Introduction to the Template for Chronic Toxicity Study with an in utero Phase¹ 

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TABLE OF CONTENTS

1. Identification of Study
2. Good Laboratory Practice
3. Executive Summary
4. Materials and Methods
   1. TEST SUBSTANCE
   2. TEST SUBSTANCE AS ADMINISTERED
   3. ANIMAL DIET
   4. TEST ANIMALS
   5. EXPERIMENTAL DESIGN
   6. MATING PROCEDURES FOR IN UTERO PHASE
   7. CULLING PROCEDURES FOR IN UTERO PHASE
   8. PARENTAL BODY WEIGHT AND FEED INTAKE FOR IN UTERO PHASE
   9. PARENTAL CAGE-SIDE OBSERVATIONS FOR IN UTERO PHASE
   10. PARENTAL REPRODUCTIVE PARAMETERS FOR IN UTERO PHASE
   11. OFFSPRING OBSERVATIONS AND BODY WEIGHT FOR IN UTERO PHASE
   12. BODY WEIGHT AND FEED INTAKE FOR CHRONIC PHASE
   13. CAGE-SIDE OBSERVATIONS FOR CHRONIC PHASE
   14. OPTHALMOLOGICAL EXAMINATION
   15. HEMATOLOGY
   16. CLINICAL CHEMISTRY
   17. URINALYSIS
   18. OTHER TESTS
   19. NECROPSY (INTERIM SACRIFICE)
   20. NECROPSY (TERMINAL)
   21. GROSS PATHOLOGY OBSERVATIONS
   22. HISTOPATHOLOGY OBSERVATIONS
   23. STATISTICAL METHODS
5. Results
   1. DOSE VERIFICATION
   2. INTAKE OF TEST SUBSTANCE
   3. PARENTAL FEED CONSUMPTION CHANGES FOR THE IN UTERO PHASE
   4. FEED EFFICIENCY FOR THE UTERO PHASE
   5. PARENTAL BODY WEIGHT CHANGES FOR THE IN UTERO PHASE
   6. PARENTAL ABNORMAL CAGE-SIDE OBSERVATIONS FOR THE IN UTERO PHASE
   7. MORTALITY IN ADULTS
   8. MATING, FERTILITY, AND REPRODUCTION
   9. OFFSPRING BODY WEIGHT CHANGES FOR IN UTERO PHASE
   10. OFFSPRING OBSERVATIONS FOR IN UTERO PHASE
   11. FEED CONSUMPTION CHANGES FOR THE CHRONIC PHASE
   12. FEED EFFICIENCY FOR THE CHRONIC PHASE
   13. BODY WEIGHT CHANGES FOR THE CHRONIC PHASE
   14. CAGE-SIDE OBSERVATIONS FOR THE CHRONIC PHASE
   15. MORTALITY IN ADULTS
   16. OPTHALMOLOGICAL EXAMINATION
   17. HEMATOLOGY
   18. CLINICAL CHEMISTRY
   19. URINALYSIS
   20. OTHER TESTS
   21. ORGAN WEIGHTS
   22. GROSS PATHOLOGY CHANGES OBSERVED
   23. HISTOPATHOLOGY CHANGES OBSERVED
   24. NEUROTOXICITY
6. Evaluation and Comments on Study
7. Summary and Conclusions
   1. BRIEF SUMMARY OF MAJOR FINDINGS FROM THE STUDY
   2. RELATIONSHIP BETWEEN DOSE AND INCIDENCE/ SEVERITY OF LESIONS OR ABNORMALITIES
   3. IS THERE A TARGET ORGAN?
   4. NOEL
8. References
9. Appendix
   1. HEMATOLOGY RESULTS
   2. CLINICAL CHEMISTRY RESULTS
   3. URINALYSIS RESULTS

Chronic Toxicity Study with an in Utero PHASE² 

Date of Submission:
Title of Petition or Notification:
Name and Address of Petitioner or Notifier:

