FINAL REPORT
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
Test Article:
Mesozeaxanthin
Sponsor:
Howard Foundation Holdings Limited
Whitehill House
Granhams Road
Great Shelford
Cambridge, CB2 5JY
United Kingdom
Testing Facility:
Gene Logic Laboratories Inc. (Gene Logic)
610 Professional Drive
Gaithersburg, MD 20879
Gene Logic Study Number:
1567-04370
Author:
C.J. George Chang, DVM, MS, PhD, DABT
Study Completion Date:
October 10, 2006
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TABLE OF CONTENTS
COMPLIANCE STATEMENT........................................................................................................................ 4
QUALITY ASSURANCE STATEMENT ........................................................................................................ 5
SIGNATURE PAGE ...................................................................................................................................... 6
SUMMARY.................................................................................................................................................... 7
STUDY PERSONNEL AND TEST SITES .................................................................................................... 8
STUDY TIMETABLE ................................................................................................................................... 10
INTRODUCTION......................................................................................................................................... 11
METHODS AND MATERIALS .................................................................................................................... 11
Test and Control Articles.................................................................................................................... 11
Test Animals and Husbandry............................................................................................................. 13
Experiment Design............................................................................................................................. 14
Observations ...................................................................................................................................... 15
Clinical Pathology .............................................................................................................................. 16
Termination, Necropsy and Histopathology....................................................................................... 17
Statistical Analyses ............................................................................................................................ 17
Record Retention ............................................................................................................................... 18
RESULTS.................................................................................................................................................... 19
Stability of Test Article Formulations.................................................................................................. 19
Formulation Homogeneity and Dose Verification .............................................................................. 19
Animal Disposition and Clinical Observations ................................................................................... 19
Body Weights and Body Weight Changes......................................................................................... 19
Ophthalmology ................................................................................................................................... 20
Clinical Pathology .............................................................................................................................. 20
Gross Pathology................................................................................................................................. 21
Organ Weights ................................................................................................................................... 21
Histopathology ................................................................................................................................... 22
CONCLUSION ............................................................................................................................................ 23
REFERENCES............................................................................................................................................ 24
ABBREVIATIONS ....................................................................................................................................... 25
TABLES
1 2 3 4 5 6 7 -
Summary of Animal Disposition and Clinical Observations .................................................... 26
Summary of Body Weights ...................................................................................................... 29
Summary of Body Weight Changes ........................................................................................ 31
Summary of Gross Pathology Observations ........................................................................... 35
Summary of Terminal Body Weights and Absolute Organ Weights........................................ 48
Summary of Organ-to-Body Weight Ratios ............................................................................ 51
Summary of Organ-to-Brain Weight Ratios............................................................................. 54
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TABLE OF CONTENTS (CONTINUED)
APPENDICES
1 - Certificates of Analysis ............................................................................................................ 57
2 - Analytical Chemistry Methods ................................................................................................. 62
3 - Results of Test Article Formulation Stability Analysis ............................................................. 84
4 - Results of Dose Verification Analysis...................................................................................... 86
5 - Individual Animal Disposition and Clinical Observations......................................................... 91
6 - Individual Body Weights ........................................................................................................ 100
7 - Individual Body Weight Changes........................................................................................... 109
8 - Ophthalmology Reports......................................................................................................... 118
9 - Clinical Pathology Evaluation and Data Reports................................................................... 122
10 - Individual Gross Pathology Observations ............................................................................. 162
11 - Individual Terminal Body Weights and Absolute Organ Weights.......................................... 171
12 - Individual Organ-to-Body Weight Ratios ............................................................................... 177
13 - Individual Organ-to-Brain Weight Ratios ............................................................................... 183
14 - Histopathology Report ........................................................................................................... 189
15 - Protocol, Amendments, and Deviations ................................................................................ 304
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COMPLIANCE STATEMENT
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
This study was conducted in compliance with the U.S. FDA Good Laboratory Practice (GLP) Regulations
for Non-clinical Laboratory Studies (21 CFR Part 58), OECD Good Laboratory Practice Principals (GLP)
[ENV/MC/CHEM(98)17], and Japanese MHLW Good Laboratory Practice (GLP) Standards (Ordinance
No. 21).
•
The test article formulation stability analysis, the dose verification analysis, and analytical
chemistry methods performed for the Sponsor by Industrial Organica were not conducted in
compliance with the above regulatory guidelines.
•
Stability analysis was not performed on lot 5 09 J1 EPZ of the formulated test article.
•
There were a few instances where initials and/or date were not recorded in a timely fashion.
Senior study personnel subsequently reviewed data; data were not compromised by the lack of
timely documentation.
•
Data entry of ‘No Visible Lesions’ for the Lacrimal Gland was not entered at the time of necropsy
for termination and recovery rats.
•
The proposed experimental completion date was not included in the protocol (OECD 8.2.3).
There were no deviations from the aforementioned regulations that affected the quality or integrity of
the study or the interpretations of the results in this report.
Study Director:
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QUALITY ASSURANCE STATEMENT
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
This study, 1567-04370 entitled “Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar
Rats with a 4-Week Recovery” was inspected/audited by Quality Assurance in accordance with Gene
Logic’s Standard Operating Procedures, the protocol, FDA, OECD, and MHLW Good Laboratory Practice
Regulations. All findings were reported to the Study Director and Testing Facility Management.
Date Reported:
Type of Audit
Date Audited
Study Director
Management
Protocol
April 13, 2005
April 13, 2005
April 13, 2005
SD 8 Dose Administration
April 28, 2005
May 3, 2005
May 3, 2005
SD 21 Dose Administration
May 11, 2005
May 18, 2005
May 18, 2005
Ophthalmology Exams
July 18, 2005
July 21, 2005
July 21, 2005
Necropsy
July 20, 2005
July 25, 2005
July 25, 2005
Raw Data/
Draft Final Report
December 1& 5-8, 2005
December 8, 2005
December 8, 2005
Histopathology Raw Data
December 12, 2005
December 13, 2005
December 13, 2005
Post/Final Report
July 5, 7 & 10, 2006
July 10, 2006
July 10, 2006
Action has been taken in response to all items listed by Quality Assurance. It is concluded that the final
report accurately reflects Gene Logic’s Standard Operating Procedures and the raw data for this study.
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SIGNATURE PAGE
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
Peer Review:
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SUMMARY
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
The purpose of this study was to determine the potential toxicity of Mesozeaxanthin when administered
once daily to male and female Han Wistar rats for 13 consecutive weeks, and to assess in a 4-week
recovery period the delayed onset of any toxicity or persistence or reversibility of any effects noted earlier
during the 13-week dosing phase. Han Wistar rats (100 total; 50/sex) were randomly assigned to one of
four groups (10-15 sex/group) and administered with Corn Oil (control) or Mesozeaxanthin at dose levels
of 2, 20, or 200 mg/kg/day (Groups 2-4, respectively) for 13 consecutive weeks by oral gavage.
Parameters evaluated included mortality, clinical observations, body weights, ophthalmology, clinical
pathology, organ weights, gross pathology, and histopathology.
No compound-related mortality, clinical signs of toxicity, changes in body weights, ophthalmology, clinical
pathology, gross pathology, or histopathology were noted.
Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) of Mesozeaxanthin in
rats is >200 mg/kg/day when administered orally for 13 consecutive weeks.
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STUDY PERSONNEL AND TEST SITES
Study Director:
Alternate Study Director:
Toxicology Associate:
Report Associate:
Head Technicians:
Technical Supervisor:
Supervisor, Necropsy:
Manager, Formulations:
Manager, In-Life Operations:
Pathology Services:
Clinical Pathologist and Pathologist:
Vice President, Toxicology:
Director, Laboratory Animal Medicine:
C.J. George Chang, DVM, MS, PhD, DABT
C. Steven Godin, PhD, DABT (From June 14 to July 5, 2005)
Karl Fraser, MS
Rachna Arora, MS
Michael Johnson (April 12 to July 1, 2005)
Jackie Quinteros (July 2 to August 17, 2005)
E. Ling Wong, BS, LATg
Angela Stahl, BS
Gary Holley, BS
Michael R. Brunty, BS
Meredith James, BS, LATG
James Szabo, DVM, PhD, DACVP
Gary W. Wolfe, PhD, DABT
John Parrish, DVM, PhD, ACLAM
Ophthalmologist:
Nancy M. Bromberg, VMD, MS, DACVO
Eye Clinic for Animals
6119 Massachusetts Avenue
Bethesda, Maryland 20816
Bioanalytical Chemistry:
(Formulation Stability,
Homogeneity, and Dose
Verification)
Jose Torres, MSc
Industrial Organica, S.A. De C.V.
Ave. Almazan No. 100
Col Topo Chico
Monterrey, Mexico
Sponsor:
Howard Foundation Holdings Limited (Howard Foundation)
Whitehill House
Granhams Road
Great Shelford
Cambridge, CB2 5JY
United Kingdom
Sponsor Representative/Study Monitor: David I. Thurnham, PhD
Howard Professor of Human Nutrition
Northern Ireland Center for Food and Health
University of Ulster
Coleraine BT52 1SA
United Kingdom
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STUDY PERSONNEL AND TEST SITES (CONTINUED)
Toxicology Operations:
(Animal Facility)
Gene Logic
620 Professional Drive
Gaithersburg, MD 20879
Laboratory Operations:
(Clinical Pathology, Histology, Pathology)
Gene Logic
18761 North Frederick Avenue, Suite A
Gaithersburg, MD 20879
Archives
Data:
Iron Mountain, Inc.
4451 Georgia Pacific Blvd., Suites L&M
Frederick, MD 21704
Histology and Preserved Specimens:
Charles River Laboratories, Preclinical
Services - Pathology Associates (PAI)
15 Worman’s Mill Court, Suite I
Frederick, MD 21701
Chemicals:
Gene Logic
18761 North Frederick Avenue, Suite A
Gaithersburg, MD 20879
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STUDY TIMETABLE
Study Initiation Date:
March 24, 2005
Experimental Start Date:
April 12, 2005
Receipt of Animals:
April 12, 2005
Randomization of Animals:
April 15, 2005
First Day of Dosing:
April 21, 2005
Last Day of Dosing:
July 19, 2005
Necropsy:
Terminal Sacrifice:
Recovery Sacrifice:
July 20, 2005
August 17, 2005
Experimental Completion Date:
July 10, 2006
Study Completion Date:
October 10, 2006
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INTRODUCTION
The purpose of this study was to determine the toxicity of Mesozeaxanthin in male and female Han Wistar
rats when administered once daily by oral gavage for 13 consecutive weeks, and to assess in a 4-week
recovery period the delayed onset of any toxicity or persistence or reversibility of any effects noted earlier
during the 13-week dosing phase. The rat was selected because it is the standard species for use in
toxicology studies per FDA and ICH guidelines, and because this study was conducted in accordance
with the regulatory guideline; alternatives could not be considered.
The oral gavage approach was
selected because it is the intended route of administration to humans.
Although mesozeaxanthin is probably not present in the human diet, it is found in the human eye and it is
possible that its origin is from lutein in the diet.
Lutein and mesozeaxanthin have slightly different
structures but share a same chemical composition; both are found in the macular tissue of the human
eye. The doses selected for the current study are based on similar doses as those used by Kruger et al
(2002) who described a toxicity study on lutein at 2, 20 and 200 mg/kg/day.
The top dose of
Mesozeaxanthin in the current study was approximately 100,000 times higher (on a body weight basis)
than the mean daily intake of natural zeaxanthin by humans (0.002 mg/kg/day).
The protocol, protocol amendments, and protocol deviations are presented in Appendix 15.
METHODS AND MATERIALS
Test and Control Articles
Neat Materials
The neat test and control articles used on this study are described in Text Table 1.
Text Table 1: Neat Test and Control Articles
Name
Lot No.
a
a
Mesozeaxanthin
a
Supplier
Purity
Description
5 11 M1 EPZ
Industrial Organica
Not provided
Orange, paste
b
Mesozeaxanthin
5 09 J1 EPZ
Industrial Organica
Not provided
Orange, solid
Corn Oil
UM0342
Spectrum Chemical
Not provided
Clear, yellow liquid
Corn Oil
P8362344
ACH Food Company
Assumed 100%
Clear, yellow liquid
Corn Oil
TV0947
Spectrum Chemical
Assumed 100%
Clear, yellow liquid
- 200 mg/mL; formulated in Corn Oil
b
- Used only for Week 13 formulations
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The stock test article formulation, Mesozeaxanthin (200 mg/mL in Corn Oil), was supplied by Industrial
Organica, Monterry, Mexico, and stored refrigerated (5 ± 3°C) and protected from light upon receipt.
Three batches of the Corn Oil used at Gene Logic for animal dosing and used for preparation of test
article dilutions were supplied by Spectrum Chemical Company, New Brunswick, NJ (2 batches) or ACH
Food Company, Memphis, TN (1 batch). All batches were received and stored at room temperature upon
arrival. Certificates of Analysis of the Mesozeaxanthin and Corn Oil, are presented in Appendix 1 and
stability information of formulated Mesozeaxanthin are presented in Appendix 3.
Reserve samples of the test article (20 mL; ~ 36.756 grams), and control article (10 mL) were taken at
Gene Logic prior to use on this study. The samples were archived at Gene Logic under the same
conditions as the test and control articles.
Any remaining test and control articles were returned to the Sponsor following completion of the study.
Dose Formulations
The Mesozeaxanthin formulation (received from the supplier) was considered 100% pure for formulation
purposes. Further dilution of the stock Mesozeaxanthin formulation for dosing purposes was adjusted
based on a stated density of 0.9189 g/mL. Dose formulations were prepared weekly and used within 8
days after the stock formulation was diluted. Prior to use, the stock Mesozeaxanthin formulation was
warmed overnight in a circulating water bath at 50°C (protected from light) and the Corn Oil was warmed
in a circulating water bath at 50°C for approximately 20 minutes before used for dilution.
Dose formulations were prepared by adding the appropriate amount of the 200 mg/mL Mesozeaxanthin
stock into a mortar, adding a small amount of Corn Oil and mixing into a paste, and then transferring the
paste to a pre-calibrated beaker. A sufficient quantity of Corn Oil was added to achieve the desired final
volume, and the formulation was then placed in a 50°C circulating water bath for 15 minutes and mixed
(using a magnetic stir plate) for approximately 10 minutes until a suspension was attained. Following
preparation, the total volume of each formulation was aliquoted into seven amber glass vials (one vial for
use on each dosing day) and stored refrigerated (approximately 2 - 8°C) until used for dosing.
Formulations were removed from the refrigerator and warmed in a water bath at approximately 40°C for
at least 15 minutes and followed by mixing on a stir plate for at least 5 minutes during the dosing period.
Excess formulation was disposed of in accordance with Gene Logic SOPs, appropriate regulatory
requirements, and information contained in the Material Safety Data Sheets.
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Dosage Sampling
Triplicate 5-mL samples were taken from the top, middle and bottom portions of each dosing formulation
in Week 1 for homogeneity analysis and dose verification. Five-mL samples of each dosing formulation
prepared for Weeks 5, 9 and 13 were also collected for dose verification. The samples were stored
refrigerated (5 ± 3°C) while protected from light and shipped to Industrial Organica, Mexico, on ice packs
for homogeneity analysis (Week 1 formulations only) and/or dose verification.
Dosage Analysis
Analyses were conducted by Industrial Organica. A summary of the analytical method and the results are
presented in Appendix 2.
Test Animals and Husbandry
Animals
Animal information is provided in Text Table 2.
Text Table 2: Animal Information
Parameter
Males
Females
Species and Strain
Han Wistar Rats
Supplier
Charles River Laboratories
Number of Animals Received
55
55
Number of Animals Used on Study
50
50
Age of Animals at First Dose
7-8 weeks
Body Weight Range at First Dose
Disposition of Extra Animals
170.50-207.90 g
129.07-149.83 g
All ten extra animals (5/sex) were transferred into the training colony at
the end of the in-life phase.
Animals were acclimated to laboratory conditions for 10 days prior to the first dose and released from
quarantine by a staff veterinarian.
During the acclimation period, each animal was identified by a
temporary number that was recorded on each cage label.
Gene Logic’s Institutional Animal Care and Use Committee (IACUC) approved this protocol and found it
to be in accordance with provisions of the USDA Animal Welfare Act, the PHS Policy on Humane Care
and Use of Laboratory Animals, and the US Interagency Research Animal Committee Principles for the
Utilization and Care of Research Animals.
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Husbandry
Animal husbandry was provided as described in Text Table 3.
Text Table 3: Husbandry
Feed
a
Certified Global Harlan Tekland Laboratory 2018 Rodent Diet
b
Water via an automatic watering system and water bottles
Water
Bedding
c
Certified hardwood bedding
Caging
Polycarbonate cages
Racks
Stainless steel racks
Animals Per Cage
One
Temperature Range
64 to 79°F
Humidity Range
30 to 70%
Light Cycle
12-hour light/12-hour dark, interrupted as necessary for study-related events
Air Changes
Minimum of 10 air changes per hour
a
The feed was analyzed by the manufacturer for concentrations of specified heavy metals, aflatoxin, chlorinated hydrocarbons,
organophosphates and specific nutrients.
b
The water was routinely analyzed for contaminants and specific microbes.
c
The bedding was analyzed by the manufacturer for acceptable levels of heavy metals, aflatoxins, bacteria, yeasts, molds, and
organophosphates prior to certification.
Feed and water were provided ad libitum, except on SD 90-91 (before terminal sacrifice) and SD 118-119
(before recovery sacrifice) when food-fasting was implemented and rats were fasted for 19-23 hours
before termination at those 2 occasions. No contaminants were known to be present in the diet, water, or
bedding at levels that might have interfered with achieving the objectives of the study.
Environmental controls were set to maintain animal room conditions as shown in Text Table 3. Actual
temperature and relative humidity in the animal room or zone were monitored continuously by a
computerized system and manually recorded at least once daily. All environmental parameters were
maintained within the protocol requirements, except as noted in Appendix 15.
Experiment Design
Group Assignment and Doses
Animals were initially accepted into the randomization pool based upon body weights and physical
examinations. Male and females were randomized separately. They were assigned to study groups
using computer-generated random numbers. At randomization the mean body weight for each group was
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not statistically different (p≤0.05) from the control mean. After the randomization process, each study
animal was assigned a unique number and identified by a cage card and ear tag. Animals were assigned
to groups as shown in Text Table 4.
Text Table 4: Study Design
Group
Treatment
Test Article
Dose Level
(mg/kg/day)
Test Article
Concentration
(mg/mL)
N
Animal Numbers
N
Animal Numbers
1
Corn Oil
0
0
15
20271-20285
15
20286-20300
2
Mesozeaxanthin
2
0.2
10
20301-20310
10
20311-20320
3
Mesozeaxanthin
20
2
10
20321-20330
10
20331-20340
4
Mesozeaxanthin
200
20
15
20341-20355
15
20356-20370
Males
Females
N = number of animals per group
Dose Administration
Dosing information is presented in Text Table 5.
Text Table 5: Dose Administration Information
Route of Administration
Oral gavage
Frequency of Dosing
Daily
Duration of Dosing
SD 1 to 90
Dose Volume
10 mL/kg; based on most recent body weight
Equipment
3-mL or 5-mL syringes with 16-gauge/ 3-inch needles
Dosing Conditions
Animals were dosed at approximately the same time each day
Observations
Animals were observed as shown in Text Table 6.
Text Table 6: Animal Observations/Measurements
Procedure
Frequency of Testing
Cageside Observations
≥ 2 Daily
Clinical Observations
SD1 (pre-dose), once weekly, and at terminal sacrifice
Body Weight
SD1 (pre-dose), once weekly, on SD 90 and 118 (non-fasted), and at
scheduled sacrifice on SD 91 and 119 (fasted)
Ophthalmological
Examinations
Prior to scheduled terminations (on all surviving animals)
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Cageside observations included observation for mortality, moribundity, general health, and signs of
toxicity.
Clinical observations included evaluation of skin and fur characteristics, eye and mucous
membranes, respiratory, circulatory, autonomic and central nervous systems, and somatomotor and
behavior patterns. Ophthalmological examinations were conducted using an indirect ophthalmoscope
following 1% Tropicamide mydriasis.
Clinical Pathology
Blood was collected for clinical pathology evaluation as shown in Text Table 7. Animals were fasted
overnight for 19-23 hrs (with water available) prior to sample collection.
Text Table 7: Clinical Pathology
Parameter
Chemistry
Hematology
Collection Day
Collection Method
Volume Collected
Tubes Used
Coagulation
Prior to necropsy
Through the retroorbital plexus, abdominal aorta or cardiac puncture when rats were
under
70% CO2/30% O2 anesthesia
~ 1 mL
~ 0.5-mL
~ 1.8-mL
2.5-mL serum separator
0.5-mL potassium EDTA
tube
1.8-mL sodium citrate tube
Hematology and Coagulation samples were stored refrigerated and clinical chemistry samples were
stored frozen before analysis. Blood samples were transported on ice packs to Gene Logic’s Clinical
Pathology Laboratory for analysis. Parameters evaluated and methods used are described in the
Appendix 9.
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Termination, Necropsy and Histopathology
Termination
On SD 91 (terminal sacrifice) and 119 (recovery sacrifice), all designated animals were euthanized by
carbon dioxide inhalation followed by exsanguination.
Necropsy
Animals were necropsied as soon as possible after the time of death. A full gross necropsy, which
included examination of the external surface of the body, all orifices, the cranial, thoracic, and abdominal
cavities, and contents within each body cavity was performed. Protocol-specified organs were weighed
as soon as possible after dissection; paired organs were weighed together. Bone marrow smears were
prepared from the sternum; bone marrow slides were air dried, fixed in methanol, and stored for possible
future evaluation. The eyes, together with optic nerves, harderian and lacrimal glands, testes and
epididymides, were fixed in modified Davidson’s fixative and transferred to 70% ethanol within 24-48
hours of collection. All other tissue samples and the animal identification (ear tag) were preserved in 10%
neutral buffered formalin (NBF).
Histopathology
All tissue samples from the Groups 1 and 4 animals sacrificed following the treatment phase and the liver,
kidneys, spleen, and stomach from Groups 2 and 3 animals were processed and evaluated. The liver,
kidneys, spleen, and stomach from the recovery sacrifice animals were also processed and evaluated.
Those tissue samples were embedded in paraffin, sectioned, stained with hematoxylin and eosin and
examined microscopically by a board-certified veterinary pathologist.
Statistical Analyses
Body weights, body weight change, absolute and relative organ weights, and clinical pathology data were
analyzed statistically.
Quantitative results were analyzed using the Kolmogorov-Smirnov test for normality, the Levene Median
test for equal variance, and by one-way Analysis of Variance (ANOVA). If either the normality or equal
variance test failed, then the analysis was continued using the non-parametric Kruskal-Wallis ANOVA on
rank-transformed data.
For parametric data, if the ANOVA indicated statistical significance among
experimental groups then the Dunnett’s t-test was used to delineate which groups (if any) differed from
the control.
For non-parametric data, if the Kruskal-Wallis ANOVA indicated statistical significance
among experimental groups then the Dunn’s test was used to delineate which groups (if any) differed
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from the control. The probability value of less than 0.05 (two-tailed) was used as the critical level of
significance for all tests.
Statistical analysis was conducted using SigmaStat™ Statistical Software, Version 1 (Jandel Scientific,
San Rafael, California). Groups with sample sizes of 1 were excluded from statistical analysis. The term
“significant” is used throughout the text of the report to indicate statistical significance at p<0.05.
Record Retention
All study data, including (but not limited to) animal data, clinical pathology data, necropsy data, histology
and pathology data, professional reports, study protocol (including amendments), final study report, and
any communications concerning the conduct of the study will be retained in the archive of Gene Logic for
a period of 5 years following completion of the final report.
Preserved tissues, blocks, and slides will be maintained for the 5-year period at the archive facility at PAI.
Following the 5-year period (or before at Sponsor’s request), the Sponsor will be contacted to determine
the disposition of these materials.
All electronic data will be maintained at Gene Logic.
Records
regarding disposition of data and specimens will be maintained at Gene Logic.
Study data generated by the Sponsor or sub-contractors will be archived by the Sponsor or subcontractors, respectively.
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RESULTS
Stability of Test Article Formulations
Stability data of formulated test article are presented in Appendix 3.
Stability data provided by the Sponsor (generated at Industrial Organica) indicated that the 200 mg/mL
stock formulation and the 0.2, 2.0, and 20.0 mg/mL formulations of Mesozeaxanthin were stable for up to
14 days after formulations when maintained at either 3-5°C or at 25°C.
Formulation Homogeneity and Dose Verification
Formulation homogeneity and dose verification data are presented in Appendix 4.
Anaylsis of dose formulations collected in Weeks 1, 5, 9, and 13 revealed that the test article was
properly formulated and stable during formulation; mean test article concentration values ranged from
92.22 to 110.4% of target concentrations.
No test article was detected in the control formulation.
Homogenity results measured on Week 1 samples indicated that the dose formulations were
homogenous with relative standard deviations being <6% for all analyzed formulations.
Animal Disposition and Clinical Observations
Group and individual animal disposition and observation data are presented in Table 1 and Appendix 5,
respectively.
No compound-related mortality or signs of toxicity were noted.
Other observations noted included
alopecia, abrasions, and hyperactivity; these observations were considered unrelated to treatment
because they occurred in both the compound-treated and control groups or only appeared sporadically in
low incidence throughout the study with no correlation to treatment or sex.
Body Weights and Body Weight Changes
Group summary and individual body weight and body weight change data are presented in Tables 2
and 3 and Appendices 6 and 7, respectively.
No compound-related body weight changes were noted.
No significant differences were noted in
absolute body weight or total body weight change over the course of the study for either sex. Statistically
significant increases in weekly body weight changes were noted as follows: 20 mg/kg/day males on
SD 22-29 and 43-50; 200 mg/kg/day males on SD 36-43; 2 mg/kg/day females on SD 43-50; and
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200 mg/kg/day females on SD 22-29 and SD 71-78. These changes were considered incidental and
unrelated to treatment because the changes were infrequent, sporadic, and not dose related.
Ophthalmology
The Ophthalmology Report is presented in Appendix 8.
No compound-related findings were noted ophthalmologically. A few findings were noted and listed in
Text Table 8. Those changes noted were considered incidental and unrelated to treatment because the
changes were noted in the control group as well as the high dose groups.
These changes were
infrequent, sporadic, not dose-related and/or without histopathological correlations.
Text Table 8
Terminal Sacrifice
Animal ID
20271
20276
20283
20286
20292
Group
1M
1M
1M
1F
1F
20297
20327
20353
1F
3M
4M
Recovery Sacrifice
Animal ID
20296
Group
1F
20297
20298
20300
20351
20353
20354
20355
20367
1F
1F
1F
4M
4M
4M
4M
4F
OS - Left eye
OD - Right eye
Observations
Crystalline corneal opacities OD
Crystalline corneal opacities OU
Crystalline corneal opacities OD
Crystalline corneal opacities OU
Crystalline corneal opacities OD
Crystalline corneal opacities, anterior
synechiation irregular pupil and retinal
degeneration OS
Pinpoint crystalline corneal opacities OS
Crystalline corneal deposits OD
Observations
Crystalline lens opacities OD
Crystalline lens opacities, Iritis, focal lens
cataract and focal retinal OD;
degeneration OS
Crystalline lens opacities OU
Crystalline lens opacities OU
Crystalline lens opacities OD
Lens opacity OS
Crystalline lens opacities OD
Crystalline lens opacities OS
Crystalline lens opacities OU
OU - both eyes
Clinical Pathology
The Clinical Pathology Evaluation and Data Reports are presented in Appendix 9.
No compound-related changes in hematology, clinical chemistry, or coagulation were noted.
20
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Review of the SD 91 data revealed significantly higher alkaline phosphatase (ALKP) activity for Groups 3
and 4 male rats when compared to male controls. Examination of the individual animal data revealed a
moderate degree of variability in these values in all dose groups, including the controls, indicating that the
differences between the controls and Groups 3 and 4 male rats were most likely the results of individual
animal variability rather than a compound effect. Total bilirubin (TBIL) concentration for Group 2 female
rats was significantly lower when compared to female controls; the difference was minimal in nature,
inconsistent with a dose response, and neither biologically or toxicologically significant.
Review of the SD 119 (recovery) data revealed significantly higher sodium (NA), total protein (TPROT),
and globulin (GLOB) concentrations for Group 4 male rats when compared to the male control rats.
These differences were minimal in nature and had no biological or toxicological significance. Prothrombin
time (PT) was significantly higher for Group 4 female rats when compared to female controls; the
difference was minor and had no biological or toxicological significance.
Gross Pathology
Gross pathology data are presented in Table 4 and Appendix 10.
No compound-related macroscopic findings were noted.
Observations at terminal sacrifice included the following: sporadic and infrequent incidences of
reddened/darkened mandibular lymph nodes in treated (2 and 200 mg/kg/day males and 20 mg/kg/day
females) and control animals; brown and/or enlarged thymus in one treated male (2 mg/kg/day) and one
treated female (200 mg/kg/day); a distended uterus in treated (2 and 20 mg/kg/day) and control females;
a cystic ovary in one treated female (20 mg/kg/day); and a mottled liver in one control female.
Observations at recovery sacrifice included a reddened brain in one treated male (200 mg/kg/day Male);
reddened mandibular lymph nodes in treated (200 mg/kg/day/sex) and control animals; and a reddened
thymus in one control female.
All findings listed above were considered incidental because they occurred infrequently, in both treated
and control animals, exhibited no dose relationship, and/or are associated with normal female
reproductive cycling events.
Organ Weights
Organ weight data are presented in Tables 5, 6 and 7 and in Appendices 11, 12 and 13.
21
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
At terminal sacrifice, the following significant differences in absolute and relative organ weight data were
noted: lower adrenal and/or adrenal/body weight ratios in all treated females; lower brain/body weight
ratios in the 20 and 200 mg/kg/day females; and higher liver/brain weight ratio in the 20 mg/kg/day
females.
At recovery sacrifice, the following significant differences in absolute and relative organ weight data were
noted: lower thymus weight, heart/body weight ratio, thymus/body weight ratio, and thymus/brain weight
ratio in the 200 mg/kg/day males. No significant differences were noted in the female data.
All organ weight changes noted above were considered incidental and unrelated to treatment, due to lack
of dose responses and/or microscopic correlations.
Histopathology
The Histopathology Report is presented in Appendix 14.
No compound-related histopathology findings were noted.
Lesions considered to be spontaneous and incidental were observed in treated and control rats. These
lesions consisted of early lesions of nephropathy (tubular regeneration; cortical, medullary and mucosal
mononuclear cell infiltrates; and mineralization within the kidney); vacuolation within the adrenal gland;
mononuclear cell infiltration within the harderian gland; hepatocellular vacuolation and mononuclear cell
infiltration within the liver; acute hemorrhage within the lung, mandibular lymph node, and thymus; dilation
of uterus; and mononuclear cell infiltration within the prostate. These lesions were noted sporadically, in
low frequency, and/or were not dose-proportional, and are recognized as background findings of rats.
Some microscopic observations seen only in compound-treated animals were also considered to be
spontaneous due to incidence and severity. On SD 91, focal, minimal, granulomatous inflammation
within the liver in animal 20363 (4F); unilateral, pelvic dilation within the kidney in animal 20329 (3M);
multifocal, minimal, histiocytosis within the lung in animal 20356 (4F); focal, minimal, perivascular
mononuclear cell infiltrate within the pancreas and focal, minimal, luminal neutrophilic infiltrate within the
prostate in animal 20348 (4M); multifocal, minimal, subacute inflammation within the stomach in animal
20301 (2M); multifocal, minimal, subacute hemorrhage within the thymus in animal 20357 (4F) and
multifocal, minimal, mononuclear cell infiltrate with the lacrimal gland in animal 20344 (4M) were
considered incidental and/or spontaneous. Multifocal, unilateral, subacute, mucosal inflammation within
the kidney in animal 20348 (4M) and animal 20282 (1M), on SD 91 and SD 119, respectively, were also
considered incidental and unrelated to the test article administration.
22
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
CONCLUSION
Under the conditions of this study, daily oral administration of Mesozeaxanthin at doses of up to 200
mg/kg/day was well tolerated in rats. The no-observed-adverse-effect-level (NOAEL) of Mesozeaxanthin
in rats is >200 mg/kg/day when administered orally for 13 consecutive weeks.
23
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Gene Logic Laboratories Inc. Study No. 1567-04370
REFERENCES
Kruger, C.L., Murphy, M., DeFreitas, Z., Pfannkuch, F., Heimbach, J. (2002). An innovative approach to
the determination of safety for a dietary ingredient derived from a new source: case study using a
crystalline lutein product. Food & Chemical Toxicity 40:1535-49.
24
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
ABBREVIATIONS
Not all abbreviations listed are used in this report.
↑
greater than control
S.D.
standard deviation
↓
less than control
RSD
relative standard deviation
>
greater than
TK
toxicokinetic
<
less than
PK
pharmacokinetic
≥
greater than or equal to
AUC
area under the curve
≤
less than or equal to
Cmax
maximum concentration
~
approximately
t 1/2
half-life
°
degree
SD
study day
%
percent
GD
gestation day
C
Celsius
PND
post-natal day
F
Fahrenheit
i.p.
intraperitoneal
L
liter
i.v.
intravenous
mL
milliliter
s.c.
subcutaneous
μL
microliter
i.m.
intramuscular
g
gram
EPA
Environmental Protection Agency
kg
kilogram
FDA
Food and Drug Administration
mg
milligram
GLP
Good Laboratory Practices
μg
microgram
GMP
Good Manufacturing Practices
ng
nanogram
IACUC
Institutional Animal Care and Use Committee
pg
picogram
ICH
International Conference on Harmonization
cm
centimeter
MHLW
Ministry of Health, Labor and Welfare
mm
millimeter
NIEHS
National Institute of Environmental Health Sciences
μm
micrometer
NTP
National Toxicology Program
sec
second
OECD
Organisation for Economic Co-operation and Development
min
minute
PHS
Public Health Service
h
hour
QA
Quality Assurance
d
day
QAU
Quality Assurance Unit
wk
week
SOP
Standard Operating Procedures
rpm
revolutions per minute
USDA
United States Department of Agriculture
NBF
neutral buffered formalin
LCA
Laboratory Corporation of America
No.
number
PAI
Pathology Associates, A Charles River Company
NA
not applicable
RACB
reproductive assessment by continuous breeding
N
number
25
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Sex: Male
Group 1
0 mg/kg
Group 2
2 mg/kg
Group 3
20 mg/kg
Group 4
200 mg/kg
Animal Disposition:
Terminal Kill
Number of Observations
Days from - to
91
Recovery Kill
Number of Observations
Days from - to
119
10
10
91
91
5
119
10
91
91
10
91
.
.
.
.
8
2
11
1
91
91
5
119
119
Clinical Observations (Dosing Phase):
Alopecia
Number of Observations
Number of Animals
Days from - to
.
.
.
71
91
22
.
.
.
91
Clinical Observations (Recovery Phase):
Abrasion
Number of Observations
Number of Animals
Days from - to
.
.
.
.
.
.
.
.
.
2
1
113
119
. – Not applicable
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
26
Group 4 - 200 mg/kg
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1 (continued)
Summary of Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Sex: Female
Group 1
0 mg/kg
Group 2
2 mg/kg
Group 3
20 mg/kg
Group 4
200 mg/kg
Animal Disposition:
Terminal Kill
Number of Observations
Days from - to
91
Recovery Kill
Number of Observations
Days from - to
119
10
10
91
91
5
119
10
91
91
10
91
.
.
.
.
4
1
1
1
91
91
5
119
119
Clinical Observations (Dosing Phase):
Abrasion
Number of Observations
Number of Animals
Days from - to
.
.
.
Number of Observations
Number of Animals
Days from - to
33
3
1
43
22
.
.
.
22
Alopecia
Hyperactive
Number of Observations
Number of Animals
Days from - to
8
9
1
91
2
1
71
78
8
8
1
64
.
