Document peDwzD256kj35Qj1VQONJGNNX
AR226-3182
DuPont-6711
TRADE SECRET
Study Title | Acute Oral Toxicity
Fixed Dose Method Laboratory Project ID: DuPont-6711
T est Guideline: OECD Guidelines for Testing of Chemicals Section 4: Health Effects, No. 420 (1992)
Author: Carol Finlay, B.A. Study Completed on: September 17,2001 Performing Laboratory: E. I. du Pont de Nemours and Company
Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050
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Acute Oral Toxicity - Fixed Dose Method
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PAGE RESERVED FOR SPECIFIC COUNTRY REQUIREM ENTS
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GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT
This study was conducted in compliance with U.S. EPA TSCA (40 CFR part 792) Good Laboratory Practice Standards, which are consistent with the OECD Principles o f Good Laboratory Practice (as revised in 1997) published in ENV/MC/CHEM(98)17 except for the items documented below. The items listed do not impact the validity of the study.
The test substance was characterized after initiation of this study. Although the characterization (ISO 9001) was not performed under Good Laboratory Practice Standards, the accuracy of the data is considered sufficient for the purposes of this study.
The dosing preparations used in the study were not analyzed for stability, homogeneity, or accuracy of concentration. The procedures used by trained staff to prepare the dosing preparations ensured:
the accuracy of concentration because the test substance was weighed on an analytical balance accurate to 3 decimal places and the vehicle in which it was suspended was accurately measured in a flask graduated in 1 mL increments,
homogeneity because the mixtures were stirred prior to dosing and while portions were removed for dose administration, and
e stability because the time between dose preparation and administration was kept to a
minimum (less than 1 hour).
.
Applicant / Sponsor: Telomer Research Program Arlington, Virginia
U.S.A.
Study Director:
Carol Finlay Q Staff Scientist
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QUALITY ASSURANCE STATEM ENT
Haskell Sample Number(s): 24691
Dates of Inspections: Conduct: May 17, 2001
Records, Reports: April 5, 2001; September 9, 10, 2001
Dates Findings Reported to: Study Director: September 10, 2001 Management: September 13, 2001
DuPont-6711
Reported by:
Sr. Quality Assurance Auditor
Date
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CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Pathology Evaluations Reported by:
>
(Lisa J. Lewis Laboratory Technician
Pathology Evaluations
Reviewed Z
>0. ^ c g 5 P R t J
G. Tracy Makovec, D.V.M. Diplomate A.C.V.P.
Reviewed bv-
Issued by Study Director:
&
James C. MI ackay II Associate Scientist
i l aoot
Date
Date
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ite
i l ^ 'lO K
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TABLE OF CONTENTS
PAGE RESERVED FOR SPECIFIC COUNTRY REQUIREM ENTS.
GOOD LABORATORY PRACTICE COMPLIANCE STATEM ENT
Q U A L IT Y A S S U R A N C E S T A T E M E N T ..........................................................
C E R T IF IC A T IO N ......................................................................................................
S T U D Y IN F O R M A T IO N .........................................................................................
S T U D Y P E R S O N N E L ...............................................................................................
S U M M A R Y ....................................................................................................................
IN T R O D U C T IO N .......................................................................................................
M A T E R IA L S A N D M E T H O D S ..........................................................................
A. Test Guidelines................................................................................... B. Test Substance.................................................................................... C. Animal Husbandry'............................................................................ D. Test Substance Preparation............................................................... E. Dosing................................................................................................
1. Sighting Study.......................................................................................................... 2. Main Study................................................................................................:...............
F. Observations.......................................................................................
1. Sighting Study........................................................................................................... 2. Main Study.................................................................................................................
R E S U L T S A N D D I S C U S S IO N ............................................................................
In -life T o x ico lo g y ..........................................................................................................
A. Sighting Study....................................................................................
!. Dose Information and Mortality Summary.......................................................... 2. Body W eights............................................................................................................ 3. Clinical S ig n s............................................................................................................
B. Main Study.........................................................................................
1. Dose Information and Mortality Summary.......................................................... 2. Body W eights............................................................................................................ 3. Clinical S ig n s...........................................................................................................
P a th o logy E v a lu a tio n s ..............................................................................................
A. Gross Observations...........................................................................
C O N C L U S IO N ............................................................................................................
R E C O R D S A N D S A M P L E S T O R A G E ...........................................................
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TABLE OF CONTENTS
A P P E N D IC E S ........................................................................................................ A. INDIVIDUAL BODY WEIGHTS................................................................................ B. INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS C. INDIVIDUAL ANIMAL GROSS OBSERVATIONS..............................................