I. Identification of Study³ 

A.    Study File Location:
B.    Study Title/Report Number:
C.    Name and Address of Testing Facility:
D.    Date of Study Report:
E.    Dates Study Conducted:
F.    Study Objective:
G.    Comments:

II. Good Laboratory Practice⁴ 

A.    Was there compliance with Good Laboratory Practice Regulations?
B.    Was a Quality Assurance (QA) Statement Included?
C.    Availability and Location of Original Data/Specimens/Test Substance:

III. Executive Summary⁵ 

 

 

IV. Materials and Methods

A. TEST SUBSTANCE⁶ 

1.     CAS name:
2.     Other name(s):
3.     CAS registry number:
4.     Molecular structure: http://www.chemfinder.com/⁷ 
5.     Purity:
6.     Impurities:
7.     Stability:
8.     Comments:

B. TEST SUBSTANCE AS ADMINISTERED⁸ 

1.     Batch/lot number:
2.     Route:
3.     Vehicle used:
4.     Tested adequately for concentration?
5.     Tested for homogeneity?
6.     Tested for stability?
7.     Problems with storage?

C. ANIMAL DIET

1. Feed

1. Type:
2. Name:
3. Availability:
4. Analysis for contaminants:
5. Comments:

2. Water

1. Source:
2. Availability:
3. Analysis for contaminants:
4. Comments:

D. TEST ANIMALS⁹ 

1.     Species/strain/substrain:
2.     Sex:
3.     Age range at initiation of study:
4.     Weight range at initiation of study:
5.     Quarantine/acclimation?
6.     Physical examination times:
7.     Number per cage:
8.     Environmental conditions:

• Temperature:
• Humidity:
• Air Changes:
• Photoperiod:

9.     Comments:

E. EXPERIMENTAL DESIGN¹⁰ 

1. Targeted dose levels; in utero phase for parental animals.

Table # [Heading]

TEST GROUP	CONC. IN DIET (ppm or mg/kg)	NUMBER OF MALES	DOSE TO MALES (mg/kg body-weight/day	number of FEmales	dose to FEmales (mg/kg body-weight/day)
CONTROL
LOW
MID
HIGH

2. Targeted dose levels for the animals in the chronic phase:

Table # [Heading]

3. Total number of animals:
4. Duration of study (including recovery period, if any):
5. Length of exposure to test substance:
6. Were animals randomized?
7. Recovery period:
8. Comments:

IVa. Materials and Methods - In Utero Phase

F. MATING PROCEDURES FOR IN UTERO PHASE¹¹ 

1. Description:
2. Comment:

G. CULLING PROCEDURES FOR IN UTERO PHASE¹² 

1. Description:
2. Comment:

H. PARENTAL BODY WEIGHT AND FEED INTAKE FOR IN UTERO PHASE ¹³

1. Parameter examined:
2. Frequency of measurement:

Table # [Heading]

 

examined	not examined
	Feed Intake, Feed Spillage, Water Intake, Body Weight, Body Weight Changes

3. Comment:

I. PARENTAL CAGE-SIDE OBSERVATIONS FOR IN UTERO PHASE¹³

1. Parameter examined:
2. Frequency of measurement:

Table # [Heading]

examined	not examined
	Appearance, Abnormal Stool, Deficiencies in care** Morbidity, Mortality, Neurotoxicity Screening (Specify parameters)***

** Deficiencies in care (inadequate construction or cleaning of the nest, pups left scattered and cold, physical abuse of pups, or inadequate lactation or feeding]
*** The parameters for neurotoxicity screening may include, but are not limited to, the following:

• Changes in skin, fur, eyes, mucous membranes, gut, posture, and response to handling,
• Occurrence of secretions/excretions or other evidence of autonomic activity such as lacrimation, piloerection, pupil size change, unusual respiratory pattern
• Presence of clonic or tonic seizure
• Stereotype behaviors such as excessive grooming and repetitive circling,
• Bizarre behavior such as self-mutilating and walking backwards,
• Gross tumor development.