.
.
43
1
1
91
3
1
64
78
85
85
.
.
.
. – Not applicable
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
27
Group 4 - 200 mg/kg
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1 (continued)
Summary of Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Sex: Female
Group 1
0 mg/kg
Group 2
2 mg/kg
Group 3
20 mg/kg
Group 4
200 mg/kg
Clinical Observations (Recovery Phase):
Abrasion
Number of Observations
Number of Animals
Days from - to
.
.
.
.
.
.
.
.
.
Alopecia
Number of Observations
Number of Animals
Days from - to
.
.
.
.
.
.
.
.
.
. – Not applicable
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
28
2
1
106
113
5
1
92
119
Group 4 - 200 mg/kg
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 2
Summary of Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
1
8
15
22
29
36
43
50
57
64
71
1m
Mean
S.D.
N
183.522
6.296
15
224.767
8.842
15
258.109
11.443
15
283.902
13.737
15
302.515
16.582
15
322.848
18.320
15
334.027
20.638
15
346.655
21.586
15
356.874
21.832
15
365.908
23.934
15
375.122
23.438
15
2m
Mean
S.D.
N
189.207
7.700
10
230.083
8.881
10
263.346
9.906
10
290.433
12.672
10
306.697
30.502
10
331.131
17.365
10
345.266
19.068
10
360.356
21.254
10
373.306
22.212
10
383.684
23.818
10
392.772
26.615
10
3m
Mean
S.D.
N
185.871
9.658
10
228.047
10.757
10
263.261
12.875
10
294.356
17.780
10
320.352
21.366
10
339.639
25.999
10
353.019
26.876
10
370.880
28.997
10
383.820
33.604
10
394.864
35.453
10
405.093
37.498
10
4m
Mean
S.D.
N
188.743
9.552
15
231.855
9.669
15
266.078
10.633
15
292.962
15.770
15
316.070
18.658
15
335.322
21.089
15
351.659
23.951
15
365.129
25.816
15
378.391
27.943
15
387.449
28.881
15
395.967
29.966
15
78
85
90
91a
Group
Sex
92
99
106
113
118
119a
1m
Mean
S.D.
N
383.239
25.954
15
387.853
27.466
15
389.308
23.074
10
379.444
21.684
10
391.218
39.132
5
393.962
42.332
5
403.942
46.704
5
407.982
50.935
5
410.084
51.972
5
398.388
47.684
5
2m
Mean
S.D.
N
400.919
28.414
10
407.050
31.438
10
408.503
31.500
10
399.231
31.691
10
.
.
.
.
.
.
.
.
.
.
.
.
Mean
S.D.
N
416.070
40.644
10
422.340
42.789
10
423.011
43.857
10
413.575
43.195
10
Mean
S.D.
N
405.358
33.323
15
412.613
34.589
15
417.059
37.126
10
407.532
37.898
10
3m
4m
m – Male
. – Not applicable
Nominal Dose: Group 1 - 0 mg/kg
0
0
.
.
0
.
.
0
0
407.414
29.154
5
406.102
27.893
5
0
.
.
0
409.916
28.539
5
0
.
.
0
415.692
29.643
5
a – fasted weights
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
29
Group 4 - 200 mg/kg
0
.
.
0
418.494
29.101
5
.
.
0
404.236
29.393
5
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 2 (continued)
Summary of Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
1
8
15
22
29
36
43
50
57
64
71
1f
Mean
S.D.
N
138.725
4.858
15
153.963
8.168
15
171.545
12.397
15
184.309
12.780
15
193.222
16.326
15
201.959
15.961
15
208.919
17.229
15
212.099
18.660
15
215.385
18.531
15
219.676
17.672
15
224.021
18.107
15
2f
Mean
S.D.
N
136.366
4.117
10
154.044
7.883
10
167.347
7.901
10
178.558
8.385
10
189.435
9.406
10
194.304
11.798
10
198.801
9.302
10
205.953
11.222
10
209.224
12.000
10
211.003
13.226
10
213.964
10.390
10
3f
Mean
S.D.
N
137.336
6.303
10
155.421
8.944
10
170.074
9.055
10
179.419
8.698
10
191.314
8.256
10
198.039
10.919
10
203.609
10.045
10
206.596
11.058
10
212.718
11.366
10
216.043
11.283
10
218.373
10.951
10
4f
Mean
S.D.
N
138.668
5.183
15
155.761
6.436
15
174.683
10.376
15
186.061
11.571
15
199.770
11.780
15
205.095
12.751
15
211.775
13.908
15
217.635
15.124
15
222.644
14.995
15
223.688
15.852
15
227.606
16.003
15
78
85
90
91a
Group
Sex
92
99
106
113
118
119a
1f
Mean
S.D.
N
224.825
19.056
15
228.080
17.765
15
224.853
17.849
10
213.175
15.697
10
240.296
12.723
5
242.498
13.233
5
244.824
12.733
5
242.846
11.641
5
244.582
13.816
5
232.918
13.693
5
2f
Mean
S.D.
N
217.025
10.291
10
217.090
9.723
10
217.508
10.009
10
209.206
9.779
10
.
.
.
.
.
.
.
.
.
.
.
.
Mean
S.D.
N
220.611
10.904
10
220.670
10.219
10
224.007
11.480
10
215.253
11.861
10
Mean
S.D.
N
232.793
15.823
15
235.987
15.794
15
235.396
16.650
10
225.747
18.752
10
3f
4f
f – Female
. – Not applicable
Nominal Dose: Group 1 - 0 mg/kg
0
0
.
.
0
.
.
0
0
240.030
12.302
5
240.910
16.199
5
0
.
.
0
244.488
17.149
5
0
.
.
0
245.822
14.214
5
a – fasted weights
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
30
Group 4 - 200 mg/kg
0
.
.
0
247.138
16.346
5
.
.
0
234.524
14.095
5
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 3
Summary of Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Base
Weight
Day
(1)
From:
To:
1m
183.522
6.2960
15
Mean
S.D.
N
41.245
4.7380
15
33.342
4.5382
15
25.793
4.0934
15
18.613
4.5347
15
20.333
3.4621
15
11.179
5.3653
15
12.629
3.3329
15
2m
189.207
7.7000
10
Mean
S.D.
N
40.876
3.8911
10
33.263
3.6313
10
27.087
4.2640
10
16.264
22.4188
10
24.434
23.3348
10
14.135
3.7518
10
3m
185.871
9.6582
10
Mean
S.D.
N
42.176
5.0927
10
35.214
5.4687
10
31.095
6.3623
10
25.996*
4.2292
10
19.287
5.7029
10
4m
188.743
9.5517
15
Mean
S.D.
N
43.111
4.2745
15
34.223
6.7880
15
26.884
5.9024
15
23.108
5.2228
15
19.252
3.5153
15
Group
Sex
1
8
8
15
15
22
22
29
29
36
36
43
43
50
50
57
57
64
64
71
71
78
10.219
3.4900
15
9.034
3.9327
15
9.214
3.3898
15
8.117
4.7804
15
15.090
5.5184
10
12.950
4.0398
10
10.378
4.1417
10
9.088
3.6140
10
8.147
6.5957
10
13.380
3.5558
10
17.861*
3.1521
10
12.940
6.3940
10
11.044
4.7760
10
10.229
5.3543
10
10.977
4.5586
10
16.337*
4.7977
15
13.471
4.5423
15
13.262
4.1229
15
9.057
2.7269
15
8.519
3.5075
15
9.391
5.9153
15
m – Male
* - Statistically different from control value, p < 0.05.
Note – Only non-fasted body weights were used for calculation of body weight changes.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
31
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 3 (continued)
Summary of Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
78
85
85
90
Absolute
Change
1
90
%
Change
1
90
85
92
113
118
2.102
2.7510
5
23.444
14.5532
5
%
Change
1
118
1m
Mean
S.D.
N
4.615
2.8896
15
0.848
4.2982
10
205.431
21.285
10
111.766
911.5637
10
2m
Mean
S.D.
N
6.131
4.6249
10
1.453
2.8081
10
219.296
27.655
10
115.867
713.1119
10
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3m
Mean
S.D.
N
6.270
3.1936
10
0.671
4.0935
10
237.140
40.023
10
127.596
820.7747
10
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4m
Mean
S.D.
N
7.255
3.1241
15
0.439
2.9677
10
228.873
37.819
10
122.060
222.1070
10
2.744
5.5694
5
-1.312
3.5189
5
9.980
4.5601
5
3.814
5.0874
5
106
113
Absolute
Change
1
118
From:
To:
2.814
3.3183
5
99
106
%
Change
85
118
Group
Sex
4.578
1.7141
5
92
99
Absolute
Change
85
118
4.040
5.0405
5
5.776
3.1248
5
2.802
4.2588
5
13.894
5.2775
5
m – Male
. – Not applicable
Note – Only non-fasted body weights were used for calculation of body weight changes.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
32
5.831
3.2563
5
3.444
1.3371
5
227.272
49.1337
5
228.636
29.8015
5
124.245
25.9029
5
120.879
18.3399
5
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 3 (continued)
Summary of Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Base
Weight
Day
1
From:
To:
1f
138.725
4.8584
15
Mean
S.D.
N
15.238
4.9223
15
17.581
5.7579
15
2f
136.366
4.1172
10
Mean
S.D.
N
17.678
4.3209
10
3f
137.336
6.3026
10
Mean
S.D.
N
4f
138.668
5.1828
15
Mean
S.D.
N
Group
Sex
1
8
8
15
15
22
22
29
29
36
36
43
43
50
50
57
57
64
64
71
71
78
12.764
2.8564
15
8.913
4.3230
15
8.737
4.7078
15
6.960
3.3522
15
3.180
3.0839
15
3.285
5.1848
15
4.291
4.0663
15
4.345
4.0581
15
0.805
3.8333
15
13.303
4.0648
10
11.211
3.0540
10
10.877
2.9248
10
4.869
5.1441
10
4.497
3.5827
10
7.152*
2.4237
10
3.271
2.2152
10
1.779
3.5405
10
2.961
4.7286
10
3.061
3.8295
10
18.085
3.9324
10
14.653
4.8179
10
9.345
2.9731
10
11.895
3.2000
10
6.725
4.0737
10
5.570
3.7531
10
2.987
4.6553
10
6.122
2.9490
10
3.325
4.3506
10
2.330
3.5468
10
2.238
2.1772
10
17.093
3.1395
15
18.922
4.8729
15
11.378
2.8139
15
13.709*
4.2658
15
5.325
4.4587
15
6.680
4.5784
15
5.860
4.7228
15
5.009
3.7264
15
1.044
3.9581
15
3.918
4.3804
15
5.187*
4.1941
15
f – Female
* - Statistically different from control value, p < 0.05.
Note – Only non-fasted body weights were used for calculation of body weight changes.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
33
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 3 (continued)
Summary of Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
85
90
%
Change
1
90
85
92
92
99
99
106
106
113
113
118
3.756
4.0210
5
2.202
2.5726
5
2.326
2.5550
5
-1.978
1.7008
5
1.736
3.6001
5
Absolute
Change
85
118
%
Change
85
118
Absolute
Change
1
118
%
Change
1
118
Group
Sex
From:
To:
1f
Mean
S.D.
N
3.255
4.8235
15
1.003
5.6569
10
87.611
15.6434
10
63.748
10.6391
10
2f
Mean
S.D.
N
0.065
4.8284
10
0.418
3.9170
10
81.142
7.7222
10
59.494
5.2778
10
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3f
Mean
S.D.
N
0.059
1.5506
10
3.337
2.0341
10
86.671
8.7568
10
63.196
6.6858
10
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4f
Mean
S.D.
N
3.194
4.4692
15
2.606
3.5214
10
97.012
13.1576
10
70.026 -2.350
8.5012 6.4623
10
5
f – Female
78
85
Absolute
Change
1
90
0.880
7.9894
5
3.578
1.2778
5
1.334
3.4291
5
1.316
3.4559
5
. – Not applicable
Note – Only non-fasted body weights were used for calculation of body weight changes.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
34
Group 4 - 200 mg/kg
8.042
4.6663
5
4.758
6.9221
5
3.484
2.2211
5
1.956
2.7354
5
102.890
9.2731
5
107.902
12.0025
5
72.557
4.8460
5
77.386
6.5734
5
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Terminal sac: SD 91
Sex:------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
adrenal gland;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
bone with marrow - femur;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
bone with marrow - sternum;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
brain;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
cecum;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
colon;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
duodenum;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
epididymis;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(-)
-
(-)
-
(-)
-
(-)
-
- = Not applicable
35
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Terminal sac: SD 91
Sex:------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
esophagus;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
eye;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
heart;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
ileum;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
jejunum;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
kidney;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
liver;
Submitted......................................................
No Visible Lesions.............................................
discoloration; mottled ........................................
(10)
10
0
(10)
10
0
(10)
10
0
(10)
10
0
(10)
9
1
(10)
10
0
(10)
10
0
(10)
10
0
lung;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
36
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Terminal sac: SD 91
Sex:------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
lymph node - mandibular;
Submitted......................................................
No Visible Lesions.............................................
discoloration; dark; multiple .................................
discoloration; red; bilateral .................................
enlargement; bilateral ........................................
(10)
9
0
1
1
(10)
9
0
1
0
(10)
10
0
0
0
(10)
8
1
1
0
(10)
10
0
0
0
(10)
10
0
0
0
(10)
9
0
1
0
(10)
10
0
0
0
lymph node - mesenteric;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
mammary gland;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
mandibular salivary gland;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
optic nerve;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
ovary;
Submitted......................................................
No Visible Lesions.............................................
cyst; clear; left .............................................
(-)
-
(-)
-
(-)
-
(-)
-
(10)
10
0
(10)
10
0
(10)
9
1
(10)
10
0
pancreas;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
- = Not applicable
37
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Terminal sac: SD 91
Sex:------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
parathyroid gland;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
pituitary;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
prostate;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(-)
-
(-)
-
(-)
-
(-)
-
nerve - sciatic;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
skeletal muscle;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
skin;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
spleen;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
stomach;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
- = Not applicable
38
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Terminal sac: SD 91
Sex:------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
testis;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(-)
-
(-)
-
(-)
-
(-)
-
thymus;
Submitted......................................................
No Visible Lesions.............................................
discoloration; brown; bilateral ...............................
enlargement; bilateral ........................................
(10)
10
0
0
(10)
9
1
1
(10)
10
0
0
(10)
10
0
0
(10)
10
0
0
(10)
10
0
0
(10)
10
0
0
(10)
9
1
0
thyroid gland;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
trachea;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
urinary bladder;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
uterus;
Submitted......................................................
No Visible Lesions.............................................
distention; bilateral .........................................
distention; left ..............................................
(-)
-
(-)
-
(-)
-
(-)
-
(10)
9
0
1
(10)
9
1
0
(10)
9
1
0
(10)
10
0
0
vagina;
Submitted......................................................
No Visible Lesions.............................................
(-)
-
(-)
-
(-)
-
(-)
-
(10)
10
(10)
10
(10)
10
(10)
10
- = Not applicable
39
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Terminal sac: SD 91
Sex:------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
spinal cord (cervical);
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
spinal cord (thoracic);
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
spinal cord (lumbar);
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
aorta;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
cervix;
Submitted......................................................
No Visible Lesions.............................................
(-)
-
(-)
-
(-)
-
(-)
-
(10)
10
(10)
10
(10)
10
(10)
10
harderian gland;
Submitted......................................................
No Visible Lesions.............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
rectum;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
- = Not applicable
40
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Terminal sac: SD 91
Sex:------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
seminal vesicle;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(-)
-
(-)
-
(-)
-
(-)
-
tongue;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
peyers patch;
Submitted.......................................................
No Visible Lesions..............................................
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
(10)
10
- = Not applicable
41
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Recovery sac: SD 119
Sex: ---- MALES ---- --- FEMALES --Dose:
0
200
0
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
5
5
5
5
adrenal gland;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
bone with marrow - femur;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
bone with marrow - sternum;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
brain;
Submitted..................................................................
No Visible Lesions.........................................................
discoloration; red; meningeal; localized ..................................
(5)
5
0
(5)
4
1
(5)
5
0
(5)
5
0
cecum;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
colon;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
duodenum;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
epididymis;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(-)
-
(-)
-
- = Not applicable
42
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Recovery sac: SD 119
Sex: ---- MALES ---- --- FEMALES --Dose:
0
200
0
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
5
5
5
5
esophagus;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
eye;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
heart;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
ileum;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
jejunum;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
kidney;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
liver;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
lung;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
43
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Recovery sac: SD 119
Sex: ---- MALES ---- --- FEMALES --Dose:
0
200
0
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
5
5
5
5
mammary gland;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
lymph node - mandibular;
Submitted..................................................................
No Visible Lesions.........................................................
discoloration; red; bilateral .............................................
(5)
2
3
(5)
1
4
(5)
3
2
(5)
2
3
mandibular salivary gland;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
lymph node - mesenteric;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
optic nerve;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
ovary;
Submitted..................................................................
No Visible Lesions.........................................................
(-)
-
(-)
-
(5)
5
(5)
5
pancreas;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
parathyroid gland;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
- = Not applicable
44
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Recovery sac: SD 119
Sex: ---- MALES ---- --- FEMALES --Dose:
0
200
0
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
5
5
5
5
pituitary;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
prostate;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(-)
-
(-)
-
nerve - sciatic;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
skeletal muscle;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
skin;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
spleen;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
stomach;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
testis;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(-)
-
(-)
-
- = Not applicable
45
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Recovery sac: SD 119
Sex: ---- MALES ---- --- FEMALES --Dose:
0
200
0
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
5
5
5
5
thymus;
Submitted..................................................................
No Visible Lesions.........................................................
discoloration; red; right .................................................
(5)
5
0
(5)
5
0
(5)
4
1
(5)
5
0
thyroid gland;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
trachea;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
urinary bladder;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
uterus;
Submitted..................................................................
No Visible Lesions.........................................................
(-)
-
(-)
-
(5)
5
(5)
5
vagina;
Submitted..................................................................
No Visible Lesions.........................................................
(-)
-
(-)
-
(5)
5
(5)
5
spinal cord (cervical);
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
spinal cord (thoracic);
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
- = Not applicable
46
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 4 (continued)
Summary of Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Recovery sac: SD 119
Sex: ---- MALES ---- --- FEMALES --Dose:
0
200
0
200
Unit: mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
5
5
5
5
spinal cord (lumbar);
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
aorta;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
cervix;
Submitted..................................................................
No Visible Lesions.........................................................
(-)
-
(-)
-
(5)
5
(5)
5
harderian gland;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
rectum;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
seminal vesicle;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(-)
-
(-)
-
tongue;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
peyers patch;
Submitted..................................................................
No Visible Lesions.........................................................
(5)
5
(5)
5
(5)
5
(5)
5
- = Not applicable
47
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 5
Summary of Terminal Body Weights and Absolute Organ Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
TBWa
Adrenal
glands
Brain
Heart
Kidneys
Liver
Spleen
Testis
b
Thymus
1m
Mean
S.D.
N
389.308
23.074
10
0.06468
0.01053
10
1.9750
0.1380
10
1.0870
0.1048
10
2.1721
0.1604
10
9.8178
0.7176
10
0.5429
0.0637
10
5.1482
0.3849
10
0.3622
0.0578
10
2m
Mean
S.D.
N
408.503
31.500
10
0.07181
0.01526
10
1.9343
0.0950
10
1.0951
0.0836
10
2.3155
0.2271
10
10.3561
0.9107
10
0.5637
0.0706
10
5.1789
0.3988
10
0.4551
0.1404
10
3m
Mean
S.D.
N
423.011
43.857
10
0.06039
0.01029
10
1.9913
0.0866
10
1.1240
0.1309
10
2.3399
0.3114
10
10.9012
1.8845
10
0.5678
0.0701
10
5.1444
0.4210
10
0.4668
0.1117
10
4m
Mean
S.D.
N
417.059
37.126
10
0.06011
0.00567
10
1.9843
0.0646
10
1.1126
0.0829
10
2.3511
0.2213
10
11.0002
1.2837
10
0.6060
0.0781
10
5.2289
0.2661
10
0.4287
0.1085
10
m – Male;
SD 90-91.
TBW – Terminal Body Weight;
b - With epididymis
Nominal Dose: Group 1 - 0 mg/kg
a - SD 90 BW was used as TBW for calculation purposes, since rats were fasted on
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
48
Group 4 - 200 mg/kg
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 5 (continued)
Summary of Terminal Body Weights and Absolute Organ Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
TBWa
Adrenal
glands
Brain
Heart
Kidneys
Liver
Ovaries
Spleen
Thymus
Uterus
b
1f
Mean
S.D.
N
224.853
17.849
10
0.08236
0.01316
10
1.9367
0.1403
10
0.7583
0.0950
10
1.4839
0.1004
10
6.2172
0.5716
10
0.1574
0.0226
10
0.4511
0.0545
10
0.3391
0.0831
10
1.0550
0.2417
10
2f
Mean
S.D.
N
217.508
10.009
10
0.06756*
0.00781
10
1.8213
0.1067
10
0.7302
0.0529
10
1.4076
0.0789
10
5.9173
0.5775
10
0.1420
0.0385
10
0.4083
0.0590
10
0.3040
0.0527
10
0.8005
0.2769
10
3f
Mean
S.D.
N
224.007
11.480
10
0.07355
0.01015
10
1.7866
0.1210
10
0.7735
0.0479
10
1.4434
0.1259
10
6.6285
0.4645
10
0.1286
0.0306
10
0.4382
0.0303
10
0.3237
0.0928
10
0.9755
0.2907
10
4f
Mean
S.D.
N
235.396
16.650
10
0.06624*
0.01227
10
1.8559
0.1169
10
0.7619
0.0440
10
1.5076
0.1324
10
6.5117
0.8397
10
0.1483
0.0298
10
0.4647
0.0894
10
0.3698
0.0530
10
0.8836
0.3594
10
f – Female
SD 90-91.
TBW – Terminal Body Weight
a - SD 90 BW was used as TBW for calculation purposes, since rats were fasted on
b – With cervix and vagina
* - Statistically different from control value, p < 0.05.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
49
Group 4 - 200 mg/kg
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 5 (continued)
Summary of Terminal Body Weights and Absolute Organ Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 119 Relative to Start Date
Group
Sex
TBWa
Adrenal
glands
Brain
Heart
Kidneys
Liver
Spleen
Testis
b
Thymus
1m
Mean
S.D.
N
410.084
51.972
5
0.05722
0.00393
5
2.0052
0.0825
5
1.1572
0.1126
5
2.3796
0.2198
5
9.8802
1.3626
5
0.5890
0.0628
5
4.9956
0.2891
5
0.3076
0.0437
5
4m
Mean
S.D.
N
418.494
29.101
5
0.05932
0.01091
5
2.0346
0.1061
5
1.0812
0.1350
5
2.3550
0.1401
5
10.4240
1.3869
5
0.5532
0.0336
5
5.0810
0.3510
5
0.2328*
0.0256
5
Brain
Heart
Kidneys
Liver
Ovaries
Spleen
Thymus
Group
Sex
TBWa
Adrenal
glands
Uterus
c
1f
Mean
S.D.
N
244.582
13.816
5
0.07124
0.01104
5
1.8498
0.2046
5
0.8306
0.0386
5
1.6108
0.1394
5
6.6812
0.1017
5
0.1596
0.0212
5
0.4832
0.0490
5
0.2994
0.0864
5
0.9200
0.1359
5
4f
Mean
S.D.
N
247.138
16.346
5
0.07440
0.01055
5
1.8922
0.1007
5
0.7920
0.1003
5
1.6356
0.1203
5
6.3954
0.6850
5
0.1484
0.0443
5
0.4758
0.0559
5
0.3018
0.0525
5
0.8752
0.1441
5
m – Male
f – Female;
were fasted on SD 118-119.
b - With epididymis
TBW – Terminal Body Weight
a - SD 118 BW was used as TBW for calculation purposes, since rats
c – With cervix and vagina
* - Statistically different from control value, p < 0.05.
Nominal Dose: Group 1 - 0 mg/kg
Group 4 - 200 mg/kg
50
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 6
Summary of Organ-to-Body Weight Ratios (%)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91
Group
Sex
Adrenal
glands
Brain
Heart
Kidneys
Liver
Spleen
Testis
a
Thymus
1m
Mean
SD
N
0.0166
0.0026
10
0.4964
0.0319
10
0.2729
0.0209
10
0.5465
0.0455
10
2.4671
0.1556
10
0.1363
0.0135
10
1.2961
0.1217
10
0.0909
0.0132
10
2m
Mean
SD
N
0.0177
0.0039
10
0.4762
0.0458
10
0.2687
0.0189
10
0.5679
0.0514
10
2.5378
0.1686
10
0.1389
0.0214
10
1.2748
0.1388
10
0.1103
0.0261
10
3m
Mean
SD
N
0.0143
0.0019
10
0.4739
0.0371
10
0.2657
0.0133
10
0.5538
0.0509
10
2.5671
0.2439
10
0.1349
0.0167
10
1.2261
0.1464
10
0.1098
0.0203
10
4m
Mean
SD
N
0.0144
0.0010
10
0.4787
0.0392
10
0.2676
0.0193
10
0.5644
0.0363
10
2.6363
0.1905
10
0.1460
0.0204
10
1.2615
0.1163
10
0.1031
0.0269
10
m – Male
a - With epididymis
Note: SD 90 body weight was used to calculate ratio since animals were fasted on SD 90-91.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
51
Group 4 - 200 mg/kg
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 6 (continued)
Summary of Organ-to-Body Weight Ratios (%)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91
Group
Sex
Adrenal
glands
Brain
Heart
Kidneys
Liver
Ovaries
Spleen
Thymus
Uterus
1f
Mean
SD
N
0.0368
0.0067
10
0.8636
0.0614
10
0.3371
0.0297
10
0.6628
0.0601
10
2.7678
0.1766
10
0.0701
0.0088
10
0.2007
0.0201
10
0.1496
0.0283
10
0.4713
0.1143
10
2f
Mean
SD
N
0.0310*
0.0029
10
0.8384
0.0533
10
0.3356
0.0178
10
0.6472
0.0236
10
2.7226
0.2626
10
0.0652
0.0176
10
0.1872
0.0211
10
0.1396
0.0228
10
0.3711
0.1386
10
3f
Mean
SD
N
0.0328*
0.0037
10
0.7981*
0.0475
10
0.3456
0.0191
10
0.6447
0.0493
10
2.9634
0.2239
10
0.0573
0.0132
10
0.1956
0.0090
10
0.1442
0.0399
10
0.4359
0.1318
10
4f
Mean
SD
N
0.0280*
0.0040
10
0.7919*
0.0729
10
0.3243
0.0153
10
0.6413
0.0454
10
2.7587
0.1984
10
0.0630
0.0119
10
0.1973
0.0370
10
0.1574
0.0219
10
0.3766
0.1574
10
f – Female
b – With cervix and vagina
* - Statistically different from control value, p < 0.05.
Note: SD 90 body weight was used to calculate ratio since animals were fasted on SD 90-91.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
52
Group 4 - 200 mg/kg
b
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 6 (continued)
Summary of Organ-to-Body Weight Ratios (%)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 119
Group
Sex
Adrenal
glands
Brain
Heart
Kidneys
Liver
Spleen
Testis
a
Thymus
1m
Mean
SD
N
0.0141
0.0011
5
0.4942
0.0550
5
0.2832
0.0138
5
0.5832
0.0379
5
2.4131
0.1937
5
0.1463
0.0293
5
1.2402
0.2244
5
0.0755
0.0105
5
4m
Mean
SD
N
0.0142
0.0023
5
0.4870
0.0231
5
0.2578*
0.0173
5
0.5642
0.0408
5
2.4849
0.1854
5
0.1325
0.0093
5
1.2201
0.1350
5
0.0557*
0.0059
5
Adrenal
glands
Brain
Heart
Group
Sex
Kidneys
Liver
Ovaries
Spleen
Thymus
Uterus
b
1f
Mean
SD
N
0.0292
0.0049
5
0.7558
0.0671
5
0.3399
0.0109
5
0.6584
0.0398
5
2.7373
0.1278
5
0.0651
0.0061
5
0.1976
0.0179
5
0.1215
0.0301
5
0.3769
0.0557
5
4f
Mean
SD
N
0.0301
0.00340
5
0.7673
0.04767
5
0.3199
0.02522
5
0.6622
0.03318
5
2.5837
0.12712
5
0.0598
0.01719
5
0.1928
0.02203
5
0.1218
0.01723
5
0.3534
0.04393
5
m – Male
f – Female
a - With epididymis
b – With cervix and vagina
Note: SD 118 body weight was used to calculate ratio since animals were fasted on SD 118-119.
* - Statistically different from control value, p < 0.05.
Nominal Dose: Group 1 - 0 mg/kg
Group 4 - 200 mg/kg
53
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 7
Summary of Organ-to-Brain Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Brain
Adrenal
glands
Heart
Kidneys
Liver
Spleen
Testis
a
Thymus
1m
Mean
S.D.
N
1.9750
0.1380
10
0.03297
0.00656
10
0.55053
0.03772
10
1.10387
0.10393
10
4.98318
0.38784
10
0.27586
0.03498
10
2.62110
0.29556
10
0.18281
0.02051
10
2m
Mean
S.D.
N
1.9343
0.0950
10
0.03727
0.00841
10
0.56775
0.05669
10
1.19844
0.11696
10
5.36754
0.55470
10
0.29214
0.03967
10
2.68629
0.27900
10
0.23656
0.07518
10
3m
Mean
S.D.
N
1.9913
0.0866
10
0.03030
0.00469
10
0.56333
0.04730
10
1.17242
0.11856
10
5.45954
0.79173
10
0.28515
0.03263
10
2.58898
0.25438
10
0.23358
0.05034
10
4m
Mean
S.D.
N
1.9843
0.0646
10
0.03028
0.00266
10
0.56060
0.03547
10
1.18576
0.11587
10
5.54157
0.59919
10
0.30496
0.03331
10
2.63472
0.09241
10
0.21568
0.05215
10
m – Male
a - With epididymis
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
54
Group 4 - 200 mg/kg
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 7 (continued)
Summary of Organ-to-Brain Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Brain
Adrenal
glands
Heart
Kidneys
Liver
Ovaries
Spleen
Thymus
Uterus
b
1f
Mean
S.D.
N
1.9367
0.1403
10
0.04286
0.00885
10
0.39119
0.03409
10
0.76842
0.06138
10
3.22036
0.32030
10
0.081190
0.009275
10
0.23396
0.03350
10
0.17391
0.03512
10
0.54481
0.12408
10
2f
Mean
S.D.
N
1.8213
0.1067
10
0.03714
0.00427
10
0.40212
0.03801
10
0.77526
0.06313
10
3.27196
0.49953
10
0.077514
0.019527
10
0.22433
0.03097
10
0.16687
0.02796
10
0.44453
0.16478
10
3f
Mean
S.D.
N
1.7866
0.1210
10
0.04114
0.00457
10
0.43494
0.04219
10
0.80968
0.07255
10
3.72634*
0.37927
10
0.071753
0.015381
10
0.24580
0.01763
10
0.18022
0.04728
10
0.54883
0.17441
10
4f
Mean
S.D.
N
1.8559
0.1169
10
0.03574
0.00635
10
0.41162
0.03046
10
0.81281
0.05682
10
3.52058
0.51855
10
0.079645
0.013069
10
0.25085
0.04870
10
0.19993
0.03189
10
0.48394
0.21844
10
f – Female
b – With cervix and vagina
* - Statistically different from control value, p < 0.05.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
Group 3 - 20 mg/kg
55
Group 4 - 200 mg/kg
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 7 (continued)
Summary of Organ-to-Brain Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 119 Relative to Start Date
Group
Sex
Brain
Adrenal
glands
Heart
Kidneys
Liver
Spleen
Testis
a
Thymus
1m
Mean
S.D.
N
2.0052
0.0825
5
0.02854
0.00135
5
0.57704
0.05052
5
1.18658
0.09679
5
4.91296
0.49336
5
0.29468
0.03970
5
2.49490
0.18058
5
0.15310
0.01762
5
4m
Mean
S.D.
N
2.0346
0.1061
5
0.02922
0.00575
5
0.53146
0.06073
5
1.16072
0.10068
5
5.12610
0.64335
5
0.27216
0.01610
5
2.50526
0.24612
5
0.11428*
0.00942
5
Group
Sex
Brain
Adrenal
glands
Heart
Kidneys
Liver
Ovaries
Spleen
Thymus
Uterus
b
1f
Mean
S.D.
N
1.8498
0.2046
5
0.03870
0.00570
5
0.45296
0.04859
5
0.87560
0.08086
5
3.64744
0.40859
5
0.086640
0.011135
5
0.26390
0.04231
5
0.16068
0.03780
5
0.49858
0.05694
5
4f
Mean
S.D.
N
1.8922
0.1007
5
0.03926
0.00476
5
0.41928
0.05530
5
0.86604
0.07369
5
3.38414
0.36618
5
0.078210
0.023135
5
0.25264
0.03717
5
0.15912
0.02398
5
0.46440
0.08468
5
m – Male
f – Female
a - With epididymis
b – With cervix and vagina
* - Statistically different from control value, p < 0.05.
Nominal Dose: Group 1 - 0 mg/kg
Group 4 - 200 mg/kg
56
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1
Certificates of Analysis
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recover
57
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
58
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
59
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
60
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
61
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 2
Analytical Chemistry Methods
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
62
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
63
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
64
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
65
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
66
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
67
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
68
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
69
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
70
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
71
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
72
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
73
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
74
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
75
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Gene Logic Laboratories Inc. Study No. 1567-04370
76
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Gene Logic Laboratories Inc. Study No. 1567-04370
77
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Gene Logic Laboratories Inc. Study No. 1567-04370
78
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Gene Logic Laboratories Inc. Study No. 1567-04370
79
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Gene Logic Laboratories Inc. Study No. 1567-04370
80
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Gene Logic Laboratories Inc. Study No. 1567-04370
81
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
82
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
83
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 3
Results of Test Article Formulation Stability Analysis
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
84
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 3
Results of Test Article Formulation Stability Analysis
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
STABILITY STUDY OF MESOZEAXANTHIN CONCENTRATE
Days
At 3-5°C
Time
0
14
Concentration mg/ml
0.2 mg/ml
361.02
362.33
2,0 mg/ml
3883
3872
20,0 mg/ml
33591
33937
200,0 mg/ml
311428
312152
Hours
Temp 25°C
0
48
361.02
367.4
3883
3877
33591
33455
311428
315184
Days
Temp 25°C
0
2
4
8
12
14
361.02
361.9
364.2
363.5
366.1
362.33
3883
3882
3960
3910
3881
3872
33591
33573
34296
33694
33763
33937
311428
315197
314119
314082
311741
312152
MESOZEAXANTHIN CONCENTRATION IN THE SUSPENSIONS
0.2 mg/ml
2,0 mg/ml
20,0 mg/ml
200,0mg/ml
0.2202222
2.36863
20.70157
189.97108
Note: The mesozeaxanthin concentration is equal to the percent of
mesozeaxanthin in the Concentrate (210.13/ 344.156x 100), times the
concentration of the suspension of the Concentrate in corn oil (as obtained by
AOAC Spectroph. UV Vis)
STABILITY IN PERCENT
Temp. 25°C
Hours
0
48
0
48
0
48
0
48
0.2 mg/ml
100
101.77
2,0 mg/ml
100
99.85
20,0 mg/ml
100
99.6
200,0 mg/ml
100
101.21
STABILITY IN PERCENT
Temp. 25°C
Days
0
2
4
8
12
14
0.2 mg/ml
100
100.24
100.88
100.68
101.38
100.36
2,0 mg/ml
100
99.97
101.98
100.7
99.95
99.72
20,0 mg/ml
100
99.95
102.1
100.31
100.51
101.03
200,0 mg/ml
100
101.21
100.86
100.85
100.1
100.23
Data Generated by Industrial Organica
85
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 4
Results of Dose Verification Analysis
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
86
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 4
Results of Dose Verification Analysis
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Study 1567-04370
Homogeneity / Dose Verification - Week 1 Formulations
Formulation, Homogeneity, and Dose Verification Results
Group 2
Group
No
2
2
2
2
2
2
2
2
2
Homogeneity
Bottom
Bottom
Bottom
Middle
Middle
Middle
Top 1
Top 2
Top 3
Average
SD
%RSD
%Target
1
2
3
1
2
3
Group 3
Mesozeaxanthin
(mg/ml)
(HPLC)
% Target
Value
Group
No
0.186
0.18
0.187
0.198
0.187
0.182
0.178
0.183
0.179
93.0
90.0
93.5
99.0
93.5
91.0
89.0
91.5
89.5
3
3
3
3
3
3
3
3
3
0.1844
0.0061
3.31
92.22
Group 4
Mesozeaxanthin
(mg/ml)
% Target Group
(HPLC)
Value
Homogeneity
No
Bottom
Bottom
Bottom
Middle
Middle
Middle
Top 1
Top 2
Top 3
1
2
3
1
2
3
1.992
1.861
1.934
1.761
2.02
1.958
1.986
1.802
2.02
Average
SD
%RSD
%Target
99.6
93.1
96.7
88.1
101
97.9
99.3
90.1
101.0
1.9260
0.0959
4.98
96.30
Data Generated by Industrial Organica
87
4
4
4
4
4
4
4
4
4
Mesozeaxanthin
(mg/ml)
(HPLC)
Homogeneity
Bottom
Bottom
Bottom
Middle
Middle
Middle
Top 1
Top 2
Top 3
Average
SD
%RSD
%Target
1
2
3
1
2
3
19.08
18.475
18.969
18.063
19.167
19.444
20.59
19.501
18.954
19.1381
0.7067
3.69
95.69
% Target
Value
95.4
92.4
94.8
90.3
95.8
97.2
103.0
97.5
94.8
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 4 (continued)
Results of Dose Verification Analysis
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Study 1567-04370
Dose Verification - Week 5 Formulations
Mix 5 (Week 5 Formulation) Dose Verification Results
Group 2
Group No
Conc.