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Acute Oral Toxicity - Fixed Dose Method STUDY INFORM ATION
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Haskell Number: 24691
CAS Registry Number: Composition:
Purity:
K now n Impurities:
Physical Characteristics: White to yellow wax Stability: The test substance appeared to be stable under the conditions of the study; no evidence of instability was observed. Sponsor: Telomer Research Program 1200 South Hayes Street Arlington, Virginia 22202-5050 U.S.A.
Study Initiated/Completed: April 2, 2001 / (see report cover page)
In-Life Initiated/Completed: April 25, 2001 / May 17, 2001
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Acute Oral Toxicity - Fixed Dose Method l
STUDY PERSONNEL Study Director: Carol Finlay, B.A.
Management: Judith C. Stadler, Ph.D., D.A.B.T. Primary Technician: James C. Mackay II
Pathologist: G. Tracy Makovec, D.V.M. Management: Steven R. Frame, D.V.M., Ph.D. Pathology Report by: Lisa J. Lewis
Toxicology Report Prparation: Wnda F. Diribokowitz
Laboratory Veterinarian: William Singleton, D.V.M., A.C.L.A.M.
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SUMMARY
Single doses o
ere administered by intragastrv intiihntmn to fasted
male and fem al^ratiTlnthe prehminifly sighting study, a single dose
was administered to fasted'female rats at a dose of 500 or 2000 mg/kg. Since no toxicity was
seen in these rats, the limit dose of 2000 mg/kg was selected for the main study.
In the main study, the test substance was administered to a group o f 5 fasted male rats and a group of 5 fasted female rats at a dose of 2000 mg/kg. The rats were observed for mortality, body weight effects, and clinical signs of toxicity for 14 days after dosing. The rats were necropsied to detect grossly observable evidence of organ or tissue damage or dysfunction.
No deaths occurred during the study. The rats exhibited no clinical signs of toxicity. No significant body weight losses occurred after dosing. No gross lesions were present in the rats at necropsy.
Under the conditions of this study, the minimum lethal dose was greater than 2000 mg/kg.
According to the guidance provided in the OECD testing guideline compound which does not present a significant acute toxic risk if sw w
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INTRODUCTION
The purpose o f this study was to assess the acute oral toxicity administered by oral gavage to male and female rats. The dose Sleeted for the main stuay, 2000 mg/kg, was derived from a preliminary sighting study. In the sighting study, no toxicity was observed in rats dosed at 500 or 2000 mg/kg.
MATERIALS AND M ETHODS
A. Test G uideline
The study design complies with the following testing guideline:
Organisation for Economic Co-Operation and Development (OECD) (1992). 420 Acute Oral Toxicity - Fixed Dose Method. Guidelinefo r Testing o f Chemicals.
B. Test Substance
The test s u b s t a n c e & M ^ B M ^ ^ J w a s supplied by the sponsor as a white to yellow wax. The test s u b ^ ^ ^ ^ t^ ^ l^ ^ ^ b e s ta b le under the conditions of the study. No evidence of instability, such as a change in color, was observed.
C. Anim al H usbandry
Male and female Crl:CD(SD)IGS BR rats were received from Charles River Laboratories, Inc., Raleigh, North Carolina. Rats were housed singly in suspended, stainless steel, wire-mesh cages. Each rat was assigned a unique identification number which was recorded on a card affixed to the cage. The rats were tail-marked, using a water-insoluble marker, witn the last 3 digits of the animal number. PMI Nutrition International, Inc. Certified Rodent LabDiet 5002 and water were available ad libitum except as noted in section E. Dosing. As specified in the Haskell Laboratory' animal health and environmental monitoring program, the following procedures are performed periodically to ensure that contaminant levels are below those that would be expected to impact the scientific integrity o f the study:
Water samples are analyzed for total bacterial counts, and the presence o f coliforms, lead, and other contaminants.
Feed samples are analyzed for total bacterial, spore and fungal counts.
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Samples from freshly washed cages and cage racks are analyzed to ensure adequate sanitation
by the cagewashers.
Certified animal feed is used, guaranteed by the manufacturer to meet specified nutritional requirements and not to exceed stated maximum concentrations o f key contaminants, including specified heavy metals, aflatoxin, chlorinated hydrocarbons, and organophosphates. The presence of these contaminants below the maximum concentration stated by the manufacturer
would not be expected to impact the integrity of the study.
The anim al health and environmental monitoring program is administered by the attending laboratory animal veterinarian. Evaluation of these data did not indicate any conditions that affected the validity of the study.
