performed by the City of Chicago are documented in files maintained by Quality Assurance.

3.3 Experimental Design

Animals were mated on four consecutive days at the supplier's facility. The day of mating was considered gestation day 0 (GDO). The body weights on GDO were obtained by the supplier after balance standardization. Of the 120 presumed pregnant rabbits which were received, 60, 30 and 30 were at GDI, GD2, and GD3, respectively, upon arrival at the animal facility. All animals were quarantined for at least 3 days before initiation of dosing (GD6). All animals were examined daily during the quarantine period, and were approved for use by the Clinical Veterinarian prior to being placed on test. One hundred animals (25 animals from each gestation day 0 subset) were randomized into the following five groups on the basis of body weight to result in 20 animals/group. Dose levels were selected on the basis of a range-finding study (UIC/TRL Study No. 137) as follows:

Group No. Treatment Dose Level (mg base/ke/dav)

Number of Females*

1 2 3 4 5**

Vehicle WR242511 WR242511 WR242511 Vitamin A (Retinol Palmitate)

0 0.5 1.3 3.5 75,000 IU/kg/day (= 300 mg/kg/day)

20 20 20 20 20

* Presumed pregnant

** The positive control agent (suspended in water at 300 mg/ml and prepared fresh daily) was administered orally at the specified dose on days 9 and 10 of gestation at a dosing volume of 1 ml/kg.

The test article was administered by gavage once daily during gestation days 6 through 18. The dosing suspensions were administered at a dosing volume of 1 ml/kg. A stock test article suspension (20 mg/ml) was prepared weekly by suspending the appropriate quantity of the test article in the vehicle (aqueous 1% methylcellulose/0.2% Tween 80). Daily dosage formulations were prepared by diluting the stock to the appropriate concentration.

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Study No.: 138

The stock and dosing suspensions were kept at 0 - 4°C. Samples of the dosage formulations used at the beginning and at the end of the dosing period were analyzed for test article concentration. Only samples within 10% of their intended concentration were used. Stability data obtained from a previous study (UIC/TRL Study No. 107) indicated that the stock formulation was stable for two weeks and the dosing suspensions were stable for 48 hours. Homogeneity data obtained form UIC/TRL Study No. 107 also demonstrated that the test article suspensions were homogeneous (coefficients of variation for sampling in the top, middle and bottom of several test suspensions were typically less than 4%).

Non-fasted body weights were recorded on GDO (by the supplier), GD4 (for randomization), and on GD6 - 18, 24 and 29. Food consumption for all animals was measured during the following 24 hr intervals: GD7/8, 9/10, 11/12, 14/15, 17/18, 23/24 and 28/29. Clinical signs were observed and recorded approximately 1-2 hours post-dosing on the days of dosing and each morning following completion of the dosing period. Animals were also observed for moribundity/mortality immediately prior to dosing and in the afternoon, and in the afternoon after the dosing period ceased.

On GD29, all rabbits were killed in random order by intravenous injection of sodium pentobarbital (50 mg/kg) via the marginal ear vein. The abdominal and thoracic cavities were opened by a ventral midline incision. The uterus was examined and weighed.

In gravid animals, the number of corpora lutea on each ovary was recorded and the ovaries were discarded after evaluation. The viability of the fetuses were checked in utero. A viable fetus was defined as one which responds to stimuli. A non-viable fetus was defined as a term fetus which does not respond to stimuli in utero or is not breathing. The number and location of fetuses, early resorption(s), late resorption(s) and the total number of implantation sites and their uterine distribution were documented using the following procedure. All implantation sites, including resorptions, were numbered in consecutive fashion beginning with the left distal uterine horn, and similarly with the right uterine horn noting the position of the cervix. An early resorption was defined as one in which it was not grossly evident that organogenesis has occurred. A late resorption was defined as one in which it was grossly evident that organogenesis had occurred. A fetus with evident autolysis was considered a late resorption. Following the cesarean section examination, the carcass of each dam was discarded.

Uteri from females that appeared nongravid were opened and placed in 10% ammonium sulfide solution for at least 10 minutes for detection of possible implantation sites. If implantation sites were detected, ovaries were evaluated as previously mentioned.

The number of fetuses in each litter was recorded. Each fetus was weighed and individually identified noting litter, uterine placement and study number. All fetuses were euthanized by ip injection of a 40% solution of sodium pentobarbital (= 0.4 ml/fetus). Subsequently, a morphological examination was performed. A detailed examination of each fetus was conducted to include the eyes, palate, head shape and extremities. Any abnormal finding was recorded.

All fetuses were freshly examined by the Staples' technique for visceral anomalies including a mid-sagittal section between the eyes (Staples, 1974). All fetuses were then skinned and eviscerated. Following staining with Alizarin Red S and then cleared in glycerin as recommended by Dawson, the skeletons were examined for alterations (Dawson, 1926). Skeletal preparations were stored in 99.5% glycerin/0.5% phenol.

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Study No.: 138

3.4 Statistical Analyses:

Maternal body weights, weight gains, absolute uterine weights, and fetal body weights were analyzed by one-way analysis of variance. If a significant F ratio was obtained (p < 0.05), Dunnett's test was used for pair-wise comparisons to the vehicle control group.

Fetal abnormalities were statistically analyzed in terms of the litter as the experimental unit. Abnormalities included malformations in addition to variations. The proportions of litters with abnormalities were compared using Fisher's exact test. Male to female fetal sex ratios were compared using the Chi-square test.

Maternal food consumption data, early and late resorptions, non-viable fetuses, viable fetuses, corporalutea (C.L.), implantations, preimplantation loss*, postimplantationloss**, and total implantation loss*** were compared using the Kruskal-Wallis test. If a significant effect was seen (p< 0.05), the Mann-Whitney U test was used for pair-wise comparisons to the vehicle control group.

•Preimplantation loss = [(# C.L. - § implantations)/#C.L.] x 100 **Postimplantation loss = [(#implantations - # live fetuses)/# implantations] x 100

***Total implantation = [(C.L. - # live fetuses)/#C.L.] x 100

Uterine weight, fetal body weights and fetal sex in animals with abortion/premature delivery were not included in the statistical analysis.

In addition to the written report, summary data tables of parameters and variability were transmitted to the Sponsor on magnetic media (computer diskette) in "ASCII" form. The transcribed data on disk were no longer considered GLP compliant.

RESULTS

4.1 Dosage Formulation Analysis

The results of dosage formulation analyses are shown in Table 2. The Analytical Chemistry Report is in Appendix 1.

All dosing suspensions were within 10% of their target concentrations at the beginning and at the end of the dosing period.

4.2 Mortality/Clinical Signs

The summary of clinical signs of toxicity is in Table 3. Individual signs are in Appendix 2.

No animal died in this study. One female in the mid dose (i.e., 1.3 mg base/kg/day) aborted on GD27 and one female in the high dose (i.e., 3.5 mg base/kg/day) had a premature delivery on GD29. In addition, one female in the positive control group aborted and was subsequently sacrificed on GD22. Neither abortion nor premature delivery was associated with or preceded by any marked maternal toxicity.

4.3 Maternal Body Weights

The summaries of maternal body weights and weight gains are in Tables 4 and 5, respectively. Individual data are contained in Appendix 3.

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No significant change in body weight/weight gain was observed in the WR242511 treatment groups. A marginal, but significant decrease in weight gain was observed in the positive control group from day 9 to day 10, (i.e., following the first of the two daily doses).

4.4 Food Consumption

The summary of mean daily food consumption is in Table 6. Individual food consumption data are contained in Appendix 4.

No decrease in food consumption was observed in any group throughout the study.

4.5 Cesarean-Section and Maternal Gross Observations

The summary of cesarean-section data is in Table 7. The Teratology Report is in Appendix 5.

All animals were pregnant except for three females in the positive control group. In the mid dose group, the female which aborted had 6 fetuses. Only one fetus could be externally evaluated and appeared normal; the rest of the fetuses were cannibalized. In the positive control group, the female which aborted had 10 fetuses with 5 apparently normal while the others were cannibalized. All aborted fetuses were discarded after examination.

4.6 Fetal Observations

The summary of fetal observation is in Table 7. The Teratology Report is in Appendix 5.

Treatment related abnormalities were not observed in fetuses of pregnant rabbits dosed with WR242511. In the positive control group (i.e., 300 mg/kg/day retinol palmitate on GD9 & 10), observations included a significant decrease in the number of viable fetuses and significant increases in % post-implantation loss, early resorptions and fetuses with external, skeletal, and visceral anomalies. Anomalies were observed mainly in the skull, caudal vertebrae, hyoid bone and in the urinary system.

DISCUSSION/CONCLUSION

This study evaluated the embryo/fetal toxicity and the teratogenic potential of WR242511 tartrate in time-mated New Zealand White (Pasteurella Free) female rabbits. Doses were 0, 0.5, 1.3, and 3.5 mg base/kg/day administered by gavage during gestation days (GD) 6 - 18 (GDO = day of observed mating). In addition, a positive control group was administered retinol palmitate, 300 mg/kg/day, on GD9 and 10 by gavage. The results are summarized in Table 1.

Apparent toxicity of the test article was limited to one abortion in the mid dose (GD27) and one premature delivery (GD29) in the high dose. No other toxic effects were seen in either the pregnant females or in the fetuses. In a previous dose range-finding study (UIC/TRL Study No. 137), early fatality of all 5 females was observed at 6 mg base/kg/day, while 2.5 mg base/kg/day showed marginal toxicity (slight decrease in female fetal weights). Accordingly, the high dose in the present study was chosen between 2.5 and 6 mg base/kg/day to induce marginal maternal toxicity, but to avoid excessive maternal fatality. Although overt maternal toxicity was not apparent in high dose animals in the present investigation, based on the results of the dose range-finding test it is believed that a dose somewhat higher than 3.5 mg base/kg/day would have resulted in excessive mortality.

In the positive control group, marginal decreases in weight gain, a significant decrease in uterine weights, and significant increases in the number of early resorptions and % post-implantation loss

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were observed. Fetal toxicity was seen in the positive control group as a significant decrease in the number of viable fetuses and a significant increase in external and internal anomalies.

Since neither overt maternal toxicity nor fetal toxicity was observed in WR242511 dose groups, 3.5 mg base/kg/day was considered at or near the no-observed effect level (NOEL) for both fetal and maternal toxicity in rabbits. In a previously conducted developmental toxicity study in rats, 2 mg base/kg/day was considered the NOEL for fetal toxicity while 0.5 mg base/kg/day was considered the NOEL for maternal toxicity (UIC/TRL Study No. 144). Taken together, rats demonstrated greater sensitivity to WR242511 than rabbits. In the rat teratology study, WR242511 did not demonstrate a developmental hazard to rat fetuses except in maternally toxic doses. Fetal body weights were reduced, but treatment-related malformations were not observed.

PERSONNEL

Study Director Reproductive Toxicologist Teratologist (PAI) Reproductive Scientist Analytical Chemist Clinical Veterinarian Veterinarian Support Tox. Lab Supervisor Lead Technician Chemistry Specialist Quality Assurance

Barry S. Levine, D.Sc, D.A.B.T. Ashraf F. Youssef, M.D., Ph.D. Michael D. Mercieca, B.S. Roberto A. Matamoros, D.V.M., Ph.D. Adam Negrusz, Ph.D. James Artwohl, D.V.M., M.S., D.A.C.L.A.M. Documented in raw data Soudabeh Soura, B.S. Documented in raw data Thomas Tolhurst, B.S. Ronald C. Schoenbeck

Report preparation was assisted by Dr. Ashraf Youssef, Ms. Soudabeh Soura and Mr. Mukesh Pitroda.

ARCHIVES

All raw data, documentation, specimens, test article reserves, and the final report are archived at the University of Illinois at Chicago, Toxicology Research Laboratory, Department of Pharmacology, 1940 W. Taylor St., Chicago, IL 60612.

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Table 1


Summary of Toxic Responses

WR242511 Retinol Palmitatc

Dose Level (mg base/kg/day) 0.0 0.5 1.3 3.5 300-

Number of Females Pregnant (Non-pregnant) 20(0) 20(0) 20(0) 20(0) 17(3)

Term Litters (Early pregnancy termination) 20(0) 20(0) 19(1)* 19(1)' wr

Clinical Signs NE NE NE NE

Maternal Body Weight Gain - NE NE NE »(?)

Food Consumption - NE NE NE NE

Uterine Weight - NE NE NE 1

Early Resorptions - NE NE NE t

Post-implantation Loss - NE NE NE f

Decrease in Fetal Body Weight (d7?) -/- NE/NE NE/NE NE/NE NE/NE

Viable Fetuses - NE NE NE 1

Total Loss/Liner - NE NE NE t

External Malformations •

NE NE NE t

Skeletal malformations - NE NE NE t

Visceral Malformations - NE NE NE t

CONCLUSIONS

This study evaluated the embryo/fetal toxicity and the teratogenic potential of WR242511 tanratc in time-mated New Zealand White (PasteureUa Free) female rabbits Doses were 0, 0 5. 1.3. and 3.5 mg base/kg/day administered by gavage during gestation days (CD) 6 - 18 (GDO - day of observed mating). In addition, a positive control group was administered retinol palmitatc. 300 mg/kg/day. on GD9 and 10 by gavage. Apparent toxicity of the test article was limited to one abortion in the raid dose (GD2T) and one premature delivery (GD29) In the high dose. No other toxic effects were seen in either the pregnant females or in the fetuses. In a previous dose range-finding study (UIOTRL Study No. 137), early fatality of all 5 females was observed at 6 mg base/kg/day. while 2.5 mg base/kg/day shewed marginal toxicity (slight decrease in female fetal weights). Accordingly, the high dose in the present study was chosen between 2.5 and 6 mg base/kg/day to induce marginal maternal toxicity. but to avoid excessive maternal fatality. Although oven maternal toxicity was not apparent in high dose animals in the present investigation, based on the results of the dose range-finding test it is believed that a dose somewhat higher than 3.5 mg base/kg/day would have resulted in excessive mortality. In the positive control group, marginal decreases In weight gain, a significant decrease in uterine weights, and significant increases m (he Dumber of early resorpbons and % pern-implantation loss were observed. Fetal toxicity was seen in the positive control group as a significant decrease in the number of viable fetuses and a significant increase in external and internal anomalies. Since neither overt maternal toxicity nor fetal toxicity was observed in WR242511 dose groups. 3.5 mg base/kg/day was considered at or near the no-observed effect level (NOEL) for both fetal and maternal toxicity in rabbits. In a previously conducted developmental toxicity study in rats. 2 mg base/kg/day was considered the NOEL for feral toxicity while 0.5 mg base/kg/day was considered the NOEL for maternal toxicity (UIOTRL Study No. 144). Taken together, rats demonstrated greater sensitivity to WR242511 than rabbits. In the rat teratology study. WR242511 did not demonstrate a developmental hazard to rat fetuses except in maternally toxic doses. Fetal body weights were reduced, but treatment-related malformations were not observed.

NE - No effect (?) - Possible Effect •mg/kg/day on GD9 & 10 "Aborted/Premature Delivery

Page 14

DEM crp

Contract No.: DAMD17-92-C-2001 Task Order No.: UIC-7N

Study No.: 138

Table 2


Dosage Formulation Analyses*

Target Concentration (mg base/ml) GD6" % Target

Target Concentration (mg base/ml) GD 18' % Target

0 0 - 0 0 -

0.5 0.46 ± 0.00 92.0 0.5 0.47 ± 0.00 94.0

1.3 126 ±0.00 96.9 1.3 1.24 ± 0.01 95.4

3.5 3.28 ± 0.01 93.7 3.5 3.47 ± 0.01 99.1

'Mean ± standard deviation for triplicate runs. hGestation Day 6 (first day of dosing) 'Gestation Day 18 (last day of dosing)

Page 15

Table 3 DEVELOPMENTAL TOXICITY (SEGMENT II)

STUDY OF WR24 2511 IN RABBITS ®sm SUMMARY OF CLINICAL SIGNS

STUDY: 138 SEX: FEMALE

IDOSE: (mg base/kg/day) Q 0.5 1.3 GROUP: 1-F 2-F 3-F

3.5 4-F

300 mg/kg/daya

5-F

Scheduled Sacrifice Animal Aborted/Sacrificed Premature Delivery

20 0 0

20 0 0

19 1 0

15 0 1

19 1 o

Total Number of Animals 20 20 20 20 20

i

Retmol Palmitate given on GD9 and GD10 only

Page 16

Table U

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 IN RABBITS asm

SUMMARY OF BODY WEIGHTS (Kilograms) (Materna 1)

SEX: FEMALE STUDY: 138

PERIOO

DOSE: (mg base/kg/day) o GROUP: 1-F

0.5 2-F

1.3 3-F

3.5 4-F

300 mg/kg/day° 5-F

DAY 0 MEAN S.D. N

DAY 5 MEAN S.D. N

DAY 6 MEAN S.D. N

DAY 7 MEAN S.D. N

DAY 8 MEAN S.D. N

DAY 9 MEAN S.D. N

DAY 10 MEAN S.D. N

DAY 11 MEAN S.D. N

DAY 12 MEAN S.D. N

DAY 13 MEAN S.D. N

P less than P less than

.05

.01

3.53 0.229

20

3.42 0.215

20

3.38 0.231

20

3.35 0.222

20

3.37 0.226

20

3.38 0.220

20

3.40 0.242

20

3.41 0.232

20

3.43 0.243

20

3.44 0.267

20

3.53 0.234

19

3.40 0.235

19

3.40 0.242

19

3.37 0.232

19

3.39 0.221

19

3.39 0.217

19

3.40 0.225

19

3.42 0.221

19

3.45 0.223

19

3.46 0.216

19

3.57 0.256

20

3.41 0.250

20

3.41 0.253

20

3.40 0.251

20

3.40 0.240

20

3.42 0.245

20

3.41 0.250

20

3.44 0.243

20

3.47 0.236

20

3.50 0.247

20

3.57 0.206

19

3.42 0.189

19

3.43 0.174

19

3.42 0.175

19

3.41 0.184

19

3.42 0.175

19

3.41 0.200

19

3.44 0.188

19

3.47 0.181

19

3.47 0.192

19

3.54 0.251

17

3.41 0.257

17

3.42 0.295

17

3.41 0.281

17

3.41 0.277

17

3.44 0.271

17

3.41 0.254

17

3.40 0.246

17

3.42 0.264

17

3.47 0.272

17

Analysis of Variance using DUNNETT'S Procedure

Recinol PalmiCate given on GD9 and GDIO only

Page 17

Table 4 (contd.)