Verific.
2
2
2
1
2
3
Average
SD
%RSD
%Target
Group 3
Mesozeaxanthin
(mg/ml)
% Target
(HPLC)
Value
Group No
0.1940
0.1900
0.1970
0.1937
0.0035
1.81
96.8
97.0
95.0
98.5
3
3
3
Conc.
Verific.
Group 4
Mesozeaxanthin
Mesozeaxanthin
(mg/ml)
(mg/ml)
% Target
Conc.
% Target
(HPLC)
(HPLC)
Value
Group No Verific.
Value
1
2
3
1.962
1.928
1.945
Average
SD
%RSD
%Target
98.1
96.4
97.3
1.945
0.0170
0.87
97.3
Data Generated by Industrial Organica
88
4
4
4
1
2
3
Average
SD
%RSD
%Target
18.35
19.48
19.77
19.20
0.75
3.91
96.0
91.8
97.4
98.8
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 4 (continued)
Results of Dose Verification Analysis
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Dose Verification - Week 9 Formulations
Mix 9 (Week 9 Formulation) Dose Verification Results
Group 2
Group 3
Group 4
Group
No
Conc.
Verific.
Mesozeaxanthin
(mg/ml)
(HPLC)
%target
Value
Group
No
Conc.
Verific.
Mesozeaxanthin
(mg/ml)
(HPLC)
%target
Value
Group
No
Conc.
Verific.
Mesozeaxanthin
(mg/ml)
(HPLC)
%target
Value
2
2
2
1
2
3
0.2200
0.2100
0.1960
110.0
105.0
98.0
3
3
3
1
2
3
2.113
2.198
2.172
105.7
109.9
108.6
4
4
4
1
2
3
22.05
21.35
22.05
110.2
106.7
110.3
Average
SD
%RSD
%Target
0.2087
0.0121
5.78
104.3
Average
SD
%RSD
%Target
2.161
0.0436
2.02
108.1
Average
SD
%RSD
%Target
21.82
0.41
1.86
109.1
Data Generated by Industrial Organica
89
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 4 (continued)
Results of Dose Verification Analysis
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Study 1567-04370
Dose Verification - Week 13 Formulations
Mix 13 (Week 13 Formulation) Dose Verification Results
Group 2
Group No
Conc.
Verific.
2
2
2
1
2
3
Average
SD
%RSD
%Target
Group 3
Mesozeaxanthin
(mg/ml)
% Target
(HPLC)
Value
0.2090
0.2300
0.2190
0.2193
0.0105
4.79
109.7
104.5
115.0
109.5
Group No
Conc.
Verific.
3
3
3
1
2
3
Group 4
Mesozeaxanthin
(mg/ml)
% Target
(HPLC)
Value
2.268
2.183
2.172
Average
SD
%RSD
%Target
113.4
109.2
108.6
2.208
0.0525
2.38
110.4
Data Generated by Industrial Organica
90
Group No
Conc.
Verific.
4
4
4
1
2
3
Average
SD
%RSD
%Target
Mesozeaxanthin
(mg/ml)
% Target
(HPLC)
Value
20.47
20.62
20.50
20.53
0.08
0.39
102.6
102.3
103.1
102.5
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 5
Individual Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
91
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Gene Logic Laboratories Inc. Study No.1567-04370
Appendix 5
Individual Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group Animal
Sex Number Clinical Sign
1m
20271 No Abnormalities
Terminal Kill
20272 No Abnormalities
Terminal Kill
20273 No Abnormalities
Terminal Kill
20274 No Abnormalities
Terminal Kill
20275 No Abnormalities
Terminal Kill
20276 No Abnormalities
Terminal Kill
20277 No Abnormalities
Terminal Kill
20278 No Abnormalities
Terminal Kill
20279 No Abnormalities
Terminal Kill
20280 No Abnormalities
Terminal Kill
20281 No Abnormalities
Recovery Kill
20282 No Abnormalities
Recovery Kill
20283 No Abnormalities
Recovery Kill
20284 No Abnormalities
Recovery Kill
20285 No Abnormalities
Recovery Kill
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
1
8
1
5
X
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9
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X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
X
.
X
.
X
.
X
.
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
.
X
.
X
.
X
.
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
.
X
.
X
.
X
.
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
.
X
.
X
.
X
.
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
X
X
X
X
X
X
X
X
X
m – Male
X – Present
. – Not applicable
Note: Additionally, cageside observations were performed twice daily. No abnormalities were noted.
Nominal Dose: Group 1 - 0 mg/kg
92
Howard Foundation
Gene Logic Laboratories Inc. Study No.1567-04370
Appendix 5 (continued)
Individual Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group Animal
Sex Number Clinical Sign
2m
20301 No Abnormalities
Terminal Kill
20302 No Abnormalities
Terminal Kill
20303 No Abnormalities
Terminal Kill
20304 No Abnormalities
Terminal Kill
20305 No Abnormalities
Terminal Kill
20306 No Abnormalities
Terminal Kill
20307 No Abnormalities
Alopecia
Alopecia
Terminal Kill
20308 No Abnormalities
Terminal Kill
20309 No Abnormalities
Alopecia
Alopecia
Terminal Kill
20310 No Abnormalities
Terminal Kill
m – Male
Site
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Side: Dorsal thoracic
Scrotum
Detected
Detected
Side: Dorsal thoracic
Side: Dorsal thoracic
Detected
X – Present
1
8
1
5
X
.
X
.
X
.
X
.
X
.
X
.
X
left .
.
.
X
.
X
left .
right .
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
.
X
.
. – Not applicable
Nominal Dose: Group 2 - 2 mg/kg
93
2
2
2
9
3
6
4
3
5
0
5
7
6
4
7
1
7
8
8
5
9
1
9
2
9
9
1
0
6
1
1
3
1
1
9
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
.
X
.
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
.
X
.
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
.
X
.
.
X
.
.
X
.
X
X
X
X
X
X
X
X
X
X
X
X
.
X
X
X
X
X
.
X
X
X
X
X
.
.
.
.
.
.
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.
Howard Foundation
Gene Logic Laboratories Inc. Study No.1567-04370
Appendix 5 (continued)
Individual Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group Animal
Sex Number Clinical Sign
3m
20321 No Abnormalities
Alopecia
Alopecia
Terminal Kill
20322 No Abnormalities
Terminal Kill
20323 No Abnormalities
Terminal Kill
20324 No Abnormalities
Terminal Kill
20325 No Abnormalities
Terminal Kill
20326 No Abnormalities
Terminal Kill
20327 No Abnormalities
Terminal Kill
20328 No Abnormalities
Terminal Kill
20329 No Abnormalities
Terminal Kill
20330 No Abnormalities
Terminal Kill
Site
Detected
Abdomen
Side: Dorsal thoracic
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
m – Male
X – Present
Nominal Dose:
Group 3 - 20 mg/kg
left
1
8
1
5
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
. – Not applicable
94
2
2
2
9
3
6
4
3
5
0
5
7
6
4
7
1
7
8
8
5
9
1
9
2
9
9
1
0
6
1
1
3
1
1
9
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
.
.
.
.
.
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.
.
Howard Foundation
Gene Logic Laboratories Inc. Study No.1567-04370
Appendix 5 (continued)
Individual Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group Animal
Sex Number Clinical Sign
4m
20341 No Abnormalities
Terminal Kill
20342 No Abnormalities
Terminal Kill
20343 No Abnormalities
Terminal Kill
20344 No Abnormalities
Terminal Kill
20345 No Abnormalities
Terminal Kill
20346 No Abnormalities
Terminal Kill
20347 No Abnormalities
Terminal Kill
20348 No Abnormalities
Terminal Kill
20349 No Abnormalities
Terminal Kill
20350 No Abnormalities
Terminal Kill
20351 No Abnormalities
Recovery Kill
20352 No Abnormalities
Recovery Kill
20353 No Abnormalities
Recovery Kill
20354 No Abnormalities
Abrasion
Recovery Kill
20355 No Abnormalities
Recovery Kill
m – Male
Site
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Hindpaw/hand: Right
Detected
X – Present
1
8
1
5
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
. – Not applicable
Nominal Dose: Group 4 - 200 mg/kg
95
2
2
2
9
3
6
4
3
5
0
5
7
6
4
7
1
7
8
8
5
9
1
9
2
9
9
1
0
6
1
1
3
1
1
9
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
.
.
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.
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X
.
X
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X
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X
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X
.
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X
.
X
.
X
.
X
.
.
X
.
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.
.
.
.
.
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.
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.
.
X
.
X
.
X
.
X
.
.
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
.
X
.
X
.
.
X
.
X
.
.
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.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
X
X
X
X
X
.
X
X
X
X
Howard Foundation
Gene Logic Laboratories Inc. Study No.1567-04370
Appendix 5 (continued)
Individual Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group Animal
Sex Number Clinical Sign
1f
20286 No Abnormalities
Terminal Kill
20287 No Abnormalities
Alopecia
Alopecia
Hyperactive
Terminal Kill
20288 No Abnormalities
Terminal Kill
20289 No Abnormalities
Terminal Kill
20290 No Abnormalities
Terminal Kill
20291 No Abnormalities
Alopecia
Terminal Kill
20292 No Abnormalities
Terminal Kill
20293 No Abnormalities
Terminal Kill
20294 No Abnormalities
Terminal Kill
20295 No Abnormalities
Terminal Kill
20296 No Abnormalities
Recovery Kill
20297 No Abnormalities
Recovery Kill
20298 No Abnormalities
Recovery Kill
20299 No Abnormalities
Recovery Kill
20300 No Abnormalities
Alopecia
Alopecia
Alopecia
Recovery Kill
f – Female
1
8
1
5
X
.
X
Forelimb: Left
.
Forelimb: Right
.
.
.
X
.
X
.
X
.
X
Chest: Ventral thoracic
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
Abdomen
.
Side: Dorsal thoracic left .
Side: Dorsal thoracic right .
.
X
.
X
.
.
.
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
.
X
.
X
.
X
.
.
.
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
Site
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
X – Present
. – Not applicable
Nominal Dose: Group 1 - 0 mg/kg
96
2
2
2
9
3
6
4
3
5
0
5
7
6
4
7
1
7
8
8
5
9
1
9
2
9
9
1
0
6
1
1
3
1
1
9
X
.
X
.
.
.
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
.
X
X
.
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
.
X
X
.
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
.
X
X
.
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
X
.
X
.
.
X
X
.
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
X
.
X
.
.
X
X
.
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
X
.
X
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X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
X
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X
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X
X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
X
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X
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X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
X
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X
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X
X
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X
X
X
X
X
X
X
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X
X
X
X
X
X
X
X
X
X
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X
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X
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X
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X
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X
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X
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X
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X
X
X
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X
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X
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X
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X
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X
X
X
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X
X
X
X
X
X
X
X
.
X
X
X
X
Howard Foundation
Gene Logic Laboratories Inc. Study No.1567-04370
Appendix 5 (continued)
Individual Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group Animal
Sex Number Clinical Sign
2f
20311 No Abnormalities
Terminal Kill
20312 No Abnormalities
Terminal Kill
20313 No Abnormalities
Terminal Kill
20314 No Abnormalities
Terminal Kill
20315 No Abnormalities
Abrasion
Alopecia
Terminal Kill
20316 No Abnormalities
Terminal Kill
20317 No Abnormalities
Terminal Kill
20318 No Abnormalities
Terminal Kill
20319 No Abnormalities
Terminal Kill
20320 No Abnormalities
Terminal Kill
f – Female
Site
Detected
Detected
Detected
Detected
Detected
Neck: Ventral
Neck: Ventral
Detected
Detected
Detected
Detected
Detected
X – Present
1
8
1
5
X
.
X
.
X
.
X
.
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
X
.
. – Not applicable
Nominal Dose: Group 2 - 2 mg/kg
97
2
2
2
9
3
6
4
3
5
0
5
7
6
4
7
1
7
8
8
5
9
1
9
2
9
9
1
0
6
1
1
3
1
1
9
X
.
X
.
X
.
X
.
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X
.
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
.
X
.
X
.
X
.
X
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X
.
X
.
X
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X
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X
.
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X
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X
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X
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X
.
X
.
X
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X
.
X
.
X
.
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
X
X
X
X
X
X
X
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X
X
X
X
X
X
X
X
X
X
X
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.
Howard Foundation
Gene Logic Laboratories Inc. Study No.1567-04370
Appendix 5 (continued)
Individual Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group Animal
Sex Number Clinical Sign
3f
20331 No Abnormalities
Terminal Kill
20332 No Abnormalities
Terminal Kill
20333 No Abnormalities
Hyperactive
Terminal Kill
20334 No Abnormalities
Terminal Kill
20335 No Abnormalities
Terminal Kill
20336 No Abnormalities
Terminal Kill
20337 No Abnormalities
Abrasion
Terminal Kill
20338 No Abnormalities
Alopecia
Alopecia
Terminal Kill
20339 No Abnormalities
Terminal Kill
20340 No Abnormalities
Terminal Kill
f – Female
Nominal Dose:
Site
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Cranium
Detected
Inguinal Right
Chest: Ventral thoracic
Detected
Detected
X – Present
1
8
1
5
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
.
X
.
.
.
X
.
X
.
. – Not applicable
Group 3 - 20 mg/kg
98
2
2
2
9
3
6
4
3
5
0
5
7
6
4
7
1
7
8
8
5
9
1
9
2
9
9
1
0
6
1
1
3
1
1
9
X
.
X
.
X
.
.
X
.
X
.
X
.
.
X
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
.
X
.
.
.
X
.
X
.
X
.
X
.
X
.
.
X
.
X
.
X
.
X
.
.
.
X
X
.
X
.
X
.
X
.
X
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X
.
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X
.
X
.
X
.
X
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.
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X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
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X
X
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X
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X
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X
X
X
X
X
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X
X
X
X
X
X
X
X
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X
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X
X
X
X
X
X
X
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.
Howard Foundation
Gene Logic Laboratories Inc. Study No.1567-04370
Appendix 5 (continued)
Individual Animal Disposition and Clinical Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group Animal
Sex Number Clinical Sign
4f
20356 No Abnormalities
Terminal Kill
20357 No Abnormalities
Terminal Kill
20358 No Abnormalities
Terminal Kill
20359 No Abnormalities
Terminal Kill
20360 No Abnormalities
Terminal Kill
20361 No Abnormalities
Terminal Kill
20362 No Abnormalities
Terminal Kill
20363 No Abnormalities
Terminal Kill
20364 No Abnormalities
Terminal Kill
20365 No Abnormalities
Terminal Kill
20366 No Abnormalities
Recovery Kill
20367 No Abnormalities
Recovery Kill
20368 No Abnormalities
Alopecia
Alopecia
Recovery Kill
20369 No Abnormalities
Recovery Kill
20370 No Abnormalities
Abrasion
Recovery Kill
f – Female
Site
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Detected
Forepaw: Left
Forepaw: Right
Detected
Detected
X – Present
Ear: Right
1
8
1
5
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
. – Not applicable
Nominal Dose: Group 4 - 200 mg/kg
99
2
2
2
9
3
6
4
3
5
0
5
7
6
4
7
1
7
8
8
5
9
1
9
2
9
9
1
0
6
1
1
3
1
1
9
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
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.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
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X
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X
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X
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X
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X
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X
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X
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X
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X
.
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X
.
X
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X
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X
.
X
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X
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X
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X
.
X
.
X
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X
.
X
.
X
.
.
.
X
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X
.
.
X
.
X
.
X
.
X
.
X
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X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
.
.
X
.
X
.
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
.
X
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.
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X
.
X
.
.
X
.
X
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X
.
X
.
X
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X
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X
.
X
.
X
.
X
.
X
.
X
.
.
X
X
.
X
.
X
.
.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
.
.
.
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.
X
.
X
.
.
X
X
.
X
.
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
.
X
.
.
X
X
.
X
.
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
.
X
.
.
X
X
.
X
.
.
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
.
X
.
.
X
X
.
X
.
.
X
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
X
X
X
X
.
X
X
X
X
X
X
.
X
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 6
Individual Body Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
100
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 6
Individual Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
1
8
15
22
29
36
43
50
57
64
71
1m
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
20281
20282
20283
20284
20285
188.59
181.38
184.05
182.12
196.65
175.37
187.16
180.00
183.05
180.40
171.09
179.18
184.77
190.33
188.69
229.05
222.59
219.24
217.22
238.57
221.08
232.07
222.20
223.83
218.76
211.25
214.46
228.72
243.83
228.63
260.61
254.14
251.95
244.11
271.50
255.53
274.42
258.60
251.15
252.84
248.03
242.10
265.48
283.34
257.83
280.00
284.05
278.47
262.57
300.93
281.68
301.95
286.73
279.63
281.70
275.94
259.47
290.72
311.87
282.82
291.72
303.17
302.80
275.61
324.47
298.90
326.13
304.67
293.09
296.92
298.54
277.66
313.42
334.69
295.94
310.63
321.95
319.87
291.95
347.12
323.28
350.48
327.72
311.90
314.30
325.68
294.02
329.91
356.04
317.87
325.75
342.11
331.23
300.32
363.46
325.84
361.91
337.38
324.03
325.34
335.59
294.03
348.95
364.75
329.71
340.13
351.26
341.52
312.73
372.50
340.03
378.02
351.56
336.83
330.82
352.27
304.30
360.35
381.33
346.18
358.61
367.01
350.41
322.56
383.14
346.74
386.30
362.91
347.88
336.80
361.22
315.69
371.24
391.69
350.91
368.62
378.60
358.69
328.69
389.34
351.97
403.09
371.85
352.74
348.97
369.64
319.42
387.94
399.04
360.02
381.96
385.66
364.49
341.11
397.29
367.45
414.41
380.38
366.37
357.83
379.61
325.52
391.41
406.08
367.26
2m
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
193.18
196.53
193.42
189.45
195.24
190.96
177.21
173.39
192.70
189.99
234.33
239.90
231.16
232.12
240.33
230.36
214.30
216.35
226.21
235.77
265.62
274.52
256.62
269.72
273.47
264.90
249.90
247.55
257.77
273.39
295.06
305.58
278.99
294.37
302.25
298.65
278.18
270.58
278.16
302.51
314.58
335.26
297.30
323.45
331.19
325.11
297.66
288.65
232.15
321.62
333.63
352.90
313.03
344.34
348.39
340.78
311.56
303.03
322.69
340.96
345.47
374.58
322.99
354.14
363.22
353.87
328.81
315.19
335.82
358.57
367.58
394.09
337.66
364.94
380.56
372.29
331.42
332.64
351.66
370.72
382.39
412.91
353.05
380.63
389.31
387.71
346.10
341.74
362.62
376.60
398.03
427.09
360.30
384.66
399.13
403.86
358.32
351.51
371.79
382.15
407.37
443.16
364.77
391.81
410.64
414.62
367.81
359.40
375.32
392.82
m – Male
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
101
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 6 (continued)
Individual Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
78
85
90
91a
92
99
106
113
118
119a
.
.
.
.
.
.
.
.
.
.
393.98
331.28
413.65
435.22
381.96
.
.
.
.
.
.
.
.
.
.
393.90
328.95
425.82
436.79
384.35
.
.
.
.
.
.
.
.
.
.
402.48
333.49
439.49
452.41
391.84
.
.
.
.
.
.
.
.
.
.
408.11
332.53
443.92
463.85
391.50
.
.
.
.
.
.
.
.
.
.
407.48
334.78
450.30
466.34
391.52
.
.
.
.
.
.
.
.
.
.
398.53
328.81
434.63
449.55
380.42
1m
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
20281
20282
20283
20284
20285
381.71
396.48
376.61
348.55
404.49
380.94
422.19
389.60
373.58
358.89
388.80
326.16
402.15
423.17
375.26
387.50
404.50
383.20
347.90
410.50
387.60
425.40
397.90
377.00
363.10
390.20
327.70
410.80
428.20
376.30
383.71
405.30
376.93
347.21
417.96
391.77
423.10
398.02
381.55
367.53
.
.
.
.
.
376.94
396.32
371.41
340.09
405.07
379.80
412.25
382.83
373.75
355.98
.
.
.
.
.
2m
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
409.23
460.35
377.60
386.44
419.10
428.21
379.14
367.97
385.00
396.15
417.10
475.40
376.50
396.70
425.00
432.80
388.30
370.90
387.10
400.70
420.30
475.39
373.64
400.46
424.84
435.41
385.07
374.34
390.71
404.87
413.39
465.84
371.02
391.94
415.90
426.60
374.16
364.22
373.56
395.68
m – Male
.
.
.
.
.
.
.
.
.
.
. – Not applicable
a – fasted weights
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
102
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 6 (continued)
Individual Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
1
8
15
22
29
36
43
50
57
64
71
3m
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
186.01
179.55
180.60
180.88
197.83
190.89
197.83
197.19
177.43
170.50
222.65
217.87
231.03
230.34
240.46
227.88
244.27
237.58
215.35
213.04
250.30
251.63
275.64
271.33
281.05
259.17
273.08
273.30
250.47
246.64
279.30
278.76
309.60
308.55
316.82
279.17
315.43
303.55
279.15
273.23
303.10
301.71
337.11
341.60
348.34
299.21
345.01
327.13
304.09
296.22
319.89
322.07
360.02
372.77
369.01
313.41
368.01
345.46
317.87
307.88
328.41
333.06
370.10
392.04
379.63
327.44
383.22
359.87
336.27
320.15
348.74
347.98
386.16
416.63
396.93
342.56
403.96
378.11
352.21
335.52
361.98
347.25
402.36
436.83
419.73
353.54
417.20
388.95
365.37
344.99
368.64
367.15
411.02
454.83
430.89
362.12
428.54
400.87
375.28
349.30
370.21
379.20
417.78
461.62
443.68
371.61
447.09
417.09
388.83
353.82
4m
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
20351
20352
20353
20354
20355
186.92
185.50
191.24
199.66
206.42
183.09
192.85
178.51
179.45
178.22
207.90
182.62
180.58
190.43
187.76
232.91
235.27
233.85
243.16
246.72
219.12
225.37
221.43
224.97
222.15
252.60
229.61
224.74
232.53
233.39
271.43
278.98
266.24
278.71
274.02
250.51
250.33
250.63
267.15
267.67
279.37
270.89
251.37
264.22
269.65
303.65
317.37
287.81
308.70
303.82
268.79
269.77
269.82
294.15
297.52
305.19
300.79
273.98
289.36
303.71
326.26
353.32
310.83
334.38
322.66
284.93
291.62
298.22
317.57
319.06
326.23
319.43
290.14
313.44
332.96
351.63
381.75
331.50
354.22
339.04
300.76
308.37
316.87
336.58
338.71
343.92
335.55
308.24
329.83
352.86
366.20
405.81
342.11
373.65
355.51
314.80
314.17
338.14
355.06
355.61
360.32
347.25
327.07
343.80
375.38
377.68
428.16
351.08
383.59
372.31
329.49
327.07
354.36
376.35
362.75
368.89
361.19
337.00
355.03
391.99
387.68
451.31
367.14
398.83
380.43
342.95
339.56
370.80
387.27
372.32
377.37
377.98
346.09
367.94
408.20
397.68
460.71
372.80
406.53
391.75
350.75
346.20
383.20
395.13
381.00
392.52
387.45
350.08
377.99
417.94
412.11
475.24
382.06
415.12
400.50
357.14
354.11
389.58
403.66
388.76
394.56
397.76
363.02
382.37
423.52
m – Male
Nominal Dose: Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
103
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 6 (continued)
Individual Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
78
85
90
91a
3m
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
378.63
383.63
431.29
483.19
455.95
380.35
458.88
424.72
399.14
364.92
384.30
384.70
435.30
496.40
462.70
386.20
467.90
430.10
404.00
371.80
381.14
385.80
428.02
495.47
469.73
386.33
471.02
435.61
404.67
372.32
378.43
378.11
423.14
488.50
455.73
378.64
458.50
424.07
391.76
358.87
4m
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
20351
20352
20353
20354
20355
418.83
496.33
392.73
427.86
409.45
369.54
364.91
397.63
415.52
399.64
389.69
407.35
363.24
390.11
437.54
424.60
507.30
399.10
439.20
415.50
373.70
376.40
403.50
426.00
400.90
399.80
412.70
366.90
398.40
445.20
430.02
503.20
396.92
438.16
419.09
375.34
374.34
405.70
425.03
402.79
.
.
.
.
.
418.29
494.44
389.10
432.98
410.73
363.47
365.49
394.72
416.21
389.89
.
.
.
.
.
m – Male
92
99
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
405.82
412.02
370.33
397.80
451.10
. – Not applicable
a – fasted weights
Nominal Dose:
Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
104
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
408.19
411.18
371.90
391.81
447.43
106
113
118
119a
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
408.22
422.14
378.15
389.95
451.12
.
.
.
.
.
.
.
.
.
.
417.51
431.03
380.46
394.14
455.32
.
.
.
.
.
.
.
.
.
.
417.87
428.95
382.39
403.09
460.17
.
.
.
.
.
.
.
.
.
.
408.13
420.57
369.28
381.24
441.96
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 6 (continued)
Individual Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
1
8
15
22
29
36
43
50
57
64
71
1f
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
20296
20297
20298
20299
20300
138.97
134.94
141.24
143.07
131.52
138.20
131.39
136.30
135.84
140.95
139.13
143.84
135.14
149.83
140.52
153.40
148.39
158.29
163.42
148.83
146.17
145.15
138.91
151.35
163.15
151.66
162.90
151.83
168.43
157.57
172.20
164.52
174.25
182.61
170.08
168.63
152.60
147.07
163.36
184.21
164.08
182.40
169.73
190.92
186.51
185.98
175.47
185.68
190.99
179.92
182.04
167.62
155.10
177.72
197.22
183.00
196.14
184.05
206.09
197.61
196.87
181.03
195.75
203.86
190.39
189.90
173.98
157.43
177.93
206.17
193.38
210.33
189.22
219.76
212.33
199.95
196.94
205.78
213.93
197.59
204.42
185.87
164.31
188.49
217.00
190.82
214.42
201.87
227.11
220.89
211.37
199.35
212.31
224.34
205.75
214.74
187.79
170.60
194.63
220.90
198.86
221.13
206.76
240.48
224.78
217.65
197.83
217.42
223.79
210.01
219.47
189.47
167.73
201.15
228.08
200.80
227.75
210.01
242.90
227.43
223.65
205.35
214.74
232.81
212.06
220.47
185.86
176.91
195.15
231.94
212.78
228.24
214.20
242.67
233.94
222.18
207.59
221.08
235.14
210.64
230.10
196.66
186.64
196.43
233.22
214.28
235.38
220.30
249.91
235.59
230.20
202.44
226.77
236.04
221.55
234.09
198.74
188.29
206.01
239.62
222.30
237.99
222.01
253.17
241.09
2f
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
140.72
134.77
140.71
136.64
143.82
133.53
131.27
133.50
136.11
132.59
169.00
152.33
159.02
153.23
164.88
148.32
145.49
146.96
152.84
148.37
179.14
165.02
167.90
171.13
179.39
162.79
152.74
167.46
164.40
163.50
186.61
177.75
179.38
181.02
191.63
173.36
161.42
180.88
182.11
171.42
194.66
187.08
189.88
193.92
205.85
189.32
171.34
189.01
194.72
178.57
203.83
193.64
196.41
193.15
216.43
182.62
176.97
195.57
202.67
181.75
204.09
198.72
198.86
201.75
215.70
191.37
183.59
203.23
203.30
187.40
210.40
207.83
204.53
206.93
228.25
197.94
187.55
211.68
210.76
193.66
211.93
209.91
208.58
214.03
234.42
199.82
190.86
211.37
214.99
196.33
218.24
215.79
213.60
211.39
235.72
197.35
193.08
212.48
218.94
193.44
216.71
215.45
215.62
216.90
232.30
202.52
198.08
222.96
217.00
202.10
f – Female
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
105
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 6 (continued)
Individual Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
78
85
90
91a
1f
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
20296
20297
20298
20299
20300
232.07
206.48
227.90
243.36
219.14
230.70
203.70
182.55
208.70
241.25
217.75
239.06
223.95
257.75
238.02
233.20
213.80
227.20
246.20
219.50
239.80
201.00
196.50
215.00
246.30
218.90
238.00
222.10
257.60
246.10
233.08
216.03
228.80
240.03
221.37
244.21
212.18
195.23
206.22
251.38
.
.
.
.
.
223.29
202.07
220.63
229.61
213.86
221.27
204.20
183.25
199.49
234.08
.
.
.
.
.
2f
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
215.73
219.59
213.68
214.43
238.15
208.67
206.07
225.70
224.08
204.15
212.80
215.20
221.40
223.10
231.80
207.00
206.10
227.20
223.20
203.10
216.43
217.51
218.75
221.37
233.90
209.12
203.37
220.39
230.09
204.15
207.84
212.58
213.11
212.30
225.29
199.26
195.51
213.41
217.42
195.34
f – Female
92
99
.
.
.
.
.
.
.
.
.
.
228.48
240.43
228.17
258.42
245.98
.
.
.
.
.
.
.
.
.
.
. – Not applicable
a – fasted weights
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
106
106
.
.
.
.
.
.
.
.
.
.
232.49
245.06
228.00
261.92
245.02
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
236.34
246.84
228.66
261.39
250.89
.
.
.
.
.
.
.
.
.
.
113
.
.
.
.
.
.
.
.
.
.
235.39
244.38
228.71
259.32
246.43
.
.
.
.
.
.
.
.
.
.
118
.
.
.
.
.
.
.
.
.
.
234.32
241.68
231.02
265.32
250.57
.
.
.
.
.
.
.
.
.
.
119a
.
.
.
.
.
.
.
.
.
.
225.43
232.51
216.48
253.07
237.10
.
.
.
.
.
.
.
.
.
.
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 6 (continued)
Individual Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
1
8
15
22
29
36
43
50
57
64
71
3f
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
143.93
129.07
130.59
149.57
139.09
139.26
133.81
137.01
132.01
139.02
169.93
142.75
146.76
170.29
154.93
152.94
149.46
154.91
153.92
158.32
184.83
161.35
164.39
186.12
167.72
174.81
166.38
160.10
167.73
167.31
188.94
169.99
173.24
195.78
175.71
184.01
181.08
166.94
178.21
180.29
204.00
181.25
188.52
207.09
187.48
192.62
192.10
184.09
189.29
186.70
217.71
189.17
197.18
218.35
193.92
193.01
193.83
188.00
196.83
192.39
215.60
191.98
204.40
224.91
204.67
203.38
198.52
194.44
202.48
195.71
222.37
192.77
196.23
228.26
205.74
207.62
203.29
198.30
206.24
205.14
228.80
200.72
201.11
235.52
215.87
211.96
210.88
207.38
209.46
205.48
234.65
205.07
212.07
235.36
220.20
208.97
216.63
209.56
215.29
202.63
233.26
207.28
211.86
238.59
218.49
214.43
217.40
211.39
225.56
205.47
4f
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
20366
20367
20368
20369
20370
147.64
135.96
146.39
140.76
136.88
137.07
136.94
133.24
138.95
130.01
132.01
136.06
140.74
145.30
142.07
168.04
149.21
160.16
161.07
149.59
157.10
152.21
150.22
155.87
149.39
148.25
154.58
152.44
165.82
162.46
194.06
168.42
186.72
183.50
161.76
176.06
165.95
169.14
171.65
160.56
162.13
174.28
175.46
184.10
186.45
204.68
174.72
198.57
195.67
173.34
189.01
179.73
177.56
179.85
172.11
170.14
188.76
187.66
201.38
197.73
220.59
197.95
216.73
209.33
183.77
205.59
194.33
190.27
194.31
185.13
182.39
202.20
200.37
212.54
201.05
225.93
203.27
216.41
216.94
189.99
211.09
196.39
192.53
194.80
184.75
193.10
203.29
211.95
221.58
214.41
231.04
204.21
226.99
219.96
194.83
221.95
202.27
192.18
198.06
196.54
200.50
219.29
214.21
230.79
223.81
239.66
223.36
232.41
228.89
193.48
228.46
202.03
199.39
205.17
202.23
202.78
224.69
220.18
235.42
226.38
244.98
228.58
235.58
232.00
196.99
236.69
217.27
203.26
210.14
204.56
207.33
225.57
229.93
240.04
226.74
246.44
227.61
232.80
227.37
197.83
238.76
215.27
202.34
212.37
202.34
211.21
233.93
226.92
246.17
233.96
241.77
232.83
245.89
233.32
202.20
239.11
221.91
204.74
214.38
207.00
213.56
231.93
235.16
254.35
235.94
f – Female
Nominal Dose: Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
107
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 6 (continued)
Individual Body Weights (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
78
85
90
91a
3f
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
237.99
208.36
215.36
240.02
218.08
216.94
216.13
214.39
227.55
211.29
236.40
209.90
216.30
238.20
221.20
217.30
215.10
214.20
228.00
210.10
242.40
212.39
219.21
243.11
224.53
219.35
221.86
214.35
231.23
211.64
236.15
204.07
210.90
234.07
217.38
204.68
213.54
208.24
220.07
203.43
4f
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
20366
20367
20368
20369
20370
253.08
231.99
247.84
237.09
216.79
246.61
222.60
204.87
221.27
212.68
221.85
236.60
239.33
260.49
238.80
255.70
242.50
244.00
242.50
215.50
250.70
227.70
208.70
223.40
217.20
221.40
244.10
250.50
258.40
237.50
257.18
237.90
252.59
242.23
217.34
256.60
231.68
211.33
226.94
220.17
.
.
.
.
.
252.01
234.84
242.21
236.81
205.00
245.08
214.23
198.94
220.32
208.03
.
.
.
.
.
f – Female
92
99
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
222.40
246.22
237.07
255.71
238.75
. – Not applicable
a – fasted weights
Nominal Dose: Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
108
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
219.76
237.19
246.93
264.02
236.65
106
113
118
119a
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
221.06
241.36
250.90
268.23
240.89
.
.
.
.
.
.
.
.
.
.