Rats were quarantined, weighed, and observed for general health for 6 days. Animal rooms were maintained on a timer-controlled, 12-hour light/12-hour dark cycle. Environmental conditions of the rooms were targeted for a temperature of 23 1C and relative humidity of 50 10%. Excursions outside these ranges were of small magnitude and/or brief duration and did not
adversely affect the validity of the study.
D. Test Substance Preparation
The test substance was melted and stirred in a water bath (approximately 75-80 C) for approximately 30 minutes to assure uniformity before each suspension was prepared.
E. Dosing
1. Sighting Study
A single oral dose
melted m d suspended in 0.5% aqueous
methylcellulose, was a to u u s te r e H ^ n tr ^ s tr ic intubation to a fasted female rat at a dose of
500 mg/kg. Since toxicity was not seen at this dose, another fasted female rat was dosed at 2000 mg/kg. The rats were fasted approximately 17 or 18 hours prior to dosing with food being
returned to the rats approximately 3 hours after dosing. The rats were approximately 9 weeks old
on the day of dosing. The individual dose volumes were calculated using the suspension
concentration and the fasted body weight obtained prior to dosing. The rats were dosed at a
volume of 10 mL per kg of body weight. The dosing suspensions were stirred prior to and
throughout the dosing procedure.
2. Main Study
Single oral doses oA H U i B ^ e l t e d and suspended in 0.5% aqueous methylcellulose, were administered by intragastric intubation to a group o f 5 fasted male rats and a group of 5 fasted female rats at a dose of 2000 mg/kg. The rats were fasted approximately 18 hours prior to dosing with food being returned to the rats approximately 3.5 hours after dosing. The rats were approximately 9 weeks old on the day o f dosing. Individual dose volumes
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were calculated using the suspension concentration and the fasted body weights obtained prior to dosing. The rats were dosed at a volume of 10 mL per kg of body weight. The dosing suspension was stirred prior to and throughout the dosing procedure.
F. Observations
1. Sighting Study
Observations for mortality and signs of illness, injury, or abnormal behavior were made daily throughout the study. The rats were observed for clinical signs of toxicity twice on the day of dosing and once each day thereafter. The rats were weighed on test days -1, 0 (day of dosing), 1, and 7. On test day 7, the rats were euthanized by carbon dioxide asphyxiation.
2. Main Study
Observations for mortality and signs of illness, injury, or abnormal behavior were made daily throughout the study. The rats were observed for clinical signs of toxicity twice on the day of dosing and once each day thereafter. The rats were weighed on test days -1, 0 (day of dosing), 1, 2, 3, 7, and 14. On test day 14, the rats were euthanized and necropsied to detect grossly observable evidence of organ or tissue damage or dysfunction. The rats were euthanized by carbon dioxide asphyxiation followed by exsanguination.
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RESULTS AND DISCUSSION
In-life Toxicology
A. Sighting Study
1. Dose Information and Mortality Summary
No deaths occurred. The dose information and the mortality data are summarized in the table below.
DOSE (mg/kg) FEMALE
500 2000
FASTED BODY WEIGHT (g)
217.4 213.7
SUSPENSION CONCENTRATION
(mg/mL)
DOSE VOLUME (mL)
MORTALITY
50 2.2 No 200 2.1 No
2. Body Weights (Appendix A)
The rats exhibited no body weight losses after dosing.
3. Clinical Signs (Appendix B)
The rats exhibited no clinical signs of toxicity.
B. M ain Study
1. Dose Information and Mortality Summary
No deaths occurred. The dose information and the mortality data are summarized in the table below.
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DOSE (mg/kg) MALE
2000 FEMALE
2000
AVERAGE FASTED BODY WEIGHT (g)
249.^
210.3
SUSPENSION CONCENTRATION
(mg/mL)
AVERAGE DOSE
VOLUME (mL)
MORTALITY RATIO
200 2.5 0/5
200 2.1 0/5
2. Body Weights (Appendix A)
The rats exhibited no significant body weight losses after dosing.
3. Clinical Signs (Appendix B)
The rats exhibited no clinical signs of toxicity. The end of the tail was missing from one male rat
during the study.
.
Pathology Evaluations
A. Gross Observations No gross lesions were present in the rats.
CONCLUSION Under the conditions o f this study, the minimum lethal dose was According to the guidance provided in the OECD testing g u i d e l i n e j ^ ^ ^ ^ ^ ^ ^ ^ ^ S H ^ 8 a compound which does not present a significant acute toxic risk if swallowed.