DEVELOPMENTAL TOXICITY (SEGMENT n) STUDY OF WR242511 IN RABBITS BSMT

SUMMARY OF BODY WEIGHTS (Kilograms)


DOSE: PERIOD

(mg base/kg/day) 0 GROUP: 1-F

0.5 2-F

1.3 3-F

3.5 4-F

300 mg/kg/day

5-F

DAY 14 MEAN S.D. N

3.48 0.258

20

3.50 0.219

19

3.53 0.239

20

3.51 0.194

19

3.49 0.265

17

DAY 15 MEAN S.D. N

3.51 0.264

20

3.53 0.223

19

3.55 0.253

20

3.53 0.198

19

3.53 0.296

17

DAY 16 MEAN S.D. N

3.52 0.260

20

3.55 0.222

19

3.55 0.240

20

3.54 0.208

19

3.55 0.312

17

DAY 17 MEAN S.D. N

3.51 0.260

20

3.56 0.244

19

3.56 0.241

20

3.54 0.221

19

3.54 0.299

17

DAY 18 MEAN S.D. N

3.52 0.255

20

3.55 0.230

19

3.54 0.239

20

3.53 0.243

19

3.54 0.308

17

DAY 24 MEAN S.D. N

3.61 0.251

20

3.61 0.253

19

3.59 0.284

20

3.63 0.242

19

3.58 0.278

16

DAY 29 MEAN S.D. N

3.65 0.262

20

3.66 0.221

19

3.68 0.250

19

3.67 0.223

19

3.64 0.274

16

* P less than ** P less than

.05

.01 Analysis o f Variance using DUNNETT'S Procedure

Retinol Palmitate given on GD9 and GD10 onLy

Page 18

Table 5

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 IN RABBITS n

SUMMARY OF WEIGHT GAINS (Kilograms)

SEX: FEMALE

(MaCerna1)

STUDY: 138

DOSE: PERIOD3

(mg base/kg/day) 0 GROUP: 1-F

0.5 2-F

1.3 3-F

3.5 4-F

300 mg/kg/day

5-F

b DAY 7 MEAN

S.D. N

-0.03 0.080

20

-0.03 0.090

19

-0.01 0.047

20

-0.01 0.079

19

-0.01 0.064

17

DAY 8 MEAN S.D. N

0.02 0.035

20

0.01 0.040

19

-0.01 0.047

20

-0.01 0.057

19

0.01 0.048

17

DAY 9 MEAN S.D. N

0.01 0.042

20

0.01 0.048

19

0.02 0.048

20

0.01 0.053

19

0.03 0.041

17

OAY 10 MEAN S.D. N

0.02 0.043

20

0.00 0.055

19

-0.01 0.029

20

-0.01 0.062

19

-0.03** 0.045

17

DAY 11 MEAN S.D. N

0.01 0.050

20

0.02 0.039

19

0.03 0.036

20

0.03 0.067

19

-0.01 0.028

17

DAY 12 MEAN S.D. N

0.02 0.044

20

0.03 0.035

19

0.03 0.051

20

0.03 0.039

19

0.03 0.031

17

DAY 13 MEAN S.D. N

0.01 0.044

20

0.01 0.032

19

0.04 0.033

20

0.01 0.059

19

0.04 0.031

17

DAY 14 MEAN S.D. N

0.04 0.044

20

0.04 0.030

19

0.02 0.052

20

0.03 0.054

19

0.03 0.029

17

DAY 15 MEAN S.D. N

0.02 0.030

20

0.03 0.028

19

0.03 0.046

20

0.02 0.038

19

0.04 0.044

17

OAY 16 MEAN S.D. N

0.02 0.027

20

0.02 0.035

19

0.00 0.033

20

0.01 0.057

19

0.02 0.038

17

P less than .05 P less than .01

Analysis o f Variance using DUNNETT S Procedure

Successive periods

Baseline is day 6

'Retinol Palmitate given on GD9 and GD10 onlv

Page 19

Table 5 (contd. )

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 IN RABBITS §w?

SUMMARY OF WEIGHT GAINS (Kilograms)


a D0SE:

PERIOD (mg base/kg/day) 0 GROUP: 1-F

0.5 2-F

1.3 3-F

3.5 4-F

300 mg/kg/day

5-F

DAY 17 MEAN S.D. N

-0.01 0.035

20

0.01 0.040

19

0.01 0.032

20

0.00 0.042

19

-0.01 0.045

17

DAY 18 MEAN S.D. N

0.00 0.029

20

-0.01 0.029

19

-0.02 0.023

20

-0.01 0.039

19

0.00 0.038

17

DAY 24 MEAN S.D. N

0.09 0.060

20

0.05 0.102

19

0.06 0.158

20

0.10 0.063

19

0.03 0.083

16

DAY 29 MEAN S.D. N

0.05 0.048

20

0.06 0.085

19

0.06 0.055

19

0.04 0.063

19

0.06 0.053

16

TOTAL GAIN MEAN S.D. N

0.27 0.112

20

0.27 0.149

19

0.28 0.090

19

0.24 0.149

19

0.20 0.127

16

P less than P less than

.05

.01 Analysis of Variance using DUNNETT' 'S Procedure

Successive periods

Recinol Palmicate given on GD9 and GD10 only

Page 20

Table 6 DEVELOPMENTAL TOXICITY (SEGMENT II)

STUDY OF WR242511 IN RABBITS ® is & n SUMMARY OP DAILY MEAN POOD CONSUMPTION (Grams)


PERIOO DOSE: (mg base/kg/day) 0 0.5 1.3 3.5 300 mg/kg/daya

GROUP: w 2-F 3-F 4-F 5-F

INTAKE (3) 130 130 126 130 130 S.D. 0.0 0.0 19.7 0.0 0.0 N 20 19 20 19 17

INTAKE (9) 130 130 130 130 130 S.D. 0.0 0.0 0.0 0.0 0.0 N 20 19 20 19 17

INTAKE <g) 130 130 130 120 130 S.D. 0.0 0.0 0.0 32.5 0.0 N 20 19 20 19 17

INTAKE (g) 129 130 129 128 130 S.D. 6.0 0.0 6.5 6.9 0.0 N 20 19 20 19 17

INTAKE (g) 130 130 130 116 130 S.D. 0.0 0.0 0.0 40.9 0.0 N 20 19 20 19 17

INTAKE (3) 130 130 130 130 130 S.O. 0.0 0.0 0.0 0.0 0.0 N 20 19 20 19 16

INTAKE <g> 130 130 130 130 130 S.D. 0.0 0.0 0.0 0.0 0.0 N 20 19 19 19 16

DAY 8

DAY 10

DAY 12

DAY 15

DAY 18

DAY 24

DAY 29

Retinol Palmitate given on GD9 and GD10 only

Page 21

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BaRE1?

APPENDIX 1

Analytical Chemistry Report

1-1

DEVELOPMENTAL TOXICITY (SI jy OF WR242511 IN RABBITS

U1C/TRL STUDY NUMBER 138

Part I:

Part U:

Identity, Purity and StabUity Study of WR242511

Dosing Formulations Analysis of WR2425U in 1% Methylcellulose/0.2% Tween 80

Analysts: Adam Negrusz A. Karl Larsen, Jr.

Study Site: Drug Disposition Research Laboratory College of Pharmacy University of Illinois at Chicago Chicago, Illinois 60612

Sponsor: Toxicology Research Laboratory University of Illinois at Chicago Chicago, Illinois 60612

Report Prepared by: Dr. Adam Negrusz

Report Prepared: January 31, 1995

Approved: January 31, 1995 Dr. Eugene F. Woods, Ph.D..-* , W Laboratory Director c -•-•

;->

bfflty^luiyif WR2I2511 Part I: Identity, Purity and Stal

Objective

The objective of this study was to confirm the identity, establish the purity and stability of WR242511.

Identification

GC-MS System

Gas Chromatograph:

Mass Selective Detector:

Analytical Column:

GC Parameters:

Hewlett-Packard Series II

Hewlett-Packard Model 5970

30 m x 0.25 mm ID, DB-5 with a 3 micron film thickness.

Injector temp. 250°C, oven temp. 70°C initial, 280°C final, 15°C/minute ramp, carrier gas - helium, flow rate 2 ml/minute, split ratio 10:1

Procedure

Subject sample (WR242511 tartrate) was submitted by the Toxicology Research Laboratory. The sample was dissolved in methanol to a concentration of 0.71 fig base/ml and a 2 /xl aliquot was injected on the column. The MSD scanned from 40 amu to 400 amu at a rate of 1 scan per second.

Results - GC-MS

The mass spectrum indicates a molecular ion m/e 373 which is in agreement with the VVR242511 free base molecular weight. Major fragments of WR242511 sample are m/e 84, 175, 203, 288.

Figure 1 shows the mass spectrum of the WR242511 sample.

Purity

Experimental

The subject sample (WR242511 tartrate) was supplied by the Toxicology Research Laboratory and stored at -20°C when it was not analyzed.

M/Slrd Description

A fine yellow powder, no obvious odor.

Spectrum

An ultraviolet spectrum (Figure 2) recorded on a Shimadzu Spectronic 200 UV spectrometer (dual beam) was obtained from a 14.2 fig base/ml solution of WR242511 prepared in mobile phase. The sample was found with maximal absorptivity observed at 212 nm and 264 nm.

HPLC System

Solvent Delivery System: Perkin-Elmer Series 3B Pump

Injector: Rheodyne 7125 with 50 fi\ sample loop

Analytical Column: Spherisorb CN 5 /z, 250 mm x 4.6 mm (Alltech)

Detector: Perkin-Elmer LC-55B UV Detector, 225 nm, 264 nm

Integrator: Spectra-Physics SP4270 Integrator

Mobile Phase: 20% methanol, 50% acetonitrile, 30% 0.01 M ammonium formate (in water), pH 3.0 (adjusted with 88% formic acid), flow 1.5 ml/minute

Procedure

Six solutions of WR242511 were prepared as follows. Twenty five mg of WR242511 tartrate sample was weighed into a 25 ml volumetric flask. The sample was dissolved in and the volume brought to mark with mobile phase. A 25 (il aliquot of each solution was immediately chromatographed at 225 nm and next at 264 nm.

Calculation of Results

Quantitations were based on the assumption of equal detector response per unit weight of all UV- absorbing components. Areas of WR242511 and other detectable components in the subject sample chromatograms were employed in the following equation to calculate the percentage of WR242511 present in the sample:

% PURITY = (area of WR242511/total area) x 100

Results m Typical chromatograms are shown in Figure 3. The subject samples were found to contain less than 1% of one UV-absorbing impurity (225 nm). At 264 nm no visible impurities were observed. Percent purity of initial WR242511 sample was found to be 99.63%, standard deviation - 0.02%, terminal 99.46% ± 0.04%. The assay results are presented in Tables 1 and 2.

FIGURE 1

MASS SPECÛÔ^TStzS?! SAMPLE

tooooa

iaaooo

Son fCZO (16.0 1S «î) «<• ~«<-2-«2$ lUof

TOO

f200

-u l^Jk

373

3SI

30O

FIGURE 2

ULTRAVIOLET SPECTRUM OF WR242511

EMIT

360 200

FIGURE 3 BfflRin CHROMATOGRAMS OF WR242511 SAMPLE, CONC. 0.71 MG BASE/ML, 225 NM,

A - INITIAL SAMPLE, B - TERMINAL SAMPLE

-T

cc

•r

0 .-•

CM O

CD

m

cs

O

O

i -i -I

'-•j

-H 1L •r

UJ l_

B

Table 1 ®M F Purity Data for WR242511

Initial Sample

Solutions

Peak Identity

1 2 3 4 5 6

A 3229 3089 3167 3535 3451 3438

WR242511 880964 873460 902359 904336 881062 888791

% Purity 99.635 99.648 99.650 99.611 99.610 99.615

Mean ± S.D. - 99.63 ± 0.02

8

Table 2

Purity Data for WR242511 Terminal Sample

M« F

Solutions

Peak Identity

1 2 3 4 5 6

A 3215 3204 3537 3467 3141 3488

WR242511 653986 635077 652265 644740 626757 644418

% Purity 99.466 99.498 99.461 99.465 99.501 99.384

Mean ± S.D. - 99.46 ± 0.04

M«jr Part II: Dosing Formulations Analysis of WR242511 in 1% Methylcellulose.'0.2%

Tween 80

Introduction

Samples from Study No. 138 were submitted by the Toxicology Research Laboratory to the Drug Disposition Research Laboratory for the quantitation of WR242511 in dosing formulations. Samples were received on November 6 and on November 18, 1994. All samples submitted were analyzed by high performance liquid chromatography by a previously described analytical method (see report Study No. 107 from February 21, 1994, Part n and Part IV).

Results

Results of dosing formulations for Study No. 138 are found in Table 3. All dosing formulations analyzed were within 10% of their target values.

10

Table 3 BB&ff

Results of Dosing Formulations Analysis for Study No. 138

November 6, 1994 • •

Sample Identification Target Concentration (mg base/ml)

Mean Concentration ± S.D. (mg base/ml)

WHITE 0 0

ORANGE WITH BLACK DOT

0.5 0.4635 ± 0.0031

PINK WITH BLACK DOT

1.3 1.2626 ± 0.0032

GREEN WITH BLACK DOT

3.5 3.2783 ± 0.0145

November 18, 1994

Sample Identification Target Concentration (mg base/ml)

Mean Concentration ± S.D. (mg base/ml)

WHITE 0 o ORANGE WITH BLACK

DOT 0.5 0.4680 ± 0.0035

PINK WITH BLACK DOT

1.3 1.2442 ± 0.0085

GREEN WITH BLACK DOT

3.5 3.4676 ± 0.0145

11

D.

APPENDIX 2

Individual Maternal Clinical Signs

2-1

DEVELOPMENTAL TOXICITY fSEGMENT II) STUDY OF WR242511 IN RABBITS

INDIVIDUAL CLINICAL SIGNS 1.111-1-

STUDY: 138 GROUP: 1-F SEX: FEMALE DAY 6-DAY 29 DOSE: 0 (mg base/kg/day)

ANIMAL # OBSERVATIONS SEVERITY LOC TIME OCCURRED

4 01 Normal DAY 6-DAY 28 Scheduled Sacrifice DAY 2 9

402 Normal DAY 6-DAY 28 Scheduled Sacrifice DAY 29



4 05 Normal DAY 6-DAY 28 Scheduled Sacrifice DAY 29




4 09 Normal DAY 6-DAY 2 8 Scheduled Sacrifice DAY 29




413 Normal DAY 6-DAY 28 Scheduled Sacrifice DAY 2 9

2-2


INDIVIDUAL CLINICAL SIGNS MA.ll

STUDY: 138 GROUP: 1-F SEX: FEMALE DAY 6-DAY 29 DOSE: 0 (mg base/kg/day)









2-3


IM- &v r? TT p-tt INDIVIDUAL CLINICAL SIGNS

STUDY: 138 DAY 6-DAY 29

ANIMAL # OBSERVATIONS

GROUP: 2-F SEX: FEMALE DOSE: 0.5 (mg baae/kg/day)

SEVERITY LOC TIME OCCURRED

421 Normal Scheduled Sacrifice









43 0 Normal Scheduled Sacrifice




DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 2 9

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

2-4

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR24 2 511 IN RABBITS.