3. Comment:

J. PARENTAL REPRODUCTIVE PARAMETERS FOR IN UTERO PHASE¹³ 

1. Reproductive parameters examined:

Table # [Heading]

examined	not examined
	Female fertility Index, Gestation Index, Gestation Length, Live-born Index, Number (Total and Per Litter) of Stillbirths and Live Births at Day 0

2. Indices Formulas:
3. Comments:

K. OFFSPRING OBSERVATIONS AND BODY WEIGHT FOR IN UTERO PHASE¹³

1. Parameter examined:
2. Frequency of measurement:

Table # [Heading]

observation	examined	not examined
CAGE- SIDE		Appearance, Gross Anomalies, Morbidity, Mortality
OTHER		Litter size (Total: Day 0, 4, 7, 14, 21), Litter Weight (Day 0, 4, 7, 14, 21), Pup Body Weight and Sex (Day 0, 4, 7, 14, 21), Sex Ratio, Viability Index (Day 0-4, 4-7, 7-14, 14-21), Weaning Index

3. Comments:

IVb. Materials and Methods - Chronic Phase

L. BODY WEIGHT AND FEED INTAKE FOR CHRONIC PHASE¹³

1. Parameter examined:
2. Frequency of measurement:

Table # [Heading]

 

examined*	not examined*
	Feed Intake, Feed Spillage, Water Intake, Body Weight, Body Weight Changes

*These parameters are recommended in Toxicological Principles for the Safety of Food Ingredients: Redbook 2000 for chronic toxicity studies.

3. Comments:

M. CAGE-SIDE OBSERVATIONS FOR CHRONIC PHASE¹³ 

1. Parameter examined:
2. Frequency of measurement:

Table # [Heading]

examined*	not examined*
	Appearance, Abnormal Stool, Morbidity, Mortality, Neurotoxicity Screening (Specify parameters)**

* These parameters are recommended in Toxicological Principles for the Safety of Food Ingredients: Redbook 2000 for chronic toxicity studies.
** The parameters for neurotoxicity screening may include, but are not limited to, the following:

• Changes in skin, fur, eyes, mucous membranes, gait, posture, and response to handling,
• Occurrence of secretions/excretions or other evidence of autonomic activity such as lacrimation, piloerection, pupil size change, unusual respiratory pattern,
• Presence of clonic or tonic seizure,
• Stereotype behaviors such as excessive grooming and repetitive circling,
• Bizarre behavior such as self-mutilating and walking backwards,
• Gross tumor development.

3. Comments:

N. OPTHALMOLOGICAL EXAMINATION

1. Parameter examined:
2. Frequency of measurement:
3. Comments:

O. HEMATOLOGY¹³ 

1. Fasting duration prior to blood collection:
2. Schedule interval for blood sample collection:
3. Method of blood collection:
4. Dose groups and number of animals tested:
5. Parameter examined:

Table # [Heading]

measurement related to	examined*	not examined*
red blood cells		Hematocrit (Hct), Hemoglobin Conc. (Hb), Mean Corp. Hb. (MCH), Mean Corp. Hb. Conc. (MCHC), Mean Corp. Volume (MCV), Total Erythrocyte Count (RBC)
white blood cells		Basophils, Eosinophils, Lymphocytes, Macrophage/Monocytes, Neutrophils, Total Leukocytes (WBC)
clotting potential		Activated Partial-Thromboplastin Time, Clotting Time, Platelet Count Prothrombin Time
others		Bone marrow cytology, Reticulocyte counts

* These parameters are recommended in Toxicological Principles for the Safety of Food Ingredients: Redbook 2000 for chronic toxicity studies.