RECORDS AND SAMPLE STORAGE
Specimens (if applicable), raw data, and the final report will be retained at Haskell Laboratory, Newark, Delaware, or at Iron Mountain Records Management, Wilmington, Delaware.
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APPENDICES
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APPENDIX A Individual Body W eights
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Animal Number
648018
INDIVIDUAL BODY WEIGHTS OF FEMALE RATS FROM SIGHTING STUDY DOSE: 500 mg/kg
Day -Ia
Day 0b
Day 1
Day 7
236.7
217.4
227.6
251.0
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Animal Number
648020
Day -Ia 231.1
Day 0b 213.7
DOSE: 2000 mg/kg
Day 1 216.0
Day 7 235.0
Weight before fasting b Fasted body weight
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Animal Number
648472 648473 648474 648475 648476
Day -1`
274.0 276.0 257.0 268.0 278.0
INDIVIDUAL BODY WEIGHTS OF MALE RATS FROM MAIN STUDY DOSE: 2000 mg/kg
Day 0b
254.1 254.8 235.6 247.7 255.7
Day 1
269.1 272.6 255.4 271.7 276.4
Day 2
295.0 292.9 272.3 287.8 297.0
Day 3
305.0 307.1 282.3 295.4 306.1
Day 7
325.0 328.5 299.9 310.4 325.1
Day 14
383.9 387.4 344.7 349.7 367.8
a Weight before fasting b Fasted body weight
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Animal Number
648488 648489 648490 648491 648492
INDIVIDUAL BODY WEIGHTS OF FEMALE RATS FROM MAIN STUDY DOSE: 2000 mg/kg
Day -la
230.0 230.0 230.0 222.0 229.0
Day 0b
213.5 214.5 211.7 201.3 210.5
Day 1
226.6 226.4 226.9 217.1 221.6
Day 2
240.6 245.3 249.5 229.4 238.9
Day 3
248.9 240.7 252.4 236.3 242.3
Day 7
261.3 246.9 251.2 247.3 244.8
Day 14
274.4 264.9 261.8 272.7 257.7
a Weight before fasting b Fasted body weight
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a ppe n d ix b
Individual Clinical Observations and M ortality Records
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INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS IN FEMALE RATS FROM SIGHTING STUDY DOSE: 500 mg/kg
Sex Animal Observation
F 648018 General observation. No Abnormality Detected Sacrificed by design
Days
0-7 7
DOSE: 2000 mg/kg
Sex Animal Observation F 648020 General observation. No Abnormality Detected Sacrificed by design
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INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS IN MALE RATS FROM MAIN STUDY DOSE: 2000 mg/kg
Sex Animal Observation M 648472 General observation, No Abnormality Detected Sacrificed by design M 648473 General observation, No Abnormality Detected Sacrificed by design M 648474 General observation. No Abnormality Detected End of tail missing Sacrificed by design M 648475 General observation. No Abnormality Detected Sacrificed by design M 648476 General observation. No Abnormality Detected Sacrificed by design
Days -1-14 14 -1-14 14 -1-4 5-14 14 -1-14 14 -1-14 14
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INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS IN FEMALE RATS FROM MAIN STUDY DOSE: 2000 mg/kg
Sex Animal Observation
F 648488 General observation. No Abnormality Detected Sacrificed by design
F 648489 General observation. No Abnormality Detected Sacrificed by design
F 648490 General observation, No Abnormality Detected Sacrificed by design
F 648491 General observation, No Abnormality Detected Sacrificed by design
F 648492 General observation. No Abnormality Detected Sacrificed by design
Days
-1-14 14 -1-14 14 -1-14 14 -1-14 14 -1-14 14
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APPENDIX C Individual Anim al Gross Observations
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INDIVIDUAL ANIMAL GROSS OBSERVATIONS IN MALE RATS FROM MAIN STUDY
LESIONS
LESION INCIDENCE ANIMAL NUMBER
TREATMENT
2000 mg /kg
GENERAL ORGAN NO ABNORMALITY DETECTED
(5)
648472 648473 648474 648475 648476
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
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INDIVIDUAL ANIMAL GROSS OBSERVATIONS IN FEMALE RATS FROM MAIN STUDY
LESIONS
GENERAL ORGAN NO ABNORMALITY DETECTED
LESION INCIDENCE ANIMAL NUMBER
TREATMENT
2000 m g/kg
(5)
648488 648489 648490 648491 648492
Figures in parentheses is the number of animals grossly examined for this tissue The absence of a number indicates the finding specified was not identified
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