MM1 INDIVIDUAL CLINICAL SIGNS

STUDY: 138 DAY 6-DAY 29


GROUP: 2-F SEX: FEMALE DOSE: 0.5(mg base/kg/day)


4 34 Normal Scheduled

435 Normal Scheduled






Sacrifice

Sacrifice

Sacrifice

Sacrifice

Sacrifice

Sacrifice

Sacrifice

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29

DAY 6-DAY 28 DAY 29


DAY 6-DAY 2 8 DAY 29

DAY 6-DAY 28 DAY 29

2-5

DEVELOPMENTAL TOXICITY (SEGMENT ZI) STUDY OF WR242511 IN RABBITS „ _ _

Mih^l INDIVIDUAL CLINICAL SIGNS

STUDY: 138 GROUP: 3-F SEX: FEMALE DAY 6-DAY 29 DOSE: 1.3(mg base/kg/day)








447 Normal DAY 6-DAY 2 8 Scheduled Sacrifice DAY 29






453 Animal Aborted/Sacrificed DAY 27 Normal DAY 6-DAY 26

2-6


alii 1;

NBIV: CNDIVIE

STUDY: 138 GROUP: 3-F SEX: FEMALE DAY 6-DAY 29 DOSE: 1.3(mg base/kg/day)









2-7


INDIVIDUAL CLINICAL SIGNS

STUDY: 138 GROUP: 4-F SEX: FEMALE DAY 6-DAY 29 DOSE: 3.5 (mg base/kg/day)




463 Normal DAY 6-DAY 28 Scheduled Sacrifice DAY 2 9



4 66 Normal DAY 6-DAY 28 Premature Delivery DAY 29








2-8


1.1111. INDIVIDUAL CLINICAL SIGNS

STUDY: 138 GROUP: 4-F SEX: FEMALE DAY 6-DAY 29 DOSE: 3.5 (mg base/kg/day)









2-9

DEVELOPMENTAL TOXICITY fSEGMENT II) STUDY OF WR24 2 511 IN RABBITS

INDIVIDUAL CLINIC SMli. STUDY: 138 DAY 6-DAY 29


GROUP: 5-F DOSE: 300 (mg/kg/day)'

SEX: FEMALE


481 Normal . . Scheduled Sacrifice

482 Normal . . Scheduled Sacrifice







489 Animal Aborted/Sacrificed Normal





DAY 9-DAY 28 DAY 29

DAY 9-DAY 28 DAY 29

DAY 9-DAY 28 DAY 29

DAY 9-DAY 28 DAY 29

DAY 9-DAY 28 DAY 29

DAY 9-DAY 28 DAY 29

DAY 9-DAY 28 DAY 29

DAY 9-DAY 28 DAY 29

DAY 2 2 DAY 9-DAY 23

DAY 9-DAY 28 DAY 29

DAY 9-DAY 28 DAY 29


DAY 9-DAY 28 DAY 29


2-10


1.S1I..I- INDIVIDUAL CLINICAL SIGNS

STUDY: 138 GROUP: 5-F SEX: FEMALE DAY 6-DAY 29 DOSE: 300 (mg/kg/day)a










2-11

DEVELOPMENTAL TOXICITY (SEGMENT ZI) STUDY OF WR242511 IN RABBITS

STUDY: 138

PER100

INCIDENCE OF OB/S.ERWJ

SEX: F

DOSE: (mg base/kg/day) 0 GROUP: 1-F

0.5 2-F

1.3 3-F

3.5 4-F

300 mg/kg/day 5-F

DAY 6 No. Observed Normal








DAY H No. Observed Normal


20 20 20 20 20 100X 20 100X 20 100X 20 100X

20 20 100X

20 20 100X

20 20 100X

20 20 100X

20 20 100X

20 20 100X

20 20 100X

20 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X


2-12

DEVELOPMENTAL TOXICITY (SEGMENT II) " HR242511 IN RABBITS

SMT INCIDENCE OF OBSERVATIONS

SEX: FEMALE

DOSE: (mg base/kg/day) 0 0.5 1.3 3.5 300 mg/kg/daya

GROUP: 1-F 2-F 3-F 4-F 5-F

STUDY: 138

PERIOD







DAY 22 No. Observed Normal Animal Aborted/Sacrificed




20 20 20 20 20 20 100X 20 100X 20 100X 20 100X . 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X 0 0 0 0 1 5X

20 20 20 20 20 20 100X 20 100X 20 100X 20 100X 20 100X

20 20 20 20 19 20 100X 20 100X 20 100X 20 100X 19 100X

20 20 20 20 19 20 100X 20 100X 20 100X 20 100X 19 100X


2-13


INCIDENCE OF OBSERVATION;


M-Mf DOSE: (mg base/kg/day) o 0.5 1.3 3.5 300 mg/kg/daya

PERIOD GROUP: 1-F 2-F 3-F 4-F 5-F

DAY 26 No. Observed 20 20 20 20 19 Normal 20 100% 20 100% 20 100% 20 100% 19 100%

DAY 27 No. Observed 20 20 20 20 19 Normal 20 100% 20 100% 19 95% 20 100% 19 100% Animal Aborted/Sacrificed 0 0 1 5% 0 0

DAY 28 No. Observed 20 20 19 20 19 Normal 20 100% 20 100% 19 100% 20 100% 19 100%

DAY 29 No. Observed 20 20 19 20 19 Scheduled Sacrifice 20 100% 20 100% 19 100% 19 95% 19 100% Premature Delivery 0 0 0 1 5% 0

Retinol Pa Imitate given on GD9 and GD10 only

2-14

Ban

APPENDIX 3

Individual Maternal Body Weight and Weight Gain Data

3-1

DEVE DM TAL TOXICITY (SEGMENT II) OF WR242511 IN RABBITS

INDIVIDUAL BODY WEIGHTS (Kilograms)

FEMALE STUDY: 138

ANIMAL # DAY 0 DAY 5 DAY 6

GROUP: 1-F SEX DOSE: 0(mg base/kg/day)

DAY 7 DAY 8 DAY 9 DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15

401 3.69 3.49 3.59 3.40 3.45 3.41 3.50 3.46 3.51 3.57 3.61 3.64 402 3.79 3.66 3.59 3.61 3.59 3.69 3.73 3.74 3.82 3.84 3.82 3.88 403 3.64 3.41 3.49 3.34 3.44 3.40 3.43 3.51 3.55 3.56 3.59 3.54 404 3.06 3.13 3.06 2.98 3.02 3.03 3.05 3.04 3.08 3.06 3.15 3.16 405 3.52 3.42 3.46 3.25 3.32 3.37 3.33 3.41 3.39 3.38 3.43 3.47 406 3.76 3.63 3.55 3.56 3.60 3.57 3.63 3.61 3.69 3.72 3.74 3.81 407 3.52 3.38 3.35 3.41 3.38 3.37 3.38 3.37 3.40 3.30 3.44 3.48 408 3.72 3.54 3.45 3.51 3.51 3.49 3.55 3.43 3.45 3.51 3.49 3.49 409 3.28 3.03 2.99 3.03 3.03 3.06 3.08 3.07 3.07 3.06 3.11 3.12 410 3.36 3.18 3.12 3.09 3.08 3.07 3.09 3.11 3.10 3.10 3.12 3.17 411 3.42 3.34 3.32 3.26 3.27 3.29 3.33 3.32 3.32 3.25 3.35 3.42 412 3.14 3.12 2.92 2.99 3.02 3.10 3.01 3.11 3.12 3.10 3.13 3.13 413 3.84 3.70 3.61 3.54 3.56 3.62 3.72 3.70 3.68 3.74 3.84 3.84 414 3.82 3.60 3.67 3.64 3.71 3.72 3.75 3.76 3.75 3.79 3.88 3.93 415 3.60 3.42 3.49 3.46 3.50 3.47 3.50 3.48 3.54 3.57 3.56 3.58 416 3.45 3.48 3.43 3.37 3.38 3.43 3.42 3.49 3.38 3.45 3.50 3.52 417 3.25 3.11 3.09 3.10 3.09 3.11 3.10 3.09 3.12 3.11 3.16 3.15 418 3.60 3.56 3.46 3.51 3.54 3.49 3.49 3.52 3.54 3.59 3.61 3.62 419 3.72 3.78 3.68 3.69 3.67 3.67 3.69 3.67 3.75 3.79 3.79 3.79 420 3.42 3.33 3.31 3.28 3.26 3.27 3.26 3.27 3.29 3.32 3.33 3.36

MEAN 3.53 3.42 3.38 3.35 3.37 3.38 3.40 3.41 3.43 3.44 3.48 3.51 S.D. 0.229 0.215 0.231 0.222 0.226 0.220 0.242 0.232 0.243 0.267 0.258 0.264 N 20 20 20 20 20 20

Data Unava 20

ilable 20 20 20 20 20

3-2


MM INDIVIDUAL BODY WEIGHTS (Kilograms)

FEMALE STUDY: 138 GROUP: 1-F SEX: DOSE: 0 (mg base/kg/day)

ANIMAL # DAY 16 DAY 17 DAY 18 DAY 24 DAY 29

401 3.67 3.67 3.65 3.71 3.78 402 3.87 3.88 3.86 4.02 4.07 403 3.60 3.66 3.59 3.71 3.75 404 3.17 3.17 3.19 3.30 3.31 405 3.45 3.46 3.46 3.55 3.62 406 3.82 3.74 3.81 4.01 4.02 407 3.51 3.48 3.48 3.58 3.60 408 3.52 3.49 3.48 3.50 3.48 409 3.11 3.10 3.10 3.21 3.24 410 3.21 3.20 3.20 3.30 3.31 411 3.39 3.40 3.44 3.51 3.54 412 3.20 3.16 3.19 3.34 3.34 413 3.84 3.84 3.85 3.81 3.91 414 3.96 3.93 3.92 3.97 3.99 415 3.57 3.61 3.62 3.72 3.70 416 3.55 3.54 3.56 3.77 3.83 417 3.18 3.18 3.18 3.27 3.31 418 3.66 3.59 3.59 3.69 3.84 419 3.78 3.82 3.79 3.80 3.88 420 3.35 3.37 3.34 3.42 3.57

MEAN 3.52 3.51 3.52 3.61 3.65 S.D. 0.260 0.260 0.255 0.251 0.262 N 20 20 20 20 20

--: Data Unavailabl e

3-3


I.11I1 INDIVIDUAL BODY WEIGHTS (Kilograms)

STUDY: 138




421 3.50 3.48 3.52 3.32 3.42 3.55 3.42 3.48 3.54 3.53 3.60 3.65 422 3.42 3.21 3.33 3.23 3.26 3.25 3.24 3.21 3.27 3.30 3.32 3.34 423 3.68 3.42 3.53 3.42 3.40 3.41 3.41 3.46 3.47 3.51 3.54 3.59 424 425 426

3.48 3.30 3.42 3.32 3.30 3.33 3.32 3.35 3.39 3.42 3.41 3.46

3.46 3.26 3.23 3.25 3.24 3.25 3.25 3.31 3.31 3.30 3.34 3.33 427 3.64 3.65 3.49 3.56 3.63 3.57 3.63 3.70 3.67 3.71 3.76 3.79 428 3.56 3.44 3.51 3.31 3.36 3.37 3.37 3.40 3.37 3.43 3.45 3.44 429 3.17 3.06 3.00 3.05 3.06 3.07 3.08 3.09 3.15 3.18 3.23 3.24 430 3.62 3.39 3.36 3.41 3.45 3.37 3.48 3.53 3.57 3.51 3.57 3.59 431 3.78 3.63 3.67 3.71 3.66 3.68 3.61 3.66 3.76 3.72 3.76 3.79 432 3.44 3.44 3.26 3.38 3.36 3.40 3.41 3.45 3.46 3.52 3.61 3.70 433 3.78 3.66 3.69 3.69 3.65 3.65 3.66 3.66 3.69 3.73 3.75 3.77 434 3.34 3.34 3.22 3.29 3.29 3.34 3.33 3.30 3.38 3.36 3.45 3.51 435 3.38 3.10 3.06 3.09 3.15 3.15 3.16 3.20 3.22 3.23 3.26 3.27 436 4.08 3.89 3.87 3.80 3.78 3.82 3.86 3.83 3.85 3.85 3.87 3.84 437 3.40 3.45 3.42 3.38 3.39 3.33 3.35 3.38 3.42 3.41 3.47 3.51 438 3.82 3.66 3.70 3.69 3.71 3.66 3.73 3.66 3.74 3.74 3.76 3.80 439 3.12 2.94 3.00 2.96 2.97 2.99 3.00 2.99 3.01 3.04 3.07 3.09 440 3.35 3.31 3.29 3.20 3.26 3.30 3.20 3.26 3.31 3.32 3.29 3.32

MEAN 3.53 3.40 3.40 3.37 3.39 3.39 3.40 3.42 3.45 3.46 3.50 3.53 S.D. 0.234 0.235 0.242 0.232 0.221 0.217 0.225 0.221 0.223 0.216 0.219 0.223 N 19 19 19 19 19 19

Data Unava 19

liable 19 1° 19 19 19

3-4


mil INDIVIDUAL BODY WEIGHTS (Kilograms)

STUDY: 138

ANIMAL «

GROUP: 2-F SEX: DOSE: 0.5(mg base/kg/day) DAY 16 DAY 17 DAY 18 DAY 24 DAY 29

FEMALE

421 3.64 3.66 3.63 3.88 3.87 422 3.35 3.35 3.34 3.40 3.28 423 3.62 3.57 3.57 3.65 3.70 424 3.44 3.47 3.48 3.36 3.51 425 -- -- -- -- b 426 3.36 3.34 3.35 3.45 3.48 427 3.80 3.82 3.79 3.95 4.00 428 3.49 3.47 3.47 3.60 3.62 429 3.28 3.27 3.22 3.27 3.33 430 3.63 3.69 3.65 3.66 3.67 431 3.85 3.88 3.90 3.86 3.90 432 3.73 3.78 3.75 3.74 3.79 433 3.81 3.85 3.86 3.88 3.92 434 3.42 3.44 3.45 3.58 3.62 435 3.31 3.29 3.33 3.14 3.45 436 3.87 3.92 3.87 3.99 3.99 437 3.53 3.61 3.60 3.62 3.71 438 3.81 3.78 3.75 3.78 3.82 439 3.13 3.08 3.12 3.22 3.39 440 3.39 3.34 3.38 3.52 3.56

MEAN 3.55 3.56 3.55 3.61 3.66 S.D. 0.222 0.244 0.230 0.253 0.221 N 19 19 19 19 19

-- Data Unava table b: Scheduled Sac rifice

3-5


s s a IF If INDIVIDUAL BODY WEIGHTS (Kilograms

STUDY: 138 GROUP: 3 -F SEX: FEMALE DOSE: 1 .3 (mg base /kg/day)

ANIMAL # DAY 0 DAY 5 DAY 6 DAY 7 DAY 8 DAY 9 DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15

441 3.50 3.45 3.56 3.54 3.52 3.47 3.39 3.50 3.54 3.68 3.59 3.75 442 3.23 3.00 3.17 3.13 3.10 3.12 3.12 3.16 3.18 3.21 3.27 3.23 443 3.80 3.75 3.84 3.77 3.73 3.73 3.76 3.72 3.83 3.89 3.84 3.90 444 3.55 3.34 3.35 3.31 3.28 3.34 3.35 3.37 3.40 3.45 3.46 3.51 445 3.63 3.45 3.41 3.36 3.45 3.38 3.38 3.43 3.54 3.58 3.63 3.67 446 3.43 3.42 3.21 3.13 3.15 3.26 3.27 3.35 3.39 3.40 3.46 3.43 447 3.17 3.08 3.03 3.03 3.03 3.00 3.01 3.05 3.07 3.08 3.08 3.08 448 3.52 3.34 3.33 3.37 3.34 3.37 3.39 3.41 3.45 3.49 3.54 3.55 449 3.62 3.57 3.39 3.39 3.43 3.40 3.38 3.42 3.46 3.49 3.52 3.52 450 3.45 3.27 3.24 3.31 3.35 3.38 3.37 3.39 3.39 3.38 3.38 3.40 451 4.06 3.92 4.02 3.97 3.88 3.95 3.95 4.00 4.00 4.02 4.01 4.07 452 3.25 3.04 3.15 3.10 3.15 3.12 3.08 3.13 3.18 3.22 3.26 3.28 453 3.83 3.38 3.53 3.49 3.49 3.52 3.52 3.54 3.57 3.62 3.64 3.70 454 3.59 3.43 3.47 3.45 3.45 3.46 3.45 3.47 3.51 3.55 3.59 3.61 455 3.89 3.50 3.47 3.53 3.57 3.55 3.52 3.59 3.57 3.63 3.60 3.67 456 3.88 3.75 3.69 3.72 3.66 3.72 3.68 3.70 3.77 3.78 3.80 3.81 457 3.18 3.06 3.04 3.07 3.00 3.06 3.06 3.06 3.12 3.13 3.17 3.21 458 3.38 3.31 3.26 3.27 3.28 3.33 3.32 3.31 3.32 3.30 3.34 3.36 459 3.55 3.42 3.39 3.43 3.36 3.42 3.40 3.39 3.40 3.45 3.46 3.46 460 3.83 3.70 3.59 3.66 3.68 3.75 3.81 3.79 3.65 3.69 3.86 3.81