225.83
245.27
248.81
265.67
243.53
.
.
.
.
.
.
.
.
.
.
226.10
245.99
245.70
272.06
245.84
.
.
.
.
.
.
.
.
.
.
215.74
234.83
231.85
255.37
234.83
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 7
Individual Body Weight Changes
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
109
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 7
Individual Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Animal
Number
Base
Weight
Day
1
1m
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
20281
20282
20283
20284
20285
2m
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
Group
Sex
From:
To:
1
8
8
15
15
22
22
29
29
36
36
43
43
50
50
57
57
64
64
71
71
78
188.59
181.38
184.05
182.12
196.65
175.37
187.16
180.00
183.05
180.40
171.09
179.18
184.77
190.33
188.69
40.46
41.21
35.19
35.10
41.92
45.71
44.91
42.20
40.78
38.36
40.16
35.28
43.95
53.50
39.94
31.56
31.55
32.71
26.89
32.93
34.45
42.35
36.40
27.32
34.08
36.78
27.64
36.76
39.51
29.20
19.39
29.91
26.52
18.46
29.43
26.15
27.53
28.13
28.48
28.86
27.91
17.37
25.24
28.53
24.99
11.72
19.12
24.33
13.04
23.54
17.22
24.18
17.94
13.46
15.22
22.60
18.19
22.70
22.82
13.12
18.91
18.78
17.07
16.34
22.65
24.38
24.35
23.05
18.81
17.38
27.14
16.36
16.49
21.35
21.93
15.12
20.16
11.36
8.37
16.34
2.56
11.43
9.66
12.13
11.04
9.91
0.01
19.04
8.71
11.84
14.38
9.15
10.29
12.41
9.04
14.19
16.11
14.18
12.80
5.48
16.68
10.27
11.40
16.58
16.47
18.48
15.75
8.89
9.83
10.64
6.71
8.28
11.35
11.05
5.98
8.95
11.39
10.89
10.36
4.73
10.01
11.59
8.28
6.13
6.20
5.23
16.79
8.94
4.86
12.17
8.42
3.73
16.70
7.35
9.11
13.34
7.06
5.80
12.42
7.95
15.48
11.32
8.53
13.63
8.86
9.97
6.10
3.47
7.04
7.24
-0.25
10.82
12.12
7.44
7.20
13.49
7.78
9.22
7.21
1.06
9.19
0.64
10.74
17.09
8.00
193.18
196.53
193.42
189.45
195.24
190.96
177.21
173.39
192.70
189.99
41.15
43.37
37.74
42.67
45.09
39.40
37.09
42.96
33.51
45.78
31.29
34.62
25.46
37.60
33.14
34.54
35.60
31.20
31.56
37.62
29.44
31.06
22.37
24.65
28.78
33.75
28.28
23.03
20.39
29.12
19.52
29.68
18.31
29.08
28.94
26.46
19.48
18.07
-46.01
19.11
19.05
17.64
15.73
20.89
17.20
15.67
13.90
14.38
90.54
19.34
11.84
21.68
9.96
9.80
14.83
13.09
17.25
12.16
13.13
17.61
22.11
19.51
14.67
10.80
17.34
18.42
2.61
17.45
15.84
12.15
14.81
18.82
15.39
15.69
8.75
15.42
14.68
9.10
10.96
5.88
15.64
14.18
7.25
4.03
9.82
16.15
12.22
9.77
9.17
5.55
9.34
16.07
4.47
7.15
11.51
10.76
9.49
7.89
3.53
10.67
1.86
17.19
12.83
-5.37
8.46
13.59
11.33
8.57
9.68
3.33
m – Male
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
110
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 7 (continued)
Individual Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal From:
Number
To:
78
85
85
90
Absolute
Change
1
90
%
Change
1
90
85
92
90
91
92
99
99
106
106
113
113
118
Absolute
Change
85
118
1m
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
20281
20282
20283
20284
20285
5.79
8.02
6.59
-0.65
6.01
6.66
3.21
8.30
3.42
4.21
1.40
1.54
8.65
5.03
1.04
-3.79
0.80
-6.27
-0.69
7.46
4.17
-2.30
0.12
4.55
4.43
.
.
.
.
.
195.12
223.92
192.88
165.09
221.31
216.40
235.94
218.02
198.50
187.13
.
.
.
.
.
103.463
123.454
104.798
90.649
112.540
123.396
126.063
121.122
108.440
103.731
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3.78
3.58
2.85
7.02
5.66
-6.77
-8.98
-5.52
-7.12
-12.89
-11.97
-10.85
-15.19
-7.80
-11.55
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
-0.08
-2.33
12.17
1.57
2.39
.
.
.
.
.
.
.
.
.
.
8.58
4.54
13.67
15.62
7.49
.
.
.
.
.
.
.
.
.
.
5.63
-0.96
4.43
11.44
-0.34
.
.
.
.
.
.
.
.
.
.
-0.63
2.25
6.38
2.49
0.02
.
.
.
.
.
.
.
.
.
.
17.28
7.08
39.50
38.14
15.22
2m
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
7.87
15.05
-1.10
10.26
5.90
4.59
9.16
2.93
2.10
4.55
3.20
-0.01
-2.86
3.76
-0.16
2.61
-3.23
3.44
3.61
4.17
227.12
278.86
180.22
211.01
229.60
244.45
207.86
200.95
198.01
214.88
117.569
141.892
93.175
111.380
117.599
128.011
117.296
115.895
102.756
113.101
.
.
.
.
.
.
.
.
.
.
-6.91
-9.55
-2.62
-8.52
-8.94
-8.81
-10.91
-10.12
-17.15
-9.19
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
m – Male
. – Not applicable
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
111
%
Change
85
118
.
.
.
.
.
.
.
.
.
.
4.428
2.161
9.615
8.907
4.045
.
.
.
.
.
.
.
.
.
.
Absolute
%
Change
Change
1
1
118
118
.
.
.
.
.
.
.
.
.
.
236.39
155.60
265.53
276.01
202.83
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
138.167
86.840
143.708
145.017
107.494
.
.
.
.
.
.
.
.
.
.
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 7 (continued)
Individual Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Animal
Number
Base
Weight
Day
1
3m
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
4m
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
20351
20352
20353
20354
20355
Group
Sex
From:
To:
1
8
8
15
15
22
22
29
29
36
36
43
43
50
50
57
57
64
64
71
71
78
186.01
179.55
180.60
180.88
197.83
190.89
197.83
197.19
177.43
170.50
36.64
38.32
50.43
49.46
42.63
36.99
46.44
40.39
37.92
42.54
27.65
33.76
44.61
40.99
40.59
31.29
28.81
35.72
35.12
33.60
29.00
27.13
33.96
37.22
35.77
20.00
42.35
30.25
28.68
26.59
23.80
22.95
27.51
33.05
31.52
20.04
29.58
23.58
24.94
22.99
16.79
20.36
22.91
31.17
20.67
14.20
23.00
18.33
13.78
11.66
8.52
10.99
10.08
19.27
10.62
14.03
15.21
14.41
18.40
12.27
20.33
14.92
16.06
24.59
17.30
15.12
20.74
18.24
15.94
15.37
13.24
-0.73
16.20
20.20
22.80
10.98
13.24
10.84
13.16
9.47
6.66
19.90
8.66
18.00
11.16
8.58
11.34
11.92
9.91
4.31
1.57
12.05
6.76
6.79
12.79
9.49
18.55
16.22
13.55
4.52
8.42
4.43
13.51
21.57
12.27
8.74
11.79
7.63
10.31
11.10
186.92
185.50
191.24
199.66
206.42
183.09
192.85
178.51
179.45
178.22
207.90
182.62
180.58
190.43
187.76
45.99
49.77
42.61
43.50
40.30
36.03
32.52
42.92
45.52
43.93
44.70
46.99
44.16
42.10
45.63
38.52
43.71
32.39
35.55
27.30
31.39
24.96
29.20
42.18
45.52
26.77
41.28
26.63
31.69
36.26
32.22
38.39
21.57
29.99
29.80
18.28
19.44
19.19
27.00
29.85
25.82
29.90
22.61
25.14
34.06
22.61
35.95
23.02
25.68
18.84
16.14
21.85
28.40
23.42
21.54
21.04
18.64
16.16
24.08
29.25
25.37
28.43
20.67
19.84
16.38
15.83
16.75
18.65
19.01
19.65
17.69
16.12
18.10
16.39
19.90
14.57
24.06
10.61
19.43
16.47
14.04
5.80
21.27
18.48
16.90
16.40
11.70
18.83
13.97
22.52
11.48
22.35
8.97
9.94
16.80
14.69
12.90
16.22
21.29
7.14
8.57
13.94
9.93
11.23
16.61
10.00
23.15
16.06
15.24
8.12
13.46
12.49
16.44
10.92
9.57
8.48
16.79
9.09
12.91
16.21
10.00
9.40
5.66
7.70
11.32
7.80
6.64
12.40
7.86
8.68
15.15
9.47
3.99
10.05
9.74
14.43
14.53
9.26
8.59
8.75
6.39
7.91
6.38
8.53
7.76
2.04
10.31
12.94
4.38
5.58
6.72
21.09
10.67
12.74
8.95
12.40
10.80
8.05
11.86
10.88
-4.87
9.59
0.22
7.74
14.02
m – Male
Nominal Dose: Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
112
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 7 (continued)
Individual Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
3m
4m
m – Male
From:
To:
Absolute
Change
1
90
%
Change
1
90
85
92
78
85
85
90
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
5.67
1.07
4.01
13.21
6.75
5.85
9.02
5.38
4.86
6.88
-3.16
1.10
-7.28
-0.93
7.03
0.13
3.12
5.51
0.67
0.52
195.13
206.25
247.42
314.59
271.90
195.44
273.19
238.42
227.24
201.82
104.903
114.871
136.999
173.922
137.441
102.384
138.093
120.909
128.073
118.370
.
.
.
.
.
.
.
.
.
.
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
20351
20352
20353
20354
20355
5.77
10.97
6.37
11.34
6.05
4.16
11.49
5.87
10.48
1.26
10.11
5.35
3.66
8.29
7.66
5.42
-4.10
-2.18
-1.04
3.59
1.64
-2.06
2.20
-0.97
1.89
.
.
.
.
.
243.10
317.70
205.68
238.50
212.67
192.25
181.49
227.19
245.58
224.57
.
.
.
.
.
130.056
171.267
107.551
119.453
103.028
105.003
94.109
127.270
136.851
126.007
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6.02
-0.68
3.43
-0.60
5.90
90
91
92
99
99
106
106
113
-2.71
-7.69
-4.88
-6.97
-14.00
-7.69
-12.52
-11.54
-12.91
-13.45
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
-11.73
-8.76
-7.82
-5.18
-8.36
-11.87
-8.85
-10.98
-8.82
-12.90
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
2.37
-0.84
1.57
-5.99
-3.67
.
.
.
.
.
.
.
.
.
.
0.03
10.96
6.25
-1.86
3.69
.
.
.
.
.
.
.
.
.
.
9.29
8.89
2.31
4.19
4.20
.
.
.
.
.
.
.
.
.
.
0.36
-2.08
1.93
8.95
4.85
.
.
.
.
.
.
.
.
.
.
18.07
16.25
15.49
4.69
14.97
. – Not applicable
Nominal Dose: Group 3 - 20 mg/kg
Absolute
Change
113
85
118
118
Group 4 - 200 mg/kg
113
%
Change
85
118
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4.520
3.937
4.222
1.177
3.363
Absolute
%
Change
Change
1
1
118
118
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
209.97
246.33
201.81
212.66
272.41
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
100.996
134.887
111.757
111.674
145.084
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 7 (continued)
Individual Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Animal
Number
Base
Weight
Day
1
1f
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
20296
20297
20298
20299
20300
2f
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
Group
Sex
From:
To:
1
8
8
15
15
22
22
29
29
36
36
43
43
50
50
57
57
64
64
71
71
78
138.97
134.94
141.24
143.07
131.52
138.20
131.39
136.30
135.84
140.95
139.13
143.84
135.14
149.83
140.52
14.43
13.45
17.05
20.35
17.31
7.97
13.76
2.61
15.51
22.20
12.53
19.06
16.69
18.60
17.05
18.80
16.13
15.96
19.19
21.25
22.46
7.45
8.16
12.01
21.06
12.42
19.50
17.90
22.49
28.94
13.78
10.95
11.43
8.38
9.84
13.41
15.02
8.03
14.36
13.01
18.92
13.74
14.32
15.17
11.10
10.89
5.56
10.07
12.87
10.47
7.86
6.36
2.33
0.21
8.95
10.38
14.19
5.17
13.67
14.72
3.08
15.91
10.03
10.07
7.20
14.52
11.89
6.88
10.56
10.83
-2.56
4.09
12.65
7.35
8.56
11.42
2.41
6.53
10.41
8.16
10.32
1.92
6.29
6.14
3.90
8.04
6.71
4.89
13.37
3.89
6.28
-1.52
5.11
-0.55
4.26
4.73
1.68
-2.87
6.52
7.18
1.94
6.62
3.25
2.42
2.65
6.00
7.52
-2.68
9.02
2.05
1.00
-3.61
9.18
-6.00
3.86
11.98
0.49
4.19
-0.23
6.51
-1.47
2.24
6.34
2.33
-1.42
9.63
10.80
9.73
1.28
1.28
1.50
7.14
6.10
7.24
1.65
8.02
-5.15
5.69
0.90
10.91
3.99
2.08
1.65
9.58
6.40
8.02
2.61
1.71
3.26
5.50
1.87
4.04
1.13
7.32
-2.41
-3.39
4.96
-5.74
2.69
1.63
-4.55
1.07
1.94
4.58
-3.07
140.72
134.77
140.71
136.64
143.82
133.53
131.27
133.50
136.11
132.59
28.28
17.56
18.31
16.59
21.06
14.79
14.22
13.46
16.73
15.78
10.14
12.69
8.88
17.90
14.51
14.47
7.25
20.50
11.56
15.13
7.47
12.73
11.48
9.89
12.24
10.57
8.68
13.42
17.71
7.92
8.05
9.33
10.50
12.90
14.22
15.96
9.92
8.13
12.61
7.15
9.17
6.56
6.53
-0.77
10.58
-6.70
5.63
6.56
7.95
3.18
0.26
5.08
2.45
8.60
-0.73
8.75
6.62
7.66
0.63
5.65
6.31
9.11
5.67
5.18
12.55
6.57
3.96
8.45
7.46
6.26
1.53
2.08
4.05
7.10
6.17
1.88
3.31
-0.31
4.23
2.67
6.31
5.88
5.02
-2.64
1.30
-2.47
2.22
1.11
3.95
-2.89
-1.53
-0.34
2.02
5.51
-3.42
5.17
5.00
10.48
-1.94
8.66
-0.98
4.14
-1.94
-2.47
5.85
6.15
7.99
2.74
7.08
2.05
f – Female
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
114
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 7 (continued)
Individual Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal
Number
1f
2f
%
Change
1
90
85
92
78
85
85
90
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
20296
20297
20298
20299
20300
1.13
7.32
-0.70
2.84
0.36
9.10
-2.70
13.95
6.30
5.05
1.15
-1.06
-1.85
-0.15
8.08
-0.12
2.23
1.60
-6.17
1.87
4.41
11.18
-1.27
-8.78
5.08
.
.
.
.
.
94.11
81.09
87.56
96.96
89.85
106.01
80.79
58.93
70.38
110.43
.
.
.
.
.
67.720
60.093
61.994
67.771
68.317
76.708
61.489
43.236
51.811
78.347
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9.58
2.43
6.07
0.82
-0.12
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
-2.93
-4.39
7.72
8.67
-6.35
-1.67
0.03
1.50
-0.88
-1.05
3.63
2.31
-2.65
-1.73
2.10
2.12
-2.73
-6.81
6.89
1.05
75.71
82.74
78.04
84.73
90.08
75.59
72.10
86.89
93.98
71.56
53.802
61.393
55.462
62.010
62.634
56.609
54.925
65.086
69.047
53.971
.
.
.
.
.
.
.
.
.
.
f – Female
From:
To:
Absolute
Change
1
90
92
99
99
106
106
113
113
118
Absolute
Change
85
118
-9.79
-13.96
-8.17
-10.42
-7.51
-22.94
-7.98
-11.98
-6.73
-17.30
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4.01
4.63
-0.17
3.50
-0.96
.
.
.
.
.
.
.
.
.
.
3.85
1.78
0.66
-0.53
5.87
.
.
.
.
.
.
.
.
.
.
-0.95
-2.46
0.05
-2.07
-4.46
.
.
.
.
.
.
.
.
.
.
-1.07
-2.70
2.31
6.00
4.14
.
.
.
.
.
.
.
.
.
.
15.42
3.68
8.92
7.72
4.47
-8.59
-4.93
-5.64
-9.07
-8.61
-9.86
-7.86
-6.98
-12.67
-8.81
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
90
91
. – Not applicable
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
115
%
Absolute
%
Change Change Change
85
1
1
118
118
118
.
.
.
.
.
.
.
.
.
.
7.044
1.546
4.016
2.997
1.816
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
95.19
97.84
95.88
115.49
110.05
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
68.418
68.020
70.949
77.081
78.316
.
.
.
.
.
.
.
.
.
.
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 7 (continued)
Individual Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Animal
Number
Base
Weight
Day
1
3f
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
4f
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
20366
20367
20368
20369
20370
Group
Sex
f – Female
From:
To:
1
8
8
15
15
22
22
29
29
36
36
43
43
50
50
57
57
64
64
71
71
78
143.93
129.07
130.59
149.57
139.09
139.26
133.81
137.01
132.01
139.02
26.00
13.68
16.17
20.72
15.84
13.68
15.65
17.90
21.91
19.30
14.90
18.60
17.63
15.83
12.79
21.87
16.92
5.19
13.81
8.99
4.11
8.64
8.85
9.66
7.99
9.20
14.70
6.84
10.48
12.98
15.06
11.26
15.28
11.31
11.77
8.61
11.02
17.15
11.08
6.41
13.71
7.92
8.66
11.26
6.44
0.39
1.73
3.91
7.54
5.69
-2.11
2.81
7.22
6.56
10.75
10.37
4.69
6.44
5.65
3.32
6.77
0.79
-8.17
3.35
1.07
4.24
4.77
3.86
3.76
9.43
6.43
7.95
4.88
7.26
10.13
4.34
7.59
9.08
3.22
0.34
5.85
4.35
10.96
-0.16
4.33
-2.99
5.75
2.18
5.83
-2.85
-1.39
2.21
-0.21
3.23
-1.71
5.46
0.77
1.83
10.27
2.84
4.73
1.08
3.50
1.43
-0.41
2.51
-1.27
3.00
1.99
5.82
147.64
135.96
146.39
140.76
136.88
137.07
136.94
133.24
138.95
130.01
132.01
136.06
140.74
145.30
142.07
20.40
13.25
13.77
20.31
12.71
20.03
15.27
16.98
16.92
19.38
16.24
18.52
11.70
20.52
20.39
26.02
19.21
26.56
22.43
12.17
18.96
13.74
18.92
15.78
11.17
13.88
19.70
23.02
18.28
23.99
10.62
6.30
11.85
12.17
11.58
12.95
13.78
8.42
8.20
11.55
8.01
14.48
12.20
17.28
11.28
15.91
23.23
18.16
13.66
10.43
16.58
14.60
12.71
14.46
13.02
12.25
13.44
12.71
11.16
3.32
5.34
5.32
-0.32
7.61
6.22
5.50
2.06
2.26
0.49
-0.38
10.71
1.09
11.58
9.04
13.36
5.11
0.94
10.58
3.02
4.84
10.86
5.88
-0.35
3.26
11.79
7.40
16.00
2.26
9.21
9.40
8.62
19.15
5.42
8.93
-1.35
6.51
-0.24
7.21
7.11
5.69
2.28
5.40
5.97
4.63
2.57
5.32
5.22
3.17
3.11
3.51
8.23
15.24
3.87
4.97
2.33
4.55
0.88
9.75
4.62
0.36
1.46
-0.97
-2.78
-4.63
0.84
2.07
-2.00
-0.92
2.23
-2.22
3.88
8.36
-3.01
6.13
7.22
-4.67
5.22
13.09
5.95
4.37
0.35
6.64
2.40
2.01
4.66
2.35
-2.00
8.24
8.18
1.98
11.31
-0.84
1.95
3.77
14.59
7.50
0.69
0.13
6.89
5.68
8.29
4.67
4.17
6.14
2.86
. – Not applicable
Nominal Dose: Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
116
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 7 (continued)
Individual Body Weight Changes (g)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day Numbers Relative to Start Date
Group
Sex
Animal From:
Number
To:
78
85
85
90
Absolute
Change
1
90
3f
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
-1.59
1.54
0.94
-1.82
3.12
0.36
-1.03
-0.19
0.45
-1.19
6.00
2.49
2.91
4.91
3.33
2.05
6.76
0.15
3.23
1.54
98.47
83.32
88.62
93.54
85.44
80.09
88.05
77.34
99.22
72.62
4f
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
20366
20367
20368
20369
20370
2.62
10.51
-3.84
5.41
-1.29
4.09
5.10
3.83
2.13
4.52
-0.45
7.50
11.17
-2.09
-1.30
1.48
-4.60
8.59
-0.27
1.84
5.90
3.98
2.63
3.54
2.97
.
.
.
.
.
109.54
101.94
106.20
101.47
80.46
119.53
94.74
78.09
87.99
90.16
.
.
.
.
.
f – Female
%
Change
1
90
68.415
64.554
67.861
62.539
61.428
57.511
65.802
56.448
75.161
52.237
%
Absolute
%
Change
Change
Change
85
1
1
118
118
118
85
92
90
91
92
99
99
106
106
113
113
118
.
.
.
.
.
.
.
.
.
.
-6.25
-8.32
-8.31
-9.04
-7.15
-14.67
-8.32
-6.11
-11.16
-8.21
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
-5.17
-3.06
-10.38
-5.42
-12.34
-11.52
-17.45
-12.39
-6.62
-12.14
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
-2.64
-9.03
9.86
8.31
-2.10
.
.
.
.
.
.
.
.
.
.
1.30
4.17
3.97
4.21
4.24
.
.
.
.
.
.
.
.
.
.
4.77
3.91
-2.09
-2.56
2.64
.
.
.
.
.
.
.
.
.
.
0.27
0.72
-3.11
6.39
2.31
.
.
.
.
.
.
.
.
.
.
4.70
1.89
-4.80
13.66
8.34
.
.
.
.
.
.
.
.
.
.
2.123
0.774
-1.916
5.286
3.512
74.194
.
74.978
.
72.546
.
72.087
.
58.781
.
87.204
.
69.184
.
58.609
.
63.325
.
69.349
.
.
1.00
.
2.12
.
- 13.43
.
-2.69
.
1.25
. – Not applicable
Nominal Dose: Group 3 - 20 mg/kg
Absolute
Change
85
118
Group 4 - 200 mg/kg
117
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
94.09
109.93
104.96
126.76
103.77
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
71.275
80.795
74.577
87.240
73.041
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 8
Ophthalmology Reports
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
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Appendix 9
Clinical Pathology Evaluation and Data Reports
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
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Gene Logic Laboratories Inc. Study No. 1567-04370
CLINICAL PATHOLOGY DATA REPORT
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
Gene Logic Study No. 1567-04370
MATERIAL AND METHODS
Specimen Processing
Blood specimens for clinical chemistry, and hematology were collected through the retroorbital plexus or
the abdominal aorta. Blood specimens for coagulation were collected through cardiac puncture or the
abdominal aorta. All samples were collected from animals under CO2 anesthesia.
Blood samples were collected on Study Day (SD) 91 (terminal sacrifice) and 119 (recovery sacrifice).
Animals were food-fasted overnight (approximately 19-23 hours), with water available, prior to sample
collection. All samples were transported to the Gene Logic Clinical Pathology Laboratory for analysis.
Serum Clinical Chemistry
A Ortho-Clinical Diagnostics Vitros chemistry analyzer was used to measure the serum concentrations of
the following clinical chemistry parameters. All reagents were obtained from Ortho-Clinical Diagnostics.
Commercially available controls were assayed each day of testing.
Parameter
Albumin/Globulin Ratio
Albumin
Alkaline Phosphatase
Alanine Aminotransferase
Abbreviation
A/G
ALB
ALKP
ALT
Units
g/dL
U/L
U/L
Aspartate
Aminotransferase
Blood Urea Nitrogen
Calcium
Cholesterol
Chloride
Creatinine
Globulin
Glucose
Potassium
AST
U/L
BUN
CA
CHOL
CL
CREA
GLOB
GLU
K
mg/dL
mg/dL
mg/dL
mmol/L
mg/dL
g/dL
mg/dL
mmol/L
125
Method
Calculated: Albumin ÷ Globulin
Bromcresol green (colorimetric)
p-Nitrophenyl-phosphate (multiple point rate)
L-Alanine+Alpha Ketoglutarate
(multiple point rate)
Aspartate+Alpha Ketoglutarate Oxaloacetate
Leuco Dye (multiple point rate)
Urease (colorimetric)
Arsenazo III Dye (colorimetric)
Cholesterol Oxidase Peroxidase (colorimetric)
Ion-selective electrode (potentiometric)
Creatinine Amidinohydrolase (two point rate)
Calculated: Total Protein - Albumin
Glucose Oxidase Peroxidase (colorimetric)
Ion-selective electrode (potentiometric)
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Parameter
Sodium
Phosphorus
Total Bilirubin
Total Protein
Triglycerides
Abbreviation
NA
PHOS
TBILI
TPROT
TRIG
Units
mmol/L
mg/dL
mg/dL
g/dL
mg/dL
Method
Ion-selective electrode (potentiometric)
Ammonium Molybdate (colorimetric)
Diazo (colorimetric)
Biuret with Lithium Hydroxide (colorimetric)
Glycerophosphate (colorimetric)
Values that were below the detection limit of the analyzer were reported as < the lowest limit of the
measured parameter.
For example, the lowest limit for cholesterol concentration determination was
50 mg/dL. A value that was observed to be less than this was reported as <50.
Hematology
The following hematology parameters were measured or calculated by the Bayer Advia 120 hematology
analyzer as indicated. All reagents were obtained from Bayer. Commercially available controls were
assayed each day of testing.
Parameter
Abbreviation
Units
White Blood Cells
WBC
K/μL
Red Blood Cells
RBC
M/μL
Hemoglobin
Hematocrit
Mean Corpuscular Volume
Mean Corpuscular
Hemoglobin
HGB
HCT
MCV
MCH
g/dL
%
fL
pg
Flow cytometry by 2 angles of light scatter
Low angle: number of nuclei present
High angle: nuclear complexity
Flow cytometry by 2 angles of light scatter
Low angle: size
High angle: hemoglobin concentration
Measured by cyanmethemoglobin
Calculated (RBC x MCV) ÷ 10
Flow cytometry by low angle light scatter
Calculated: (HGB ÷ RBC) x 10
Method
Mean Corpuscular
Hemoglobin Concentration
Mean Platelet Volume
Platelets
MCHC
g/dL
Calculated: (HGB ÷ [RBC x MCV]) x 1000
MPV
PLT
fL
K/μL
Flow cytometry by low angle light scatter
Flow cytometry by 2 angles of light scatter
Low angle: size
High angle: refractive index
Absolute Neutrophils
Absolute Lymphocytes
Absolute Monocytes
Absolute Eosinophils
Absolute Basophils
Absolute Reticulocytes
ABNEUT
ABLYMP
ABMONO
ABEOS
ABBAS
ABSRET
K/µL
K/µL
K/µL
K/µL
K/µL
109/L
Individual cell types initially determined as % WBC.
Absolute cell counts were calculated by the Advia 120
by multiplying the total white blood cell count by the
decimal expression of the percentage of the individual
cell population
Same as RBC plus zero angle light scatter-light
absorption (cells stained with oxazine 750 absorb more
light than mature RBCs). Absolute reticulocyte counts
were calculated by the Advia 120 by multiplying total red
blood cell count by the decimal expression of the
reticulocyte percent.
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When the white blood cell differential or reticulocyte count could not be calculated by the Advia 120 due
to mechanical or sample limitations, a manual count was performed. When platelet counts could not be
determined due to the presence of platelet clumping, a visual observation of increased, adequate, or
decreased was made for the platelet count in lieu of a numerical value. The same observation was
reported for the mean platelet volume value.
Blood smears for cellular morphology were prepared and stained using a quick Romanowsky type stain.
Cellular morphology was determined by visual examination of the stained blood smear, and reported only
if abnormal.
Coagulation
Coagulation parameters were measured on a Beckman Coulter ACL 1000 coagulation analyzer. All
reagents were obtained from Beckman Coulter. Coagulation control samples were analyzed each day of
testing.
Parameter
Abbreviation
Units
Method
Prothrombin Time
PT
seconds
Laser-nephelometric centrifugal analyzer
Activated Partial Thromboplastin Time
APTT
seconds
Laser-nephelometric centrifugal analyzer
Data Analyses
Quantitative results were analyzed using the Kolmogorov-Smirnov test for normality, the Levene Median
test for equal variance, and by One-Way Analysis of Variance (ANOVA). If either the normality or equal
variance test failed, then the analysis was continued using the non-parametric Kruskal-Wallis ANOVA on
rank-transformed data. For parametric data, if the ANOVA indicated statistical significance among
experimental groups, then the Dunnett’s t-test was used to delineate which groups (if any) differed from
the control. For non-parametric data, if the Kruskal-Wallis ANOVA indicated statistical significance among
experimental groups, then the Dunn’s test was used to delineate which groups (if any) differed from the
control. The probability value of less than 0.05 (two-tailed) was used as the critical level of significance
for all tests.
Values of > or < a number are presented in the tables, but are not included in means, standard
deviations, or statistical analysis unless otherwise indicated. Qualitative gradings or observations are
also not included in statistical analysis. Groups with sample sizes of 1 were excluded from statistical
analysis; when the sample size of 1 occurred in the control group, no analysis was conducted.
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All statistical analyses were performed using SigmaStat™ Statistical Software Version 1.0 (Jandel
Scientific, San Rafael, CA).
ABBREVIATIONS
The following abbreviations may appear in the text of this report or in the attached tables.
ANI
Appear
CAO
CL
CMP
CRE
DEC
dL
F
FEC
fL
g
HJB
HPF
HYP
INC
INS
K
L
LA
LPF
mg
M
anisocytosis
appearance
calcium oxalate crystals
clotted
clumped
crenated cells
decreased
deciliter
female
fecal contamination
femtoliters
gram
Howell Jolly bodies
high power field
hypochromic
increased
instrument malfunction
thousands
liter
lab accident
low power field
milligram
millions or male
ABBREVIATION TABLE
mL
mmol
Morph
N
NA
NC
Neg
ng
NR
NS
NSR
pg
PLY
POI
QNS
ROU
Sl
SPM
TGT
TPC
U
UCR
μL
milliliter
millimols
morphology
normal
not applicable
no clotting seen
negative
nanograms
no result
no specimen/none seen
no sample received
picograms
polychromasia
poikilocytosis
quantity not sufficient
rouleaux
slightly
sperm
target cells
triple phosphate crystals
units
unidentified crystal
microliter
SPECIMEN DISPOSITION
On SD 91, the clinical chemistry sample for animal 20330 (3M) was moderately hemolyzed. The
coagulation samples for animals 20275 (1M), 20288 (1F), 20332 (3F) 20357 (4F), 20362 (4F) and 20365
(4F) were clotted.
On SD 119, the coagulation sample for animal 20354 (4M) was clotted.
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GROUP DESIGNATION AND DOSAGE LEVELS
Group designation, treatment, dose levels, and animal distribution are presented below.
Test Article
Concentration
(mg/mL)
13-week
Treatment
Animals
4-week
Recovery
Animals
M
F
M
F
M
F
Total
Group
Treatment
Test Article
Dose Level
(mg/kg/day)
1
Corn Oil
0
0
10
10
5
5
15
15
2
Mesozeaxanthin
2
0.2
10
10
0
0
10
10
3
Mesozeaxanthin
20
2
10
10
0
0
10
10
4
Mesozeaxanthin
200
20
10
10
5
5
15
15
Note: The first 10 surviving rats/sex/group were sacrificed after 13 weeks of treatment, the remaining rats were sacrificed after a
4-week recovery period.
M: Male; F: Female
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Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
Group Summary Tables
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Group Summary Data
04370 DAY 91
Clinical Chemistry
Sex
GLU
mg/dL
BUN
mg/dL
CREA
mg/dL
NA
mmol/L
K
mmol/L
CL
mmol/L
CA
mg/dL
Mean
SD
N
M
116.20
35.43
10
14.70
2.98
10
0.66
0.07
10
147.70
1.49
10
5.97
0.36
10
102.60
2.46
10
10.95
0.22
10
Mean
SD
N
M
105.60
20.93
10
13.40
2.76
10
0.66
0.05
10
148.30
0.95
10
6.09
0.15
10
101.90
0.99
10
10.97
0.29
10
Mean
SD
N
M
110.10
12.99
10
13.40
2.91
10
0.63
0.08
10
148.80
1.55
10
6.25
0.31
10
102.40
3.20
10
11.00
0.31
10
Mean
SD
N
M
107.20
8.66
10
14.30
3.56
10
0.66
0.07
10
147.90
0.99
10
6.13
0.28
10
102.20
1.48
10
10.79
0.26
10
Mean
SD
N
F
91.60
12.45
10
15.70
1.06
10
0.71
0.13
10
148.40
1.84
10
5.85
0.34
10
103.10
3.31
10
11.06
0.37
10
Mean
SD
N
F
100.70
12.49
10
17.80
2.44
10
0.67
0.09
10
147.50
1.27
10
5.75
0.28
10
105.20
2.70
10
10.87
0.31
10
Mean
SD
N
F
106.10
27.17
10
16.50
1.35
10
0.60
0.05
10
147.00
1.15
10
5.48
0.20
10
103.10
2.64
10
10.93
0.27
10
Mean
SD
N
F
98.50
12.43
10
17.80
2.62
10
0.61
0.06
10
147.00
0.82
10
5.66
0.32
10
102.50
2.07
10
10.82
0.35
10
Group 1
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
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Group Summary Data
04370 DAY 91
Clinical Chemistry
Sex
PHOS
mg/dL
CHOL
mg/dL
TRIG
mg/dL
TPROT
g/dL
ALB
g/dL
GLOB
g/dL
Group 1
Mean
SD
N
M
8.09
1.56
10
74.20
13.57
10
66.00
15.02
10
6.40
0.21
10
3.41
0.15
10
2.99
0.14
10
Mean
SD
N
M
7.81
0.85
10
79.20
13.60
10
73.80
18.43
10
6.54
0.40
10
3.54
0.25
10
3.00
0.22
10
Mean
SD
N
M
8.25
1.61
10
82.20
13.35
10
79.20
24.72
10
6.82
0.38
10
3.63
0.23
10
3.19
0.20
10
Mean
SD
N
M
7.20
0.72
10
72.33
9.90
9
71.60
18.43
10
6.69
0.39
10
3.54
0.29
10
3.15
0.20
10
Mean
SD
N
F
7.55
2.08
10
73.29
16.02
7
46.90
10.44
10
6.91
0.42
10
3.87
0.31
10
3.04
0.13
10
Mean
SD
N
F
6.56
2.06
10
74.13
9.42
8
46.10
9.57
10
6.78
0.47
10
3.78
0.39
10
3.00
0.16
10
Mean
SD
N
F
6.53
0.95
10
76.38
12.87
8
54.10
18.32
10
6.87
0.29
10
3.90
0.19
10
2.97
0.13
10
Mean
SD
N
F
6.82
1.05
10
72.60
15.19
10
60.50
15.54
10
7.08
0.21
10
3.91
0.22
10
3.17
0.15
10
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
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Group Summary Data
04370 DAY 91
Clinical Chemistry
Sex
A/G
AST
U/L
ALT
U/L
ALKP
U/L
TBILI
mg/dL
Mean
SD
N
M
1.14
0.08
10
65.30
6.91
10
67.90
11.19
10
130.60
30.97
10
0.13
0.05
9
Mean
SD
N
M
1.18
0.09
10
68.50
7.72
10
69.00
15.11
10
143.80
52.38
10
0.17
0.05
9
Mean
SD
N
M
1.14
0.07
10
75.50
29.27
10
74.40
16.85
10
181.00*
48.78
10
0.22
0.15
9
Mean
SD
N
M
1.13
0.11
10
65.20
5.90
10
63.80
12.91
10
184.00*
95.60
10
0.18
0.04
6
Mean
SD
N
F
1.27
0.07
10
66.60
10.71
10
44.90
7.20
10
66.00
23.76
10
0.23
0.05
10
Mean
SD
N
F
1.26
0.12
10
65.60
6.72
10
50.70
9.96
10
72.00
20.04
10
0.13*
0.07
10
Mean
SD
N
F
1.31
0.06
10
68.80
12.50
10
52.10
8.75
10
70.60
12.26
10
0.18
0.04
9
Mean
SD
N
F
1.24
0.11
10
62.80
6.27
10
48.50
6.47
10
85.00
29.47
10
0.18
0.04
10
Group 1
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
* - Statistically different from control value, p < 0.05.
