Document e7zn35JdNx2bqzO8pkX1JMpRq
TRADE SECRET
AR226-3182
DuPont-6711
Study Title
Jff^ Acute Oral Toxicity
Fixed Dose Method
Laboratory Project ID: DuPont-6711
TEST 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 Font 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_________ '_______DuPont-6711 PAGE RESERVED FOR SPECIFIC COUNTRY REQUIREMENTS
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Acute Oral Toxicity - Fixed Dose Method
DuPont-6711
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 of 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
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:
^^/Igf. ^L^_________ Cfarol Finlay ^ Staff Scientist
{/} - ^U-t' ^ Date
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.cute Oral Toxicity - Fixed Dose Method
QUALITY ASSURANCE STATEMENT
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:
^^l^Qf0^ ( } '
--
c ^
r^--~ fJoseph C. Hamill
Sr. Quality Assurance Auditor
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Date
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Acute Oral Toxicity - Fixed Dose Method
_______DuPont-6711
CERTIFICATION
We, the undersigned, declare that this report provides an accurate evaluation of data obtained from this study.
Pathology Evohiations Reported by:
* >
L^CL
C^'\i \I ^ J-^-/y rU-isa J. Lewis LaWratwy Technician
Pathology Evaluations Reviewed by;
&
^J.
^W^y^ ^k ^\ ------^ \1AA^ V G. Tracy Makovec, D.V.M. Diplomate A.C.V.P.
</^Jraf^rj^fe4^s Reviewed by:
<
C. Macleay n Associate Scientist
Issued by Study Director:
f {L/\J^ fiCV\.[.JLt^
Ca^lFmlay, B.A.Q
Staff Scientist
t^-Sgo -aoot
Date
^-r<f s<'\ Date
V\-^jUfsL^i Dafe
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Acute Oral Toxicity - Fixed Dose Method
DuPont-6711
TABLE OF CONTENTS
Page
PAGE RESERVED FOR SPECIFIC COUNTRY REQUIREMENTS................................... 2
GOOD LABORATORY PRACTICE COMPLIANCE STATEMENT.................................. 3
QUALITY ASSURANCE STATEMENT...................................................................................4
CERTIFICATION ........................................................................................................................5
STUDY INFORMATION............................................................................................................. 8
STUDY PERSONNEL.................................................................................................................. 9
SUMMARY.................................................................................................................................. 10
INTRODUCTION....................................................................................................................... 11
MATERIALS AND METHODS ............................................................................................... 11
A. Test Guidelines.................................................................................................................. 11
B. Test Substance................................................................................................................... 11
C. Animal Husbandry............................................................................................................ 11
D. Test Substance Preparation............................................................................................... 12
E.
12 Dosing...............................................................................................................................
1.
Sighting
12
Study........................................................................................................................................
2. Main Study ..........................................................;.......................,,.........................................................12
F.
13
Observations......................................................................................................................
1. Sighting Study......................................................................................................................................13
2. Main Study............................................................................................................................................. 13
RESULTS AND DISCUSSION ................................................................................................. 14
In-life A.
B.
Toxicology......................................................................................................................... 14
Sighting
14
Study...................................................................................................................
1. Dose Information and Mortality Summary............................................................................................. 14
2. Body Weights........................................................................................................................................ 14
3. Clinical Signs ......................................................................................................................................... 14
Main Study........................................................................................................................ 14
1. Dose Information and Mortality Summary............................................................................................. 14
2. Body Weights.........................................................................................................................................15 3. Clinical Signs .........................................................................................................................................15
Pathology Evaluations................................................................................................................ 15 A. Gross Observations ........................................................................................................... 15
CONCLUSION............................................................................................................................ 15
RECORDS AND SAMPLE STORAGE ................................................................................... 15
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DuPont-6711
___
TABLE OF CONTENTS
Page
APPENDICES............................................................................................................................. 16 A. INDIVIDUAL BODY WEIGHTS.......................................................................................................................17 B. INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS...............................................21 C. INDIVIDUAL ANIMAL GROSS OBSERVATIONS...................................................-...................................^
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Acute Oral Toxicity - Fixed Dose Method
STUDY INFORMATION
9th Collective Nomenclature: Synonyms/Codes:,
DuPont-6711
fc Haskell Number: 24691
sy CAS Registry Number:
Composition:!
Purity:^
Known 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
STUDY PERSONNEL
Study Director: Management:
Primary Technician:
Carol Finlay, B.A. Judith C. Stadler, Ph.D., D.A.B.T. James C. Mackay D
Pathologist:
Management: Pathology Report by:
G. Tracy Makovec, D.V.M. Steven R. Frame, D.V.M., Ph.D.
Lisa J. Lewis
Toxicology Report Preparation: Wanda F. Diribokowilz
Laboratory Veterinarian: William Singleton, D.V.M., A.C.L.A.M.
DuPont-6711
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Acute Oral Toxicity - Fixed Dose Method
DuPont-6711
SUMMARY
oJHIIBU|U|Bwere Single doses
administered by intragastricmtubation to fasted
^l^^l|HHBBil male and femaleTats. In the preliminarysighting study, a single dose
was administered to fasted'female rats at a dose of 500 or 2000 mg/kg. Smcenotoxicity 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 of 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 oftoxicity 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 oftoxicity. 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 swallowed.
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Acute Oral Toxicity - Fixed Dose Method
DuPont-6711
INTRODUCTION
o f _ _ _ _ _ The purpose of this study was to assess the acute oral toxicity
administered by oral gavage to male and female rats. The dose selected for the main study, 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 METHODS
A.