MEAN 3.57 3.41 3.41 3.40 3.40 3.42 3.41 3.44 3.47 3.50 3.53 3.55 S.O. 0.256 0.250 0.253 0.251 0.240 0.245 0.250 0.243 0.236 0.247 0.239 0.253 N 20 20 20 20 20 20 20 20 20 20 20 20

--: Data Unava ilable

3-6


INDIVID (Kilograms)

STUDY: 138

ANIMAL #

GROUP: 3-F SEX: FEMALE DOSE: 1.3 (lag baae/lcg/day) DAY 16 DAY 17 DAY 18 DAY 24 DAY 29

441 3.71 3.71 3.67 3.81 3.85 442 3.25 3.27 3.28 3.37 3.44 443 3.85 3.89 3.88 3.93 4.02 444 3.49 3.53 3.50 3.65 3.70 445 3.65 3.63 3.65 3.77 3.89 446 3.48 3.43 3.43 3.47 3.51 447 3.08 3.11 3.11 3.15 3.18 448 3.55 3.53 3.52 3.63 3.67 449 3.47 3.50 3.48 3.60 3.65 450 3.41 3.43 3.42 3.58 3.61 451 4.02 4.06 4.05 4.23 4.21 452 3.32 3.35 3.27 3.40 3.52 453 3.69 3.64 3.62 3.08 -- 454 3.60 3.62 3.60 3.45 3.66 455 3.66 3.67 3.63 3.73 3.71 456 3.83 3.87 3.82 3.84 3.82 457 3.21 3.19 3.16 3.22 3.29 458 3.35 3.35 3.35 3.44 3.52 459 3.53 3.55 3.51 3.61 3.67 460 3.84 3.78 3.76 3.91 3.98

MEAN 3.55 3.56 3.54 3.59 3.68 S.D. 0.240 0.241 0.239 0.284 0.250 N 20 20 20 20 19

--: Data UnavailabI e

3-7


mM.l INDIVIDUAL BODY WEIGHTS (Kilograms)

STUDY: 138




461 3.70 3.65 3.62 3.59 3.58 3.54 3.52 3.53 3.58 3.64 3.69 3.73 462 3.42 3.31 3.42 3.24 3.25 3.27 3.26 3.31 3.35 3.37 3.42 3.48 463 464 465

3.40 3.20 3.32 3.25 3.23 3.25 3.13 3.28 3.30 3.33 3.35 3.31

3.66 3.49 3.54 3.51 3.45 3.48 3.42 3.52 3.52 3.44 3.59 3.62 466 3.59 3.55 3.43 3.53 3.51 3.52 3.45 3.57 3.60 3.63 3.65 3.61 467 3.36 3.28 3.27 3.25 3.23 3.26 3.25 3.26 3.26 3.29 3.34 3.34 468 3.56 3.39 3.39 3.46 3.46 3.39 3.47 3.45 3.48 3.54 3.62 3.70 469 3.54 3.45 3.42 3.43 3.43 3.50 3.48 3.51 3.49 3.49 3.52 3.49 470 3.30 3.12 3.16 3.09 3.16 3.14 3.13 3.14 3.17 3.19 3.23 3.25 471 3.80 3.60 3.62 3.60 3.62 3.62 3.60 3.61 3.64 3.67 3.70 3.76 472 3.35 3.16 3.13 3.21 3.20 3.22 3.24 3.22 3.22 3.27 3.31 3.34 473 3.82 3.65 3.67 3.66 3.70 3.64 3.71 3.71 3.71 3.69 3.73 3.74 474 3.48 3.40 3.37 3.41 3.41 3.40 3.41 3.44 3.45 3.48 3.54 3.53 475 3.65 3.49 3.62 3.59 3.57 3.63 3.68 3.72 3.70 3.75 3.75 3.77 476 3.64 3.52 3.44 3.45 3.48 3.45 3.47 3.36 3.49 3.49 3.55 3.55 477 4.11 3.82 3.72 3.72 3.72 3.73 3.80 3.77 3.80 3.84 3.84 3.88 478 3.58 3.22 3.25 3.42 3.22 3.39 3.24 3.42 3.41 3.22 3.29 3.38 479 3.26 3.26 3.24 3.21 3.13 3.12 3.13 3.14 3.22 3.23 3.21 3.22 480 3.61 3.49 3.52 3.40 3.44 3.42 3.35 3.40 3.49 3.45 3.32 3.39

MEAN 3.57 3.42 3.43 3.42 3.41 3.42 3.41 3.44 3.47 3.47 3.51 3.53 S.D. 0.206 0.189 0.174 0.175 0.184 0.175 0.200 0.188 0.181 0.192 0.194 0.198 N 19 19 19 19 19 19 19 19 19 19 19 19

--: Data UnavaiI able

3-8

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 Ijt RABBITS

Mill INDIVIDUAL BODY WEIGHTS (Kilograms)

STUDY: 138 GROUP; DOSE:

ANIMAL U DAY 16

4-F , SEX: 3 . 5(mg base/kg/day)

DAY 17 DAY 18 DAY 24 DAY 29

FEMALE

461 3.74 3.72 3.76 3.76 3.81 462 3.48 3.47 3.48 3.58 3.57 463 3.37 3.33 3.27 3.36 3.38 464 -- -- -- -- b 465 3.61 3.65 3.64 3.75 3.79 466 3.70 3.69 3.70 3.72 3.74 467 3.36 3.35 3.36 3.46 3.48 468 3.67 3.63 3.61 3.70 3.71 469 3.50 3.56 3.53 3.58 3.65 470 3.27 3.26 3.25 3.38 3.40 471 3.75 3.79 3.78 4.05 3.91 472 3.36 3.37 3.36 3.49 3.51 473 3.79 3.85 3.86 4.01 4.05 474 3.55 3.55 3.58 3.64 3.68 475 3.85 3.76 3.83 3.85 3.86 476 3.57 3.53 3.53 3.67 3.79 477 3.87 3.91 3.90 3.92 4.04 478 3.45 3.48 3.42 3.54 3.64 479 3.24 3.22 3.22 3.36 3.41 480 3.21 3.14 3.03 3.10 3.26

MEAN 3.54 3.54 3.53 3.63 3.67 S.D. 0.208 0.221 0.243 0.242 0.223 S 19 19 19 19 19

--: Data Unava table b: Scheduled Sacrifice

3-9

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 INKRABBITS

miii INDIVIDUAL BODY WEIGHTS (Kilograms)

STUDY: 138


GROUP: 5-F a SEX: FEMALE DOSE: 300 (mg/kgAday)a

DAY 7 DAY 8 DAY 9 DAY 10 DAY 11 OAY 12 DAY 13 DAY 14 DAY 15

481 3.65 3.42 3.49 3.43 3.39 3.46 3.39 3.38 3.45 3.50 3.56 3.58 482 3.21 3.06 3.18 3.09 3.11 3.11 3.09 3.10 3.13 3.11 3.13 3.12 483 3.57 3.32 3.44 3.38 3.37 3.40 3.37 3.35 3.38 3.47 3.48 3.45 484 485 486

3.99 3.68 3.90 3.82 3.84 3.84 3.73 3.71 3.75 3.80 3.84 3.91

3.72 3.72 3.65 3.61 3.69 3.71 3.62 3.62 3.65 3.72 3.73 3.87 487 3.19 3.01 2.92 2.94 2.98 2.99 3.00 3.01 2.97 2.99 2.99 2.98 488 3.50 3.43 3.43 3.39 3.45 3.44 3.41 3.39 3.44 3.46 3.49 3.54 489 490

3.37 3.33 3.12 3.14 3.15 3.15 3.20 3.21 3.20 3.23 3.27 3.33

491 492 3.52 3.43 3.32 3.43 3.53 3.52 3.47 3.48 3.49 3.56 3.59 3.62 493 3.29 3.27 3.25 3.20 3.20 3.35 3.30 3.22 3.27 3.32 3.35 3.36 494 3.26 3.13 3.18 3.15 3.10 3.17 3.16 3.13 3.12 3.21 3.29 3.34 495 3.99 3.89 4.02 3.96 3.90 3.95 3.90 3.85 3.93 3.97 3.99 4.11 496 3.80 3.82 3.79 3.78 3.76 3.79 3.77 3.77 3.81 3.83 3.84 3.89 497 3.62 3.44 3.48 3.41 3.45 3.46 3.47 3.49 3.51 3.57 3.54 3.61 498 3.70 3.51 3.47 3.56 3.54 3.53 3.59 3.56 3.55 3.62 3.60 3.64 499 3.31 3.13 3.10 3.13 3.13 3.18 3.12 3.16 3.18 3.19 3.26 3.28 500 3.57 3.37 3.37 3.47 3.40 3.40 3.37 3.36 3.39 3.39 3.42 3.45

MEAN 3.54 3.41 3.42 3.41 3.41 3.44 3.41 3.40 3.42 3.47 3.49 3.53 S.D. 0.251 0.257 0.295 0.281 0.277 0.271 0.254 0.246 0.264 0.272 0.265 0.296 N 17 17 17 17 17 17

Data Unava 17

ilable 17 17 17 17 17

Retinol Palmitate given on GD9 and GDIO only

3-10


INDIVIDUAL BODY WEIGHTS

STUDY: 138

ANIMAL #

GROUP: 5-F - SEX: FEMALE DOSE: 300 (mg/kg/day)a

DAY 16 DAY 17 DAY 18 DAY 24 DAY 29

481 3.56 3.52 3.52 3.59 3.66 482 3.18 3.16 3.14 3.20 3.21 483 3.45 3.44 3.44 3.44 3.59 484 3.99 4.01 3.99 3.99 4.01 485 -- -- -- -- b 486 3.94 3.84 3.85 3.84 3.87 487 2.97 2.99 3.01 3.02 3.03 488 3.54 3.54 3.53 3.57 3.59 489 3.34 3.29 3.28 d d 490 -- -- -- -- b 491 -- -- -- -- b 492 3.64 3.72 3.63 3.68 3.68 493 3.34 3.37 3.35 3.48 3.55 494 3.32 3.29 3.30 3.39 3.45 495 4.17 4.07 4.18 3.96 3.96 496 3.84 3.85 3.83 3.90 3.99 497 3.65 3.65 3.65 3.76 3.76 498 3.70 3.68 3.68 3.74 3.86 499 3.28 3.30 3.29 3.35 3.49 500 3.46 3.45 3.46 3.39 3.51

MEAN 3.55 3.54 3.54 3.58 3.64 S.D. 0.312 0.299 0.308 0.278 0.274 N 17 17 17 16 16

Data Unavailabl e b: Scheduled Sacrif ice d: Sacrificed Moribund


3-11

I DEVELC 5PMENTA L Toxicnm fj£$E9 SENT II) STUDY OF WR24251S, m 3BIfflS F

INDIVIDUAL WEIGHT GAIN (Kilograms)3

STUDY: 138 GROUP: 1-F SEX: FEMALE DOSE: 0(mg base /kg/day)

ANIMAL # DAY7b DAY 8 DAY 9 DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 DAY 17

401 -0.19 0.05 -0.04 0.09 -0.04 0.05 0.06 0.04 0.03 0.03 0.00 402 0.02 -0.02 0.10 0.04 0.01 0.08 0.02 -0.02 0.06 -0.01 0.01 403 -0.15 0.10 -0.04 0.03 0.08 0.04 0.01 0.03 -0.05 0.06 0.06 404 -0.08 0.04 0.01 0.02 -0.01 0.04 -0.02 0.09 0.01 0.01 0.00 405 -0.21 0.07 0.05 -0.04 0.08 -0.02 -0.01 0.05 0.04 -0.02 0.01 406 0.01 0.04 -0.03 0.06 -0.02 0.08 0.03 0.02 0.07 0.01 -0.08 407 0.06 -0.03 -0.01 0.01 -0.01 0.03 -0.10 0.14 0.04 0.03 -0.03 408 0.06 0.00 -0.02 0.06 -0.12 0.02 0.06 -0.02 0.00 0.03 -0.03 409 0.04 0.00 0.03 0.02 -0.01 0.00 -0.01 0.05 0.01 -0.01 -0.01 410 -0.03 -0.01 -0.01 0.02 0.02 -0.01 0.00 0.02 0.05 0.04 -0.01 411 -0.06 0.01 0.02 0.04 -0.01 0.00 -0.07 0.10 0.07 -0.03 0.01 412 0.07 0.03 0.08 -0.09 0.10 0.01 -0.02 0.03 0.00 0.07 -0.04 413 -0.07 0.02 0.06 0.10 -0.02 -0.02 0.06 0.10 0.00 0.00 0.00 414 -0.03 0.07 0.01 0.03 0.01 -0.01 0.04 0.09 0.05 0.03 -0.03 415 -0.03 0.04 -0.03 0.03 -0.02 0.06 0.03 -0.01 0.02 -0.01 0.04 416 -0.06 0.01 0.05 -0.01 0.07 -0.11 0.07 0.05 0.02 0.03 -0.01 417 0.01 -0.01 0.02 -0.01 -0.01 0.03 -0.01 0.05 -0.01 0.03 0.00 418 0.05 0.03 -0.05 0.00 0.03 0.02 0.05 0.02 0.01 0.04 -0.07 419 0.01 -0.02 0.00 0.02 -0.02 0.08 0.04 0.00 0.00 -0.01 0.04 420 -0.03 -0.02 0.01 -0.01 0.01 0.02 0.03 0.01 0.03 -0.01 0.02

MEAN -0.03 0.02 0.01 0.02 0.01 0.02 0.01 0.04 0.02 0.02 -0.01 S.O. 0.080 0.035 0.042 0.043 0.050 0.044 0.044 0.044 0.030 0.O27 0.035 N 20 20 20 20 20 20 20 20 20 20 20

- -: Data Unavailable

Successive periods

Baseline is day 6

3-12

DEVELOPMENTAL TOXICITY (SEGME^Tr STUDY OF WR242511 IN RABBITS

INDIVIDUAL WEIGHT GAIN (Kilograms)

FEMALE STUDY: 138 GROUP: 1-F SEX: DOSE: 0 (mg base/kg/day)

TOTAL ANIMAL U DAY 18 DAY 24 DAY 29 GAIN

401 -0.02 0.06 0.07 0.19 402 -0.02 0.16 0.05 0.48 403 -0.07 0.12 0.04 0.26 404 0.02 0.11 0.01 0.25 405 0.00 0.09 0.07 0.16 406 0.07 0.20 0.01 0.47 407 0.00 0.10 0.02 0.25 408 -0.01 0.02 -0.02 0.03 409 0.00 0.11 0.03 0.25 410 0.00 0.10 0.01 0.19 411 0.04 0.07 0.03 0.22 412 0.03 0.15 0.00 0.42 413 0.01 -0.04 0.10 0.30 414 -0.01 0.05 0.02 0.32 415 0.01 0.10 -0.02 0.21 416 0.02 0.21 0.06 0.40 417 0.00 0.09 0.04 0.22 418 0.00 0.10 0.15 0.38 419 -0.03 0.01 0.08 0.20 420 -0.03 0.08 0.15 0.26

MEAN 0.00 0.09 0.05 0.27 S.D. 0.029 0.060 0.048 0.112 N 20 20 20 20

Data Unava itable b: Scheduled Sacrifice

Successive periods

3-13

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 IN RABB^TE^)

ill m IF i INDIVIDUAL WEIGHT GAIN (Kilograms)3

STUDY: 138 GROUP: 2-F SEX: FEMALE DOSE: 0.5 (mg baa e/kg/day)

ANIMAL # DAY 7b DAY 8 DAY 9 DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 DAY 17

421 -0.20 0.10 0.13 -0.13 0.06 0.06 -0.01 0.07 0.05 -0.01 0.02 422 -0.10 0.03 -0.01 -0.01 -0.03 0.06 0.03 0.02 0.02 0.01 0.00 423 -0.11 -0.02 0.01 0.00 0.05 0.01 0.04 0.03 0.05 0.03 -0.05 424 425 426

-0.10 -0.02 0.03 -0.01 0.03 0.04 0.03 -0.01 0.05 -0.02 0.03

0.02 -0.01 0.01 0.00 0.06 0.00 -0.01 0.04 -0.01 0.03 -0.02 427 0.07 0.07 -0.06 0.06 0.07 -0.03 0.04 0.05 0.03 0.01 0.02 428 -0.20 0.05 0.01 0.00 0.03 -0.03 0.06 0.02 -0.01 0.05 -0.02 429 0.05 0.01 0.01 0.01 0.01 0.06 0.03 0.05 0.01 0.04 -0.01 430 0.05 0.04 -0.08 0.11 0.05 0.04 -0.06 0.06 0.02 0.04 0.06 431 0.04 -0.05 0.02 -0.07 0.05 0.10 -0.04 0.04 0.03 0.06 0.03 432 0.12 -0.02 0.04 0.01 0.04 0.01 0.06 0.09 0.09 0.03 0.05 433 0.00 -0.04 0.00 0.01 0.00 0.03 0.04 0.02 0.02 0.04 0.04 434 0.07 0.00 0.05 -0.01 -0.03 0.08 -0.02 0.09 0.06 -0.09 0.02 435 0.03 0.06 0.00 0.01 0.04 0.02 0.01 0.03 0.01 0.04 -0.02 436 -0.07 -0.02 0.04 0.04 -0.03 0.02 0.00 0.02 -0.03 0.03 0.05 437 -0.04 0.01 -0.06 0.02 0.03 0.04 -0.01 0.06 0.04 0.02 0.08 438 -0.01 0.02 -0.05 0.07 -0.07 0.08 0.00 . 0.02 0.04 0.01 -0.03 439 -0.04 0.01 0.02 0.01 -0.01 0.02 0.03 0.03 0.02 0.04 -0.05 440 -0.09 0.06 0.04 -0.10 0.06 0.05 0.01 -0.03 0.03 0.07 -0.05