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Group Summary Data
04370 DAY 91
Hematology
Sex
WBC
K/uL
RBC
M/uL
HGB
g/dL
HCT
%
MCV
fL
MCH
Pg
MCHC
g/dL
Mean
SD
N
M
7.66
2.15
10
9.43
0.49
10
16.88
0.75
10
51.00
2.72
10
54.12
1.93
10
17.94
0.95
10
33.16
1.39
10
Mean
SD
N
M
8.53
2.96
10
9.21
0.29
10
16.73
0.71
10
50.29
2.31
10
54.58
1.29
10
18.17
0.78
10
33.29
1.15
10
Mean
SD
N
M
9.48
1.88
10
9.15
0.33
10
16.83
0.78
10
50.41
2.10
10
55.11
1.19
10
18.41
0.94
10
33.40
1.42
10
Mean
SD
N
M
9.29
2.37
10
9.14
0.64
10
16.59
1.10
10
49.69
3.50
10
54.37
0.64
10
18.16
0.76
10
33.39
1.20
10
Mean
SD
N
F
6.30
2.36
10
8.58
0.34
10
16.08
0.41
10
48.70
2.03
10
56.74
1.20
10
18.76
0.39
10
33.09
0.92
10
Mean
SD
N
F
5.44
1.17
10
8.64
0.56
10
15.97
0.69
10
48.19
2.79
10
55.83
1.42
10
18.53
0.90
10
33.18
1.25
10
Mean
SD
N
F
6.18
1.61
10
8.45
0.37
10
15.80
0.52
10
46.64
2.84
10
55.18
1.33
10
18.74
0.67
10
33.94
1.72
10
Mean
SD
N
F
6.01
1.34
10
8.60
0.62
10
16.28
0.86
10
48.49
3.25
10
56.45
1.46
10
18.98
0.80
10
33.58
0.97
10
Group 1
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
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Group Summary Data
04370 DAY 91
Hematology
Sex
PLT
K/uL
MPV ABNEUT ABLYMP ABMONO
fL
K/uL
K/uL
K/uL
ABEOS
K/uL
ABBAS ABSRET
K/uL
109/L
Group 1
Mean
SD
N
M
647.10
97.37
10
8.95
1.22
10
1.30
0.91
10
6.10
1.65
10
0.13
0.07
10
0.06
0.03
10
0.02
0.02
10
167.52
15.83
10
Mean
SD
N
M
744.20
88.75
10
9.22
1.35
10
1.47
0.55
10
6.77
2.83
10
0.16
0.07
10
0.08
0.04
10
0.02
0.02
10
181.79
23.08
10
Mean
SD
N
M
657.70
82.23
10
9.06
1.26
10
1.49
0.45
10
7.62
1.52
10
0.19
0.07
10
0.09
0.05
10
0.03
0.02
10
167.03
22.23
10
Mean
SD
N
M
684.00
88.34
10
9.06
1.23
10
1.46
0.56
10
7.55
1.84
10
0.13
0.10
10
0.06
0.05
10
0.04
0.06
10
160.14
33.00
10
Mean
SD
N
F
665.80
175.94
10
9.36
1.56
10
1.01
0.61
10
4.52
1.92
10
0.11
0.06
10
0.21
0.42
10
0.02
0.02
10
210.64
70.27
10
Mean
SD
N
F
646.10
99.00
10
9.75
2.49
10
0.97
0.41
10
4.21
0.96
10
0.21
0.27
10
0.08
0.04
10
0.03
0.02
10
183.28
32.71
10
Mean
SD
N
F
719.10
76.45
10
8.75
1.26
10
0.88
0.36
10
5.08
1.50
10
0.11
0.07
10
0.06
0.02
10
0.02
0.03
10
189.96
23.65
10
Mean
SD
N
F
708.60
101.91
10
8.83
0.81
10
0.95
0.26
10
4.81
1.06
10
0.13
0.04
10
0.06
0.04
10
0.02
0.02
10
198.84
34.33
10
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
135
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Group Summary Data
04370 DAY 91
Coagulation
Sex
APTT
SEC
PT
SEC
Mean
SD
N
M
33.16
15.82
9
14.44
0.43
9
Mean
SD
N
M
40.10
17.05
8
14.28
0.40
8
Mean
SD
N
M
37.10
13.06
9
15.00
0.58
9
Mean
SD
N
M
34.06
14.97
7
14.90
0.59
7
Mean
SD
N
F
32.14
10.32
7
14.64
0.64
7
Mean
SD
N
F
32.08
14.64
8
14.81
0.68
8
Mean
SD
N
F
25.94
12.10
8
14.71
0.52
8
Mean
SD
N
F
25.87
10.60
7
14.51
0.56
7
Group 1
Group 2
Group 3
Group 4
Group 1
Group 2
Group 3
Group 4
136
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Group Summary Data
04370 DAY 119
Clinical Chemistry
Sex
GLU
mg/dL
BUN
mg/dL
CREA
mg/dL
NA
mmol/L
K
mmol/L
CL
mmol/L
CA
mg/dL
Mean
SD
N
M
107.40
7.02
5
20.60
1.82
5
0.74
0.13
5
150.60
0.89
5
6.85
0.21
5
104.20
1.48
5
11.14
0.36
5
Mean
SD
N
M
114.00
5.61
5
19.40
4.28
5
0.76
0.05
5
154.20*
2.59
5
6.75
0.33
5
105.40
1.95
5
11.24
0.51
5
Mean
SD
N
F
92.20
8.07
5
19.60
3.21
5
0.84
0.11
5
153.20
3.19
5
6.68
0.75
5
104.20
1.79
5
11.30
0.40
5
Mean
SD
N
F
94.80
9.88
5
18.80
3.11
5
0.76
0.15
5
154.00
2.00
5
6.73
0.80
5
105.80
0.84
5
11.42
0.43
5
Group 1
Group 4
Group 1
Group 4
* - Statistically different from control value, p < 0.05.
137
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Group Summary Data
04370 DAY 119
Clinical Chemistry
Sex
PHOS
mg/dL
CHOL
mg/dL
TRIG
mg/dL
TPROT
g/dL
ALB
g/dL
GLOB
g/dL
Group 1
Mean
SD
N
M
8.14
1.94
5
81.20
16.50
5
65.40
25.58
5
6.78
0.31
5
3.76
0.19
5
3.02
0.22
5
Mean
SD
N
M
7.88
0.92
5
79.00
14.76
5
70.60
21.62
5
7.40*
0.42
5
4.06
0.40
5
3.34*
0.15
5
Mean
SD
N
F
7.66
1.41
5
101.60
22.57
5
45.40
8.02
5
7.96
0.78
5
4.70
0.58
5
3.26
0.29
5
Mean
SD
N
F
8.34
1.10
5
79.80
17.68
5
45.40
8.38
5
7.80
0.52
5
4.64
0.45
5
3.16
0.18
5
Group 4
Group 1
Group 4
* - Statistically different from control value, p < 0.05.
138
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Group Summary Data
04370 DAY 119
Clinical Chemistry
Sex
A/G
AST
U/L
ALT
U/L
ALKP
U/L
TBILI
mg/dL
Mean
SD
N
M
1.25
0.10
5
77.00
9.92
5
59.80
15.74
5
97.20
19.59
5
0.20
0.00
4
Mean
SD
N
M
1.22
0.13
5
77.00
10.07
5
46.20
7.63
5
118.40
32.64
5
0.20
0.00
2
Mean
SD
N
F
1.45
0.15
5
74.40
6.88
5
38.20
8.87
5
51.60
10.31
5
0.26
0.05
5
Mean
SD
N
F
1.47
0.14
5
76.00
6.63
5
35.20
12.93
5
49.40
9.86
5
0.20
0.07
5
Group 1
Group 4
Group 1
Group 4
139
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Group Summary Data
04370 DAY 119
Hematology
Sex
WBC
K/uL
RBC
M/uL
HGB
g/dL
HCT
%
MCV
fL
MCH
Pg
MCHC
g/dL
Mean
SD
N
M
8.02
0.91
5
9.41
0.73
5
16.86
0.53
5
51.98
2.90
5
55.28
1.30
5
17.94
0.80
5
32.50
0.97
5
Mean
SD
N
M
8.11
1.52
5
9.78
0.45
5
17.14
0.75
5
53.72
3.20
5
54.90
0.93
5
17.56
0.11
5
31.94
0.70
5
Mean
SD
N
F
5.39
0.91
5
8.95
0.14
5
16.76
0.11
5
52.00
0.81
5
58.12
1.28
5
18.74
0.32
5
32.24
0.46
5
Mean
SD
N
F
5.02
0.51
5
8.68
1.20
5
16.28
1.95
5
50.28
6.53
5
58.00
1.27
5
18.78
0.57
5
32.42
0.69
5
Group 1
Group 4
Group 1
Group 4
140
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Group Summary Data
04370 DAY 119
Hematology
Sex
PLT
K/uL
MPV ABNEUT ABLYMP ABMONO
fL
K/uL
K/uL
K/uL
ABEOS
K/uL
ABBAS ABSRET
K/uL
109/L
Group 1
Mean
SD
N
M
690.40
70.33
5
7.84
0.50
5
1.40
0.27
5
6.20
0.84
5
0.19
0.05
5
0.13
0.03
5
0.04
0.01
5
188.00
15.06
5
Mean
SD
N
M
617.80
126.16
5
8.12
0.23
5
1.45
0.46
5
6.22
1.11
5
0.23
0.07
5
0.10
0.03
5
0.06
0.02
5
197.66
33.33
5
Mean
SD
N
F
611.40
85.03
5
8.26
0.52
5
0.84
0.30
5
4.27
0.83
5
0.12
0.03
5
0.08
0.08
5
0.02
0.01
5
188.24
46.79
5
Mean
SD
N
F
663.20
102.16
5
7.80
0.31
5
1.19
0.23
5
3.54
0.56
5
0.12
0.02
5
0.09
0.02
5
0.04
0.02
5
212.74
50.05
5
Group 4
Group 1
Group 4
141
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Group Summary Data
04370 DAY 119
Coagulation
Sex
APTT
SEC
PT
SEC
Mean
SD
N
M
25.48
6.62
5
15.00
0.39
5
Mean
SD
N
M
39.43
16.51
4
15.10
0.48
4
Mean
SD
N
F
31.46
8.40
5
14.78
0.42
5
Mean
SD
N
F
25.00
4.00
4
15.53*
0.43
4
Group 1
Group 4
Group 1
Group 4
* - Statistically different from control value, p < 0.05.
142
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
Individual Animal Data
143
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Clinical Chemistry
Accession Animal
Number Number
Group
Sex
GLU
mg/dL
BUN
mg/dL
CREA
mg/dL
NA
mmol/L
K
mmol/L
CL
mmol/L
CA
mg/dL
3031527
3031528
3031529
3031530
3031531
3031532
3031533
3031534
3031535
3031536
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
1
1
1
1
1
1
1
1
1
1
M
M
M
M
M
M
M
M
M
M
110
116
108
213
97
126
100
94
97
101
12
11
12
15
12
15
17
20
15
18
0.6
0.6
0.6
0.6
0.8
0.6
0.7
0.7
0.7
0.7
149
149
149
147
148
146
146
147
146
150
5.7
6.0
6.2
5.2
6.1
6.1
5.9
5.8
6.0
6.6
99
101
103
104
103
108
102
103
103
100
10.8
10.6
10.8
11.4
11.1
11.0
11.0
11.0
10.8
11.0
3031557
3031558
3031559
3031560
3031561
3031562
3031563
3031564
3031565
3031566
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
2
2
2
2
2
2
2
2
2
2
M
M
M
M
M
M
M
M
M
M
104
130
94
155
104
88
94
93
100
94
13
10
9
13
13
15
19
13
14
15
0.6
0.6
0.6
0.7
0.7
0.7
0.7
0.7
0.7
0.6
149
147
149
148
147
149
149
149
147
149
6.1
6.0
5.8
6.2
6.2
6.2
6.0
6.1
6.1
6.3
101
103
102
102
101
102
101
102
104
101
10.8
10.4
11.0
11.3
10.7
11.2
11.2
11.3
10.8
11.0
3031577
3031578
3031579
3031580
3031581
3031582
3031583
3031584
3031585
3031586
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
3
3
3
3
3
3
3
3
3
3
M
M
M
M
M
M
M
M
M
M
103
110
100
112
102
106
106
119
100
143
13
11
11
11
12
17
16
11
13
19
0.6
0.6
0.5
0.6
0.6
0.6
0.7
0.6
0.7
0.8
149
147
149
148
150
148
150
147
148
152
6.0
5.9
6.3
6.4
6.1
6.1
6.4
6.0
6.2
7.0
99
106
101
101
101
103
100
106
99
108
10.7
10.7
10.9
10.9
11.1
10.8
11.3
11.1
10.8
11.7
3031597
3031598
3031599
3031600
3031601
3031602
3031603
3031604
3031605
3031606
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
4
4
4
4
4
4
4
4
4
4
M
M
M
M
M
M
M
M
M
M
112
126
115
97
105
101
105
106
107
98
13
8
11
15
13
16
19
12
17
19
0.6
0.5
0.7
0.7
0.7
0.7
0.7
0.7
0.6
0.7
149
147
147
147
149
147
147
149
148
149
6.2
6.0
5.9
6.7
6.1
6.4
6.2
5.7
6.4
6.0
101
104
102
101
100
104
104
102
103
101
10.8
10.5
10.7
10.4
10.7
11.2
10.9
10.7
11.2
10.8
144
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Clinical Chemistry
Accession Animal
Number Number
Group
Sex
GLU
mg/dL
BUN
mg/dL
CREA
mg/dL
NA
mmol/L
K
mmol/L
CL
mmol/L
CA
mg/dL
3031542
3031543
3031544
3031545
3031546
3031547
3031548
3031549
3031550
3031551
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
1
1
1
1
1
1
1
1
1
1
F
F
F
F
F
F
F
F
F
F
98
89
92
99
72
95
98
85
114
74
15
15
16
17
17
15
14
17
16
15
0.7
0.7
0.6
0.9
0.6
0.7
0.5
0.9
0.8
0.7
150
146
148
149
146
149
149
146
150
151
5.5
5.6
5.7
6.5
5.6
6.3
5.9
6.0
5.6
5.8
100
101
101
105
99
105
105
106
109
100
10.8
10.6
11.6
11.5
10.7
11.0
10.8
11.2
11.5
10.9
3031567
3031568
3031569
3031570
3031571
3031572
3031573
3031574
3031575
3031576
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
2
2
2
2
2
2
2
2
2
2
F
F
F
F
F
F
F
F
F
F
84
95
114
117
86
89
109
102
115
96
16
17
21
18
19
14
15
17
20
21
0.6
0.7
0.6
0.7
0.7
0.6
0.6
0.7
0.9
0.6
148
145
150
147
147
148
147
147
148
148
6.4
5.6
5.5
5.5
5.6
6.0
5.9
5.7
5.5
5.9
104
103
105
102
105
104
104
110
110
105
10.9
10.2
10.8
10.8
11.3
11.0
11.2
10.6
10.9
11.0
3031587
3031588
3031589
3031590
3031591
3031592
3031593
3031594
3031595
3031596
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
3
3
3
3
3
3
3
3
3
3
F
F
F
F
F
F
F
F
F
F
98
105
77
100
123
85
88
174
102
109
13
18
17
16
16
17
17
17
17
17
0.6
0.6
0.5
0.6
0.6
0.7
0.6
0.6
0.6
0.6
148
148
146
147
149
148
146
146
146
146
5.5
5.7
5.4
5.4
5.1
5.6
5.8
5.6
5.2
5.6
103
105
101
103
102
100
106
99
107
105
11.0
10.8
10.6
10.9
10.8
10.9
10.8
11.6
10.8
11.1
3031612
3031613
3031614
3031615
3031616
3031617
3031618
3031619
3031620
3031621
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
4
4
4
4
4
4
4
4
4
4
F
F
F
F
F
F
F
F
F
F
122
113
81
86
91
90
97
103
102
100
19
17
16
15
21
14
21
18
21
16
0.6
0.6
0.7
0.6
0.5
0.6
0.7
0.6
0.6
0.6
148
148
147
146
147
148
146
146
147
147
5.6
5.7
5.7
6.1
5.2
6.2
5.3
5.5
5.6
5.7
101
101
104
103
102
100
101
107
104
102
10.3
10.7
10.6
11.2
10.8
11.5
10.6
10.6
10.9
11.0
145
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Clinical Chemistry
Accession Animal
Number
Number
Group
Sex
PHOS
mg/dL
CHOL
mg/dL
TRIG
mg/dL
TPROT
g/dL
ALB
g/dL
GLOB
g/dL
3031527
3031528
3031529
3031530
3031531
3031532
3031533
3031534
3031535
3031536
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
1
1
1
1
1
1
1
1
1
1
M
M
M
M
M
M
M
M
M
M
6.5
6.0
7.9
11.4
8.0
9.4
8.1
7.5
9.0
7.1
64
59
70
67
74
70
82
106
84
66
41
53
69
66
70
75
78
93
50
65
6.1
6.5
6.5
6.2
6.4
6.3
6.3
6.8
6.3
6.6
3.4
3.5
3.3
3.3
3.3
3.4
3.4
3.7
3.2
3.6
2.7
3.0
3.2
2.9
3.1
2.9
2.9
3.1
3.1
3.0
3031557
3031558
3031559
3031560
3031561
3031562
3031563
3031564
3031565
3031566
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
2
2
2
2
2
2
2
2
2
2
M
M
M
M
M
M
M
M
M
M
7.7
7.1
6.4
9.7
7.5
8.0
7.9
8.2
8.0
7.6
82
62
96
87
75
86
66
83
58
97
84
89
82
45
60
84
100
72
45
77
5.9
6.3
6.6
6.5
6.3
7.1
7.1
6.8
6.1
6.7
3.2
3.6
3.6
3.6
3.4
3.8
3.8
3.8
3.1
3.5
2.7
2.7
3.0
2.9
2.9
3.3
3.3
3.0
3.0
3.2
3031577
3031578
3031579
3031580
3031581
3031582
3031583
3031584
3031585
3031586
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
3
3
3
3
3
3
3
3
3
3
M
M
M
M
M
M
M
M
M
M
6.5
7.5
8.4
7.1
8.5
7.3
8.0
8.5
8.3
12.4
101
63
82
86
102
75
88
78
63
84
65
81
63
58
88
94
137
51
69
86
6.7
6.0
7.1
6.9
6.8
6.8
7.3
6.6
6.7
7.3
3.6
3.2
4.0
3.6
3.6
3.5
3.9
3.6
3.5
3.8
3.1
2.8
3.1
3.3
3.2
3.3
3.4
3.0
3.2
3.5
3031597
3031598
3031599
3031600
3031601
3031602
3031603
3031604
3031605
3031606
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
4
4
4
4
4
4
4
4
4
4
M
M
M
M
M
M
M
M
M
M
6.5
6.1
6.6
7.6
6.6
8.4
7.5
7.4
7.9
7.4
73
50
74
75
84
81
77
<50
66
71
66
64
61
55
82
69
73
70
57
119
6.3
6.2
6.4
6.6
7.4
6.8
6.4
6.7
7.1
7.0
3.6
3.1
3.3
3.4
4.0
3.6
3.2
3.7
3.9
3.6
2.7
3.1
3.1
3.2
3.4
3.2
3.2
3.0
3.2
3.4
146
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Clinical Chemistry
Accession Animal
Number
Number
Group
Sex
PHOS
mg/dL
CHOL
mg/dL
TRIG
mg/dL
TPROT
g/dL
ALB
g/dL
GLOB
g/dL
3031542
3031543
3031544
3031545
3031546
3031547
3031548
3031549
3031550
3031551
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
1
1
1
1
1
1
1
1
1
1
F
F
F
F
F
F
F
F
F
F
4.1
6.0
6.7
9.8
7.3
7.9
6.3
10.6
10.2
6.6
<50
68
85
52
87
<50
68
58
<50
95
39
38
41
44
68
39
37
51
58
54
6.8
6.3
7.5
7.2
6.7
6.8
6.9
6.3
7.2
7.4
3.7
3.4
4.3
4.0
3.8
3.9
3.9
3.4
4.1
4.2
3.1
2.9
3.2
3.2
2.9
2.9
3.0
2.9
3.1
3.2
3031567
3031568
3031569
3031570
3031571
3031572
3031573
3031574
3031575
3031576
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
2
2
2
2
2
2
2
2
2
2
F
F
F
F
F
F
F
F
F
F
6.3
4.6
4.2
5.8
7.7
6.6
6.2
5.5
11.6
7.1
<50
66
73
61
79
<50
83
84
64
83
33
45
62
40
52
50
55
33
51
40
6.4
6.3
7.5
6.8
6.6
6.9
7.5
6.5
6.2
7.1
3.4
3.6
4.5
3.8
3.6
3.8
4.4
3.5
3.4
3.8
3.0
2.7
3.0
3.0
3.0
3.1
3.1
3.0
2.8
3.3
3031587
3031588
3031589
3031590
3031591
3031592
3031593
3031594
3031595
3031596
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
3
3
3
3
3
3
3
3
3
3
F
F
F
F
F
F
F
F
F
F
4.7
6.2
5.3
6.6
6.8
6.6
7.7
7.5
6.5
7.4
62
<50
63
63
<50
78
91
95
77
82
99
47
52
43
35
48
54
44
48
71
6.9
6.3
6.7
6.6
6.9
6.9
7.1
7.3
6.8
7.2
3.9
3.6
3.8
3.7
4.0
4.0
4.0
4.2
3.7
4.1
3.0
2.7
2.9
2.9
2.9
2.9
3.1
3.1
3.1
3.1
3031612
3031613
3031614
3031615
3031616
3031617
3031618
3031619
3031620
3031621
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
4
4
4
4
4
4
4
4
4
4
F
F
F
F
F
F
F
F
F
F
5.0
5.5
6.4
7.3
8.2
7.4
6.1
7.0
7.3
8.0
76
57
96
71
68
97
66
55
58
82
78
77
36
49
51
84
52
56
69
53
6.7
7.2
7.1
6.9
6.9
7.4
7.1
7.3
7.0
7.2
3.7
4.1
4.1
3.8
3.5
4.3
3.9
3.9
3.9
3.9
3.0
3.1
3.0
3.1
3.4
3.1
3.2
3.4
3.1
3.3
147
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Clinical Chemistry
Accession
Number
Animal
Number
Group
Sex
A/G
AST
U/L
ALT
U/L
ALKP
U/L
TBILI
mg/dL
3031527
3031528
3031529
3031530
3031531
3031532
3031533
3031534
3031535
3031536
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
1
1
1
1
1
1
1
1
1
1
M
M
M
M
M
M
M
M
M
M
1.3
1.2
1.0
1.1
1.1
1.2
1.2
1.2
1.0
1.2
68
56
63
66
72
77
58
62
72
59
68
55
70
60
56
74
78
73
89
56
195
133
142
83
133
112
104
129
159
116
0.2
0.1
0.1
0.2
0.1
0.1
0.1
0.2
<.1
0.1
3031557
3031558
3031559
3031560
3031561
3031562
3031563
3031564
3031565
3031566
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
2
2
2
2
2
2
2
2
2
2
M
M
M
M
M
M
M
M
M
M
1.2
1.3
1.2
1.2
1.2
1.2
1.2
1.3
1.0
1.1
76
62
75
66
60
69
70
82
57
68
66
71
80
46
51
83
74
90
51
78
103
237
220
108
98
135
175
138
80
144
0.2
0.2
0.2
0.2
0.1
0.2
0.2
0.1
<.1
0.1
3031577
3031578
3031579
3031580
3031581
3031582
3031583
3031584
3031585
3031586
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
3
3
3
3
3
3
3
3
3
3
M
M
M
M
M
M
M
M
M
M
1.2
1.1
1.3
1.1
1.1
1.1
1.2
1.2
1.1
1.1
65
75
71
55
74
68
63
74
54
156
77
71
110
56
63
81
82
68
51
85
234
167
195
283
174
186
169
109
150
143
0.1
<.1
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.6
3031597
3031598
3031599
3031600
3031601
3031602
3031603
3031604
3031605
3031606
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
4
4
4
4
4
4
4
4
4
4
M
M
M
M
M
M
M
M
M
M
1.3
1.0
1.1
1.1
1.2
1.1
1.0
1.2
1.2
1.1
59
76
56
65
67
60
70
68
68
63
85
57
41
63
74
66
68
48
74
62
138
201
109
184
445
177
164
137
141
144
0.2
<.1
<.1
0.1
0.2
<.1
0.2
<.1
0.2
0.2
148
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Clinical Chemistry
Accession
Number
Animal
Number
Group
Sex
A/G
AST
U/L
ALT
U/L
ALKP
U/L
TBILI
mg/dL
3031542
3031543
3031544
3031545
3031546
3031547
3031548
3031549
3031550
3031551
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
1
1
1
1
1
1
1
1
1
1
F
F
F
F
F
F
F
F
F
F
1.2
1.2
1.3
1.3
1.3
1.3
1.3
1.2
1.3
1.3
50
62
57
71
57
76
61
74
74
84
42
45
48
43
51
44
35
41
39
61
44
64
66
93
50
51
43
51
114
84
0.2
0.2
0.2
0.2
0.3
0.3
0.2
0.2
0.2
0.3
3031567
3031568
3031569
3031570
3031571
3031572
3031573
3031574
3031575
3031576
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
2
2
2
2
2
2
2
2
2
2
F
F
F
F
F
F
F
F
F
F
1.1
1.3
1.5
1.3
1.2
1.2
1.4
1.2
1.2
1.2
68
67
68
63
71
69
66
50
74
60
35
67
50
50
53
66
51
40
46
49
51
90
84
60
49
100
102
59
62
63
0.1
0.1
0.1
0.1
0.3
0.1
0.2
0.1
0.1
0.1
3031587
3031588
3031589
3031590
3031591
3031592
3031593
3031594
3031595
3031596
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
3
3
3
3
3
3
3
3
3
3
F
F
F
F
F
F
F
F
F
F
1.3
1.3
1.3
1.3
1.4
1.4
1.3
1.4
1.2
1.3
64
67
71
61
72
64
96
53
82
58
47
54
58
63
63
38
59
42
51
46
91
65
74
68
54
55
87
64
70
78
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.2
<.1
0.1
3031612
3031613
3031614
3031615
3031616
3031617
3031618
3031619
3031620
3031621
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
4
4
4
4
4
4
4
4
4
4
F
F
F
F
F
F
F
F
F
F
1.2
1.3
1.4
1.2
1.0
1.4
1.2
1.2
1.3
1.2
58
70
66
65
69
50
69
62
60
59
63
50
45
55
47
50
43
42
47
43
114
125
61
138
68
74
83
58
63
66
0.2
0.1
0.2
0.2
0.2
0.2
0.1
0.2
0.2
0.2
149
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Hematology
Accession Animal
Number Number
Group
Sex
WBC
K/uL
RBC
M/uL
HGB
g/dL
HCT
%
MCV
fL
MCH
Pg
MCHC
g/dL
3031527
3031528
3031529
3031530
3031531
3031532
3031533
3031534
3031535
3031536
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
1
1
1
1
1
1
1
1
1
1
M
M
M
M
M
M
M
M
M
M
3.69
5.29
6.43
7.14
11.30
8.78
8.49
7.64
9.33
8.46
9.34
8.85
9.75
9.62
10.07
8.83
8.89
10.10
9.17
9.67
16.3
15.5
17.8
17.4
16.6
17.7
16.4
17.7
16.8
16.6
49.5
48.4
55.8
54.5
51.8
48.7
47.8
53.2
50.0
50.3
53.0
54.8
57.2
56.7
51.4
55.1
53.8
52.6
54.6
52.0
17.5
17.5
18.2
18.1
16.5
20.0
18.5
17.5
18.4
17.2
33.0
32.0
31.9
31.9
32.2
36.4
34.3
33.3
33.6
33.0
3031557
3031558
3031559
3031560
3031561
3031562
3031563
3031564
3031565
3031566
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
2
2
2
2
2
2
2
2
2
2
M
M
M
M
M
M
M
M
M
M
3.86
6.03
7.84
5.08
9.20
11.34
11.81
10.84
7.29
12.03
9.14
9.43
9.66
9.38
9.24
9.21
8.66
9.46
8.90
9.02
16.2
16.2
17.2
17.7
15.9
17.2
16.9
17.5
15.6
16.9
49.5
50.0
54.1
53.0
49.8
51.3
47.6
51.8
46.6
49.2
54.2
53.0
56.0
56.4
54.0
55.7
54.9
54.7
52.3
54.6
17.7
17.2
17.8
18.9
17.2
18.6
19.5
18.5
17.6
18.7
32.6
32.4
31.8
33.5
31.9
33.5
35.5
33.9
33.5
34.3
3031577
3031578
3031579
3031580
3031581
3031582
3031583
3031584
3031585
3031586
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
3
3
3
3
3
3
3
3
3
3
M
M
M
M
M
M
M
M
M
M
11.25
7.87
8.54
8.52
11.74
12.30
10.69
9.00
6.72
8.14
9.01
9.34
9.59
9.28
9.15
9.48
9.35
8.55
8.75
8.97
17.2
16.4
17.4
16.1
16.1
17.1
17.6
16.7
15.6
18.1
51.0
50.3
53.4
51.4
50.8
51.3
51.9
47.8
46.0
50.2
56.6
53.9
55.6
55.5
55.5
54.2
55.4
55.9
52.6
55.9
19.1
17.6
18.1
17.4
17.6
18.0
18.8
19.5
17.8
20.2
33.8
32.7
32.6
31.3
31.7
33.3
33.9
34.8
33.8
36.1
3031597
3031598
3031599
3031600
3031601
3031602
3031603
3031604
3031605
3031606
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
4
4
4
4
4
4
4
4
4
4
M
M
M
M
M
M
M
M
M
M
9.95
6.12
5.90
8.16
7.44
11.22
13.32
9.43
10.55
10.76
9.10
8.70
8.61
8.85
10.31
10.05
8.68
8.36
9.22
9.50
16.1
15.1
15.1
15.9
18.2
17.9
16.3
16.5
17.3
17.5
50.0
46.2
46.3
48.4
56.0
54.8
47.6
46.2
50.2
51.2
54.9
53.1
53.8
54.7
54.3
54.5
54.8
55.3
54.5
53.8
17.7
17.3
17.5
17.9
17.7
17.8
18.7
19.8
18.8
18.4
32.2
32.6
32.5
32.8
32.5
32.6
34.2
35.8
34.5
34.2
150
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Hematology
Accession Animal
Number Number
Group
Sex
WBC
K/uL
RBC
M/uL
HGB
g/dL
HCT
%
MCV
fL
MCH
Pg
MCHC
g/dL
3031542
3031543
3031544
3031545
3031546
3031547
3031548
3031549
3031550
3031551
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
1
1
1
1
1
1
1
1
1
1
F
F
F
F
F
F
F
F
F
F
6.70
4.10
9.68
4.70
6.38
10.42
5.42
4.02
3.80
7.75
8.89
8.86
8.85
8.69
8.96
8.23
8.04
8.14
8.57
8.60
16.3
16.4
16.3
16.4
16.2
15.9
15.1
15.7
16.2
16.3
50.7
50.8
51.2
49.1
49.5
48.4
46.2
45.0
47.4
48.7
57.0
57.4
57.8
56.5
55.2
58.8
57.5
55.3
55.3
56.6
18.4
18.6
18.4
18.8
18.1
19.3
18.8
19.3
18.9
19.0
32.2
32.4
31.9
33.4
32.8
32.9
32.7
34.9
34.1
33.6
3031567
3031568
3031569
3031570
3031571
3031572
3031573
3031574
3031575
3031576
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
2
2
2
2
2
2
2
2
2
2
F
F
F
F
F
F
F
F
F
F
7.36
5.73
5.63
4.90
5.21
6.47
5.24
3.19
4.35
6.29
8.84
9.03
8.45
9.68
8.21
8.93
8.28
7.71
8.24
9.01
15.3
15.8
15.4
16.8
15.9
16.9
15.7
14.9
16.2
16.8
47.5
50.3
48.4
52.4
47.0
50.0
46.1
42.3
47.9
50.0
53.7
55.7
57.3
54.1
57.3
56.0
55.7
54.9
58.1
55.5
17.3
17.5
18.2
17.3
19.4
18.9
19.0
19.4
19.6
18.7
32.2
31.4
31.8
32.0
33.8
33.8
34.1
35.3
33.8
33.6
3031587
3031588
3031589
3031590
3031591
3031592
3031593
3031594
3031595
3031596
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
3
3
3
3
3
3
3
3
3
3
F
F
F
F
F
F
F
F
F
F
8.93
6.10
4.96
7.04
3.64
8.28
5.61
5.80
4.75
6.70
8.86
8.75
8.23
9.15
8.63
8.33
8.06
8.14
8.16
8.15
16.4
15.6
15.3
16.3
15.9
16.5
15.2
15.4
16.2
15.2
50.4
49.4
46.4
50.1
49.0
45.8
43.4
43.3
44.5
44.1
56.8
56.5
56.4
54.7
56.8
54.9
53.9
53.2
54.5
54.1
18.5
17.9
18.6
17.8
18.5
19.8
18.9
19.0
19.8
18.6
32.5
31.6
33.0
32.5
32.5
36.0
35.0
35.6
36.3
34.4
3031612
3031613
3031614
3031615
3031616
3031617
3031618
3031619
3031620
3031621
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
4
4
4
4
4
4
4
4
4
4
F
F
F
F
F
F
F
F
F
F
7.43
5.93
3.76
5.40
8.68
6.50
5.15
5.40
6.24
5.59
8.01
9.49
8.74
9.01
8.58
8.64
8.76
7.85
9.29
7.58
15.6
17.0
16.0
17.0
16.0
17.6
16.5
15.0
16.9
15.2
46.4
53.3
49.3
50.9
48.1
51.0
48.7
43.1
50.3
43.8
57.9
56.2
56.5
56.6
56.1
59.0
55.5
54.9
54.1
57.7
19.5
18.0
18.3
18.8
18.7
20.4
18.8
19.2
18.1
20.0
33.6
31.9
32.3
33.3
33.3
34.6
33.8
34.9
33.5
34.6
151
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Hematology
Accession
Number
Animal
Number
Group
Sex
PLT
K/uL
3031527
3031528
3031529
3031530
3031531
3031532
3031533
3031534
3031535
3031536
MPV ABNEUT ABLYMP ABMONO ABEOS ABBAS ABSRET
fL
K/uL
K/uL
K/uL
K/uL
K/uL
109/L
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
1
1
1
1
1
1
1
1
1
1
M
M
M
M
M
M
M
M
M
M
701
653
618
633
601
418
709
639
780
719
6.90
8.30
8.40
8.10
8.30
11.30
9.60
10.00
9.10
9.50
0.52
0.80
1.33
1.49
3.54
0.53
0.95
0.58
1.45
1.78
2.99
4.32
4.83
5.43
7.30
8.08
7.29
6.86
7.57
6.36
0.11
0.07
0.11
0.09
0.29
0.18
0.10
0.08
0.15
0.16
0.07
0.03
0.09
0.08
0.06
0.00
0.07
0.05
0.04
0.09
0.00
0.02
0.03
0.02
0.05
0.00
0.03
0.02
0.04
0.03
159.4
151.2
186.5
157.1
176.7
143.1
171.1
195.1
168.3
166.7
3031557
3031558
3031559
3031560
3031561
3031562
3031563
3031564
3031565
3031566
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
2
2
2
2
2
2
2
2
2
2
M
M
M
M
M
M
M
M
M
M
834
750
678
579
745
691
815
777
883
690
7.80
8.80
8.40
12.30
8.40
9.00
8.10
9.70
10.60
9.10
2.20
1.26
1.17
0.87
1.40
2.36
1.65
0.76
1.10
1.95
1.54
4.49
6.33
4.01
7.44
8.61
9.80
9.97
5.91
9.58
0.04
0.12
0.16
0.10
0.16
0.18
0.24
0.11
0.17
0.30
0.08
0.09
0.13
0.03
0.10
0.09
0.12
0.00
0.06
0.11
0.00
0.02
0.02
0.04
0.03
0.04
0.00
0.00
0.03
0.04
205.5
203.6
145.2
200.5
151.9
192.6
199.0
182.5
154.2
182.9
3031577
3031578
3031579
3031580
3031581
3031582
3031583
3031584
3031585
3031586
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
3
3
3
3
3
3
3
3
3
3
M
M
M
M
M
M
M
M
M
M
584
675
580
637
694
728
816
579
715
569
7.60
8.00
8.50
9.10
8.10
8.10
9.20
11.00
9.80
11.20
2.23
1.16
1.12
1.04
2.14
1.48
1.60
1.89
1.22
1.06
8.53
6.33
7.02
7.16
9.21
10.30
8.73
6.75
5.28
6.84
0.28
0.12
0.27
0.15
0.17
0.21
0.13
0.27
0.10
0.24
0.10
0.19
0.06
0.09
0.10
0.13
0.09
0.09
0.07
0.00
0.06
0.03
0.02
0.03
0.05
0.06
0.05
0.00
0.02
0.00
160.8
177.6
161.2
173.0
201.1
180.5
192.3
144.8
150.4
128.6
3031597
3031598
3031599
3031600
3031601
3031602
3031603
3031604
3031605
3031606
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
4
4
4
4
4
4
4
4
4
4
M
M
M
M
M
M
M
M
M
M
818
720
554
613
602
702
674
792
754
611
6.90
7.90
8.50
8.20
8.60
11.00
9.80
10.00
9.80
9.90
1.26
1.38
0.77
0.98
1.19
1.91
2.62
1.04
1.48
1.94
8.31
4.48
4.93
7.18
5.99
8.82
9.95
8.30
9.07
8.50
0.12
0.15
0.09
0.00
0.11
0.22
0.32
0.09
0.00
0.22
0.14
0.07
0.05
0.00
0.06
0.07
0.06
0.00
0.00
0.11
0.05
0.01
0.02
0.00
0.05
0.09
0.20
0.00
0.00
0.00
220.9
142.0
111.8
159.9
166.0
187.9
113.4
151.7
172.3
175.5
152
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Hematology
Accession Animal
Number Number
Group
Sex
PLT
K/uL
MPV ABNEUT ABLYMP ABMONO ABEOS ABBAS ABSRET
fL
K/uL
K/uL
K/uL
K/uL
K/uL
109/L
3031542
3031543
3031544
3031545
3031546
3031547
3031548
3031549
3031550
3031551
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
1
1
1
1
1
1
1
1
1
1
F
F
F
F
F
F
F
F
F
F
803
595
563
830
630
957
628
355
521
776
7.80
7.70
8.60
9.80
8.50
9.40
9.00
13.00