Test Guideline
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. Guideline/or Testing of Chemicals.
B.
Test Substance
The test substance------^--------HflHwas.subpypthlieesdponsor as a white to yellow
wax. The test substanceappearedTobestableunder the conditions of the study. No evidence of
instability, such as a change in color, was observed.
C. Animal Husbandry
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, with the last 3 digits of the animal number. PMI Nutrition International, me. 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 of the study:
Water samples are analyzed for total bacterial counts, and the presence ofcolifbrms, lead, and other contaminants.
Feed samples are analyzed for total bacterial, spore and fungal counts.
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.cute Oral Toxicity - Fixed Dose Method___________________DuPont-6711
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 of 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 animal 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 maintainedon a timer-cohtrolled, 12-hbur lighf/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 75-80C) for
IP\
approximately 30 minutes to assure uniformity before each suspension was prepared.
^
E.
Dosing
1.
Sighting Study
A single oral dose ^I^^BH|^BB|B melted and suspended in 0.5% aqueous
methylcellulose, was administered by intragastric 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
fUBBH^^IIR1^6^^ Single oral doses
an(^ suspended in 0.5% aqueous
methylcellulose, were administered by intragastric intubation to a group of 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 of dosing. Individual dose volumes
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Acute Oral Toxicity - Fixed Dose Method___________________DuPont-6711
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 oftoxicity 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 oftoxicity 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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.cute Oral Toxicity - Fixed Dose Method
DuPont-6711
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 oftoxicity.
B.
Main 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
'Acute Oral Toxicity - Fixed Dose Method
AVERAGE FASTED BODY
WEIGHT (g)
SUSPENSION CONCENTRATION
(mg/mL)
249.<5
200
210.3
200
AVERAGE DOSE
VOLUME (mL)
2.5
2.1
DuPont-6711
MORTALITY RATIO
0/5 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 oftoxicity. 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 of this study, the minimum lethal dose was gri According to the guidance provided in the OECD testing guideline}
compound which does not present a significant acute toxic risk if swallowed.
0 mg/kg..
s a
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.
Coffipany Samtized. Dcss not contain TSCA C'?.\
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Acute Oral Toxicity - Fixed Dose Method
DuPont-6711
APPENDICES
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Acute Oral Toxicity - Fixed Dose Method___________________DuPont-6711
APPENDIX A Individual Body Weights
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Acute Oral Toxicity - Fixed Dose Method
Animal Number
648018
INDIVIDUAL BODY WEIGHTS OF FEMALE RATS FROM SIGHTING STUDY
DOSE: 500mg/kg
Day -I3
236.7
Day O"
217.4
Day 1
227.6
Day 7
251.0
Animal Number
648020
Day -1 231.1
Day 013
213.7
DOSE: 2000mg/kg
Day 1
Day 7
216.0
235.0
a Weight before fasting b Fasted body weight
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\.cute Oral Toxicity - Fixed Dose Method
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
D OSE: 2000 mg/:kg
Day O"
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
Da
325.0
3
328.5
3
299.9
3
310.4
3
325.1
3
" Weight before fasting b Fasted body weight
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Acute Oral Toxicity - Fixed Dose Method
Animal
Number
648488 648489 648490 648491 648492
INDIVIDUAL BODY WEIGHTS OF FEMALE RATS FROM MAIN STUDY
DOSE: 2000mg/kg
Day -1"
230.0 230.0 230.0 222.0 229.0
Day O"
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
Da
261.3
2
246.9
2
251.2
2
247.3
2
244.8
2
3 Weight before fasting b Fasted body weight
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.cute Oral Toxicity - Fixed Dose Method
DuPont-6711
APPENDIX B Individual Clinical Observations and Mortality Records
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Acute Oral Toxicity - Fixed Dose Method
INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS IN FEMALE RATS FROM SI DOSE: 500mg/kg
Sex
Animal Observation
F
648018 General observation. No Abnormality Detected
Sacrificed by design
Days
0-7
7
DOSE: 2000mg/kg
Sex
Animal Observation
F
648020 General observation. No Abnormality Detected
Sacrificed by design
Days
0-7
7
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JlBAcute Oral Toxicity - Fixed Dose Method
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INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS IN MALE RATS FROM M
DOSE: 2000mg/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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'Acute Oral Toxicity - Fixed Dose Method
INDIVIDUAL CLINICAL OBSERVATIONS AND MORTALITY RECORDS IN FEMALE RATS FROM DOSE: 2000mg/kg
Sex
Animal Observation
648488 648489 648490 648491 648492
General observation. No Abnormality Detected Sacrificed by design General observation. No Abnormality Detected Sacrificed by design General observation. No Abnormality Detected Sacrificed by design General observation. No Abnormality Detected Sacrificed by design 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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Acute Oral Toxicity - Fixed Dose Method___________________DuPont-6711
APPENDIX C Individual Animal Gross Observations
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Acute Oral Toxicity - Fixed Dose Method
INDIVIDUAL ANIMAL GROSS OBSERVATIONS IN MALE RATS FROM MAIN STUD
LESIONS
|LESION I | ANIMAL
TREATMENT
GENERAL ORGAN NO ABNORMALITY DETECTED
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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Acute Oral Toxicity - Fixed Dose Method
INDIVIDUAL ANIMAL GROSS OBSERVATIONS IN FEMALE RATS FROM MAIN STU
LESIONS
LESION I ANIMAL
TREATMENT
GENERAL ORGAN NO ABNORMALITY DETECTED
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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