MEAN -0.03 0.01 0.01 0.00 0.02 0.03 0.01 0.04 0.C3 0.02 0.01 S.O. 0.090 0.040 0.048 0.055 0.039 0.035 0.032 0.030 0.028 0.035 0.040 N 19 19 19 19 19

-: Data 19

Unavailab I 19

e 19 19 19 19

"Successive periods

Baseline is day 6

3-14

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 IN RABBITS-

IIA IF IF INDIVIDUAL WEIGHT GAIN (Kilograms)3

STUDY: 138 GROUP: 2-F SEX: DOSE: 0.5(mg base/kg/day)

TOTAL ANIMAL # DAY 18 DAY 24 DAY 29 GAIN

FEMALE

421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440

-0.03 -0.01 0.00 0.01

0.01 -0.03 0.00

-0.05 04 02 03 01 01 04 05

-0.01 -0.03 0.04 0.04

0.25 0.06 0.08

-0.12

0.10 0.16 0.13 0.05 0.01

-0.04 -0.01 0.02 0.13

-0.19 0.12 0.02 0.03 0.10 0.14

-0.01 -0.12 0.05 0.15

b 0.03 0.05 0.02 0.06 0.01 0.04 0.05 0.04 0.04 0.31 0.00 0.09 0.04 0.17 0.04

0.35 -0.05 0.17 0.09

0.25 0.51 0.11 0.33 0.31 0.23 0.53 0.23 0.40 0.39 0.12

29 12 39 27

MEAN -0.01 S.D. 0.029 N 19

Data UnavaiI able

0.05 0.06 0.27 0.102 0.085 0.149

19 19 19 b: Scheduled Sacrifice

Successive periods

3-15

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF pm2£25H IN RABBITS

INDIVIDUAL WEIGHT GAIN (Kilograms)3

STUDY: 138 GROUP: 3-F SEX: FEMALE

DAY 7

DOSE: 1.3 (mg has e/kg/day)

ANIMAL # DAY 8 DAY 9 DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 DAY 17

441 -0.02 -0.02 -0.05 -0.08 0.11 0.04 0.14 -0.09 0.16 -0.04 0.00 442 -0.04 -0.03 0.02 0.00 0.04 0.02 0.03 0.06 -0.04 0.02 0.02 443 -0.07 -0.04 0.00 0.03 -0.04 0.11 0.06 -0.05 0.06 -0.05 0.04 444 -0.04 -0.03 0.06 0.01 0.02 0.03 0.05 0.01 0.05 -0.02 0.04 445 -0.05 0.09 -0.07 0.00 0.05 0.11 0.04 0.05 0.04 -0.02 -0.02 446 -0.08 0.02 0.11 0.01 0.08 0.04 0.01 0.06 -0.03 0.05 -0.05 447 0.00 0.00 -0.03 0.01 0.04 0.02 0.01 0.00 0.00 0.00 0.03 448 0.04 -0.03 0.03 0.02 0.02 0.04 0.04 0.05 0.01 0.00 -0.02 449 0.00 0.04 -0.03 -0.02 0.04 0.04 0.03 0.03 0.00 -0.05 0.03 450 0.07 0.04 0.03 -0.01 0.02 0.00 -0.01 0.00 0.02 0.01 0.02 451 -0.05 -0.09 0.07 0.00 0.05 0.00 0.02 -0.01 0.06 -0.05 0.04 452 -0.05 0.05 -0.03 -0.04 0.05 0.05 0.04 0.04 0.02 0.04 0.03 453 -0.04 0.00 0.03 0.00 0.02 0.03 0.05 0.02 0.06 -0.01 -0.05 454 -0.02 0.00 0.01 -0.01 0.02 0.04 0.04 0.04 0.02 -0.01 0.02 455 0.06 0.04 -0.02 -0.03 0.07 -0.02 0.06 -0.03 0.07 -0.01 0.01 456 0.03 -0.06 0.06 -0.04 0.02 0.07 0.01 0.02 0.01 0.02 0.04 457 0.03 -0.07 0.06 0.00 0.00 0.06 0.01 0.04 0.04 0.00 -0.02 458 0.01 0.01 0.05 -0.01 -0.01 0.01 -0.02 0.04 0.02 -0.01 0.00 459 0.04 -0.07 0.06 -0.02 -0.01 0.01 0.05 0.01 0.00 0.07 0.02 460 0.07 0.02 0.07 0.06 -0.02 -0.14 0.04 0.17 -0.05 0.03 -0.06

MEAN -0.01 -0.01 0.02 -0.01 0.03 0.03 0.04 0.02 0.03 0.00 0.01 S.D. 0.047 0.047 0.048 0.029 0.036 0.051 0.033 0.052 0.046 0.033 0.032 N 20 20 20 20 20

-: Data 20

Unavailab I 20 20 20 20 20

Successive periods

Baseline is day 6

3-16


Mill INDIVIDUAL WEIGHT GAIN (Kilograms)3

STUDY: 138 GROUP: 3-F SEX: FEMALE DOSE: 1.3(mg base/kg/day)

ANIMAL # DAY 18 DAY 24 DAY 29 GAIN

441 -0.04 0.14 0.04 0.29 442 0.01 0.09 0.07 0.27 443 -0.01 0.05 0.09 0.18 444 -0.03 0.15 0.05 0.35 445 0.02 0.12 0.12 0.48 446 0.00 0.04 0.04 0.30 447 0.00 0.04 0.03 0.15 448 -0.01 0.11 0.04 0.34 449 -0.02 0.12 0.05 0.26 450 -0.01 0.16 0.03 0.37 451 -0.01 0.18 -0.02 0.19 452 -0.08 0.13 0.12 0.37 453 -0.02 -0.54 -- -0.45 454 -0.02 -0.15 0.21 0.19 455 -0.04 0.10 -0.02 0.24 456 -0.05 0.02 -0.02 0.13 457 -0.03 0.06 0.07 0.25 458 0.00 0.09 0.08 0.26 459 -0.04 0.10 0.06 0.28 460 -0.02 0.15 0.07 0.39

MEAN -0.02 0.06 0.06 0.24 S.O. 0.023 0.158 0.055 0.185 N 20 20 19 20

Data Unava liable b: Scheduled Sac rifice

a Successive periods

3-17


INDIVIDUAL WEIGHT GAIN (Kilograms) a

STUDY: 138 GROUP: 4-F SEX: FEMALE DOSE: 3. 5 (nig bas e/kg/day)

ANIHAL # DAY7b DAY 8 DAY 9 DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 DAY 17

461 -0.03 -0.01 -0.04 -0.02 0.01 0.05 0.06 0.05 0.04 0.01 -0.02 462 -0.18 0.01 0.02 -0.01 0.05 0.04 0.02 0.05 0.06 0.00 -0.01 463 464 465

-0.07 -0.02 0.02 -0.12 0.15 0.02 0.03 0.02 -0.04 0.06 -0.04

-0.03 -0.06 0.03 •0.06 0.10 0.00 -0.08 0.15 0.03 -0.01 0.04 466 0.10 -0.02 0.01 -0.07 0.12 0.03 0.03 0.02 -0.04 0.09 -0.01 467 -0.02 -0.02 0.03 -0.01 0.01 0.00 0.03 0.05 0.00 0.02 -0.01 468 0.07 0.00 -0.07 0.08 -0.02 0.03 0.06 0.08 0.08 -0.03 -0.04 469 0.01 0.00 0.07 -0.02 0.03 -0.02 0.00 0.03 -0.03 0.01 0.06 470 -0.07 0.07 -0.02 -0.01 0.01 0.03 0.02 0.04 0.02 0.02 -0.01 471 -0.02 0.02 0.00 -0.02 0.01 0.03 0.03 0.03 0.06 -0.01 0.04 472 0.08 -0.01 0.02 0.02 -0.02 0.00 0.05 0.04 0.03 0.02 0.01 473 -0.01 0.04 -0.06 0.07 0.00 0.00 -0.02 0.04 0.01 0.05 0.06 474 0.04 0.00 -0.01 0.01 0.03 0.01 0.03 0.06 -0.01 0.02 0.00 475 -0.03 -0.02 0.06 0.05 0.04 -0.02 0.05 0.00 0.02 0.08 -0.09 476 0.01 0.03 -0.03 0.02 -0.11 0.13 0.00 0.06 0.00 0.02 -0.04 477 0.00 0.00 0.01 0.07 -0.03 0.03 0.04 0.00 0.04 -0.01 0.04 478 0.17 -0.20 0.17 -0.15 0.18 -0.01 -0.19 0.07 0.09 0.07 0.03 479 -0.03 -0.08 -0.01 0.01 0.01 0.08 0.01 -0.02 0.01 0.02 -0.02 480 -0.12 0.04 -0.02 -0.07 0.05 0.09 -0.04 -0.13 0.07 -0.18 -0.07

MEAN -0.01 -0.01 0.01 -0.01 0.03 0.03 0.01 0.03 0.02 0.01 0.00 S.D. 0.079 0.057 0.053 0.062 0.067 0.039 0.059 0.054 0.038 0.057 0.042 N 19 19 19 19 19 19 19 19 19 19 19

--: Data Unavailabl e

Successive periods

Baseline is day 6

3-18

DEVELOPMENTAL TOXICITY (SEGMENT rij STUDY OF WR242511 IN RABBITS

INDIVIDUAL ILMJLS CJAL WEIGHTrGAPN (Kilograms)'

STUDY: 138 GROUP: 4-F SEX: DOSE: 3.5 (mg base/kg/day)

TOTAL ANIMAL # DAY 18 DAY 24 DAY 29 GAIN

FEMALE

461 0.04 0.00 0.05 0.19 462 0.01 0.10 -0.01 0.15 463 -0.06 0.09 0.02 0.06 464 -- -- b -- 465 -0.01 0.11 0.04 0.25 466 0.01 0.02 0.02 0.31 467 0.01 0.10 0.02 0.21 468 -0.02 0.09 0.01 0.32 469 -0.03 0.05 0.07 0.23 470 -0.01 0.13 0.02 0.24 471 -0.01 0.27 -0.14 0.29 472 -0.01 0.13 0.02 0.38 473 0.01 0.15 0.04 0.38 474 0.03 0.06 0.04 0.31 475 0.07 0.02 0.01 0.24 476 0.00 0.14 0.12 0.35 477 -0.01 0.02 0.12 0.32 478 -0.06 0.12 0.10 0.39 479 0.00 0.14 0.05 0.17 480 -0.11 0.07 0.16 -0.26

MEAN -0.01 0.10 0.04 0.24 S.D. 0.039 0.063 0.063 0.149 N 19 19 19 19

Data Unava liable b: Scheduled Sac rifice

Successive periods

3-19

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR24251!tTSEN--RABBITS

:TY (SEG: ft, INDIVIDUAL WEIGHT GAINcKil. jgrams^

STUDY: 138 GROUP: DOSE:

5-F 300 (mg/kg7 day)c

SEX: FEMALE

ANIMAL # DAY 7b DAY 8 DAY 9 DAY 10 DAY 11 DAY 12 DAY 13 DAY 14 DAY 15 DAY 16 DAY 17

481 -0.06 -0.04 0.07 -0.07 -0.01 0.07 0.05 0.06 0.02 -0.02 -0.04 482 -0.09 0.02 0.00 -0.02 0.01 0.03 -0.02 0.02 -0.01 0.06 -0.02 483 -0.06 -0.01 0.03 -0.03 -0.02 0.03 0.09 0.01 -0.03 0.00 -0.01 484 485 486

-0.08 0.02 0.00 -0.11 -0.02 0.04 0.05 0.04 0.07 0.08 0.02

-0.04 0.08 0.02 -0.09 0.00 0.03 0.07 0.01 0.14 0.07 -0.10 487 0.02 0.04 0.01 0.01 0.01 -0.04 0.02 0.00 -0.01 -0.01 0.02 488 -0.04 0.06 -0.01 -0.03 -0.02 0.05 0.02 0.03 0.05 0.00 0.00 489 490

0.02 0.01 0.00 0.05 0.01 -0.01 0.03 0.04 0.06 0.01 -0.05

491 492 0.11 0.10 -0.01 -0.05 0.01 0.01 0.07 0.03 0.03 0.02 0.08 493 -0.05 0.00 0.15 -0.05 -0.08 0.05 0.05 0.03 0.01 -0.02 0.03 494 -0.03 -0.05 0.07 -0.01 -0.03 -0.01 0.09 0.08 0.05 -0.02 -0.03 495 -0.06 -0.06 0.05 -0.05 -0.05 0.08 0.04 0.02 0.12 0.06 -0.10 496 -0.01 -0.02 0.03 -0.02 0.00 0.04 0.02 0.01 0.05 -0.05 0.01 497 -0.07 0.04 0.01 0.01 0.02 0.02 0.06 -0.03 0.07 0.04 0.00 498 0.09 -0.02 -0.01 0.06 -0.03 -0.01 0.07 -0.02 0.04 0.06 -0.02 499 0.03 0.00 0.05 -0.06 0.04 0.02 0.01 0.07 0.02 0.00 0.02 500 0.10 -0.07 0.00 -0.03 -0.01 0.03 0.00 0.03 0.03 0.01 -0.01

MEAN -0.01 0.01 0.03 -0.03 -0.01 0.03 0.04 C.03 0.04 0.02 -0.01 S.O. 0.064 0.048 0.041 0.045 0.028 0.031 0.031 0.029 0.044 0.038 0.045 N 17 17 17 17 17 17 17 17 17 17 17

- -: Data Unavailabl 1

Successive periods

Baseline is day 6

'Retinol Palmitate given on GD9 and GDIO only

3-20

DEVELOPMENTAL TOXICITY STUDY OF WR24251

SEGMENT II) "ITS

TY fSEGME

iff FT INDIVIDUAL WEIGHT GAIN (Kilograms)3

STUDY: 138 GROUP: 5-F DOSE: 300 (mg/kg/day)c


SEX: FEMALE

TOTAL GAIN

481 0.00 0.07 0.07 0.17 482 -0.02 0.06 0.01 0.03 483 0.00 0.00 0.15 0.15 484 -0.02 0.00 0.02 0.11 485 -- -- b -- 486 0.01 -0.01 0.03 0.22 487 0.02 0.01 0.01 0.11 488 -0.01 0.04 0.02 0.16 489 -0.01 d d -- 490 -- -- b -- 491 -- -- b -- 492 -0.09 0.05 0.00 0.36 493 -0.02 0.13 0.07 0.30 494 0.01 0.09 0.06 0.27 495 0.11 -0.22 0.00 -0.06 496 -0.02 0.07 0.09 0.20 497 0.00 0.11 0.00 0.28 498 0.00 0.06 0.12 0.39 499 -0.01 0.06 0.14 0.39 500 0.01 -0.07 0.12 0.14

MEAN 0.00 0.03 0.06 0.20 S.D. 0.038 0.083 0.053 0.127 N 17 16 16 16

Unavailable b: Scheduled Sacrif ice d: Sacrificed Moribund

Successive periods

'Retinol Palmitate given on GD9 and GD10 only

3-21

®!/*\ 11

APPENDIX 4

Individual Maternal Food Consumption Data

4-1


INDIVIDUAL DAILY l-M-I-I ILY FOOD CONSUM PTION (Grams)

STUDY: 138

ANIMAL #

GROUP: 1-F SEX: FEMALE DOSE: 0 (mg base/kg/day)

DAY 8 DAY 10 DAY 12 DAY 15 DAY 18 DAY 24 DAY 29

401 130 130 130 130 130 130 130 402 130 130 130 130 130 130 130 403 130 130 130 130 130 130 130 404 130 130 130 130 130 130 130 405 130 130 130 130 130 130 130 406 130 130 130 130 130 130 130 407 130 130 130 130 130 130 130 408 130 130 130 130 130 130 130 409 130 130 130 130 130 130 130 410 130 130 130 103 130 130 130 411 130 130 130 130 130 130 130 412 130 130 130 130 130 130 130 413 130 130 130 130 130 130 130 414 130 130 130 130 130 130 130 415 130 130 130 130 130 130 130 416 130 130 130 130 130 130 130 417 130 130 130 130 130 130 130 418 130 130 130 130 130 130 130 419 130 130 130 130 130 130 130 420 130 130 130 130 130 130 130

MEAN 130 130 130 129 130 130 130 S.D. 0.0 0.0 0.0 6.0 0.0 0.0 0.0 N 20 20 20

-: Data 20

UnavaiI able 20 20 20

U- 2


lllil INDIVIDUAL DAILY FOOD CONSUMPTION (Grams)