10.70
9.10
0.71
0.71
1.67
0.82
0.65
1.63
0.71
0.28
0.68
2.20
5.68
3.24
6.26
3.67
5.51
8.19
4.52
3.58
3.04
1.54
0.13
0.08
0.22
0.12
0.12
0.18
0.08
0.12
0.04
0.04
0.06
0.04
1.39
0.05
0.05
0.26
0.05
0.04
0.04
0.08
0.05
0.01
0.06
0.02
0.02
0.06
0.02
0.00
0.00
0.00
176.9
238.4
150.2
223.3
148.2
374.9
269.9
157.2
187.1
180.3
3031567
3031568
3031569
3031570
3031571
3031572
3031573
3031574
3031575
3031576
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
2
2
2
2
2
2
2
2
2
2
F
F
F
F
F
F
F
F
F
F
721
668
680
678
598
669
678
620
394
755
7.60
8.50
8.30
9.10
8.80
10.00
8.50
10.50
16.40
9.80
1.03
1.50
1.37
1.26
0.62
1.22
1.14
0.29
0.43
0.81
6.03
3.93
4.04
3.41
4.29
4.90
3.76
2.68
3.81
5.26
0.14
0.15
0.09
0.10
0.11
0.18
0.20
0.96
0.08
0.12
0.08
0.08
0.03
0.07
0.15
0.09
0.08
0.13
0.02
0.04
0.04
0.03
0.05
0.04
0.01
0.04
0.03
0.00
0.01
0.02
127.8
193.2
230.2
201.3
152.9
215.2
170.9
145.8
199.6
195.9
3031587
3031588
3031589
3031590
3031591
3031592
3031593
3031594
3031595
3031596
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
3
3
3
3
3
3
3
3
3
3
F
F
F
F
F
F
F
F
F
F
708
771
614
845
776
643
766
686
758
624
7.80
8.20
7.50
7.80
8.00
8.80
8.60
11.30
10.60
8.90
0.95
1.05
0.98
0.78
0.40
1.16
0.77
1.62
0.52
0.56
7.61
4.86
3.65
5.96
3.13
7.04
4.64
3.89
4.09
5.91
0.20
0.09
0.20
0.12
0.04
0.00
0.08
0.17
0.10
0.11
0.05
0.06
0.08
0.05
0.07
0.08
0.05
0.11
0.05
0.04
0.07
0.01
0.01
0.07
0.00
0.00
0.02
0.00
0.00
0.03
234.7
181.1
190.1
178.6
196.2
205.3
216.9
161.0
169.8
165.9
3031612
3031613
3031614
3031615
3031616
3031617
3031618
3031619
3031620
3031621
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
4
4
4
4
4
4
4
4
4
4
F
F
F
F
F
F
F
F
F
F
626
805
670
637
842
751
665
820
749
521
8.10
9.20
8.40
8.30
7.30
9.20
9.40
10.20
9.10
9.10
1.31
1.15
0.38
0.78
1.12
1.04
0.83
0.97
1.05
0.89
5.71
4.48
3.27
4.46
7.22
5.15
4.10
4.32
4.85
4.49
0.17
0.16
0.08
0.08
0.20
0.18
0.10
0.11
0.15
0.11
0.17
0.07
0.04
0.04
0.04
0.06
0.06
0.00
0.09
0.05
0.02
0.02
0.00
0.01
0.04
0.04
0.02
0.00
0.04
0.02
190.1
169.9
211.6
177.4
186.3
277.1
231.2
186.5
159.0
199.3
153
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Coagulation
Accession
Number
Animal
Number
Group
Sex
APTT
SEC
PT
SEC
3031527
3031528
3031529
3031530
3031532
3031533
3031534
3031535
3031536
20271
20272
20273
20274
20276
20277
20278
20279
20280
1
1
1
1
1
1
1
1
1
M
M
M
M
M
M
M
M
M
36.30
67.90
23.80
46.60
23.40
33.90
22.20
16.70
27.60
14.80
14.30
14.80
14.30
14.30
14.70
13.50
14.40
14.90
3031558
3031559
3031560
3031561
3031562
3031563
3031564
3031565
3031566
20302
20303
20304
20305
20306
20307
20308
20309
20310
2
2
2
2
2
2
2
2
2
M
M
M
M
M
M
M
M
M
39.50
66.80
57.50
26.40
40.20
48.10
>120
26.10
16.20
14.00
14.20
14.40
14.20
13.50
14.50
>60
14.70
14.70
3031578
3031579
3031580
3031581
3031582
3031583
3031584
3031585
3031586
20322
20323
20324
20325
20326
20327
20328
20329
20330
3
3
3
3
3
3
3
3
3
M
M
M
M
M
M
M
M
M
29.20
44.10
28.30
40.00
36.90
41.70
23.00
25.20
65.50
15.10
15.20
14.60
15.10
14.70
14.70
14.60
14.60
16.40
3031598
3031599
3031600
3031601
3031602
3031603
3031605
3031606
20342
20343
20344
20345
20346
20347
20349
20350
4
4
4
4
4
4
4
4
M
M
M
M
M
M
M
M
63.20
35.40
20.30
39.60
34.20
19.50
26.20
>120
15.90
14.80
14.90
14.40
14.40
14.40
15.50
>60
154
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 91
Coagulation
Accession
Number
Animal
Number
Group
Sex
APTT
SEC
PT
SEC
3031542
3031543
3031545
3031546
3031547
3031548
3031551
20286
20287
20289
20290
20291
20292
20295
1
1
1
1
1
1
1
F
F
F
F
F
F
F
28.40
46.30
24.80
47.00
20.90
29.50
28.10
15.50
15.20
15.20
14.30
14.10
13.90
14.30
3031567
3031568
3031569
3031570
3031571
3031572
3031573
3031574
3031575
3031576
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
2
2
2
2
2
2
2
2
2
2
F
F
F
F
F
F
F
F
F
F
35.40
>120
15.80
56.20
29.50
46.20
>120
22.90
36.70
13.90
14.80
QNS
13.70
14.70
14.60
15.00
>60
15.50
15.90
14.30
3031589
3031590
3031591
3031592
3031593
3031594
3031595
3031596
20333
20334
20335
20336
20337
20338
20339
20340
3
3
3
3
3
3
3
3
F
F
F
F
F
F
F
F
46.70
14.00
18.50
40.40
15.10
29.00
25.60
18.20
15.10
14.40
14.60
14.10
14.10
14.90
14.90
15.60
3031612
3031614
3031615
3031616
3031617
3031619
3031620
20356
20358
20359
20360
20361
20363
20364
4
4
4
4
4
4
4
F
F
F
F
F
F
F
27.00
42.60
19.60
15.00
22.10
17.00
37.80
14.60
14.90
14.70
14.00
13.50
14.90
15.00
155
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 119
Clinical Chemistry
Accession Animal
Number Number
Group
Sex
GLU
mg/dL
BUN
mg/dL
CREA
mg/dL
NA
mmol/L
K
mmol/L
CL
mmol/L
CA
mg/dL
3033075
3033076
3033077
3033078
3033079
20281
20282
20283
20284
20285
1
1
1
1
1
M
M
M
M
M
117
110
109
100
101
21
23
20
21
18
0.6
0.8
0.6
0.9
0.8
150
151
150
150
152
6.9
6.5
7.0
7.0
7.0
104
105
106
102
104
10.7
10.8
11.4
11.5
11.3
3033085
3033086
3033087
3033088
3033089
20351
20352
20353
20354
20355
4
4
4
4
4
M
M
M
M
M
119
119
108
108
116
25
19
20
13
20
0.8
0.8
0.7
0.7
0.8
151
155
152
157
156
6.8
7.1
6.2
6.9
6.7
103
108
104
106
106
10.6
11.2
10.9
11.7
11.8
3033080
3033081
3033082
3033083
3033084
20296
20297
20298
20299
20300
1
1
1
1
1
F
F
F
F
F
95
104
90
82
90
22
20
18
23
15
0.7
0.8
0.8
0.9
1.0
149
153
153
153
158
6.0
6.3
6.5
6.6
8.0
102
104
103
106
106
10.9
11.1
11.5
11.1
11.9
3033090
3033091
3033092
3033093
3033094
20366
20367
20368
20369
20370
4
4
4
4
4
F
F
F
F
F
106
93
87
104
84
15
22
18
17
22
0.6
0.8
0.7
0.7
1.0
153
151
155
156
155
5.5
6.7
7.0
6.8
7.7
107
105
106
105
106
11.1
11.1
11.2
11.6
12.1
156
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 119
Clinical Chemistry
Accession Animal
Number
Number
Group
Sex
PHOS
mg/dL
CHOL
mg/dL
TRIG
mg/dL
TPROT
g/dL
ALB
g/dL
GLOB
g/dL
3033075
3033076
3033077
3033078
3033079
20281
20282
20283
20284
20285
1
1
1
1
1
M
M
M
M
M
6.0
6.8
11.0
8.1
8.8
91
58
87
99
71
65
44
63
108
47
6.7
6.6
6.5
7.3
6.8
3.9
3.5
3.7
4.0
3.7
2.8
3.1
2.8
3.3
3.1
3033085
3033086
3033087
3033088
3033089
20351
20352
20353
20354
20355
4
4
4
4
4
M
M
M
M
M
7.7
7.4
6.7
8.7
8.9
78
58
74
97
88
52
82
45
97
77
6.9
7.5
7.1
8.0
7.5
3.7
3.9
3.8
4.7
4.2
3.2
3.6
3.3
3.3
3.3
3033080
3033081
3033082
3033083
3033084
20296
20297
20298
20299
20300
1
1
1
1
1
F
F
F
F
F
7.2
6.0
7.2
8.1
9.8
74
119
118
80
117
34
53
45
53
42
7.1
8.0
8.2
7.4
9.1
4.2
4.5
5.1
4.2
5.5
2.9
3.5
3.1
3.2
3.6
3033090
3033091
3033092
3033093
3033094
20366
20367
20368
20369
20370
4
4
4
4
4
F
F
F
F
F
8.3
7.2
9.4
7.3
9.5
81
77
68
109
64
35
47
40
48
57
7.2
7.5
7.8
8.6
7.9
4.3
4.4
4.4
5.4
4.7
2.9
3.1
3.4
3.2
3.2
157
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 119
Clinical Chemistry
Accession
Number
Animal
Number
Group
Sex
A/G
AST
U/L
ALT
U/L
ALKP
U/L
TBILI
mg/dL
3033075
3033076
3033077
3033078
3033079
20281
20282
20283
20284
20285
1
1
1
1
1
M
M
M
M
M
1.4
1.1
1.3
1.2
1.2
91
80
79
66
69
87
51
60
50
51
114
86
87
122
77
0.2
<.1
0.2
0.2
0.2
3033085
3033086
3033087
3033088
3033089
20351
20352
20353
20354
20355
4
4
4
4
4
M
M
M
M
M
1.2
1.1
1.2
1.4
1.3
77
75
70
69
94
46
51
46
34
54
89
171
102
102
128
<.1
<.1
<.1
0.2
0.2
3033080
3033081
3033082
3033083
3033084
20296
20297
20298
20299
20300
1
1
1
1
1
F
F
F
F
F
1.5
1.3
1.7
1.3
1.5
68
83
68
73
80
50
39
38
39
25
53
64
36
56
49
0.2
0.3
0.3
0.2
0.3
3033090
3033091
3033092
3033093
3033094
20366
20367
20368
20369
20370
4
4
4
4
4
F
F
F
F
F
1.5
1.4
1.3
1.7
1.5
79
79
82
65
75
17
42
41
27
49
34
51
61
48
53
0.1
0.2
0.2
0.3
0.2
158
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 119
Hematology
Accession Animal
Number Number
Group
Sex
WBC
K/uL
RBC
M/uL
HGB
g/dL
HCT
%
MCV
fL
MCH
Pg
MCHC
g/dL
3033075
3033076
3033077
3033078
3033079
20281
20282
20283
20284
20285
1
1
1
1
1
M
M
M
M
M
6.62
8.02
8.40
7.94
9.11
9.50
8.87
9.54
10.51
8.64
17.0
16.3
17.0
17.6
16.4
52.9
50.3
52.6
55.9
48.2
55.6
56.7
55.1
53.2
55.8
17.8
18.3
17.8
16.8
19.0
32.1
32.4
32.4
31.5
34.1
3033085
3033086
3033087
3033088
3033089
20351
20352
20353
20354
20355
4
4
4
4
4
M
M
M
M
M
6.40
10.20
7.65
9.09
7.23
9.58
9.83
9.11
10.14
10.23
16.9
17.2
16.0
17.8
17.8
51.8
53.3
49.7
56.3
57.5
54.0
54.2
54.6
55.5
56.2
17.7
17.5
17.6
17.6
17.4
32.7
32.3
32.2
31.6
30.9
3033080
3033081
3033082
3033083
3033084
20296
20297
20298
20299
20300
1
1
1
1
1
F
F
F
F
F
4.90
5.31
4.21
6.54
5.99
8.92
9.14
8.88
9.04
8.78
16.9
16.7
16.6
16.8
16.8
52.1
52.5
50.8
51.7
52.9
58.5
57.4
57.3
57.2
60.2
19.0
18.3
18.7
18.6
19.1
32.5
31.8
32.7
32.5
31.7
3033090
3033091
3033092
3033093
3033094
20366
20367
20368
20369
20370
4
4
4
4
4
F
F
F
F
F
4.47
5.62
5.49
4.67
4.85
6.59
9.00
9.40
8.87
9.54
12.8
17.2
17.3
16.9
17.2
38.7
52.2
53.1
52.9
54.5
58.7
58.0
56.5
59.7
57.1
19.4
19.1
18.4
19.0
18.0
33.1
33.0
32.6
31.8
31.6
159
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 119
Hematology
Accession Animal
Number Number
Group
Sex
PLT
K/uL
MPV ABNEUT
fL
K/uL
ABLYMP ABMONO ABEOS ABBAS ABSRET
K/uL
K/uL
K/uL
K/uL
109/L
3033075
3033076
3033077
3033078
3033079
20281
20282
20283
20284
20285
1
1
1
1
1
M
M
M
M
M
649
637
683
671
812
7.80
7.80
8.60
7.80
7.20
1.53
1.12
1.38
1.20
1.79
4.73
6.47
6.61
6.34
6.84
0.13
0.16
0.21
0.19
0.25
0.15
0.15
0.12
0.09
0.12
0.03
0.05
0.04
0.05
0.04
202.6
177.6
171.4
205.0
183.4
3033085
3033086
3033087
3033088
3033089
20351
20352
20353
20354
20355
4
4
4
4
4
M
M
M
M
M
518
581
535
624
831
7.90
8.50
8.00
8.10
8.10
1.14
2.22
1.48
1.28
1.11
4.93
7.41
5.64
7.36
5.74
0.13
0.32
0.25
0.20
0.23
0.09
0.11
0.13
0.12
0.06
0.06
0.06
0.08
0.07
0.02
176.0
210.5
171.5
179.7
250.6
3033080
3033081
3033082
3033083
3033084
20296
20297
20298
20299
20300
1
1
1
1
1
F
F
F
F
F
505
539
646
664
703
8.40
8.60
8.00
7.50
8.80
0.60
1.29
0.54
0.87
0.91
4.12
3.56
3.46
5.37
4.86
0.09
0.17
0.12
0.11
0.11
0.03
0.22
0.03
0.09
0.04
0.02
0.02
0.01
0.04
0.01
165.3
188.5
141.5
180.3
265.6
3033090
3033091
3033092
3033093
3033094
20366
20367
20368
20369
20370
4
4
4
4
4
F
F
F
F
F
635
571
580
814
716
8.20
7.40
7.90
7.90
7.60
1.17
0.93
1.54
1.24
1.06
3.04
4.41
3.68
3.07
3.50
0.15
0.11
0.10
0.12
0.14
0.09
0.05
0.09
0.12
0.09
0.01
0.05
0.03
0.06
0.05
272.6
190.8
168.4
260.5
171.4
160
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Individual Animal Data
04370 DAY 119
Coagulation
Accession
Number
Animal
Number
Group
Sex
APTT
SEC
PT
SEC
3033075
3033076
3033077
3033078
3033079
20281
20282
20283
20284
20285
1
1
1
1
1
M
M
M
M
M
20.40
28.30
22.60
20.30
35.80
14.60
15.50
15.30
14.90
14.70
3033085
3033086
3033087
3033089
20351
20352
20353
20355
4
4
4
4
M
M
M
M
40.50
61.60
33.00
22.60
14.90
15.80
15.00
14.70
3033080
3033081
3033082
3033083
3033084
20296
20297
20298
20299
20300
1
1
1
1
1
F
F
F
F
F
31.70
19.40
42.40
29.00
34.80
14.10
14.70
14.90
15.20
15.00
3033091
3033092
3033093
3033094
20367
20368
20369
20370
4
4
4
4
F
F
F
F
29.80
26.80
21.80
21.60
15.60
15.80
14.90
15.80
161
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 10
Individual Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
162
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 10
Individual Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Group: 1
Dose: 0 mg/kg
Sex: Male
Animal
Number
Mode Of Death
Death
Day (Week)
20271
TERMINAL KILL
91
(13)
No Visible Lesions
20272
TERMINAL KILL
91
(13)
lymph node - mandibular; discoloration; red; bilateral; present
lymph node - mandibular; enlargement; bilateral
Any remaining protocol required tissues, which have been examined, have no visible lesions
20273
TERMINAL KILL
91
(13)
No Visible Lesions
20274
TERMINAL KILL
91
(13)
No Visible Lesions
20275
TERMINAL KILL
91
(13)
No Visible Lesions
20276
TERMINAL KILL
91
(13)
No Visible Lesions
20277
TERMINAL KILL
91
(13)
No Visible Lesions
20278
TERMINAL KILL
91
(13)
No Visible Lesions
20279
TERMINAL KILL
91
(13)
No Visible Lesions
20280
TERMINAL KILL
91
(13)
No Visible Lesions
20281
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20282
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20283
RECOVERY KILL
119
(17)
No Visible Lesions
20284
RECOVERY KILL
119
(17)
No Visible Lesions
20285
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
Observation(s)
163
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 10 (continued)
Individual Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Group: 2
Dose: 2 mg/kg
Sex: Male
Animal
Number
Mode Of Death
Death
Day (Week)
20301
TERMINAL KILL
91
(13)
No Visible Lesions
20302
TERMINAL KILL
91
(13)
thymus; discoloration; brown; bilateral; present
thymus; enlargement; bilateral
Any remaining protocol required tissues, which have been examined, have no visible lesions
20303
TERMINAL KILL
91
(13)
No Visible Lesions
20304
TERMINAL KILL
91
(13)
No Visible Lesions
20305
TERMINAL KILL
91
(13)
No Visible Lesions
20306
TERMINAL KILL
91
(13)
No Visible Lesions
20307
TERMINAL KILL
91
(13)
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20308
TERMINAL KILL
91
(13)
No Visible Lesions
20309
TERMINAL KILL
91
(13)
No Visible Lesions
20310
TERMINAL KILL
91
(13)
No Visible Lesions
Observation(s)
164
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 10 (continued)
Individual Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Group: 3
Dose: 20 mg/kg
Sex: Male
Animal
Number
Mode Of Death
Death
Day (Week)
20321
TERMINAL KILL
91
(13)
No Visible Lesions
20322
TERMINAL KILL
91
(13)
No Visible Lesions
20323
TERMINAL KILL
91
(13)
No Visible Lesions
20324
TERMINAL KILL
91
(13)
No Visible Lesions
20325
TERMINAL KILL
91
(13)
No Visible Lesions
20326
TERMINAL KILL
91
(13)
No Visible Lesions
20327
TERMINAL KILL
91
(13)
No Visible Lesions
20328
TERMINAL KILL
91
(13)
No Visible Lesions
20329
TERMINAL KILL
91
(13)
No Visible Lesions
20330
TERMINAL KILL
91
(13)
No Visible Lesions
Observation(s)
165
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 10 (continued)
Individual Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Group: 4
Dose: 200 mg/kg
Sex: Male
Animal
Number
Mode Of Death
Death
Day (Week)
20341
TERMINAL KILL
91
(13)
No Visible Lesions
20342
TERMINAL KILL
91
(13)
No Visible Lesions
20343
TERMINAL KILL
91
(13)
No Visible Lesions
20344
TERMINAL KILL
91
(13)
No Visible Lesions
20345
TERMINAL KILL
91
(13)
lymph node - mandibular; discoloration; dark; multiple; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20346
TERMINAL KILL
91
(13)
No Visible Lesions
20347
TERMINAL KILL
91
(13)
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20348
TERMINAL KILL
91
(13)
No Visible Lesions
20349
TERMINAL KILL
91
(13)
No Visible Lesions
20350
TERMINAL KILL
91
(13)
No Visible Lesions
20351
RECOVERY KILL
119
(17)
No Visible Lesions
20352
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20353
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20354
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20355
RECOVERY KILL
119
(17)
brain; meningeal; discoloration; red; localized; present
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
Observation(s)
166
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 10 (continued)
Individual Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Group: 1
Dose: 0 mg/kg
Sex: Female
Animal
Number
Mode Of Death
Death
Day (Week)
20286
TERMINAL KILL
91
(13)
No Visible Lesions
20287
TERMINAL KILL
91
(13)
No Visible Lesions
20288
TERMINAL KILL
91
(13)
No Visible Lesions
20289
TERMINAL KILL
91
(13)
No Visible Lesions
20290
TERMINAL KILL
91
(13)
No Visible Lesions
20291
TERMINAL KILL
91
(13)
liver; discoloration; mottled: papillary process - present
uterus; distention; left: clear fluid filled - present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20292
TERMINAL KILL
91
(13)
No Visible Lesions
20293
TERMINAL KILL
91
(13)
No Visible Lesions
20294
TERMINAL KILL
91
(13)
No Visible Lesions
20295
TERMINAL KILL
91
(13)
No Visible Lesions
20296
RECOVERY KILL
119
(17)
No Visible Lesions
20297
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral - present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20298
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20299
RECOVERY KILL
119
(17)
thymus; discoloration; red; right; present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20300
RECOVERY KILL
119
(17)
No Visible Lesions
Observation(s)
167
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 10 (continued)
Individual Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Group: 2
Dose: 2 mg/kg
Sex: Female
Animal
Number
Mode Of Death
Death
Day (Week)
20311
TERMINAL KILL
91
(13)
No Visible Lesions
20312
TERMINAL KILL
91
(13)
No Visible Lesions
20313
TERMINAL KILL
91
(13)
No Visible Lesions
20314
TERMINAL KILL
91
(13)
No Visible Lesions
20315
TERMINAL KILL
91
(13)
No Visible Lesions
20316
TERMINAL KILL
91
(13)
No Visible Lesions
20317
TERMINAL KILL
91
(13)
No Visible Lesions
20318
TERMINAL KILL
91
(13)
No Visible Lesions
20319
TERMINAL KILL
91
(13)
No Visible Lesions
20320
TERMINAL KILL
91
(13)
uterus; distention; bilateral: clear fluid filled, preset
Any remaining protocol required tissues, which have been examined, have no visible lesions
Observation(s)
168
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 10 (continued)
Individual Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Group: 3
Dose: 20 mg/kg
Sex: Female
Animal
Number
Mode Of Death
Death
Day (Week)
20331
TERMINAL KILL
91
(13)
No Visible Lesions
20332
TERMINAL KILL
91
(13)
No Visible Lesions
20333
TERMINAL KILL
91
(13)
No Visible Lesions
20334
TERMINAL KILL
91
(13)
No Visible Lesions
20335
TERMINAL KILL
91
(13)
No Visible Lesions
20336
TERMINAL KILL
91
(13)
No Visible Lesions
lymph node - mandibular; discoloration; red; bilateral - present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20337
TERMINAL KILL
91
(13)
uterus; distention; bilateral: clear fluid filled - present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20338
TERMINAL KILL
91
(13)
ovary; cyst; clear; left: clear fluid filled; 3x7x1mm, present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20339
TERMINAL KILL
91
(13)
No Visible Lesions
20340
TERMINAL KILL
91
(13)
No Visible Lesions
Observation(s)
169
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 10 (continued)
Individual Gross Pathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Group: 4
Dose: 200 mg/kg
Sex: Female
Animal
Number
Mode Of Death
Death
Day (Week)
20356
TERMINAL KILL
91
(13)
No Visible Lesions
20357
TERMINAL KILL
91
(13)
thymus; discoloration; brown; bilateral, present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20358
TERMINAL KILL
91
(13)
No Visible Lesions
20359
TERMINAL KILL
91
(13)
No Visible Lesions
20360
TERMINAL KILL
91
(13)
No Visible Lesions
20361
TERMINAL KILL
91
(13)
No Visible Lesions
20362
TERMINAL KILL
91
(13)
No Visible Lesions
20363
TERMINAL KILL
91
(13)
No Visible Lesions
20364
TERMINAL KILL
91
(13)
No Visible Lesions
20365
TERMINAL KILL
91
(13)
No Visible Lesions
20366
RECOVERY KILL
119
(17)
No Visible Lesions
20367
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral, present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20368
RECOVERY KILL
119
(17)
No Visible Lesions
20369
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral - present
Any remaining protocol required tissues, which have been examined, have no visible lesions
20370
RECOVERY KILL
119
(17)
lymph node - mandibular; discoloration; red; bilateral - present
Any remaining protocol required tissues, which have been examined, have no visible lesions
Observation(s)
170
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 11
Individual Terminal Body Weights and Absolute Organ Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
171
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 11
Individual Terminal Body Weights and Absolute Organ Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
TBW**
Adrenal
glands
Brain
Heart
Kidneys
Liver
1m
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
383.71
405.30
376.93
347.21
417.96
391.77
423.10
398.02
381.55
367.53
0.0850
0.0604
0.0678
0.0554
0.0657
0.0775
0.0678
0.0609
0.0504
0.0559
1.776
1.846
1.950
1.904
1.940
2.019
2.227
2.113
2.096
1.879
1.042
1.112
1.074
1.009
1.103
0.991
1.312
1.179
1.106
0.942
2.191
2.132
2.243
1.947
2.383
1.887
2.352
2.227
2.100
2.259
10.145
10.320
9.599
8.724
9.667
9.581
11.362
10.010
9.664
9.106
0.471
0.564
0.591
0.544
0.566
0.683
0.534
0.510
0.478
0.488
5.049
4.971
5.902
5.027
4.864
5.355
4.939
4.944
4.720
5.711
0.340
0.280
0.391
0.302
0.374
0.338
0.484
0.412
0.356
0.345
2m
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
420.30
475.39
373.64
400.46
424.84
435.41
385.07
374.34
390.71
404.87
0.0766
0.0473
0.0518
0.0768
0.0664
0.0865
0.0827
0.0599
0.0753
0.0948
2.015
1.958
1.915
1.975
1.895
1.776
1.957
2.067
1.783
2.002
1.121
1.100
0.967
1.215
1.161
1.216
1.072
1.040
1.018
1.041
2.455
2.315
2.007
2.435
2.520
2.348
2.274
2.073
2.027
2.701
11.849
10.794
9.174
10.874
10.382
11.242
10.400
8.897
9.682
10.267
0.480
0.562
0.531
0.565
0.482
0.543
0.583
0.540
0.632
0.719
4.761
4.845
5.140
5.382
4.948
5.492
4.838
4.918
5.455
6.010
0.425
0.810
0.436
0.309
0.388
0.526
0.473
0.329
0.456
0.399
m – Male
TBW – Terminal Body Weight
a - With epididymis
**Note – SD 90 TBW was used to determine ratio.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
172
Spleen
Testis
a
Thymus
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 11 (continued)
Individual Terminal Body Weights and Absolute Organ Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
TBW**
Adrenal
glands
Brain
Heart
Kidneys
3m
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
381.14
385.80
428.02
495.47
469.73
386.33
471.02
435.61
404.67
372.32
0.0546
0.0419
0.0553
0.0796
0.0695
0.0533
0.0583
0.0641
0.0615
0.0658
1.978
1.931
2.102
2.107
2.083
1.878
2.038
1.882
1.971
1.943
1.001
0.955
1.237
1.355
1.227
0.977
1.203
1.129
1.107
1.049
2.404
2.043
2.568
3.051
2.262
1.985
2.424
2.235
2.356
2.071
10.109
9.139
11.795
14.929
10.384
9.573
12.706
11.015
10.891
8.471
0.642
0.478
0.582
0.710
0.554
0.536
0.507
0.613
0.522
0.534
5.252
5.681
4.922
5.662
4.721
4.964
5.219
5.635
4.455
4.933
0.342
0.403
0.524
0.540
0.688
0.375
0.493
0.501
0.311
0.491
4m
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
430.02
503.20
396.92
438.16
419.09
375.34
374.34
405.70
425.03
402.79
0.0638
0.0682
0.0528
0.0626
0.0547
0.0549
0.0568
0.0566
0.0682
0.0625
1.949
2.009
1.896
1.938
2.096
1.967
1.961
1.925
2.049
2.053
1.091
1.199
1.145
1.119
1.255
1.003
1.059
1.012
1.182
1.061
2.627
2.503
2.334
2.514
2.417
1.988
2.060
2.349
2.576
2.143
11.568
12.941
9.877
12.002
12.148
9.199
10.784
9.827
11.931
9.725
0.617
0.629
0.567
0.516
0.749
0.488
0.662
0.570
0.679
0.583
4.938
5.426
4.878
4.889
5.376
5.369
5.021
5.338
5.503
5.551
0.409
0.449
0.423
0.320
0.428
0.276
0.344
0.524
0.455
0.659
m – Male
TBW – Terminal Body Weight
a - With epididymis
**Note – SD 90 TBW was used to determine ratio.
Nominal Dose: Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
173
Liver
Spleen
Testis
a
Thymus
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 11 (continued)
Individual Terminal Body Weights and Absolute Organ Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
TBW**
Adrenal
glands
Brain
Heart
Kidneys
Liver
Ovaries
1f
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
233.08
216.03
228.80
240.03
221.37
244.21
212.18
195.23
206.22
251.38
0.0847
0.0710
0.0697
0.0878
0.0732
0.0899
0.1119
0.0700
0.0885
0.0769
1.910
1.996
1.901
2.004
1.798
2.132
1.689
1.815
2.024
2.098
0.793
0.669
0.756
0.770
0.759
0.978
0.638
0.669
0.759
0.792
1.438
1.530
1.372
1.543
1.339
1.604
1.580
1.350
1.567
1.516
6.468
5.942
6.770
6.689
6.119
7.207
6.169
5.326
5.610
5.872
2f
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
216.43
217.51
218.75
221.37
233.90
209.12
203.37
220.39
230.09
204.15
0.0656
0.0748
0.0616
0.0638
0.0681
0.0600
0.0590
0.0770
0.0820
0.0637
1.902
1.820
1.596
1.802
1.985
1.873
1.719
1.789
1.854
1.873
0.759
0.691
0.780
0.792
0.788
0.660
0.641
0.722
0.745
0.724
1.395
1.357
1.436
1.421
1.508
1.339
1.413
1.357
1.556
1.294
5.427
6.274
7.031
6.454
5.978
5.330
6.156
5.594
5.769
5.160
f – Female
TBW – Terminal Body Weight
b – With cervix and vagina
**Note – SD 90 TBW was used to determine ratio.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
174
Spleen
Thymus
Uterus
0.126
0.168
0.173
0.187
0.127
0.190
0.149
0.140
0.154
0.160
0.512
0.434
0.482
0.413
0.456
0.509
0.496
0.335
0.414
0.460
0.442
0.263
0.298
0.425
0.268
0.409
0.240
0.261
0.342
0.443
0.974
1.157
0.759
0.912
0.747
1.294
1.338
0.811
1.346
1.212
0.161
0.128
0.098
0.194
0.144
0.183
0.063
0.145
0.156
0.148
0.439
0.354
0.438
0.395
0.503
0.350
0.320
0.389
0.485
0.410
0.286
0.304
0.300
0.337
0.353
0.328
0.177
0.363
0.275
0.317
0.416
0.875
1.120
0.660
0.508
0.767
0.726
0.790
0.775
1.368
b
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 11 (continued)
Individual Terminal Body Weights and Absolute Organ Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