6. Comment:

P. CLINICAL CHEMISTRY¹³ 

1.     Fasting duration prior to blood collection:
2.     Schedule interval for blood sample collection:
3.     Method of blood collection:
4.     Dose groups and number of animals tested:
5.     Parameter examined:

Table # [Heading]

measurement related to	examined	not examined
electrolyte balance		Calcium*, Chloride*,**, Phosphorus*, Potassium*,**, Sodium*,**
Blood Sugar		Glucose*,**
liver function: A) hepato-cellular (recommend at least 3 out of 5) B) Hepatobiliary (recommend at least 3 out of 5)		Alanine Aminotransferase (ALT or SGPT)*,** ,Aspartate Aminotransferase (AST or SGOT)*, Glutamate Dehydrogenase*, Sorbitol Dehydrogenase*, Total Bile Acids*
		Alkaline Phosphatase (ALP)*,**, Gamma-Glutamyl Transferase (GGT)*,**, Total Bile Acids*, Total Bilirubin*, 5' Nucleotidase*
kidney function		Creatinine*,**, Urea Nitrogen*,**
others(acid/base balance, cholinesterases, hormones, lipids, methemoglobin, and proteins)		Albumin (A)*, Globulin* (G, calculated) or A/G Ratio*, Total Cholesterol*, Cholinesterase*, Total protein*,**, Fasting Triglycerides*

* These parameters are recommended in Toxicological Principles for the Safety of Food Ingredients: Redbook 2000 for chronic toxicity studies.
** These parameters should generally be given priority when adequate volumes of blood samples can not be obtained from test animals.

6.     Comments:

Q. URINALYSIS¹⁴ 

1.     Describe the frequency of urine sample collection:
2.     Parameter examined:

Table # [Heading]

examined	not examined
	Glucose*, Microscopic Evaluation for Sediment and presence of blood/blood cells*, pH*, Protein*, Specific Gravity*, Volume*

* These parameters are recommended in Toxicological Principles for the Safety of Food Ingredients: Redbook 2000 for chronic toxicity studies.

3.     Comments:

R. OTHER TESTS¹⁵ 

1.     Observations:
2.     Comments:

S. NECROPSY (INTERIM SACRIFICE)¹⁶ 

1.     Was there an interim sacrifice?
2.     Dose groups and number of animals:
3.     Organs/Tissues weighed:

Table # [Heading]

examined	not examined
	Adrenals*, Brain*, Epididymides*, Heart*, Kidneys*, Liver*, Spleen*, Testes*, Thyroid/parathyroid*, Thymus*, Ovaries*, Uterus*

* These parameters are recommended in Toxicological Principles for the Safety of Food Ingredients: Redbook 2000 for chronic toxicity studies.

4.     Comments:

T. NECROPSY (TERMINAL)

1.     Organs/Tissues weighed:

Table # [Heading]

examined	not examined
	Adrenals*, Brain*, Epididymides*, Heart*, Kidneys*, Liver*, Spleen*, Testes*, Thyroid/parathyroid*, Thymus*, Ovaries*, Uterus*

* These parameters are recommended in Toxicological Principles for the Safety of Food Ingredients: Redbook 2000 for chronic toxicity studies.

2.     Comments:

 

U. GROSS PATHOLOGY OBSERVATIONS

1.     Organs/Tissues Examined:
2.     Comments:

V. HISTOPATHOLOGY OBSERVATIONS

1.     Organs/Tissues were collected from which dose groups?
2.     Organs/Tissues were examined from which dose groups?
3.     How were the organs/tissues prepared for histopathology observation?
4.     Organs/Tissues collected:

Table # [Heading]

system	examined	not examined
digestive		Salivary Gland*, Esophagus*, Stomach*, Duodenum*, Jejunum*, Ileum*, Cecum*, Colon, Rectum*, Gall Bladder* (in case of mice), Liver* (middle, left and triangular lobes), Pancreas*
respiratory		Nasal Turbinates*, Trachea*, Lung* (with main-stem bronchi)
cardio-vascular		Aorta*, Heart*
reticulo- endothelial/hematopoietic		Bone Marrow *(sternum), Lymph Nodes* (1 related to route of administration, and 1 from a distant location), Spleen*, Thymus*
urogenital		Kidneys*, Ovaries* and fallopian tubes*, Corpus Uteri*, Cervix Uteri*, Prostate*, Seminal Vesicle* (if present), Testes*, Urinary Bladder*, Vagina*
neurologic		Brain* (at least 3 different levels), Spinal-Cervical*, Spinal-Lumbar*, Spinal-Midthoracic*, Sciatic Nerve*, Harderian Gland* (if present)
glandular		Adrenals*, Mammary Glands*, Pituitary Glands*, Thyroid/Parathyroid Glands*, Thymus*, Zymbal's Gland* (if present)
other		Bone (Femur)*, Eyes*, Skeletal Muscle*, Skin*, Epididymis*

* These parameters are recommended in Toxicological Principles for the Safety of Food Ingredients: Redbook 2000 for chronic toxicity studies.

5.     Comments:

W. STATISTICAL METHODS

1.     Methods of statistical analysis:

Table # [Heading]

methods of statistical analysis	parameters tested

2.     Comments:

V. Results

A. DOSE VERIFICATION¹⁷ 

1.     Were doses verified?

Table # [Heading]

dose group	targeted concentration (ppm or mg/kg)	concentrations found in feed (ppm or mg/kg)	standard Deviation	N*
low
mid
high

* Number of measurements (N)

2.     Verified by:
3.     Comments:

B. INTAKE OF TEST SUBSTANCE¹⁸

1.     Intake during in utero phase:

Table # [Heading]

 

dose group	daily dose (mg/kg body-weight/day)
control	0
low
mid
high

2.     Intake during the chronic phase:

 
Table # [Heading]

 

dose group	daily dose (mg/kg body-weight/day)
control	0
low
mid
high

3.     Comments:

Va. Results - In Utero Phase

C. PARENTAL FEED CONSUMPTION CHANGES FOR THE IN UTERO PHASE¹⁹ 

1.     Observations during Pre-mating and Post-mating:
2.     Observations during Gestation:
3.     Observations during Lactation:
4.     Comments:

D. FEED EFFICIENCY FOR THE UTERO PHASE²⁰

1. Was feed efficiency calculated?
2. Comments:

E. PARENTAL BODY WEIGHT CHANGES FOR THE IN UTERO PHASE²¹ 

1. Observations during Premating and Postmating:
2. Observations during Gestation:
3. Observations during Lactation:
4. Comments:

F. PARENTAL ABNORMAL CAGE-SIDE OBSERVATIONS FOR THE IN UTERO PHASE²² 

1. Observations during Premating and Postmating:
2. Observations during Gestation:
3. Observations during Lactation:
4. Comments:

G. MORTALITY IN ADULTS ²³ 

1.     Observations:
2.     Comments:

H. MATING, FERTILITY, AND REPRODUCTION

1. Observations:

Table # [Heading]

PREGNANCY

	Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)
Number of Females Paired
Number of Females Achieving Pregnancy
Female Fertility Index (%)

 

MATERNAL WASTAGE

	Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)
Number Died
Number Died Pregnant
Number Died Nonpregnant
Number Aborted
Number Premature Delivery

 

GESTATION

	Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)
Gestation Length	Mean (S.D.)
Gestation Index

 

CORPORA LUTEA

	Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)
Total Number Corpora Lutea
Corpora Lutea/Dam	Mean (S.D.)

 

IMPLANTATIONS

	Females
0 (Control)
Total Number Implantations
Implantations/Dam	Mean (S.D.)