STUDY: 138

ANIMAL #

GROUP: 2-F SEX: FEMALE DOSE: 0.5 (mg base/kg/day)


421 130 130 130 130 130 130 130 422 130 130 130 130 130 130 130 423 130 130 130 130 130 130 130 424 130 130 130 130 130 130 130 425 -- -- -- -- -- -- -- 426 130 130 130 130 130 130 130 427 130 130 130 130 130 130 130 428 130 130 130 130 130 130 130 429 130 130 130 130 130 130 130 430 130 130 130 130 130 130 130 431 130 130 130 130 130 130 130 432 130 130 130 130 130 130 130 433 130 130 130 130 130 130 130 434 130 130 130 130 130 130 130 435 130 130 130 130 130 130 130 436 130 130 130 130 130 130 130 437 130 130 130 130 130 130 130 438 130 130 130 130 130 130 130 439 130 130 130 130 130 130 130 440 130 130 130 130 130 130 130

MEAN 130 130 130 130 130 130 130 S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 N 19 19 19 19 19 19 19

--: Data Unavailable

4-3

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR2425L1 IN RABBITS

W[? £Tr

INDIVIDUAL DAILY FOOD CONSUMPTION (Grams)

STUDY: 138 GROUP: 3-F SEX: FEMALE DOSE: 1.3(mg base/kg/day)

ANIMAL # DAY 8 DAY 10 DAY 12 DAY 15 DAY 18 DAY 24 DAY 29

441 130 130 130 130 130 130 130 442 130 130 130 130 130 130 130 443 130 130 130 130 130 130 130 444 130 130 130 130 130 130 130 445 130 130 130 130 130 130 130 446 42 130 130 101 130 130 130 447 130 130 130 130 130 130 130 446 130 130 130 130 130 130 130 449 130 130 130 130 130 130 130 450 130 130 130 130 130 130 130 451 130 130 130 130 130 130 130 452 130 130 130 130 130 130 130 453 130 130 130 130 130 130 -- 454 130 130 130 130 130 130 130 455 130 130 130 130 130 130 130 456 130 130 130 130 130 130 130 457 130 130 130 130 130 130 130 458 130 130 130 130 130 130 130 459 130 130 130 130 130 130 130 460 130 130 130 130 130 130 130

MEAN 126 130 130 129 130 130 130 S.D. 19.7 0.0 0.0 6.5 0.0 0.0 0.0 N 20 20 20

-: Data 20

UnavaiI able 20 20 19

4-4


[51 1}

INDIVIDUAL DAILY FOOD CONSUMPTION (Grams)

STUDY: 138

ANIMAL #



461 130 130 130 130 0 130 130 462 130 130 130 130 130 130 130 463 130 130 130 130 130 130 130 464 -- -- -- -- -- -- -- 465 130 130 130 130 130 130 130 466 130 130 130 130 130 130 130 467 130 130 130 130 130 130 130 468 130 130 130 130 130 130 130 469 130 130 130 130 130 130 130 470 130 130 130 130 117 130 130 471 130 130 130 130 130 130 130 472 130 130 130 130 130 130 130 473 130 130 130 130 130 130 130 474 130 130 130 130 130 130 130 475 130 130 130 130 130 130 130 476 130 130 130 130 130 130 130 477 130 130 130 130 130 130 130 478 130 130 66 130 130 130 130 479 130 130 130 130 130 130 130 480 130 130 0 100 0 130 130

MEAN 130 130 120 128 116 130 130 S.D. 0.0 0.0 32.5 6.9 40.9 0.0 0.0 N 19 19 19

--: Data 19

Unavaitable 19 19 19

4-5

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242 511 IN RABBITS

INDIVIDUAL JDiffiY/SoOD CONSUMPTION (Grams)

STUDY: 138 GROUP: 5-F SEX: FEMALE DOSE: 300 (mg/kg/day)a

ANIMAL # DAY 8 DAY 10 DAY 12 DAY 15 DAY 18 DAY 24 DAY 29

481 130 130 130 130 130 130 130 482 130 130 130 130 130 130 130 483 130 130 130 130 130 130 130 484 130 130 130 130 130 130 130 485 486 130 130 130 130 130 130 130 487 130 130 130 130 130 130 130 488 130 130 130 130 130 130 130 489 130 130 130 130 130 d d 490 491 492 130 130 130 130 130 130 130 493 130 130 130 130 130 130 130 494 130 130 130 130 130 130 130 495 130 130 130 130 130 130 130 496 130 130 130 130 130 130 130 497 130 130 130 130 130 130 130 498 130 130 130 130 130 130 130 499 130 130 130 130 130 130 130 500 130 130 130 130 130 130 130

MEAN 130 130 130 130 130 130 130 S.D. 0.0 0.0 0.0 0.0 0.0 0.0 0.0 N 17 17 17 17 17 16 16

--: Data Unavailable d: Sacrificed Moribund

a Retinol Palmitate given on GD9 and GD10 only

4-6

®$^jT

APPENDIX 5

Teratology Report

5-1

Pathology Associates, Inc.

Suite I 15 Worman's Mill Court

Frederick, MO 21701 (301) 663-1644

(301) 663-8994 FAX

DIM IF IF IATOLOGV REPORT TERATOLO

FOR


UIC/TRL STUDY NUMBER: 138

PREPARED FOR

TOXICOLOGY RESEARCH LABORATORY (TRL) UNIVERSITY OF ILLINOIS AT CHICAGO (UIC)

DEPARTMENT OF PHARMACOLOGY 1940 W.TAYLOR ST.

CHICAGO, IL 60612-7353

BBfllFir Draft Report Study No. 138

TABLE OF CONTENTS

Section Page No.

I. QUALITY ASSURANCE STATEMENT 4

II. MATERIALS AND METHODS 5

A. Cesarean Section 5

B. Fetal Evaluation 6

1. External Examination 6 2. Visceral Examination 6 3. Skeletal Examination 6

C. Statistical Analyses 6

III. RESULTS 7

A. Survival and Pregnancy 7 B. Maternal Gross Necropsy 8 C. Cesarean Section Data 8 D. Fetal Morphological Observations 8

IV. DISCUSSION AND CONCLUSIONS 9

V REFERENCES 10

3EM1T Draft Report Study No. 138

INDEX OF TABLES AND APPENDICES

Table Page No.

1. Summary of Pregnancy Status 11

2. Summary of Gross Necropsy Observations 12

3. Summary of Cesarean Section Data 13

4. Summary of Fetal Observations (Absolute) - Malformations 15

5. Summary of Fetal Observations (Absolute) - Variations 16

6. Summary of Fetal Observations (Percent) - Malformations 18

7. Summary of Fetal Observations (Percent) - Variations 19

Appendix

A. Individual Maternal Gross Necropsy Observations 21

B. Individual Cesarean Section Data 26

C. Individual Gravid Uterus And Fetal Body Weight Data 31

D. Individual Fetal Morphological Observations 36

lfJb ft f U Pathology Associates, Inc.

Suite I 15 Woman's Mill Court

Frederick, MD 21701 (301) 663-1644

(301) 663-8994 FAX

I. QUALITY ASSURANCE STATEMENT

This teratology project has been inspected and audited by the PAI Quality Assurance Unit (QAU) as required by the Good Laboratory Practice (GLP) regulations promulgated by the U.S. Food and Drug Administration. The following table is a record of the inspections/audits performed and reported by the QAU.

Date of Inspection

03/30/95 04/05/95 04/07/95 04/14/95

Phase Inspected

Skeletal Examination Individual Animal Data (Raw Data) Individual Animal Data (Data Entry) Draft Teratology Report

Date Findings Reported to Management/ Study Teratologist

03/30/95 04/17/95 04/17/95 04/17/95

April 17,1995

Patricia L. Bussard Quality Assurance Auditor

Date

TRL STUDY NUMBER: 138 DEVELOPMENTAL TOXICITY (SEGMENT II) STUDY OF WR242511 IN RABBITS

LiU /si if u

Draft Report Study No. 138

Developmental Toxicity (Segment II) Study of WR242511 in Rabbits

II. MATERIALS AND METHODS

A. Cesarean Section

On gestation day 29, all rabbits were euthanized in a random order by intravenous injection of sodium pentobarbital. The abdominal and thoracic cavities were opened by a ventral midline incision and the uterus and ovaries removed from the body. A gross necropsy was then performed. Abnormalities were recorded. Gross findings did not indicate the necessity of retaining any tissue samples containing gross lesions in 10% neutral buffered formalin for possible histopathological examination. Following the gross necropsy examination, the carcass of each dam was discarded.

The uterus was examined and weighed. For gravid females, the number of corpora lutea on each ovary was recorded and the ovaries were discarded after evaluation. The uterus was opened and the development of the fetuses was classified using the following criteria:

Viable fetus: a term fetus which responds to stimuli. Nonviable fetus: a term fetus which did not respond to stimuli in utero or was not

breathing. Early resorption: an implantation for which it was not grossly evident that organogenesis

had occurred. Late resorption: an implantation for which it was grossly evident that organogenesis had

occurred. A fetus with autolysis was considered a late resorption.

The number and location of fetuses, early resorption(s), late resorption(s) and their uterine position were documented using the following procedure. All implantation sites were numbered in consecutive fashion per uterine horn beginning with the left distal horn and proceeding to the cervix and then similarly for the right uterine horn beginning with the distal end and proceeding to the cervix. Uteri with no evidence of pregnancy were placed in 10% aqueous ammonium sulfide solution for detection of possible implantation sites.

ID 1 £ ^ ]/ Draft Report Study No. 138

B. Fetal Evaluation

1. External Examination

A detailed examination of each fetus was conducted to include the eyes, palate, head shape, extremities and general body integument. The fetuses were then weighed and euthanized by intraperitoneal injection of a 40% sodium pentobarbital solution (approximately 0.4 ml/fetus).

2. Visceral Examination

Each fetus was dissected and the abdominal, thoracic and cranial cavities opened and the internal organs examined as described by Staples (1974). During the examination, the fetal sex was determined. The fetuses were then individually tagged.

3. Skeletal Examination

Following the visceral examination, the fetuses were retained in 95% alcohol for skeletal examination. These fetuses were macerated in 1% potassium hydroxide, stained with Alizarin Red S and cleared with glycerin (Dawson, 1926). The fetuses were then examined for skeletal formation and ossification.

C. Statistical Analyses

The incidences or the means and standard deviations of the maternal and fetal observations were calculated. Gravid uterus weights and fetal body weights were analyzed by a one-way analysis of variance (ANOVA). If a significant F ratio was obtained (p < 0.05), Dunnett's test was used for pairwise comparisons of each treatment groups to the control group.

The numbers of early and late resorptions, nonviable fetuses, viable fetuses, total implantation sites and corpora lutea and the percent preimplantation loss, post- implantation loss and total loss/litter were compared across groups using the Kruskal- Wallis nonparametric ANOVA test. If a significant effect occurred (p < 0.05), the Wilcoxon (Mann-Whitney U) test was used for pairwise comparisons of each treated group to the control group.

IS L£J 3 1/ Draft Report Study No. 138

Calculations were as follows:

Pre-implantation loss % = it-Corpora lutea - #lmplants X 100 ^Corpora Lutea

Post-implantation loss % = #lmplants - #Viable fetuses X 100 #lmplants

Total loss/litter % = ^Corpora lutea - #Viable fetuses X 100 ^Corpora Lutea

Male to female fetal sex ratios were compared by using the Chi-square test. The incidences of malformations and variations were compared using the Fisher's exact test with the litter as the experimental unit. The total number of litters with external, visceral and skeletal malformations as well as the total number of litters with malformations and variations were also statistically compared. The percent of fetuses and litters with malformations and variations were calculated and reported, however, these data were not statistically analyzed.

Statistical analyses of the cesarean section and fetal morphological examination data were performed using an IBM• compatible computer with SAS computer programs (SAS/STAT User's Guide, 1989).

III. RESULTS

A. Survival and Pregnancy

Table 1 (Summary Data)

One female each in the 1.3 mg base/kg/day group aborted on gestation day 27 and one female in the 3.5 mg base/kg/day group prematurely delivered on gestation day 29. One female in the positive control group aborted on gestation day 22. The pregnancy rate was 100% in the vehicle control and the 1.3 mg base/kg/day groups, 95% in the 0.5 and 3.5 mg base/kg/day groups and 85% in the positive control group.

EBfln Draft Report Study No. 138

B. Maternal Gross Necropsy

Table 2 (Summary Data) Appendix A (Individual Data)

No apparent treatment-related changes were observed in the 0.5, 1.3 and 3.5 mg base/kg/day groups or in the positive control group.

C. Cesarean Section Data

Table 3 (Summary Data) Appendices B and C (Individual Data)

There were no biologically meaningful differences between the vehicle control and the WR242511 treated groups in the cesarean section parameters measured, including the mean numbers of corpora lutea, implantation sites, pre-implantation loss, viable and nonviable fetuses, early and late resorptions, post-implantation loss, total loss/litter, fetal sex ratios, and gravid uterus and fetal weights. In the 3.5 mg base/kg/day group, slight increases were noted in the mean number of early resorptions and percentages of post- implantation loss and total loss/litter. The increases were attributed to one litter with total resorptions and were, therefore, not considered to be related to treatment with WR242511. Treatment-related differences noted in the positive control group included statistically significant increases in the numbers of early resorptions, and the percent post-implantation loss, the percent total loss/litter and a corresponding decrease in the mean number of viable fetuses. In addition, the gravid uterus weight was significantly reduced in the positive control group. The reduction in the uterus weight was attributable to the reduced number of viable fetuses in the group.

D. Fetal Morphological Observations

Tables 4-7 (Summary Data) Appendix D (Individual Data)

No statistically significant or apparent treatment-related malformations or developmental variations were observed at the 0.5, 1.3 or 3.5 mg base/kg/day levels. In the positive control group, statistical increases were observed in the number of litters with external, visceral, and skeletal malformations. The external malformations primarily involved structures of the head including the cranium, jaws, palate, and pinnae. In

8

/y C p


addition, a significant increase in tail anomalies was noted. The visceral malformations primarily included kidney and/or ureter anomalies. Skeletal malformations included skull, vertebral, caudal vertebrae and hyoid anomalies. The incidences of developmental variations in the positive control group was comparable to the vehicle control group.

IV. DISCUSSION AND CONCLUSIONS

This study was conducted to evaluate the embryo/fetal toxicity and the teratogenic potential of WR242511 in rabbits.

One female each in the 1.3 and 3.5 mg base/kg/day groups prematurely delivered. Premature delivery is not uncommon and the low incidence observed in this study did not indicate any treatment-related effects. Overall pregnancy and maternal gross necropsy findings were not affected by treatment with WR242511. Cesarean section data were comparable between the vehicle control and the 0.5, 1.3 and 3.5 mg base/kg/day groups. Similarly, no biologically meaningful differences were noted in the fetal morphological examination data from the vehicle control vs the WR242511 treated groups.

The use of Vitamin A (Retinol Palmitate) as a positive control agent was effective in producing a teratogenic response. A dose level of 300 mg/kg/day, administered on gestation days 9 and 10, resulted in increased post-implantation loss and percent total loss/litter as characterized by an increase in early resorptions and a decrease in viable fetuses. A decrease in gravid uterus weights associated with the lower number of surviving fetuses was also observed. The incidences of external, visceral and skeletal malformations were significantly increased. Salient findings were primarily related to the structures of the head (including the skull), kidneys and ureters, and vertebral column (including the tail).

In conclusion, no maternal toxicity was observed, as determined by survival and gross necropsy findings. No evidence of embryo/fetal toxicity or teratogenicity was produced at any level tested. The no-effect level for developmental toxicity of WR242511 in rabbits was established at 3.5 mg base/kg/day. Results of the positive control group demonstrated that the procedures utilized in the conduct of this study were sufficiently sensitive to identify potential developmental toxicants.

Date: Michael D. Mercieca, B.S. Teratologist

9

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V. REFERENCES

Staples, R.E. (1974). Detection of visceral alterations in mammalian fetuses. Teratol. 9.A-37.

Dawson, AB (1926). A note on the cleared specimens with Alizarin Red S. Stain Technol. 1:123-124.

SAS Institute Inc., SAS/STAT User's Guide, Version 6, Fourth Edition, Volume 2 Cary, NC:SAS Institute Inc., 1989. 846 pp.

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APPENDIX 6

Protocol and Amendments

L 6-1

I?


Study No.: 138

DEVELOPMENTAL TOXICITY (SEGMENT II) STUDYTJF WR242511 IN RABBITS

1.0 PURPOSE OF THE STUDY:

The purpose of this study is to evaluate the embryo/fetal toxicity and the teratogenic-potential of the test article in New Zealand White rabbits. The protocol conforms to the standards of the U.S. Food and Drug Administration, the requirements of the Committee on Safety of Medicines in Great Britain, and the Organization for Economic Cooperation and Development. The protocol for this study was approved by the UIC Animal Care Committee (Appendix 1).