TBW**
Adrenal
glands
Brain
Heart
Kidneys
Liver
Ovaries
3f
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
242.40
212.39
219.21
243.11
224.53
219.35
221.86
214.35
231.23
211.64
0.0903
0.0619
0.0604
0.0848
0.0675
0.0684
0.0833
0.0689
0.0713
0.0787
1.862
1.842
1.697
2.035
1.686
1.585
1.826
1.798
1.771
1.764
0.848
0.669
0.748
0.765
0.780
0.805
0.800
0.740
0.794
0.786
1.540
1.391
1.302
1.658
1.585
1.433
1.283
1.489
1.315
1.438
7.128
6.094
6.081
6.811
7.007
7.010
6.088
7.223
6.258
6.585
4f
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
257.18
237.90
252.59
242.23
217.34
256.60
231.68
211.33
226.94
220.17
0.0710
0.0738
0.0851
0.0622
0.0508
0.0827
0.0643
0.0674
0.0499
0.0552
1.683
1.961
2.060
1.784
1.920
1.875
1.717
1.823
1.939
1.797
0.799
0.785
0.788
0.728
0.736
0.854
0.710
0.728
0.755
0.736
1.362
1.610
1.705
1.577
1.432
1.718
1.413
1.427
1.415
1.417
7.763
6.752
6.796
6.758
6.155
7.878
5.571
5.506
6.195
5.743
f – Female
TBW – Terminal Body Weight
b – With cervix and vagina
**Note – SD 90 TBW was used to determine ratio.
Nominal Dose:
Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
175
Spleen
Thymus
Uterus
0.133
0.159
0.129
0.149
0.098
0.099
0.159
0.078
0.168
0.114
0.438
0.418
0.406
0.511
0.463
0.441
0.428
0.419
0.440
0.418
0.308
0.372
0.146
0.440
0.340
0.245
0.300
0.253
0.434
0.399
0.859
0.668
0.577
1.162
0.923
1.375
1.419
0.762
0.843
1.167
0.146
0.174
0.205
0.109
0.169
0.161
0.127
0.131
0.113
0.148
0.539
0.448
0.523
0.433
0.626
0.508
0.473
0.339
0.419
0.339
0.444
0.387
0.425
0.345
0.368
0.360
0.295
0.355
0.290
0.429
1.023
0.648
0.656
0.749
0.790
1.132
1.635
1.193
0.513
0.497
b
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 11 (continued)
Individual Terminal Body Weights and Absolute Organ Weights
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 119 Relative to Start Date
Group
Sex
Animal
Number
TBW**
Adrenal
glands
Brain
Heart
Kidneys
1m
20281
20282
20283
20284
20285
398.53
328.81
434.63
449.55
380.42
0.0551
0.0533
0.0594
0.0630
0.0553
2.051
1.954
2.020
2.106
1.895
1.140
0.975
1.212
1.273
1.186
2.415
2.078
2.684
2.422
2.299
10.861
8.355
9.995
11.515
8.675
0.579
0.605
0.493
0.601
0.667
5.236
5.304
4.583
4.958
4.897
0.272
0.307
0.322
0.373
0.264
4m
20351
20352
20353
20354
20355
408.13
420.57
369.28
381.24
441.96
0.0605
0.0508
0.0624
0.0476
0.0753
2.007
2.186
1.895
2.013
2.072
1.135
1.060
0.969
0.957
1.285
2.285
2.210
2.395
2.309
2.576
10.314
9.902
9.515
9.552
12.837
0.599
0.576
0.524
0.522
0.545
4.953
4.711
5.019
5.660
5.062
0.244
0.255
0.192
0.249
0.224
Group
Sex
Animal
Number
TBW
Adrenal
glands
Brain
Heart
Kidneys
Liver
Ovaries
1f
20296
20297
20298
20299
20300
225.43
232.51
216.48
253.07
237.10
0.0702
0.0892
0.0614
0.0631
0.0723
1.573
1.978
1.712
1.908
2.078
0.823
0.789
0.800
0.876
0.865
1.567
1.523
1.465
1.685
1.814
6.718
6.731
6.507
6.766
6.684
4f
20366
20367
20368
20369
20370
215.74
234.83
231.85
255.37
234.83
0.0647
0.0764
0.0848
0.0839
0.0622
1.753
1.857
2.028
1.892
1.931
0.754
0.716
0.770
0.968
0.752
1.589
1.515
1.583
1.830
1.661
5.883
6.035
6.222
7.592
6.245
m – Male
f – Female
TBW – Terminal Body Weight
**Note – SD 118 TBW was used to determine ratio.
Nominal Dose: Group 1 - 0 mg/kg
Group 4 - 200 mg/kg
Liver
a - With epididymis
176
Spleen
Testis
a
Thymus
Spleen
Thymus
0.159
0.153
0.128
0.180
0.178
0.524
0.489
0.404
0.523
0.476
0.208
0.368
0.237
0.410
0.274
0.852
0.895
0.885
0.812
1.156
0.087
0.212
0.151
0.149
0.143
0.465
0.544
0.400
0.515
0.455
0.235
0.270
0.298
0.341
0.365
0.875
0.813
0.766
1.123
0.799
b – With cervix and vagina
Uterus
b
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 12
Individual Organ-to-Body Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
177
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 12
Individual Organ-to-Body Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
Adrenal
glands
Brain
Heart
Kidneys
1m
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
0.0222
0.0149
0.0180
0.0160
0.0157
0.0198
0.0160
0.0153
0.0132
0.0152
0.4628
0.4555
0.4811
0.4698
0.4787
0.4981
0.5264
0.5309
0.5493
0.5113
0.2716
0.2744
0.2650
0.2490
0.2721
0.2445
0.3101
0.2962
0.2899
0.2563
0.5710
0.5260
0.5534
0.4804
0.5880
0.4656
0.5559
0.5595
0.5504
0.6146
2.6439
2.5463
2.3684
2.1525
2.3851
2.3639
2.6854
2.5149
2.5328
2.4776
2m
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
0.0182
0.0100
0.0139
0.0192
0.0156
0.0199
0.0215
0.0160
0.0193
0.0234
0.4794
0.4119
0.5125
0.4932
0.4461
0.4079
0.5082
0.5522
0.4563
0.4945
0.2667
0.2314
0.2588
0.3034
0.2733
0.2793
0.2784
0.2778
0.2606
0.2571
0.5841
0.4870
0.5371
0.6081
0.5932
0.5393
0.5905
0.5538
0.5188
0.6671
2.8192
2.2706
2.4553
2.7154
2.4437
2.5819
2.7008
2.3767
2.4781
2.5359
m – Male
Liver
a
Thymus
0.1227
0.1392
0.1458
0.1342
0.1396
0.1685
0.1262
0.1281
0.1253
0.1328
1.3158
1.2265
1.4562
1.2403
1.2001
1.3212
1.1673
1.2421
1.2371
1.5539
0.0886
0.0691
0.0965
0.0745
0.0923
0.0834
0.1144
0.1035
0.0933
0.0939
0.1142
0.1182
0.1421
0.1411
0.1135
0.1247
0.1514
0.1443
0.1618
0.1776
1.1328
1.0192
1.3757
1.3440
1.1647
1.2613
1.2564
1.3138
1.3962
1.4844
0.1011
0.1704
0.1167
0.0772
0.0913
0.1208
0.1228
0.0879
0.1167
0.0986
Spleen
Testis
a - With epididymis
Note: SD 90 body weight was used to calculate ratio since animals were fasted on SD 90-91.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
178
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 12 (continued)
Individual Organ-to-Body Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
Adrenal
glands
Brain
Heart
Kidneys
Liver
Spleen
Testis
a
Thymus
3m
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
0.0143
0.0109
0.0129
0.0161
0.0148
0.0138
0.0124
0.0147
0.0152
0.0177
0.5190
0.5005
0.4911
0.4253
0.4434
0.4861
0.4327
0.4320
0.4871
0.5219
0.2626
0.2475
0.2890
0.2735
0.2612
0.2529
0.2554
0.2592
0.2736
0.2817
0.6307
0.5295
0.6000
0.6158
0.4816
0.5138
0.5146
0.5131
0.5822
0.5562
2.6523
2.3688
2.7557
3.0131
2.2106
2.4779
2.6975
2.5286
2.6913
2.2752
0.1684
0.1239
0.1360
0.1433
0.1179
0.1387
0.1076
0.1407
0.1290
0.1434
1.3780
1.4725
1.1499
1.1428
1.0050
1.2849
1.1080
1.2936
1.1009
1.3249
0.0897
0.1045
0.1224
0.1090
0.1465
0.0971
0.1047
0.1150
0.0769
0.1319
4m
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
0.0148
0.0136
0.0133
0.0143
0.0131
0.0146
0.0152
0.0140
0.0160
0.0155
0.4532
0.3992
0.4777
0.4423
0.5001
0.5241
0.5239
0.4745
0.4821
0.5097
0.2537
0.2383
0.2885
0.2554
0.2995
0.2672
0.2829
0.2494
0.2781
0.2634
0.6109
0.4974
0.5880
0.5738
0.5767
0.5297
0.5503
0.5790
0.6061
0.5320
2.6901
2.5717
2.4884
2.7392
2.8987
2.4508
2.8808
2.4222
2.8071
2.4144
0.1435
0.1250
0.1428
0.1178
0.1787
0.1300
0.1768
0.1405
0.1598
0.1447
1.1483
1.0783
1.2290
1.1158
1.2828
1.4304
1.3413
1.3158
1.2947
1.3781
0.0951
0.0892
0.1066
0.0730
0.1021
0.0735
0.0919
0.1292
0.1071
0.1636
m – Male
a - With epididymis
Note: SD 90 body weight was used to calculate ratio since animals were fasted on SD 90-91.
Nominal Dose:
Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
179
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 12 (continued)
Individual Organ-to-Body Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
Adrenal
glands
1f
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
2f
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
f – Female
Brain
Heart
Kidneys
Liver
Ovaries
Spleen
0.0363
0.0329
0.0305
0.0366
0.0331
0.0368
0.0527
0.0359
0.0429
0.0306
0.8195
0.9239
0.8309
0.8349
0.8122
0.8730
0.7960
0.9297
0.9815
0.8346
0.3402
0.3097
0.3304
0.3208
0.3429
0.4005
0.3007
0.3427
0.3681
0.3151
0.6170
0.7082
0.5997
0.6428
0.6049
0.6568
0.7447
0.6915
0.7599
0.6031
2.7750
2.7505
2.9589
2.7867
2.7642
2.9511
2.9074
2.7281
2.7204
2.3359
0.0541
0.0778
0.0756
0.0779
0.0574
0.0778
0.0702
0.0717
0.0747
0.0636
0.2197
0.2009
0.2107
0.1721
0.2060
0.2084
0.2338
0.1716
0.2008
0.1830
0.1896
0.1217
0.1302
0.1771
0.1211
0.1675
0.1131
0.1337
0.1658
0.1762
0.4179
0.5356
0.3317
0.3800
0.3374
0.5299
0.6306
0.4154
0.6527
0.4821
0.0303
0.0344
0.0282
0.0288
0.0291
0.0287
0.0290
0.0349
0.0356
0.0312
0.8788
0.8367
0.7296
0.8140
0.8487
0.8957
0.8453
0.8117
0.8058
0.9175
0.3507
0.3177
0.3566
0.3578
0.3369
0.3156
0.3152
0.3276
0.3238
0.3546
0.6446
0.6239
0.6565
0.6419
0.6447
0.6403
0.6948
0.6157
0.6763
0.6338
2.5075
2.8845
3.2142
2.9155
2.5558
2.5488
3.0270
2.5382
2.5073
2.5276
0.0744
0.0588
0.0448
0.0876
0.0616
0.0875
0.0310
0.0658
0.0678
0.0725
0.2028
0.1628
0.2002
0.1784
0.2150
0.1674
0.1573
0.1765
0.2108
0.2008
0.1321
0.1398
0.1371
0.1522
0.1509
0.1568
0.0870
0.1647
0.1195
0.1553
0.1922
0.4023
0.5120
0.2981
0.2172
0.3668
0.3570
0.3585
0.3368
0.6701
b – With cervix and vagina
Note: SD 90 body weight was used to calculate ratio since animals were fasted on SD 90-91.
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
180
Thymus
Uterus
b
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 12 (continued)
Individual Organ-to-Body Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
Adrenal
glands
3f
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
0.0373
0.0291
0.0276
0.0349
0.0301
0.0312
0.0375
0.0321
0.0308
0.0372
0.7682
0.8673
0.7741
0.8371
0.7509
0.7226
0.8230
0.8388
0.7659
0.8335
0.3498
0.3150
0.3412
0.3147
0.3474
0.3670
0.3606
0.3452
0.3434
0.3714
0.6353
0.6549
0.5940
0.6820
0.7059
0.6533
0.5783
0.6947
0.5687
0.6795
2.9406
2.8692
2.7741
2.8016
3.1207
3.1958
2.7441
3.3697
2.7064
3.1114
0.0549
0.0749
0.0588
0.0613
0.0436
0.0451
0.0717
0.0364
0.0727
0.0539
0.1807
0.1968
0.1852
0.2102
0.2062
0.2010
0.1929
0.1955
0.1903
0.1975
0.1271
0.1751
0.0666
0.1810
0.1514
0.1117
0.1352
0.1180
0.1877
0.1885
0.3544
0.3145
0.2632
0.4780
0.4111
0.6269
0.6396
0.3555
0.3646
0.5514
4f
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
0.0276
0.0310
0.0337
0.0257
0.0234
0.0322
0.0278
0.0319
0.0220
0.0251
0.6544
0.8243
0.8156
0.7365
0.8834
0.7307
0.7411
0.8626
0.8544
0.8162
0.3107
0.3300
0.3120
0.3005
0.3386
0.3328
0.3065
0.3445
0.3327
0.3343
0.5296
0.6768
0.6750
0.6510
0.6589
0.6695
0.6099
0.6752
0.6235
0.6436
3.0185
2.8382
2.6905
2.7899
2.8320
3.0701
2.4046
2.6054
2.7298
2.6084
0.0568
0.0731
0.0812
0.0450
0.0778
0.0627
0.0548
0.0620
0.0498
0.0672
0.2096
0.1883
0.2071
0.1788
0.2880
0.1980
0.2042
0.1604
0.1846
0.1540
0.1726
0.1627
0.1683
0.1424
0.1693
0.1403
0.1273
0.1680
0.1278
0.1948
0.3978
0.2724
0.2597
0.3092
0.3635
0.4412
0.7057
0.5645
0.2261
0.2257
f – Female
Brain
Heart
Kidneys
Liver
Ovaries
Spleen
b – With cervix and vagina
Note: SD 90 body weight was used to calculate ratio since animals were fasted on SD 90-91.
Nominal Dose: Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
181
Thymus
Uterus
b
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 12 (continued)
Individual Organ-to-Body Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wister Rats with a 4-Week Recovery
Day: 119 Relative to Start Date
Group
Sex
Animal
Number
Adrenal
glands
Brain
Heart
Kidneys
Liver
Spleen
Testis
a
Thymus
1m
20281
20282
20283
20284
20285
0.0135
0.0159
0.0132
0.0135
0.0141
0.5033
0.5837
0.4486
0.4516
0.4840
0.2798
0.2912
0.2692
0.2730
0.3029
0.5927
0.6207
0.5960
0.5194
0.5872
2.6654
2.4957
2.2196
2.4692
2.2157
0.1421
0.1807
0.1095
0.1289
0.1704
1.2850
1.5843
1.0178
1.0632
1.2508
0.0668
0.0917
0.0715
0.0800
0.0674
4m
20351
20352
20353
20354
20355
0.0145
0.0118
0.0163
0.0118
0.0164
0.4803
0.5096
0.4956
0.4994
0.4503
0.2716
0.2471
0.2534
0.2374
0.2792
0.5468
0.5152
0.6263
0.5728
0.5598
2.4682
2.3084
2.4883
2.3697
2.7896
0.1433
0.1343
0.1370
0.1295
0.1184
1.1853
1.0983
1.3125
1.4042
1.1000
0.0584
0.0594
0.0502
0.0618
0.0487
Group
Sex
Animal
Number
Adrenal
glands
Brain
Heart
Kidneys
Liver
Ovaries
Spleen
Thymus
Uterus
b
1f
20296
20297
20298
20299
20300
0.0300
0.0369
0.0266
0.0238
0.0289
0.6713
0.8184
0.7411
0.7191
0.8293
0.3512
0.3265
0.3463
0.3302
0.3452
0.6687
0.6302
0.6341
0.6351
0.7239
2.8670
2.7851
2.8166
2.5501
2.6675
0.0679
0.0633
0.0554
0.0678
0.0710
0.2236
0.2023
0.1749
0.1971
0.1900
0.0888
0.1523
0.1026
0.1545
0.1094
0.3636
0.3703
0.3831
0.3060
0.4613
4f
20366
20367
20368
20369
20370
0.0286
0.0311
0.0345
0.0308
0.0253
0.7753
0.7549
0.8254
0.6954
0.7855
0.3335
0.2911
0.3134
0.3558
0.3059
0.7028
0.6159
0.6443
0.6726
0.6756
2.6019
2.4534
2.5324
2.7906
2.5403
0.0385
0.0862
0.0615
0.0548
0.0582
0.2057
0.2211
0.1628
0.1893
0.1851
0.1039
0.1098
0.1213
0.1253
0.1485
0.3870
0.3305
0.3118
0.4128
0.3250
m – Male
f – Female
a - With epididymis
b – With cervix and vagina
Note: SD 118 body weight was used to calculate ratio since animals were fasted on SD 118-119.
Nominal Dose: Group 1 - 0 mg/kg
Group 4 - 200 mg/kg
182
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 13
Individual Organ-to-Brain Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
183
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 13
Individual Organ-to-Brain Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
Brain
Adrenal
glands
Heart
Kidneys
Liver
Spleen
1m
20271
20272
20273
20274
20275
20276
20277
20278
20279
20280
1.776
1.846
1.950
1.904
1.940
2.019
2.227
2.113
2.096
1.879
0.0479
0.0327
0.0348
0.0291
0.0339
0.0384
0.0304
0.0288
0.0240
0.0297
0.5867
0.6024
0.5508
0.5299
0.5686
0.4908
0.5891
0.5580
0.5277
0.5013
1.2337
1.1549
1.1503
1.0226
1.2284
0.9346
1.0561
1.0540
1.0019
1.2022
5.7123
5.5905
4.9226
4.5819
4.9830
4.7454
5.1019
4.7373
4.6107
4.8462
2m
20301
20302
20303
20304
20305
20306
20307
20308
20309
20310
2.015
1.958
1.915
1.975
1.895
1.776
1.957
2.067
1.783
2.002
0.0380
0.0242
0.0270
0.0389
0.0350
0.0487
0.0423
0.0290
0.0422
0.0474
0.5563
0.5618
0.5050
0.6152
0.6127
0.6847
0.5478
0.5031
0.5709
0.5200
1.2184
1.1823
1.0480
1.2329
1.3298
1.3221
1.1620
1.0029
1.1368
1.3492
5.8804
5.5128
4.7906
5.5058
5.4786
6.3300
5.3143
4.3043
5.4302
5.1284
m – Male
a - With epididymis
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
184
a
Thymus
0.2652
0.3055
0.3031
0.2857
0.2918
0.3383
0.2398
0.2414
0.2281
0.2597
2.8429
2.6928
3.0267
2.6402
2.5072
2.6523
2.2178
2.3398
2.2519
3.0394
0.1914
0.1517
0.2005
0.1586
0.1928
0.1674
0.2173
0.1950
0.1698
0.1836
0.2382
0.2870
0.2773
0.2861
0.2544
0.3057
0.2979
0.2612
0.3545
0.3591
2.3628
2.4745
2.6841
2.7251
2.6111
3.0923
2.4722
2.3793
3.0595
3.0020
0.2109
0.4137
0.2277
0.1565
0.2047
0.2962
0.2417
0.1592
0.2557
0.1993
Testis
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 13 (continued)
Individual Organ-to-Brain Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
Brain
Adrenal
glands
Heart
Kidneys
Liver
Spleen
Testis
3m
20321
20322
20323
20324
20325
20326
20327
20328
20329
20330
1.978
1.931
2.102
2.107
2.083
1.878
2.038
1.882
1.971
1.943
0.0276
0.0217
0.0263
0.0378
0.0334
0.0284
0.0286
0.0341
0.0312
0.0339
0.5061
0.4946
0.5885
0.6431
0.5891
0.5202
0.5903
0.5999
0.5616
0.5399
1.2154
1.0580
1.2217
1.4480
1.0859
1.0570
1.1894
1.1876
1.1953
1.0659
5.1107
4.7328
5.6113
7.0854
4.9851
5.0974
6.2345
5.8528
5.5256
4.3598
0.3246
0.2475
0.2769
0.3370
0.2660
0.2854
0.2488
0.3257
0.2648
0.2748
2.6552
2.9420
2.3416
2.6872
2.2664
2.6432
2.5608
2.9942
2.2603
2.5389
0.1729
0.2087
0.2493
0.2563
0.3303
0.1997
0.2419
0.2662
0.1578
0.2527
4m
20341
20342
20343
20344
20345
20346
20347
20348
20349
20350
1.949
2.009
1.896
1.938
2.096
1.967
1.961
1.925
2.049
2.053
0.0327
0.0339
0.0278
0.0323
0.0261
0.0279
0.0290
0.0294
0.0333
0.0304
0.5598
0.5968
0.6039
0.5774
0.5988
0.5099
0.5400
0.5257
0.5769
0.5168
1.3479
1.2459
1.2310
1.2972
1.1531
1.0107
1.0505
1.2203
1.2572
1.0438
5.9354
6.4415
5.2094
6.1930
5.7958
4.6767
5.4992
5.1049
5.8228
4.7370
0.3166
0.3131
0.2991
0.2663
0.3573
0.2481
0.3376
0.2961
0.3314
0.2840
2.5336
2.7008
2.5728
2.5227
2.5649
2.7295
2.5604
2.7730
2.6857
2.7038
0.2099
0.2235
0.2231
0.1651
0.2042
0.1403
0.1754
0.2722
0.2221
0.3210
m – Male
a - With epididymis
Nominal Dose: Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
185
a
Thymus
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 13 (continued)
Individual Organ-to-Brain Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
Brain
Adrenal
glands
Heart
Kidneys
Liver
Ovaries
1f
20286
20287
20288
20289
20290
20291
20292
20293
20294
20295
1.910
1.996
1.901
2.004
1.798
2.132
1.689
1.815
2.024
2.098
0.0443
0.0356
0.0367
0.0438
0.0407
0.0422
0.0663
0.0386
0.0437
0.0367
0.4152
0.3352
0.3977
0.3842
0.4221
0.4587
0.3777
0.3686
0.3750
0.3775
0.7529
0.7665
0.7217
0.7700
0.7447
0.7523
0.9355
0.7438
0.7742
0.7226
3.3864
2.9770
3.5613
3.3378
3.4032
3.3804
3.6525
2.9344
2.7717
2.7989
0.06597
0.08417
0.09100
0.09331
0.07063
0.08912
0.08822
0.07713
0.07609
0.07626
2f
20311
20312
20313
20314
20315
20316
20317
20318
20319
20320
1.902
1.820
1.596
1.802
1.985
1.873
1.719
1.789
1.854
1.873
0.0345
0.0411
0.0386
0.0354
0.0343
0.0320
0.0343
0.0430
0.0442
0.0340
0.3991
0.3797
0.4887
0.4395
0.3970
0.3524
0.3729
0.4036
0.4018
0.3865
0.7334
0.7456
0.8997
0.7886
0.7597
0.7149
0.8220
0.7585
0.8393
0.6909
2.8533
3.4473
4.4054
3.5816
3.0116
2.8457
3.5812
3.1269
3.1117
2.7549
0.08465
0.07033
0.06140
0.10766
0.07254
0.09770
0.03665
0.08105
0.08414
0.07902
f – Female
b – With cervix and vagina
Nominal Dose: Group 1 - 0 mg/kg
Group 2 - 2 mg/kg
186
Thymus
Uterusb
0.2681
0.2174
0.2536
0.2061
0.2536
0.2387
0.2937
0.1846
0.2045
0.2193
0.2314
0.1318
0.1568
0.2121
0.1491
0.1918
0.1421
0.1438
0.1690
0.2112
0.5099
0.5797
0.3993
0.4551
0.4155
0.6069
0.7922
0.4468
0.6650
0.5777
0.2308
0.1945
0.2744
0.2192
0.2534
0.1869
0.1862
0.2174
0.2616
0.2189
0.1504
0.1670
0.1880
0.1870
0.1778
0.1751
0.1030
0.2029
0.1483
0.1692
0.2187
0.4808
0.7018
0.3663
0.2559
0.4095
0.4223
0.4416
0.4180
0.7304
Spleen
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 13 (continued)
Individual Organ-to-Brain Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 91 Relative to Start Date
Group
Sex
Animal
Number
Brain
Adrenal
glands
Heart
Kidneys
Liver
Ovaries
Spleen
Thymus
Uterusb
3f
20331
20332
20333
20334
20335
20336
20337
20338
20339
20340
1.862
1.842
1.697
2.035
1.686
1.585
1.826
1.798
1.771
1.764
0.0485
0.0336
0.0356
0.0417
0.0400
0.0432
0.0456
0.0383
0.0403
0.0446
0.4554
0.3632
0.4408
0.3759
0.4626
0.5079
0.4381
0.4116
0.4483
0.4456
0.8271
0.7552
0.7672
0.8147
0.9401
0.9041
0.7026
0.8281
0.7425
0.8152
3.8281
3.3084
3.5834
3.3469
4.1560
4.4227
3.3341
4.0172
3.5336
3.7330
0.07143
0.08632
0.07602
0.07322
0.05813
0.06246
0.08708
0.04338
0.09486
0.06463
0.2352
0.2269
0.2392
0.2511
0.2746
0.2782
0.2344
0.2330
0.2484
0.2370
0.1654
0.2020
0.0860
0.2162
0.2017
0.1546
0.1643
0.1407
0.2451
0.2262
0.4613
0.3626
0.3400
0.5710
0.5474
0.8675
0.7771
0.4238
0.4760
0.6616
4f
20356
20357
20358
20359
20360
20361
20362
20363
20364
20365
1.683
1.961
2.060
1.784
1.920
1.875
1.717
1.823
1.939
1.797
0.0422
0.0376
0.0413
0.0349
0.0265
0.0441
0.0374
0.0370
0.0257
0.0307
0.4747
0.4003
0.3825
0.4081
0.3833
0.4555
0.4135
0.3993
0.3894
0.4096
0.8093
0.8210
0.8277
0.8840
0.7458
0.9163
0.8229
0.7828
0.7298
0.7885
4.6126
3.4431
3.2990
3.7881
3.2057
4.2016
3.2446
3.0203
3.1949
3.1959
0.08675
0.08873
0.09951
0.06110
0.08802
0.08587
0.07397
0.07186
0.05828
0.08236
0.3203
0.2285
0.2539
0.2427
0.3260
0.2709
0.2755
0.1860
0.2161
0.1886
0.2638
0.1973
0.2063
0.1934
0.1917
0.1920
0.1718
0.1947
0.1496
0.2387
0.6078
0.3304
0.3184
0.4198
0.4115
0.6037
0.9522
0.6544
0.2646
0.2766
f – Female
b – With cervix and vagina
Nominal Dose: Group 3 - 20 mg/kg
Group 4 - 200 mg/kg
187
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 13 (continued)
Individual Organ-to-Brain Weight Ratios
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Day: 119 Relative to Start Date
Group
Sex
Animal
Number
Brain
Adrenal
glands
Heart
Kidneys
Liver
Spleen
1m
20281
20282
20283
20284
20285
2.051
1.954
2.020
2.106
1.895
0.0269
0.0273
0.0294
0.0299
0.0292
0.5558
0.4990
0.6000
0.6045
0.6259
1.1775
1.0635
1.3287
1.1500
1.2132
5.2955
4.2758
4.9480
5.4677
4.5778
4m
20351
20352
20353
20354
20355
2.007
2.186
1.895
2.013
2.072
0.0301
0.0232
0.0329
0.0236
0.0363
0.5655
0.4849
0.5113
0.4754
0.6202
1.1385
1.0110
1.2639
1.1470
1.2432
5.1390
4.5297
5.0211
4.7452
6.1955
Animal
Number
Brain
Adrenal
glands
Heart
Kidneys
Liver
Ovaries
Spleen
Thymus
Uterusb
1f
20296
20297
20298
20299
20300
1.573
1.978
1.712
1.908
2.078
0.0446
0.0451
0.0359
0.0331
0.0348
0.5232
0.3989
0.4673
0.4591
0.4163
0.9962
0.7700
0.8557
0.8831
0.8730
4.2708
3.4029
3.8008
3.5461
3.2166
0.10108
0.07735
0.07477
0.09434
0.08566
0.3331
0.2472
0.2360
0.2741
0.2291
0.1322
0.1860
0.1384
0.2149
0.1319
0.5416
0.4525
0.5169
0.4256
0.5563
4f
20366
20367
20368
20369
20370
1.753
1.857
2.028
1.892
1.931
0.0369
0.0411
0.0418
0.0443
0.0322
0.4301
0.3856
0.3797
0.5116
0.3894
0.9064
0.8158
0.7806
0.9672
0.8602
3.3560
3.2499
3.0680
4.0127
3.2341
0.04963
0.11416
0.07446
0.07875
0.07405
0.2653
0.2929
0.1972
0.2722
0.2356
0.1341
0.1454
0.1469
0.1802
0.1890
0.4991
0.4378
0.3777
0.5936
0.4138
Group
Sex
m – Male
f – Female
a - With epididymis
Nominal Dose: Group 1 - 0 mg/kg
a
Thymus
0.2823
0.3096
0.2441
0.2854
0.3520
2.5529
2.7144
2.2688
2.3542
2.5842
0.1326
0.1571
0.1594
0.1771
0.1393
0.2985
0.2635
0.2765
0.2593
0.2630
2.4679
2.1551
2.6485
2.8117
2.4431
0.1216
0.1167
0.1013
0.1237
0.1081
b – With cervix and vagina
Group 4 - 200 mg/kg
188
Testis
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 14
Histopathology Report
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
189
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
190
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
191
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
adrenal gland;
Examined..............................................
Within Normal Limits..................................
vacuolation; multifocal ..............................
minimal ............................................
(10)
7
(3)
3
(0)
0
(0)
0
(0)
0
(0)
0
(10)
5
(5)
5
(10)
9
(1)
1
(0)
0
(0)
0
(0)
0
(0)
0
(10)
10
(0)
0
brain;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
bone with marrow - femur;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
bone with marrow - sternum;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
(10)
10
0
(0)
0
0
(0)
0
0
(10)
10
0
(9)
9
1
(0)
0
0
(0)
0
0
(10)
10
0
cecum;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
colon;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
duodenum;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
epididymis;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(-)
-
(-)
-
(-)
-
(-)
-
-
= Not applicable
192
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
esophagus;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
eye;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
harderian gland;
Examined..............................................
Within Normal Limits..................................
infiltrate; mononuclear cell; focal ..................
minimal ............................................
(10)
10
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(10)
9
(1)
1
(10)
9
(1)
1
(0)
0
(0)
0
(0)
0
(0)
0
(10)
9
(1)
1
heart;
Examined..............................................
Within Normal Limits..................................
hemorrhage; acute; myocardial; locally extensive .....
minimal ............................................
(10)
9
(1)
1
(0)
0
(0)
0
(0)
0
(0)
0
(10)
10
(0)
0
(10)
10
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(10)
10
(0)
0
ileum;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
jejunum;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
193
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
kidney;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
infiltrate; mononuclear cell; cortical; focal ........
minimal ............................................
infiltrate; mononuclear cell; medullary; focal .......
minimal ............................................
infiltrate; mononuclear cell; mucosal; focal .........
minimal ............................................
infiltrate; mononuclear cell; mucosal; multifocal.....
minimal ............................................
inflammation; subacute; mucosal; unilateral; multifocal
mild ...............................................
mineralization; multifocal ...........................
minimal ............................................
regeneration; tubular; multifocal ....................
minimal ............................................
dilation; pelvic; unilateral .........................
present, no grade assigned .........................
(10)
0
0
(1)
1
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(9)
9
(0)
0
(10)
1
0
(0)
0
(1)
1
(0)
0
(0)
0
(0)
0
(2)
2
(9)
9
(0)
0
194
(10)
0
0
(1)
1
(0)
0
(0)
0
(0)
0
(0)
0
(4)
4
(10)
10
(1)
1
(10)
0
0
(3)
3
(1)
1
(1)
1
(0)
0
(1)
1
(3)
3
(10)
10
(0)
0
(10)
0
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(5)
5
(10)
10
(0)
0
(10)
0
0
(0)
0
(1)
1
(0)
0
(0)
0
(0)
0
(6)
6
(10)
10
(0)
0
(9)
0
1
(1)
1
(0)
0
(0)
0
(1)
1
(0)
0
(3)
3
(9)
9
(0)
0
(10)
0
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(8)
8
(10)
10
(0)
0
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
liver;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
infiltrate; mononuclear cell; multifocal .............
minimal ............................................
inflammation; granulomatous; focal ...................
minimal ............................................
vacuolation; hepatocellular; multifocal ..............
minimal ............................................
(10)
1
0
(9)
9
(0)
0
(0)
0
(10)
2
0
(8)
8
(0)
0
(0)
0
(10)
2
0
(8)
8
(0)
0
(0)
0
(10)
1
0
(9)
9
(0)
0
(1)
1
(10)
2
0
(8)
8
(0)
0
(0)
0
(10)
0
0
(10)
10
(0)
0
(0)
0
(9)
1
1
(8)
8
(0)
0
(0)
0
(10)
1
0
(9)
9
(1)
1
(0)
0
lung;
Examined..............................................
Within Normal Limits..................................
hemorrhage; acute; multifocal ........................
minimal ............................................
granuloma; multifocal ................................
minimal ............................................
histiocytosis; multifocal ............................
minimal ............................................
(10)
8
(1)
1
(1)
1
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(10)
9
(1)
1
(0)
0
(0)
0
(10)
10
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(10)
7
(2)
2
(0)
0
(1)
1
mandibular salivary gland;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
195
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
mammary gland;
Examined..............................................
Within Normal Limits..................................
(-)
-
(-)
-
(-)
-
(-)
-
(10)
10
(0)
0
(0)
0
(10)
10
lymph node - mandibular;
Examined..............................................
Within Normal Limits..................................
hemorrhage; acute; multifocal ........................
minimal ............................................
mild ...............................................
moderate ...........................................
(10)
2
(8)
4
4
0
(1)
0
(1)
0
0
1
(0)
0
(0)
0
0
0
(10)
3
(7)
3
3
1
(10)
3
(7)
6
1
0
(0)
0
(0)
0
0
0
(1)
0
(1)
0
1
0
(10)
4
(6)
3
3
0
lymph node - mesenteric;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
- = Not applicable
196
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
optic nerve;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
(9)
9
1
(0)
0
0
(0)
0
0
(10)
10
0
(9)
9
1
(0)
0
0
(0)
0
0
(10)
10
0
ovary;
Examined..............................................
Within Normal Limits..................................
(-)
-
(-)
-
(-)
-
(-)
-
(10)
10
(0)
0
(1)
1
(10)
10
pancreas;
Examined..............................................
Within Normal Limits..................................
infiltrate; mononuclear cell; perivascular; focal.....
minimal ............................................