 

BIRTHS - DAY 0

	Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)
Number Stillborn - Total Per Litter	Mean (SD) N
Number Live-Born - Total Per Litter	Mean (SD) N
Live-Born Index (%)

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

2. Comments:

I. OFFSPRING BODY WEIGHT CHANGES FOR IN UTERO PHASE²⁴

1. Observations:

 

Table # [Heading]

Pup Weight (gm)

Sex	Males				Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)				0 (Control)
Day 0	Mean (SD) N
Day 4	Mean (SD) N
Day 7	Mean (SD) N
Day 14	Mean (SD) N
Day 21	Mean (SD) N

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

2. Comments:

J. OFFSPRING OBSERVATIONS FOR IN UTERO PHASE ²⁵ 

1. Observations:

Table # [Heading]

 

DAILY DOSE (mg/kg body-weight/day)	0 (Control)
LITTER SIZE
Number Born - Total Per Litter	Mean (SD) N
Day 0 - Total Per Litter	Mean (SD) N
Day 4 -Total Per Litter	Mean (SD) N
Day 7 -Total Per Litter	Mean (SD) N
Day 14 - Total Per Litter	Mean (SD) N
Day 21 - Total Per Litter	Mean (SD) N
LITTER WEIGHT (G)
Day 0	Mean (SD) N
Day 4	Mean (SD) N
Day 7	Mean (SD) N
Day 14	Mean (SD) N
Day 21	Mean (SD) N
VIABILITY INDICES
Day 0-4	Mean (SD) N
Day 4-7	Mean (SD) N
Day 7-14	Mean (SD) N
Day 14-21	Mean (SD) N
WEANING INDEX
SEX RATIO
Day 0
Day 21

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

3.     Comments:

Vb. Results - Chronic Phase

K. FEED CONSUMPTION CHANGES FOR THE CHRONIC PHASE²⁶

1. Observations:
2. feed consumption table (and/or graph)²⁷ :

Table # [Heading]

FEED CONSUMPTION (gm feed/ kg body-weight/day)
Sex	Males				Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)				0 (Control)
Day 0	Mean (SD) N
Day A	Mean (SD) N
Day B	Mean (SD) N
Day C	Mean (SD) N
Day D	Mean (SD) N

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

3. Comments:

L. FEED EFFICIENCY FOR THE CHRONIC PHASE²⁸ 

1. Was feed efficiency calculated?
2. Comments:

M. BODY WEIGHT CHANGES FOR THE CHRONIC PHASE²⁹ 

1. Observations:
2. body weight table (and/or graph)³⁰ :

Table # [Heading]

body weight (gm/day)
Sex	Males				Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)				0 (Control)
Day 0	Mean (SD) N
Day A	Mean (SD) N
Day B	Mean (SD) N
Day C	Mean (SD) N
Day D	Mean (SD) N

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

3. Comments:

N. CAGE-SIDE OBSERVATIONS FOR THE CHRONIC PHASE

1. observation³¹ :

Table # [Heading]

cage-side observation (specify parameters32 )
Sex	Males				Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)				0 (Control)
Day 0	N
Day A	N
Day B	N
Day C	N
Day D	N

N: Number of Animals with abnormal observation

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

2. Comments:

O. MORTALITY IN ADULTS³³

1. Observations:
2. mortality table (and/or graph)³⁴ :

Table # [Heading]

mortality (%)
Sex	Males				Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)				0 (Control)
Day 0
Day A
Day B
Day C
Day D

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

3. Comments:

P. OPTHALMOLOGICAL EXAMINATION

1. Observations:
2. Comments:

Q. HEMATOLOGY

1. Observations³⁵ :

Table # [Heading]³⁶ 

 

(specify parameter)
Sex	Males				Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)				0 (Control)
Day 0	Mean (SD) N
Day A	Mean (SD) N
Day B	Mean (SD) N
Day C	Mean (SD) N
Day D	Mean (SD) N

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

3. Comments:

R. CLINICAL CHEMISTRY³⁷ 

1. Observations:

Table # [Heading]³⁸ 

 

hematology results (specify parameter)
Sex	Males				Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)				0 (Control)
Day 0	Mean (SD) N
Day A	Mean (SD) N
Day B	Mean (SD) N
Day C	Mean (SD) N
Day D	Mean (SD) N