2.0

3.0

4.0

SPONSOR:

2.1 Name: U.S. Army Medical Materiel Development Activity

2.2 Address: Fort Detrick Frederick, MD 21702-5009

2.3 Representative: George J. Schieferstein, Ph.D.

TESTING FACILITY:

3.1 Name: Toxicology Research Laboratory (TRL;

3.2 Address: University of Illinois at Chicago (UIC) Department of Pharmacology 1940 W. Taylor St. Chicago, IL 60612-7353

3.3 Studv Director Barry S. Levine, D.Sc, D.A.B.T

DATES:

4.1 Proposed Initiation of In-Life Phase (Dav 0): 10/31/94

4.2 ProDosed ComDletion of In-Life Phase: 12/02/94 4.3 Proposed Studv Completion Date

(Draft Final Report): 03/02/95

I

PRTL138 Page 1

REVISED PAGE .7// STUDYNfr /ST INITIAL

5.0 TEST ARTICLE '•

5.1 Name or Code No:

®M(Fir Contract No.: DAMD17-92-C-2001


5.2

5.3

5.4

5.5

5.6

WR242511 Tartrate Bottle Number - BM05816

TRL Chemical No:

Physical Description:

1720614

Yellow powder

Storage Conditions to Maintain Stability:

5.4.1 Temperature: -20 to-15°C.

5.4.2 Humiditv: Ambient conditions at -20 to -15CC.

5.4.3 Light: Protect from light.

5.4.4 Special Requirements: None.

Special Handling Procedures: Standard safety precautions will be followed including gloves, eye protection, mask! and lab coats.

Log of Test Article: The amount, date, identity of person(s) removing aliquots and the purpose for which each aliquot of the test article was removed from the batch will be documented. At termination of the study, all unused test article will be returned to the Sponsor.

-6.0 PERSONNEL:

Study Director Reproductive Toxicologist Teratologist (PAT) Reproductive Scientist Analytical Chemist Clinical Veterinarian Veterinarian Support Tox. Lab Supervisor Lead Technician Chemistry Specialist Quality Assurance

Barry S. Levine, D.Sc, D.A.B.T. Ashraf F. Youssef, M.D., Ph.D. Michael D. Mercieca, B.S. Roberto A. Matamoros, D.V.M., Ph.D. Adam Negrusz, Ph.D. James Artwohl, D.V.M., M.S., D.A.C.L.A.M. Documented in raw data Soudabeh Soura, B.S. Documented in raw data Thomas To 1 hurst, B.S. Ronald C. Schoenbeck

0

PRTL138 Page 2

REVISED PAGE A41 STUDY NfV !3? INIT1AI •>- ^>^

DATE: ljMl£i

7.0 TEST SYSTEM:

7.1

7.2

7.3

Species:

Strain:

SexfsVNumber:

7.4 Weiaht of Animals:

7.5 Ase of Animals:

7.6 Source of Animals:

®MO Contract No.: DAMD17-92-C-2001


Rabbit

New Zealand White (Pasteurella Free)

100 time mated females, a few days apart in two shipments (day 0 = day of observed mating)

3.0 - 5.0 kg at start of study

5 to 8 months at study initiation. The animal supplier will provide birth dates on individual animals.

HRP, Inc. Denver. PA

7.7 Justification for Selection of Test Svstem: The FDA requires the use of two animal species, one being a non-rodent, in preclinical developmental toxicity studies. The rabbit is a standard and accepted non-rodent species for regulatory developmental toxicology studies, and is specified by the Sponsor. In addition, the New Zealand white rabbit was selected because .it has demonstrated sensitivity to developmental toxicants and historical data and experience exist.

7.8 Procedure for Unique Identification of Test Svstem: Each animal will be given a study- unique (ear-tag) number by the Supplier and a separate study-unique number (ear-tag) upon arrival at UIC. The cage card will additionally contain the study number, test or control article identification, dose level, and treatment group. Raw data records and specimens will also be identified by the unique animal number.

7.9 Housing: The animals will be housed jp an AAALAC-accredited facility. Animals will be singly housed in stainless steel cages in a temperature (61-69°F) and humidity (30 - 70%) controlled room with a 14 hour light/10 hour dark cycle. The cage size, 0.32 nr area and 38.0 cm height, is adequate to house rabbits for this study as described in the Guide for the Care and Use of Laboratory Animals, DHHS (NIH) No. 86.23.

7.10 Quarantine Procedure: Animals will be quarantined for at least 3 days during the time from receipt until dosing is initiated on day 6 of gestation. During the quarantine period the animals will be observed daily for signs of illness and all unusual observations will be reported to the Study Director, Toxicologist or Veterinarian. Animals will be examined during quarantine and approved for use by the veterinarian prior to being placed on test. Any sickly animal will be either eliminated prior to the test animal selection process or replaced by a healthy animal following this procedure but prior to initiation of treatment under the direction of the Study Director or Toxicologist. Quarantine release will be documented on the Clinical Veterinarian Log by a veterinarian prior to study initiation.

p I DATE: *////;/d H_

nna^n Contract No.: DAMD17-92-C-2001


7.11 Food: The animals will be fasted on the day of arrival. They will receive approximately 25 g of Purina High Fiber Certified Rabbit Chow #5325 (PMI Feeds, Inc., St. Louis, MO) on the second day, which will be gradually increased over a few days to approximately 100-130 g/day. This regimen is recommended by the animal supplier (HRP, Inc.) to reduce the incidence of intestinal problems. On the days of measured food consumption, an exact amount of 130 g will be provided.

7.12 Water: Tap water from an automatic watering system in which the room distribution lines are flushed daily will be provided ad libitum from arrival until termination. The water is untreated with additional chlorine or HC1.

7.13 There are no known contaminants in the feed or water which are expected to influence the study. A copy of the feed certification will be kept with the study records. The results of the most current comprehensive chemical analyses of Chicago water are documented in files maintained by Quality Assurance.

7.14 It is not known if the animals will experience pain or distress during the study. Analgesic or anesthetic agents will confound the ability to determine the toxic potential of the test article, and therefore will not be used. If an animal is in severe pain or distress, following consultation with the veterinary staff, it will be euthanized in accordance with standard operating procedures.

8.0 EXPERIMENTAL DESIGN:

8.1 Treatment Groups:

Dose Level Number of Treatment (rr 2 base/k&'dav') Females*

Vehicle 0 20 WR242511 0.5 20 . WR242511 1.3 20 WR242511 3.5 20 Vitamin A 75,000 IU/kg/day 20 (Retinol Palmitate) (=300 mg/kg/day)

1 2 -»

4

Presumed pregnant

The positive control agent, will be administered orally at the specified dose on days 9 and 10 of gestation at a dosing volume of 1 ml/kg.

Dose levels were selected on the basis of a range-finding study (UIC/TRL Study No. 137). The number of animals, 20/dose level, is the number of animals required by the 1966 FDA Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use (Goldenthal Guidelines), and is the number of animals indicated by the Sponso in Task Order UIC-7, Modification 3.

PRTL138

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REVISED PAGE /3?

DATE. INITIAL . / ///o/9i

jf*

L

BBfiffTI Contract No.: DAMD17-92-C-2001

Task Order No.: UIC-7N StudvNo.: 138

8.2 Frequency and Route of Administration of Test Article: The test article will be administeredônce daily by gavage during the period of major organogenesis, gestation days 6 through 18. It will be given at a dosing volume of 1 ml/kg. The control group will receive the vehicle at the same dosing volume. The specific volume to be administered will be adjusted on the basis of each animal's most recent body weight.

8.3 Justification of Route(s): The oral route is a convenient and accepted procedure for administering a specific amount of a test article to each animal. It mimics potential human exposure conditions and is specified by the Sponsor.

8.4 Procedure to Control Bias during the Assignment of Animals to Treatment Groups: During the quarantine/pretest period, animals judged to be healthy and meeting acceptable body weight requirements will be assigned to the study at random using a randomization procedure on the basis of body weight.

8.5 Test Article Vehicle: 1% Methylcellulose/0.2% Tween 80. .

8.6 Test Article Dosage Form Preparation and Analyses: The dosage formulations for the test article will be prepared daily by diluting a stock formulation (made weekly) to appropriate concentration. Stability data obtained from a previous study (UIC/TRL Study No. 106) indicated that the dosing suspensions are stable for 48 hours at the dosage formulations being tested, and the stock formulation is stable for two weeks. Homogeneity data-obtained from UIC/TRL Study.No. 107 demonstrated that the test article suspensions are homogeneous (coefficients of variation for sampling in the top, middleand bottom of several test suspensions were typically less than 4%). The stock test article suspension will be prepared by suspending the appropriate quantity of test article in the vehicle using a mortar and pestle. Stock and dosing suspensions will be stored at 0 - 4°C. Samples of the dosage formulations (including controls and stock suspensions) used at the beginning and at the end of the dosing period will be analyzed for test article concentration prior to use. Only samples within 10% of their intended concentration will be used.

8.7 Frequency of Observations. Test Analyses and Measurements:

8.7.1 Mortality Check: All animals will be observed twice daily, at least six hours apart for moribundity/mortality.

8.7.2 Clinical Signs: All animals will be observed daily for clinical signs of toxicity approximately 1-2 hours after dosing, and in the morning after completion of the dosing period. Moribund animals will be sacrificed on that day and the uterine contents will be examined as described in section 8.7.6.

8.7.4 Bodv Weights: Individual body weights will be recorded on day 0 of gestation, at randomization, and on gestation days 6-18, 24 and 29.

8.7.5 Food Consumption: Food consumption for all animals will be measured during the following 24 hour intervals: days 7/8, 9/10, 11/12, 14/15, 17/18, 23/24, 28/29.

PRTL138 Page 5 REVISED PAGE /^V

10: l2£. INITIAL i HATP - "ft/4S

$/m Contract No.: DAMD17-92-C-2001 Task Order No.: UIC-7N

StudvNo.: 138

8.7.6 Sacrifice: On day 29 of presumed gestation, all surviving female rabbits will be killed^ by intravenous injection of sodium pentobarbital (50 mg/kg) via the marginal ear vein.

8.7.7 Cesarean-Sectioning Observations: The abdominal and thoracic cavities will be opened by a ventral midline incision and the contents examined. In gravid animals, the ovaries will be examined. The number of corpora lutea on each ovary will be recorded (ovaries discarded after evaluation). The gravid uterus will be examined and weighed. The number and location of viable and nonviable fetuses* in utero, early and late resorptions** and the total number of implantation sites will be recorded.

The uterine position of each fetus will be documented using the following procedure. All implantation sites, including resorptions, will be numbered in consecutive fashion beginning with the left distal uterine horn, and similarly with the right distal uterine horn, noting the position of the cervix. Maternal tissues will only be saved for histopathological examination in 10% neutral buffered formalin as deemed necessary by the gross findings. The carcass of each dam will then be discarded.

•A viable fetus is defined as one which responds to stimuli. A non viable fetus is defined as a term fetus, which does not respond to stimuli in utero or is not breathing.

8.7.8

**An early resorption is defined as one in which it is not grossly evident that organogenesis has occurred. A late resorption is defined as one in which it is grossly evident that organogenesis has occurred. A fetus with evident autolysis is considered a late resorption.

Confirmation of Pregnancv: Uteri from females that appear nongravid will be opened and placed for approximately 10 minutes in ammonium sulfide solution (10%) for detection of possible implantation sites. If any implantation site is detected, the ovaries will be examined as in 8.7.7.

8.7.9 Necropsv: Rabbits which die will be examined for the cause of death. Rabbits which require termination due to moribund condition will be killed and examined. Necropsy will occur on the same calendar day on which death or termination occurs. Examination will not be performed if precluded by postmortem autolysis. Pregnancy status and uterine contents will be recorded. Maternal tissues with gross lesions appropriate for retention will be fixed in neutral buffered 10% formalin for possible future evaluation. Exception: (Parovarian cysts will be discarded: these are common, spontaneous lesions in rabbits). Viscera which appear normal will be discarded. Naturally-delivered pups will be examined to the extent possible using the same methods described for fetuses.

PRTL138

L Page 6

REVISED PAGE STUDY NO J2Z INITIAL: I

DATF- l'//Q/6l

te

Contract No.: DAMD17-92-C-2001 OH fil fi\ fP c-3 Task Order No.: UIC-7N ^ UU Ml If [J Study No.: 138

8.7.10 Fetal Gross Observations: Fetuses will be removed from the uterus and placed in individual containers. After weights are recorded, each fetus will be

' individually identified noting litter, uterine placement and study number.

8.7.11 Fetal Morpholoeical Examination

8.7.11.1 External: A detailed examination of each fetus will be conducted to include the eyes, palate, trunk and extremities. Any abnormal finding will be recorded. Late resorptions will be recorded and the tissue discarded or kept in formalin 10% as deemed necessary by the Study Director or the Reproductive Toxicologist.

8.7.11.2 Visceral Evaluation: All live fetuses will be examined for visceral anomalies and will be sexed internally employing the Staples' fresh tissue dissection techniques (Staples, 1974). All fetuses will be euthanized by I.P. injection of a 40% solution of sodium pentobarbital (0.4 ml/fetus). Fetal examination will include evaluation of the eyes and the brain by a mid-sagittal section. The remaining carcases will be retained in 95 % ethyl alcohol.

8.7.11.3 Skeletal Evaluation: Following completion of the visceral examination, all fetuses will be eviscerated and skinned for subsequent staining with Alizarin Red S for evaluation of the fetal skeletons (Dawson. 1926). Skeletal preparations will be stored [?. 99.5% glycerin and 0.5% phenol and will be retained.

8.7.12 Statistical Analyses

Maternal body weights, weight gains, uterine absolute and relative weight (% body weight), and fetal ccdy weights will be analyzed by a one-way analysis of variance. If a significant F ratio is obtained (p< 0.05), Dunnett's test will be used for pairwise comparisons to the control group.

Tne incidence of fetal abnormalities will be examined in terms of the fetal and litter percentages (% abnormal fetuses/group & % abnormal litters/group). Abnormalities will include malformations in addition to variations. The proportions of litters with abnormalities and male to female fetal sex ratios will be compared by using the Chi-square test criterion with Yate*s correction for 2x2 contingency tables and/or Fisher's exact probability test.

D f~ REVISED ?AGc

PRTL138 ?ige" lSTUDY NO—L-—INITIAL. I DATS: ,-'-••*_

BfiffH Contract No.: DAMD17-92-C-2001

Task Order No.: U1C-7N Study No.: 138

Maternal food consumption data, the numbers of resorptions, non viable fetuses, viable fetuses, corpora lutea (C.L.), implantations, preimplantation loss* and postimplantation loss** will be compared using the Kruskal-Willis test. If a significant effect is seen (p< 0.05), the Mann-Whitney U test will be used for pairwise comparisons to the control group.

•Preimplantation loss • # C.L. - M implantations

** Postimplantation loss = # implantations - # live fetuses

Other statistical analyses will be conductedâs deemed necessary and will be documented in the raw data-

in addition to the written report, summary data tables of parameters and variability will be transmitted to the Sponsor on magnetic media (computer diskette) in "ASCII" form. The transcribed data on disk will no longer be considered GLP compliant.

9.0 RECORDS TO BE MAINTAINED:

All data generated during the conduct of the study, except those that are generated as direct computer input, shall be recorded directly, promptly, and accurately in ink in bound books with prenumbered pages or on worksheets that shall be bound during or at the conclusion of the nonclinical laboratory study. All appropriate computer and machine output shall be bound during or at the conclusion of the study. All data entries shall be dated on the day of entry and signed or initialed by the person entering the data.

Any changes in entries for whatever reason (e.g., to correct an error or transposition) shall be made so as not to obscure the original entry, shall indicate the reason for such change, and shall

• be dated and signed or identified at the time of data input. In computer driven collection systems', the operator responsible for direct data input shall be identified at the time of data input. Any changes in computer entries for whatever reason (e.g., to correct an error or transposition) shall be made in such a manner so as not to obscure the original entry, if possible, shall indicate the reason for such change, and shall be dated and the responsible individual shall be identified.

All recorded data shall be reviewed, signed, and dated by a knowledgeable person, other than the person making the entry, to assure adherence to procedures and to verify observations.

Upon completion of the study and submission of the final report, all raw data, documentation, specimens, test article reserves and other materials necessary to reconstruct the study will be stored in the TRL archives maintained by Quality Assurance.

All changes or revisions, and reasons therefore, to this protocol once it is approved shall be documented, signed by the Study Director and Sponsor, dated and maintained with the protocol.

PRTL138 Paae S

L STUDY NO-

REVISED PAGE /3r INITIAL:^

DATE: 'Jg££Ll

L

B El ft 51 Contract No.: DAMD17-92-C-2001


10.0 REGULATORY REQUIREMENTS:

.This study will be performed in compliance with the UIC/TRL Quality Assurance Program designed to conform with FDA Good Laboratory Practice Regulations and EPA Good Laboratory Practice Standards.

Will this study be submitted to a regulatory agency? Yes If so, to which agency(ies)? Food and Drug Administration Does the Sponsor Request that test article samples be returned? Possiblv: direction will be provided bv the Sponsor. Does the Sponsor request that samples of the test article/carrier mixture(s) be returned to the Sponsor? No

11.0 REFERENCES:

Dawson, AB (1926). A note on the staining of cleared specimens with Alizarin Red S. Stain Technol. 1:123-124.