(10)
10
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(10)
9
(1)
1
(10)
10
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(10)
10
(0)
0
parathyroid gland;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
(10)
10
0
(0)
0
0
(0)
0
0
(10)
10
0
(9)
9
1
(0)
0
0
(0)
0
0
(9)
9
1
pituitary;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
(9)
9
1
(0)
0
0
(0)
0
0
(9)
9
1
(9)
9
1
(0)
0
0
(0)
0
0
(7)
7
3
- = Not applicable
197
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
nerve - sciatic;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
(10)
10
0
(0)
0
0
(0)
0
0
(10)
10
0
(10)
10
0
(0)
0
0
(0)
0
0
(9)
9
1
seminal vesicle;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(-)
-
(-)
-
(-)
-
(-)
-
skeletal muscle;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
skin;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
spinal cord;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
- = Not applicable
198
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
spleen;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
(10)
10
0
(10)
10
0
(10)
10
0
(10)
10
0
(10)
10
0
(10)
10
0
(9)
9
1
(10)
10
0
stomach;
Examined..............................................
Within Normal Limits..................................
inflammation; subacute; multifocal ...................
minimal ............................................
(10)
10
(0)
0
(10)
9
(1)
1
(10)
10
(0)
0
(10)
10
(0)
0
(10)
10
(0)
0
(10)
10
(0)
0
(10)
10
(0)
0
(10)
10
(0)
0
testis;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(-)
-
(-)
-
(-)
-
(-)
-
thymus;
Examined..............................................
Within Normal Limits..................................
hemorrhage; acute; multifocal ........................
minimal ............................................
hemorrhage; subacute; multifocal .....................
minimal ............................................
(10)
7
(3)
3
(0)
0
(1)
1
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(10)
5
(5)
5
(0)
0
(10)
7
(3)
3
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(10)
3
(6)
6
(1)
1
thyroid gland;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
- = Not applicable
199
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
Sex:
Dose:
Unit:
Number of Animals:
trachea;
Examined..............................................
Within Normal Limits..................................
------------ MALES ------------ ----------- FEMALES ----------0
2
20
200
0
2
20
200
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
10
10
10
10
10
10
10
10
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
urinary bladder;
Examined..............................................
(7)
Within Normal Limits..................................
5
Not Examined: NOT PRESENT ............................
3
Not Examined: Unsatisfactory Section, Precludes Evaluation 0
infiltrate; mononuclear cell; mucosal; multifocal.....
(2)
minimal ............................................
2
(0)
0
0
0
(0)
0
(0)
0
0
0
(0)
0
(10)
10
0
0
(0)
0
(9)
9
0
1
(0)
0
(0)
0
0
0
(0)
0
(0)
0
0
0
(0)
0
(10)
10
0
0
(0)
0
uterus;
Examined..............................................
Within Normal Limits..................................
dilation; luminal; bilateral; diffuse ................
present, no grade assigned .........................
dilation; luminal; unilateral; diffuse ...............
present, no grade assigned .........................
(-)
(-)
(-)
-
(-)
(-)
(-)
-
(-)
(-)
(-)
-
(10)
9
(0)
0
(1)
1
(1)
0
(0)
0
(1)
1
(1)
0
(1)
1
(0)
0
(10)
8
(0)
0
(2)
2
(-)
(-)
(-)
-
- = Not applicable
200
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
aorta;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
cervix;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
(-)
-
(-)
-
(-)
-
(-)
-
(9)
9
1
(0)
0
0
(0)
0
0
(10)
10
0
lacrimal glands;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
infiltrate; mononuclear cell; multifocal .............
minimal ............................................
(10)
10
0
(0)
0
(0)
0
0
(0)
0
(0)
0
0
(0)
0
(10)
9
0
(1)
1
(10)
10
0
(0)
0
(0)
0
0
(0)
0
(0)
0
0
(0)
0
(9)
9
1
(0)
0
prostate;
Examined..............................................
Within Normal Limits..................................
infiltrate; mononuclear cell; multifocal .............
minimal ............................................
infiltrate; neutrophilic; luminal; focal .............
minimal ............................................
(10)
8
(2)
2
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(0)
0
(10)
8
(1)
1
(1)
1
(-)
(-)
(-)
-
(-)
(-)
(-)
-
(-)
(-)
(-)
-
(-)
(-)
(-)
-
- = Not applicable
201
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Terminal Sac (SD 91)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
------------ MALES ------------ ----------- FEMALES ----------Dose:
0
2
20
200
0
2
20
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
10
10
10
10
10
10
10
10
rectum;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
(10)
10
0
(0)
0
0
(0)
0
0
(10)
10
0
(10)
10
0
(0)
0
0
(0)
0
0
(9)
9
1
tongue;
Examined..............................................
Within Normal Limits..................................
(10)
10
(0)
0
(0)
0
(10)
10
(10)
10
(0)
0
(0)
0
(10)
10
peyers patch;
Examined..............................................
Within Normal Limits..................................
Not Examined: NOT PRESENT ............................
(9)
9
1
(0)
0
0
(0)
0
0
(10)
10
0
(7)
7
3
(0)
0
0
(0)
0
0
(10)
10
0
vagina;
Examined..............................................
Within Normal Limits..................................
(-)
-
(-)
-
(-)
-
(-)
-
(10)
10
(0)
0
(0)
0
(10)
10
- = Not applicable
202
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Table 1
Summary of Histopathology Observations- Recovery Sac (SD 119)
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Sex:
---- MALES ---- ---- FEMALES ---Dose:
0
200
0
200
Unit:
mg/kg
mg/kg
mg/kg
mg/kg
Number of Animals:
5
5
5
5
kidney;
Examined.........................................................
Within Normal Limits.............................................
infiltrate; mononuclear cell; cortical; focal ...................
minimal .......................................................
infiltrate; mononuclear cell; mucosal; focal ....................
minimal .......................................................
infiltrate; mononuclear cell; mucosal; multifocal ...............
minimal .......................................................
inflammation; subacute; mucosal; unilateral; multifocal .........
minimal .......................................................
mineralization; multifocal ......................................
minimal .......................................................
regeneration; tubular; multifocal ...............................
minimal .......................................................
(5)
0
(0)
0
(1)
1
(0)
0
(1)
1
(3)
3
(5)
5
(5)
0
(1)
1
(0)
0
(1)
1
(0)
0
(3)
3
(5)
5
(5)
0
(1)
1
(0)
0
(0)
0
(0)
0
(4)
4
(5)
5
(5)
0
(0)
0
(0)
0
(0)
0
(0)
0
(3)
3
(5)
5
liver;
Examined.........................................................
Within Normal Limits.............................................
infiltrate; mononuclear cell; multifocal ........................
minimal .......................................................
vacuolation; hepatocellular; multifocal .........................
minimal .......................................................
(5)
0
(5)
5
(0)
0
(5)
1
(4)
4
(1)
1
(5)
0
(5)
5
(0)
0
(5)
0
(5)
5
(0)
0
spleen;
Examined.........................................................
Within Normal Limits.............................................
(5)
5
(5)
5
(5)
5
(5)
5
stomach;
Examined.........................................................
Within Normal Limits.............................................
(5)
5
(5)
5
(5)
5
(5)
5
203
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20271
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lung;
granuloma; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; mild
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
epididymis
esophagus
ileum
jejunum
mandibular salivary gland
parathyroid gland
pituitary
nerve - sciatic
seminal vesicle
spleen
stomach
testis
thymus
aorta
lacrimal glands
prostate
rectum
The following tissues have not been examined:
—————————————————————————————————————————————
optic nerve; NOT PRESENT
204
bone with marrow - sternum
eye
harderian gland
lymph node - mesenteric
skeletal muscle
skin
thyroid gland
trachea
tongue
peyers patch
cecum
heart
pancreas
spinal cord
urinary bladder
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20272
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lung;
hemorrhage; acute; multifocal; minimal
lymph node - mandibular; discoloration; red; bilateral
hemorrhage; acute; multifocal; mild .
lymph node - mandibular; enlargement; bilateral
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
epididymis
esophagus
ileum
jejunum
mandibular salivary gland
pancreas
parathyroid gland
nerve - sciatic
seminal vesicle
spleen
stomach
testis
thymus
lacrimal glands prostate
rectum
tongue
The following tissues have not been examined:
—————————————————————————————————————————————
pituitary; NOT PRESENT
urinary bladder; NOT PRESENT
205
bone with marrow - sternum
eye
harderian gland
lymph node - mesenteric
skeletal muscle
skin
thyroid gland
trachea
peyers patch
cecum
heart
optic nerve
spinal cord
aorta
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20273
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
adrenal gland;
vacuolation; multifocal; minimal
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; mild
The following tissues were within normal limits:
————————————————————————————————————————————————
brain
bone with marrow - femur
duodenum
epididymis
esophagus
jejunum
lung
mandibular salivary
pancreas
parathyroid gland
pituitary
spinal cord
spleen
stomach
urinary bladder
aorta
lacrimal glands
bone with marrow - sternum
cecum
eye
harderian gland
heart
gland
lymph node - mesenteric
nerve - sciatic
seminal vesicle
skeletal muscle
testis
thymus
thyroid gland
prostate
rectum
tongue
206
colon
ileum
optic nerve
skin
trachea
peyers patch
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20274
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
epididymis
esophagus
ileum
jejunum
liver
lung
optic nerve
pancreas
parathyroid gland
pituitary
skin
spinal cord
spleen
stomach
urinary bladder
aorta
lacrimal glands
prostate
207
bone with marrow - sternum
cecum
eye
harderian gland
heart
mandibular salivary gland
lymph node - mesenteric
nerve - sciatic
seminal vesicle
skeletal muscle
testis
thyroid gland
trachea
rectum
tongue
peyers patch
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20275
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
adrenal gland;
vacuolation; multifocal; minimal
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
brain
bone with marrow - femur
bone with marrow - sternum
cecum
duodenum
epididymis
esophagus
eye
harderian gland
heart
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
pancreas
parathyroid gland
pituitary
nerve - sciatic
seminal vesicle
skeletal muscle
spinal cord
spleen
stomach
testis
thyroid gland
trachea
lacrimal glands
prostate
rectum
tongue
peyers patch
The following tissues have not been examined:
—————————————————————————————————————————————
urinary bladder; NOT PRESENT
208
colon
ileum
optic nerve
skin
aorta
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20276
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
heart;
hemorrhage; acute; locally extensive; minimal; myocardial
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
epididymis
esophagus
jejunum
lung
mandibular salivary gland
pancreas
parathyroid gland
pituitary
nerve - sciatic
spinal cord
spleen
stomach
testis
aorta
lacrimal glands
prostate
rectum
The following tissues have not been examined:
—————————————————————————————————————————————
urinary bladder; NOT PRESENT
209
bone with marrow - sternum
eye
harderian gland
lymph node - mesenteric
seminal vesicle
skeletal muscle
thymus
thyroid gland
tongue
peyers patch
cecum
ileum
optic nerve
skin
trachea
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20277
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
adrenal gland;
vacuolation; multifocal; minimal
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
urinary bladder;
infiltrate; mononuclear cell; multifocal; minimal; mucosal
prostate;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
brain
bone with marrow - femur
duodenum
epididymis
esophagus
jejunum
lung
mandibular salivary
optic nerve
pancreas
parathyroid gland
skin
spinal cord
spleen
trachea
aorta
lacrimal glands
bone with marrow - sternum
cecum
colon
eye
harderian gland
heart
ileum
gland
lymph node - mandibular
lymph node - mesenteric
pituitary
nerve - sciatic
seminal vesicle
skeletal muscle
stomach
testis
thymus
thyroid gland
rectum
tongue
peyers patch
210
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20278
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
urinary bladder;
infiltrate; mononuclear cell; multifocal; minimal; mucosal
prostate;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
bone with marrow - sternum
cecum
colon
duodenum
epididymis
esophagus
eye
harderian gland
heart
ileum
jejunum
lung
mandibular salivary gland
lymph node - mandibular
lymph node - mesenteric
optic nerve
pancreas
parathyroid gland
pituitary
nerve - sciatic
seminal vesicle
skeletal muscle
skin
spinal cord
spleen
stomach
testis
thymus
thyroid gland
trachea
aorta
lacrimal glands
rectum
tongue
The following tissues have not been examined:
—————————————————————————————————————————————
peyers patch; NOT PRESENT
211
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20279
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
infiltrate; mononuclear cell; focal; minimal; cortical
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; mild
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
bone with marrow - sternum
cecum
colon
duodenum
epididymis
esophagus
eye
harderian gland
heart
ileum
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
optic nerve
pancreas
parathyroid gland
pituitary
nerve - sciatic
seminal vesicle
skeletal muscle
skin
spinal cord
spleen
stomach
testis
thymus
thyroid gland
trachea
urinary bladder
aorta
lacrimal glands
prostate
rectum
tongue
peyers patch
212
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20280
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
bone with marrow - sternum
cecum
colon
duodenum
epididymis
esophagus
eye
harderian gland
heart
ileum
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
pancreas
parathyroid gland pituitary
nerve - sciatic
seminal vesicle
skeletal muscle
skin
spinal cord
spleen
stomach
testis
thyroid gland
trachea
urinary bladder
aorta
lacrimal glands
prostate
rectum
tongue
peyers patch
optic nerve
The following tissues have not been examined:
—————————————————————————————————————————————
213
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20281
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
infiltrate; mononuclear cell; focal; minimal; mucosal
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
214
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20282
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
inflammation; subacute; multifocal; minimal; unilateral; mucosal
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
215
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20283
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
216
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20284
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
217
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20285
Group: 1
Sex: Male
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
218
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20286
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
optic nerve
ovary
nerve - sciatic
skeletal muscle
skin
spinal cord
thyroid gland
trachea
urinary bladder
uterus
rectum
tongue
vagina
peyers patch
The following tissues have not been examined:
—————————————————————————————————————————————
219
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mandibular
pancreas
parathyroid gland
pituitary
spleen
stomach
thymus
aorta
cervix
lacrimal glands
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20287
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
optic nerve
ovary
pancreas
parathyroid gland
skin
spinal cord
spleen
stomach
urinary bladder
uterus
aorta
cervix
peyers patch
vagina
220
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mesenteric
pituitary
nerve - sciatic
skeletal muscle
thymus
thyroid gland
trachea
lacrimal glands
rectum
tongue
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20288
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
ovary
pancreas
pituitary
nerve - sciatic
spleen
stomach
thymus
thyroid gland
aorta
cervix
lacrimal glands
rectum
The following tissues have not been examined:
—————————————————————————————————————————————
optic nerve; NOT PRESENT
parathyroid gland; NOT PRESENT
221
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mesenteric
skeletal muscle
skin
spinal cord
trachea
urinary bladder
uterus
tongue
peyers patch
vagina
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20289
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
liver
lung
mandibular salivary gland
optic nerve
ovary
pancreas
parathyroid gland
skin
spinal cord
spleen
stomach
urinary bladder
uterus
aorta
cervix
vagina
The following tissues have not been examined:
—————————————————————————————————————————————
222
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mesenteric
pituitary
nerve - sciatic
skeletal muscle
thymus
thyroid gland
trachea
lacrimal glands
tongue
peyers patch
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20290
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
harderian gland;
infiltrate; mononuclear cell; focal; minimal
kidney;
regeneration; tubular; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; mild
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
liver
lung
mandibular salivary gland
optic nerve
ovary
pancreas
parathyroid gland
skin
spinal cord
spleen
stomach
uterus
aorta
cervix
lacrimal glands
mammary gland
The following tissues have not been examined:
—————————————————————————————————————————————
urinary bladder; UNSATISFACTORY SECTION, PRECLUDES EVALUATION
223
bone with marrow - sternum
cecum
heart
ileum
jejunum
mammary gland
lymph node - mesenteric
pituitary
nerve - sciatic
skeletal muscle
thymus
thyroid gland
trachea
tongue
vagina
peyers patch
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20291
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
No Microscopic evidence of Macroscopic Observation
infiltrate; mononuclear cell; multifocal; minimal
uterus; uterus; distention; left; present,
dilation; diffuse; present,; unilateral; luminal .........
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
optic nerve
ovary
pancreas
parathyroid gland
skin
spinal cord
spleen
stomach
urinary bladder
aorta
cervix
lacrimal glands
mammary gland
The following tissues have not been examined:
—————————————————————————————————————————————
peyers patch; NOT PRESENT
224
bone with marrow - sternum
cecum
harderian gland
heart
ileum
lymph node - mandibular
lymph node - mesenteric
pituitary
nerve - sciatic
skeletal muscle
thymus
thyroid gland
trachea
rectum
tongue
vagina
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20292
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
adrenal gland;
vacuolation; multifocal; minimal
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
brain
bone with marrow - femur
duodenum
esophagus
eye
lung
mandibular salivary gland
ovary
pancreas
parathyroid gland
spinal cord
spleen
stomach
aorta
lacrimal glands
rectum
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mesenteric
pituitary
nerve - sciatic
skeletal muscle
thyroid gland
trachea
urinary bladder
tongue
peyers patch
vagina
The following tissues have not been examined:
—————————————————————————————————————————————
cervix; NOT PRESENT
225
colon
jejunum
optic nerve
skin
uterus
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20293
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
optic nerve
ovary
pancreas
parathyroid gland
skin
spinal cord
spleen
stomach
urinary bladder
uterus
aorta
cervix
vagina
rectum
The following tissues have not been examined:
—————————————————————————————————————————————
226
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mesenteric
pituitary
nerve - sciatic
skeletal muscle
thymus
thyroid gland
trachea
lacrimal glands
tongue
peyers patch
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20294
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
optic nerve
ovary
skeletal muscle
skin
spinal cord
spleen
urinary bladder
uterus
aorta
cervix
vagina
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mandibular
pancreas
parathyroid gland
nerve - sciatic
stomach
thyroid gland
trachea
lacrimal glands
rectum
tongue
The following tissues have not been examined:
—————————————————————————————————————————————
pituitary; NOT PRESENT
peyers patch; NOT PRESENT
227
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20295
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
cecum
esophagus
eye
harderian gland
heart
ileum
mandibular salivary gland
mammary gland
lymph node - mesenteric
pancreas
parathyroid gland
pituitary
skeletal muscle
skin
stomach
thyroid gland
trachea
urinary bladder
uterus
lacrimal glands
rectum
tongue
vagina
nerve - sciatic
The following tissues have not been examined:
—————————————————————————————————————————————
bone with marrow - sternum; NOT PRESENT
peyers patch; NOT PRESENT
228
colon
jejunum
optic nerve
spinal cord
aorta
duodenum
lung
ovary
spleen
cervix
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20296
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
infiltrate; mononuclear cell; focal; minimal; cortical
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
229
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20297
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
230
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20298
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
231
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20299
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
232
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20300
Group: 1
Sex: Female
Species:Rat
Strain: Wistar
Test Material: corn oil
Dose: 0 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
233
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20301
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
stomach;
inflammation; subacute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
kidney
liver
spleen
234
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20302
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
thymus;
No Microscopic evidence of Macroscopic Observation
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
thymus
235
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20303
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
236
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20304
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
infiltrate; mononuclear cell; focal; minimal; medullary
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
237
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20305
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
liver
spleen
stomach
238
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20306
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
239
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20307
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular; discoloration; red; bilateral; present, no grade
hemorrhage; acute; multifocal; moderate ....................................
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
240
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20308
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
241
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20309
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
242
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20310
Group: 2
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
243
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20311
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
244
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20312
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
245
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20313
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
246
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20314
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
247
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20315
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
248
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20316
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
249
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20317
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
250
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20318
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
251
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20319
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
252
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20320
Group: 2
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 2 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
infiltrate; mononuclear cell; focal; minimal; medullary
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
uterus; distention; bilateral; present,
dilation; diffuse; present; unilateral; luminal .........
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
253
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20321
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
254
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20322
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
infiltrate; mononuclear cell; focal; minimal; cortical
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
255
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20323
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
256
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20324
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
257
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20325
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
258
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20326
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
259
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20327
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
liver
spleen
stomach
260
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20328
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
—————————————————————————————
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
261
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20329
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
dilation; present; unilateral; pelvic
The following tissues were within normal limits:
————————————————————————————————————————————————
liver
spleen
stomach
262
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20330
Group: 3
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
263
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20331
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
264
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20332
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
infiltrate; mononuclear cell; focal; minimal; cortical
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
265
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20333
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
266
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20334
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
267
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20335
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
268
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20336
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular; discoloration; red; bilateral; present, no grade
hemorrhage; acute; multifocal; mild
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
269
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20337
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
uterus; distention; bilateral;
dilation; diffuse; present; bilateral; luminal ..........
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
270
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20338
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
infiltrate; mononuclear cell; multifocal; minimal; mucosal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
ovary;
No Microscopic evidence of Macroscopic Observation
The following tissues were within normal limits:
————————————————————————————————————————————————
ovary
spleen
stomach
271
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20339
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
None
The following tissues were within normal limits:
————————————————————————————————————————————————
stomach
The following tissues have not been examined:
—————————————————————————————————————————————
kidney; NOT PRESENT
liver; NOT PRESENT
spleen; NOT PRESENT
272
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats
with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
—————————————————————————
Animal No.: 20340
Group: 3
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 20 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
—————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
liver
spleen
stomach
273
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20341
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
harderian gland;
infiltrate; mononuclear cell; focal; minimal
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
epididymis
esophagus
jejunum
lung
mandibular salivary gland
optic nerve
pancreas
parathyroid gland
pituitary
skin
spinal cord
spleen
stomach
urinary bladder
aorta
lacrimal glands
prostate
bone with marrow - sternum
cecum
eye
heart
ileum
lymph node - mandibular
lymph node - mesenteric
nerve - sciatic
seminal vesicle
skeletal muscle
testis
thyroid gland
trachea
rectum
tongue
peyers patch
274
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20342
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
adrenal gland;
vacuolation; multifocal; minimal
kidney;
infiltrate; mononuclear cell; focal; minimal; mucosal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; mild
The following tissues were within normal limits:
————————————————————————————————————————————————
brain
bone with marrow - femur
duodenum
epididymis
esophagus
jejunum
lung
mandibular salivary
pancreas
parathyroid gland
pituitary
spinal cord
spleen
stomach
urinary bladder
aorta
lacrimal glands
bone with marrow - sternum
cecum
eye
harderian gland
heart
gland
lymph node - mesenteric
nerve - sciatic
seminal vesicle
skeletal muscle
testis
thymus
thyroid gland
prostate
rectum
tongue
275
colon
ileum
optic nerve
skin
trachea
peyers patch
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20343
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
adrenal gland;
vacuolation; multifocal; minimal
kidney;
infiltrate; mononuclear cell; focal; minimal; cortical
regeneration; tubular; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
prostate;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
brain
bone with marrow - femur
duodenum
epididymis
esophagus
jejunum
liver
lung
optic nerve
pancreas
parathyroid gland
skin
spinal cord
spleen
urinary bladder
aorta
lacrimal glands
bone with marrow - sternum
eye
harderian gland
mandibular salivary gland
pituitary
nerve - sciatic
stomach
testis
rectum
tongue
276
cecum
colon
heart
ileum
lymph node - mesenteric
seminal vesicle
skeletal muscle
thyroid gland
trachea
peyers patch
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20344
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
adrenal gland;
vacuolation; multifocal; minimal
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
lacrimal glands;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
brain
bone with marrow - femur
bone with marrow - sternum
cecum
duodenum
epididymis
esophagus
eye
harderian gland
heart
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
pancreas
parathyroid gland
pituitary
nerve - sciatic
seminal vesicle
skeletal muscle
spinal cord
spleen
stomach
testis
thymus
thyroid gland
urinary bladder
aorta
prostate
rectum
tongue
peyers patch
277
colon
ileum
optic nerve
skin
trachea
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20345
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
adrenal gland;
vacuolation; multifocal; minimal
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
vacuolation; hepatocellular; multifocal; minimal
lung;
hemorrhage; acute; multifocal; minimal
lymph node - mandibular; discoloration; dark; multiple; present, no grade
hemorrhage; acute; multifocal; moderate
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
brain
bone with marrow - femur
duodenum
epididymis
esophagus
jejunum
mandibular salivary gland
parathyroid gland
pituitary
nerve - sciatic
spleen
stomach
testis
lacrimal glands
prostate
rectum
bone with marrow - sternum
eye
harderian gland
lymph node - mesenteric
seminal vesicle
skeletal muscle
thyroid gland
trachea
tongue
peyers patch
278
cecum
heart
optic nerve
skin
urinary bladder
colon
ileum
pancreas
spinal cord
aorta
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20346
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
infiltrate; mononuclear cell; focal; minimal; medullary
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
bone with marrow - sternum
cecum
colon
duodenum
epididymis
esophagus
eye
harderian gland
heart
ileum
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
optic nerve
pancreas
parathyroid gland
pituitary
nerve - sciatic
seminal vesicle
skeletal muscle
skin
spinal cord
spleen
stomach
testis
thymus
thyroid gland
trachea
urinary bladder
aorta
lacrimal glands
prostate
tongue
peyers patch
rectum
The following tissues have not been examined:
—————————————————————————————————————————————
279
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20347
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
infiltrate; mononuclear cell; focal; minimal; cortical
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular; discoloration; red; bilateral; present, no grade
hemorrhage; acute; multifocal; mild
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
bone with marrow - sternum
cecum
colon
duodenum
epididymis
esophagus
eye
harderian gland
heart
ileum
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
optic nerve
pancreas
parathyroid gland
pituitary
nerve - sciatic
seminal vesicle
skeletal muscle
skin
spinal cord
spleen
stomach
testis
thymus
thyroid gland
trachea
urinary bladder
aorta
lacrimal glands
prostate
rectum
tongue
peyers patch
280
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20348
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
inflammation; subacute; multifocal; mild; unilateral; mucosal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
pancreas;
infiltrate; mononuclear cell; focal; minimal; perivascular
thymus;
hemorrhage; acute; multifocal; minimal
prostate;
infiltrate; neutrophilic; focal; minimal; luminal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
bone with marrow - sternum
cecum
colon
duodenum
epididymis
esophagus
eye
harderian gland
heart
ileum
jejunum
lung
mandibular salivary gland
lymph node - mandibular
lymph node - mesenteric
optic nerve
parathyroid gland
seminal vesicle
skin
spinal cord
spleen
stomach
testis
thyroid gland
trachea
urinary bladder
aorta
lacrimal glands
rectum
tongue
peyers patch
nerve – sciatic
skeletal muscle
The following tissues have not been examined:
—————————————————————————————————————————————
pituitary; NOT PRESENT
281
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20349
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
adrenal gland;
vacuolation; multifocal; minimal
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; mild
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
brain
bone with marrow - femur
bone with marrow - sternum
cecum
duodenum
epididymis
esophagus
eye
harderian gland
heart
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
pancreas
parathyroid gland
pituitary
nerve - sciatic
seminal vesicle
skeletal muscle
spinal cord
spleen
stomach
testis
thyroid gland
trachea
aorta
lacrimal glands
prostate
rectum
tongue
peyers patch
282
colon
ileum
optic nerve
skin
urinary bladder
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20350
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
infiltrate; mononuclear cell; focal; minimal; cortical
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
epididymis
esophagus
ileum
jejunum
lung
mandibular salivary
lymph node - mesenteric
optic nerve
pancreas
seminal vesicle
skeletal muscle
skin
spinal cord
thymus
thyroid gland
trachea
urinary bladder
rectum
tongue
peyers patch
283
bone with marrow - sternum
cecum
eye
harderian gland
heart
gland
lymph node - mandibular
parathyroid gland
pituitary
nerve - sciatic
spleen
stomach
testis
aorta
lacrimal glands
prostate
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20351
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
infiltrate; mononuclear cell; multifocal; minimal; mucosal
regeneration; tubular; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
liver
spleen
stomach
284
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20352
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
285
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20353
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
286
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20354
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
infiltrate; mononuclear cell; focal; minimal; cortical
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
vacuolation; hepatocellular; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
287
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20355
Group: 4
Sex: Male
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
288
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20356
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
lung;
histiocytosis; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; mild
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
liver
mandibular salivary gland
optic nerve
ovary
pancreas
parathyroid gland
skin
spinal cord
spleen
stomach
urinary bladder
uterus
aorta
cervix
peyers patch
vagina
289
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mesenteric
pituitary
nerve - sciatic
skeletal muscle
thymus
thyroid gland
trachea
lacrimal glands
rectum
tongue
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20357
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
thymus; discoloration; brown; bilateral;
hemorrhage; subacute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
optic nerve
ovary
skeletal muscle
skin
spinal cord
spleen
urinary bladder
uterus
aorta
cervix
peyers patch
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mandibular
pancreas
parathyroid gland
nerve - sciatic
stomach
thyroid gland
trachea
rectum
tongue
vagina
The following tissues have not been examined:
—————————————————————————————————————————————
pituitary; NOT PRESENT
lacrimal glands; NOT PRESENT
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Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20358
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lung;
hemorrhage; acute; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
mandibular salivary gland
mammary gland
ovary
pancreas
parathyroid gland
pituitary
spinal cord
spleen
stomach
thyroid gland
aorta
cervix
lacrimal glands
rectum
291
bone with marrow - sternum
harderian gland
heart
lymph node - mesenteric
nerve - sciatic
skeletal muscle
trachea
urinary bladder
tongue
peyers patch
cecum
ileum
optic nerve
skin
uterus
vagina
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20359
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
optic nerve
ovary
pancreas
pituitary
spinal cord
spleen
stomach
thyroid gland
aorta
cervix
lacrimal glands
tongue
The following tissues have not been examined:
—————————————————————————————————————————————
parathyroid gland; NOT PRESENT
rectum; NOT PRESENT
292
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mesenteric
nerve - sciatic
skeletal muscle
skin
trachea
urinary bladder
uterus
peyers patch
vagina
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20360
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; mild
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
optic nerve
ovary
pancreas
parathyroid gland
spinal cord
spleen
stomach
thyroid gland
aorta
cervix
lacrimal glands
rectum
The following tissues have not been examined:
—————————————————————————————————————————————
pituitary; NOT PRESENT
293
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mesenteric
nerve - sciatic
skeletal muscle
skin
trachea
urinary bladder
uterus
tongue
peyers patch
vagina
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20361
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
uterus;
dilation; diffuse; present; unilateral; luminal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
optic nerve
ovary
pancreas
parathyroid gland
spinal cord
spleen
stomach
thyroid gland
cervix
lacrimal glands
rectum
tongue
The following tissues have not been examined:
—————————————————————————————————————————————
pituitary; NOT PRESENT
294
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mesenteric
nerve - sciatic
skeletal muscle
skin
trachea
urinary bladder
aorta
peyers patch
vagina
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20362
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
lung;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
mandibular salivary gland
mammary gland
optic nerve
ovary
pancreas
parathyroid gland
skin
spinal cord
spleen
stomach
uterus
aorta
cervix
lacrimal glands
vagina
urinary bladder
The following tissues have not been examined:
—————————————————————————————————————————————
295
bone with marrow - sternum
cecum
harderian gland
heart
ileum
lymph node - mandibular
lymph node - mesenteric
pituitary
nerve - sciatic
skeletal muscle
thymus
thyroid gland
trachea
rectum
tongue
peyers patch
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20363
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
harderian gland;
infiltrate; mononuclear cell; focal; minimal
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
inflammation; granulomatous; focal; minimal
lymph node - mandibular;
hemorrhage; acute; multifocal; mild
thymus;
hemorrhage; acute; multifocal; minimal
uterus;
dilation; diffuse; present; unilateral; luminal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
lung
mandibular salivary gland
mammary gland
ovary
pancreas
parathyroid gland
pituitary
spinal cord
spleen
stomach
thyroid gland
cervix
lacrimal glands
rectum
tongue
296
bone with marrow - sternum
heart
ileum
lymph node - mesenteric
nerve - sciatic
skeletal muscle
trachea
urinary bladder
peyers patch
vagina
cecum
jejunum
optic nerve
skin
aorta
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20364
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
thymus;
hemorrhage; acute; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
optic nerve
ovary
skeletal muscle
skin
spinal cord
spleen
urinary bladder
uterus
aorta
cervix
peyers patch
vagina
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mandibular
pancreas
parathyroid gland
pituitary
stomach
thyroid gland
trachea
lacrimal glands
rectum
tongue
The following tissues have not been examined:
—————————————————————————————————————————————
nerve - sciatic; NOT PRESENT
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Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20365
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 07/20/2005
Study Day No. (Week): 91 (13)
Mode of Death: TERMINAL KILL
Date of Necropsy: 07/20/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
adrenal gland
brain
bone with marrow - femur
colon
duodenum
esophagus
eye
jejunum
lung
mandibular salivary gland
lymph node - mesenteric
optic nerve
ovary
nerve - sciatic
skeletal muscle
skin
spinal cord
thyroid gland
trachea
urinary bladder
uterus
rectum
tongue
peyers patch
vagina
298
bone with marrow - sternum
cecum
harderian gland
heart
ileum
mammary gland
lymph node - mandibular
pancreas
parathyroid gland
pituitary
spleen
stomach
thymus
aorta
cervix
lacrimal glands
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20366
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
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Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20367
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
300
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Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20368
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
301
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Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20369
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
mineralization; multifocal; minimal
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
302
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Appendix 1 (continued)
Individual Histopathology Observations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin in Han Wistar Rats with a 4-Week Recovery
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Animal No.: 20370
Group: 4
Sex: Female
Species:Rat
Strain: Wistar
Test Material: mesozeaxanthin
Dose: 200 mg/kg
Route: Gavage
Study Type: Acute Toxicity
Date of Death
: 08/17/2005
Study Day No. (Week): 119 (17)
Mode of Death: RECOVERY KILL
Date of Necropsy: 08/17/2005
Pathologist: Sophie BouchihaOlson
——————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————
Histo Pathology Observations:
kidney;
regeneration; tubular; multifocal; minimal
liver;
infiltrate; mononuclear cell; multifocal; minimal
The following tissues were within normal limits:
————————————————————————————————————————————————
spleen
stomach
303
Howard Foundation
Gene Logic Laboratories Inc. Study No. 1567-04370
Appendix 15
Protocol, Amendments, and Deviations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
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Appendix 15 (continued)
Protocol, Amendments, and Deviations
Thirteen-Week Oral (Gavage) Toxicity of Mesozeaxanthin
in Han Wistar Rats with a 4-Week Recovery
The following protocol deviations were noted:
The animal room temperature was outside the protocol-specified range (64-79°F) on SD 110 (Week
16) at 58°F and on SD 81 (Week 12) at 62°F.
The cage card for animal number 20330 that contained raw data pertaining to the animal’s necropsy
was lost at necropsy. However, observations for this animal had been entered into Provantis (data
capture) Pathology Module prior to card being lost as verified by the recorder.
On SD -2 (04/19/05) the PM cageside observation (CSO) was not performed. On SD -1 (4/20/05) the
AM and PM CSO’s were not performed.
On SD 64, animals were without access to water for approximately 4 hours. The automatic watering
system was temporarily disconnected to allow for cleaning of the watering systems, due to the results
of water sample analyses indicating an unacceptable level of bacteria.
Male and female animals were outside the protocol specified body weight range on the first day of
dosing. Male animal range was specified at 150-170 g (actual 170.5-207.9 g); female animal range
was specified at 105-125 g (actual 129.07-149.83 g).
Additional body weights and physical exam data was collected on April 19, 2005.
On July 20, 2006, the first 14 animals were bled by abdominal aorta instead of cardiac puncture as
requested by the study directive issued the same day.
Some tissues were not microscopically examined or only one of a paired organ was examined, due to
sectioning difficulties or technical errors. Non-examined tissues are identified in Appendix 1 (listed in
individual animal data sheets) of the Pathology Report.
Some clinical pathology tests were not analyzed due to clotted samples, insufficient specimen
volumes, or other reasons. On SD 91, the clinical chemistry sample for animal 20330 (3M) was
moderately hemolyzed. The coagulation samples for animals 20275 (1M), 20288 (1F), 20332 (3F)
20357 (4F), 20362 (4F) and 20365 (4F) were clotted. On SD 119, the coagulation sample for animal
20354 (4M) was clotted.
There is no documentation that lacrimal glands were observed grossly at terminal and recovery
necropies, although those lacrimal glands were preserved and subsequently processed and
examined.
Amendment 1 required mammary glands to be collected, preserved, and examined only from the
females; mammary glands for the males were also collected and preserved.
All rats were euthanized using CO2.
The above-mentioned deviations did not impact this study, nor did they affect the quality or integrity of the
study or the interpretation of the results in this report.
334