Dunnett, CW (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1129.

DTSC (1992). The assessment of developmental and reproductive risks. Toxicology and'Risk Assessment Section, Department of Toxic Substances Control (DTSC), California Environmental Protection Agency, Sacramento. CA. Review Draft dated March, 1992.

EPA (1984b). Guideline for the health assessment of suspect developmental toxicants. Draft document from the Office of Research and Development, EPA, Washington, D.C.

EPA (1985). Hazard evaluation division standard evaluation procedure: Teratology Studies. U.S. Environmental Protection Agency, Office of Pesticide Programs, document EPA- 540/9.85.018.

FDA (1982). Toxicological principles for safety assessment of direct food additives and color additives used in food. Bureau of Foods, Food and Drug Administration, Washington, D.C.

Gad, S and Weil, CS (1988). Statistics and Experimental Design for Toxicologists, 2nd ed. pp53-70, 147-176, Telforel Press. Caldwell, NJ.

Hayes, W (1989). Principles and Methods of Toxicology, pp 311-361, Raven press. New York, NY.

HRP, Inc. Rabbit quality and consistency. HRP NZW time-mated conception rates. (9/3/92).

PRTL138 Page 9 REVISED PAGE /p^

M—INITIAL/. PATE- '////. tfi

STUDY NO 121 .1N1TJA1

I

©MR Contract No.: DAMD17-92-C-2001


Snedecot, GW and Cochran, WG (1967). Variance test for homogenicity of the binomial distribution. Statistical Method, 6th Edition, pp. 240-241, Iowa State University Press. Ames, IA. '""•

U.S. Department of Health and Human Services (1985). Guide for the Care and Use of Laboratory Animals. Prepared by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources. Commission on Life Sciences, National Research Council. Public Health Service, National Institutes of Health, NIH Publications No. 86-23.

U.S. Environmental Protection Agency (1991). Guidelines for developmental toxicity risk assessment. Notice. Fed. Regist. 56: 63798-63826.

U.S. Food and Drug Administration (1966). Guidelines for reproduction studies for safety evaluation of drugs for human use.

Wilson, J.G. (1965). Methods for administering drugs and detecting malformations in experimental animals. In: Teratology Principles and Techniques (Wilson, J.G. and Warkany, J., eds). Chicago Press, pp. 262-277.

PRTL133 Page ;.i

REVISED PAGE ^ STUDY NO-—^£— INITIAL.

DATE: 'jMh


Study No.: 138

12.0 PROTOCOL APPROVAL:

STUDY DIRECTOR: Barry S.

®/^/FF

rry S. Levirfe^rXSc, D.AB.T. Date

ûdAxJMUMoluJ^ il/**k QUALITY ASSURANCE: ^HdJUJ<s4A/g£J#AlMJC U/*Z/93 Ronald Schoenbeck Date

SPONSOR APPROVAL: George J. SchieTerstein, Ph.D. Date Contracting Officer's

Representative (COR)

COMMENTS FROM THE COR:

PRTL138 Page 10

• ^ The University of Illinois at Chicago

Office of the Vice Chancellor for Research (M/C 672) 310 Administrative Office Building 1737 West Polk Street Chicago. Illinois 60612-7227 (312)996-4995 Appendix 1

M«F

November 22,1993

Bany S. Levine Med-Pharmacology 312 BGRC, M/C 868

Dear Dr. Levine:

The protocol indicated below has been reviewed in accordance with the Animal Care Policies of the University of Illinois at Chicago and approved on July 20, 1993.

Title of Application: Developmental Toxicity Study of WR242511 In Rabbits

ACC Number: 93-077-9

This institution has Animal Welfare Assurance Number A3460.01 on file with the Office for Protection from Research Risks, NTH. Please transmit this letter of acceptable verification of your research protocol to your sponsor.

Thank you for complying with the Animal Care Policies and Procedures of UIC.

Sincerely yours,

Josephine B. Miller, Ph.D. Chair, Animal Care Committee

JBM:st xc:BRL

PROTOCOL AMENDMENT

Study No.: 138

Title: ' Developmental Toxicity Study of WlbSl/^R^bit^J

1. Page 2 Section 5.1

Indicate the Botde Number of the test article; "BM05816".

Reason: Sponsor requested that the specific bottle number be included in the protocol.

2. Page 4 Section 7

Add the following section:

"7.14 It is not known if the animals will experience pain or distress during the study. Analgesic or anesthetic agents will confound the ability to determine the toxic potential of the test article, and therefore will not be used. If an animal is in severe pain or distress, following consultation with the veterinary staff, it will be euthanized in accordance with standard operating procedures."

Reason: Sponsor requested addition to the protocol.

3. Page 3 . Section 7.3

Delete from the text "unconfirmed".

Reason: Time mated females will be provided.

- 4. Page 3 Section 7.10

Replace the first sentence to read "Animals will be quarantined for at least 3 days during the time of receipt until dosing is initiated on day 6 of gestation."

Reason: Clarification of the period of quarantine.


Add the following sentence: "On the days of measured food consumption an exact amount of 130 g will be provided."

j. Reason: Clarification of the procedure of measuring food consumption.

Page 1

[

PROTOCOL AMENDMENT

Study No.: 138

Title: ' Developmental Toxicity Study ofWR242511 in Rabbits


A. Change dosing volume of positive control agent from "5 ml/kg" to "1 ml/kg".

B. Add the following sentence "The number of animals, 20/dose level, is the number of animals required by the 1966 FDA Guidelines for Reproduction Studies for Safety Evaluation of Drugs for Human Use (Goldenthal Guidelines), and is the number of animals indicated by the Sponsor in Task Order UIC-7, Modification 3."

Reason: Mistake in the protocol (A) and Sponsor requested addition to the protocol (B).


Change dosing volume from "5 ml/kg" to "1 ml/kg".

Reason: Mistake in the protocol.


Change the text as follows to indicate that stability and homogeneity testing have been performed in previous toxicity studies; "The dosage formulations for the test article will be prepared daily by diluting a stock formulation (made weekly) to appropriate concentration. Stability data obtained from a previous study (UIC/TRL Study No. 106) indicated that the dosing suspensions are stable for 48 hours at the dosage formulations being tested, and the stock formulation is stable

• for two weeks. Homogeneity data obtained from UIC/TRL Study No. 107 demonstrated that the test article suspensions are homogeneous (coefficients of variation for sampling in the top, middle and bottom of several test suspensions were typically less than 4%).

The stock test article suspension will be prepared by suspending the appropriate quantity of test article in the vehicle using a mortar and pestle. Stock and dosing suspensions will be stored at 0 - 4°C. Samples of the dosage formulations (including controls and stock suspensions) used at the beginning and at the end of the dosing period will be analyzed for test article concentration prior to use. Only samples within 10% of their intended concentration will be used."

Reason: Correction and Sponsor requested addition of the protocol.

9. Page 5 Section 8.7.5

Change the first food consumption day from 6/7 to 7/8.

Reason: To allow for the gradual feeding regimen as described in section 7.12 to be completed.

Page 2

L

L

DB«ir PROTOCOL AMENDMENT

Study No.: 138 • •

Title: Developmental Toxicity Study of WR242511 in Rabbits


Add "(= 50 mg/kg)" after "sodium pentobarbital".

Reason: Clarification of the dose of pentobarbital used for euthanasia.


Add the following sentence: "If any implantation site is detected, the ovaries will be examined as in 8.7.7".

Reason: If pregnancy evidence is confirmed, ovarian changes should be examined.


Change second sentence from "crown-rump length is" to "crown-rump lengths are".

Reason: Mistake in the protocol.

Approvals:

STUDY DIRECTOR: \Ul0h3 Barry^S". Levin^, D~.Sc. D.A.B.T. Date

SPONSOR APPROVAL: Jtlll/fl • Date

Contracting Officer's Representative (COR)

Page 3

PROTOCOL Ag^l* R |?

Study No: 138

Title: • Developmental Toxfcity Study of WR242511 in Rabbits

13. Page 1

Add to the tide the phrase (Segment II) to read "Developmental Toxicity (Segment II) Study of WR242511 in Rabbits

Reason: More precision in reflecting the nature of the study as discussed with the Sponsor.


Add the following dates:

Proposed Initiation of In-life Phase fDav 0): 10/31/94

Proposed Completion of In-life Phase: 12/02/94

Proposed Studv Completion Date . (Draft Final Report: 03/02/95

Reason: Dates were not finalized when the protocol was submitted.


Replace Teratologist (PAT) Helen Jamieson, B.S. by Michael D. Mercieca, B.S.

Reason: To reflect changes in personnel.


Add the following: "a few days apart in two shipments (day 0 = day of observed mating)"

Reason: To clarify the date for calculating various dates.

17. Page 3 Section 7.6 and Page 4 Section 7.11

Replace Hazelton Research Products, Inc. by HRP, Inc.

Reason: To reflect the correct name.

Pase 1

PROTOCOL A ''

Study No: 138 /••-

Title: ' Developmental Toxicity Study of WR242511 in Rabbits


Replace the first three sentences by the following:

"Each animal will be given a study-unique (ear-tag) number by the Supplier and a separate study- unique number (ear-tag) upon arrival at UIC."

Reason: To clarify the procedure.


Change Ralston Purina Company to PMI Feeds, Inc.

Reason: Change in company name.


A. The following doses were assigned to Groups 1-5:

Dose Level Group No. Treatment (ms base/ks/dav)

1 Vehicle 0 2 WR242511 0.5 3 WR242511 1.3 4 WR242511 3.5 5 (Retinol Palmitate) 75,000 IU/kg/day (=300 mg/kg/day)

B. Correct "vitamine" to "vitamin".

C. Change "will be" to "were" in the first sentence of the paragraph.

Reason: A. The doses of the test article have now been determined and the teratogenic dose in rabbits of Retinol Palmitate was reduced based on preliminary studies performed by TRL.

B. To correct a typographical error.

C. To reflect that the dose-range-finding study has been done, from which dose levels were chosen.

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PROTOCOL AMENDMEtH j] ffl b

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Study No: 138

Title: Developmental Toxictty Study ofWR242511 in Rabbits

21. Page 5 Section 8.7.4 and Page 6 Section 8.7.6

Replace "day 30" by "day 29".

Reason: Change in procedures.


Change gestation days for body weight measurements to be days 6-18, 24 and 29.

Reason: Change in procedure.


Replace the sentence "and continuing from the proximal to distal right uterine horn" by the sentence "and similarly with the right distal uterine hom. noting the position of the cervix."

Reason: To clarify the procedure.


Change the ammonium sulfide solution concentration from 0.5% to 10%.

Reason: To match the Pathology Associate. Inc.. standard operationg procedure.


Delete this phrase from second sentence "and crown-rump lengths are measured".

Reason: Body weight measurement is sufficient to assess fetal toxicity.

26. Page 7 Section 8.7.11.2

Replace the section after the first sentence to read as follows:

All fetuses will be euthanized by I.P. injection of 40% solution of sodium pentobarbital (0.4 ml/fetus). Fetal examination will include evaluation of the eyes and the brain by a mid-coronal section. The remaining carcases will be retained in 95% ethyl alcohol.

Reason: To clarify procedure.

Page 3

•fiSaiFF PROTOCOL AMENDME1

Study No: 138

Title: . Developmental Totf city Study of WR242511 in Rabbits


Change the end of the first sentence to read "..subsequent staining with Alizarin Red S for evaluation of the fetal skeletons (Dawson, 1926). Skeletal preparations will be stored in 99.5% glycerin and 0.5% phenol and will be retained."

Reason: Alizarin Red S is a preferred technical method with similar evaluation efficiency to the double staining method and is less time consuming. The phenol is added to prevent molding.


Replace the first three paragraphs by the following:

Maternal body weights, weight gains, uterine absolute and relative weight (% body weight), and fetal body weights will be analyzed by a one-way analysis of variance. If a significant F ratio is obtained (p<0.05), Dunnetrs test will be used for pairwise comparisons to the control group.

The incidence of fetal abnormalities will be examined in terms of the fetal and litter percentages (% 'abnormal fetuses/group & % abnormal liners/group). Abnormalities will include malformations in addition to variations. The proportions of liners with abnormalities and male to female fetal sex ratios will be compared by using the Chi-square test criterion with Yate*s correction for 2x2 contingency tables and or Fisher's exact probability' test.

Maternal food consumption data, the numbers of resorptions, non viable fetuses, viable fetuses. corpora lutea (C.L.), implantations, preimplantation loss* and postimplantation loss*" will be compared using the Kruskal-Wailis test. If a significant effect is seen (p<0.05), the Mann- Whitney U test will be used for pairwise comparisons to the control group.

•Preimplantation loss = # C.L. - # implantations

* "Postimplantation loss = # implantations - # live fetuses

Other statistical analyses will be conducted as deemed necessary and will be documented in the raw data.

Reason: To represent more appropriately the statistical analysis procedures.


Delete "Kimmer and "Staples" references and add the following references:

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PROTOCOL AMENDMENT' ULJ ^ U [|

Study No: 138

Title: • Developmental Toxfcity Study of WR242511 in Rabbits

29. Page 9 Section 11.0 (continued)

Dawson, AB (1926). A note on the staining of cleared specimens with Alizarin Red S. Stain Technol. 1:123-124.

Dunnett, CW (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1129.

DTSC (1992). The assessment of developmental and reproductive risks. Toxicology and Risk Assessment Section, Department of Toxic Substances Control (DTSC), California Environmental Protection Agency, Sacramento, CA. Review Draft dated March, 1992.

EPA (1984b). Guideline for the health assessment of suspect developmental toxicants. Draft document from the Office of Research and Development. EPA, Washington, D.C.

EPA (1985). Hazard evaluation division standard evaluation procedure: Teratology Studies. U.S. Environmental Protection Agency, Office of Pesticide Programs, document EPA-540/9.85.018.

FDA (1982). Toxicological principles for safety assessment of direct food additives and color additives used in food. Bureau of Foods, Food and Drug Administration. Washington, D.C.

Gad, S and Weil. CS (1988). Statistics and Experimental Design for Toxicologists, 2nd ed. pp53-70, 147-176, Telforel Press. Caldwell. NJ.

Hayes, W (1989). Principles and Methods of Toxicology, pp 311-361, Raven press. New York. NY.

HRP, Inc. Rabbit quality and consistency. HRP NZW time-mated conception rates. (9/3/92).

Snedecot, GW and Cochran, WG (1967). Variance test for homogenicity of the binomial distribution. Statistical Method, 6th Edition, pp. 240-241, Iowa State University Press. Ames, IA.

U.S. Department of Health and Human Services (1985). Guide for the Care and Use of Laboratory Animals. Prepared by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources. Commission on Life Sciences. National Research Council. Public Health Service, National Institutes of Health, NTH Publications No. 86-23.

U.S. Environmental Protection Agency (1991). Guidelines for developmental toxicity

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Study No: 138

Title: • Developmental Toxicity Study of WR242511 in Rabbits

risk assessment. Notice. Fed. Regist. 56: 63798-63826.

U.S. Food and Drug Administration (1966). Guidelines for reproduction studies for safety evaluation of drugs for human use.

Reason: Correction and expansion of the reference list as required by the Sponsor.

APPROVAL:

STUDY DIRECTOR: Barry S. Ovine] D.Sc. D.A.B.T.

"/'d/Qy Date

SPONSOR APPROVAL: "uyufet^ George J. Sfchieferstein, Ph.D. Contracting Officer's Representative (COR)

Date

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MENtfiWS- PROTOCOL AMENIMBW h ^ UU Ln FF

Study No: 138 •' Contract No.: UIC-7N Title: Developmental Toxicity (Segment II) Study of WR242511 in Rabbits


At the sentence before the last sentence replace "mid-coronal" by "mid-sagittal"

Reason: Change in procedure with similar outcome of the results.

Approvals:

STUDY DIRECTOR: -• / I dllV ^î *JMICIT

Barry S. Levine, D.Sc, D.A.B.T. Date

SPONSOR APPROVAL: -^J/L cAA>uÛj£z>^ 3^3/'?^ George J. Schieferstein, Ph.D. Date

(jU,d )

M H

APPENDIX 7

Study Deviations

L 7-1

BftiFir Contract No.: DAMD17-92-C-2001 Task Order No.: UIC-7N

Study No.: 138


Study Deviations*

Deviation Type Specific Deviation

Protocol

Effect on Study

Temperature was out of range None, deviation was minimal, on few occasions.

Protocol Humidity was out of range on None, deviation was minimal, one occasion.

Protocol Relative uterine weight (% body None; mistake in protocol, weight) was not calculated. Statistical analysis should be

based on absolute uterine weights.

*The detailed "Deviation Reports" are contained in the raw data which are archived at the Toxicology Research Laboratory, University of Illinois at Chicago, Department of Pharmacology, 1940 W. Taylor St., Chicago, IL 60612.

The above deviations did not affect the integrity of the study.

Barry S. Levine, D.Sc.,D.A.B.T.

Date

7-2

Documents

Contract No.: DAMD17-92-C-2001 Task Order No. - DTIC