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

2. Comments:

S. URINALYSIS³⁹ 

1. Observations:

 

Table # [Heading]⁴⁰ 

 

urinalysis results (specify parameter)
Sex	Males				Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)				0 (Control)
Day 0	Mean (SD) N
Day A	Mean (SD) N
Day B	Mean (SD) N
Day C	Mean (SD) N
Day D	Mean (SD) N

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

2. Comments:

T. OTHER TESTS⁴¹ 

1. Observations:

Table # [Heading]⁴² 

 

specify parameter
Sex	Males				Females
DAILY DOSE (mg/kg body-weight/day)	0 (Control)				0 (Control)
Day 0	Mean (SD) N
Day A	Mean (SD) N
Day B	Mean (SD) N
Day C	Mean (SD) N
Day D	Mean (SD) N

(Specify a method of statistical analysis): * p<0.05, ** p<0.01

2. Comments:

U. ORGAN WEIGHTS⁴³ 

1.     Observations:

 

Table # [Heading]

sex		males				females
DAILY DOSE (mg/kg body-weight/day)		0 (CONTROL)				0 (CONTROL)
NUMBER OF ANIMALS
BODY WEIGHT (gram)a
BRAIN
Absolute Weighta	gram
Per Body Weighta	%
ADRENALS
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
EPIDIDYMIDES
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
HEART
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
KIDNEYS
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
LIVER
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
SPLEEN
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
TESTES
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
THYROID and PARATHYROID
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
THYMUS
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
OVARIES
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%
UTERUS
Absolute Weighta	gram
Per Body Weighta	%
Per Brain Weighta	%

a: Group means at the end of terminal necropsy are shown.

(Specify methods of statistical analysis): * p<0.05, ** p<0.01

2.     Comments:

V. GROSS PATHOLOGY CHANGES OBSERVED⁴⁴ 

1.     Observations:
2.     Comments:

W. HISTOPATHOLOGY CHANGES OBSERVED⁴⁵ 

1.     Observations:

Table # [Heading)

 

NUMBER OF ANIMALS WITH, GROSS, NON-NEOPLASTIC, OR NEOPLASTIC LESIONS
SEX	males				females
DAILY DOSE (mg/kg body-weight/day)	0 (CONTROL)				0 (CONTROL)
NUMBER OF ANIMALS EXAMINED
DIGESTIVE SYSTEM
ORGAN/TISSUE #
GROSS LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
RESPIRATORY SYSTEM
ORGAN/TISSUE #
GROSS LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
CARDIOVASCULAR SYSTEM
ORGAN/TISSUE #
GROSS LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
RETICULO-ENDOTHELIAL /HEMATOPOIETIC SYSTEM
ORGAN/TISSUE #
GROSS LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
UROGENITAL SYSTEM
ORGAN/TISSUE #
GROSS LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
GLANDULAR SYSTEM
ORGAN/TISSUE #
GROSS LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NON-NEOPLASTIC LESION
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS
NEOPLASTIC LESIONS

(Specify methods of statistical analysis): * p<0.05, ** p<0.01

# Organs/tissues listed under section IV.V.

In general, data at end of dosing period can be shown; however, if there were additional noteworthy findings at earlier timepoints, these should be included. Note severity of lesions as needed.

2.     Comments:

X. NEUROTOXICITY⁴⁶ 

1.     Observations:

Table # [Heading]

	NUMBER OF ANIMALS
SEX	males				females
DAILY DOSE (mg/kg body-weight/day)	0 (CONTROL)				0 (CONTROL)
NUMBER OF ANIMALS EXAMINED
OBSERVATIONS OF NERVOUS SYSTEM TOXICITY +
OBSERVATION
OBSERVATION
OBSERVATION
GROSS- AND HISTO-PATHOLOGY CHANGES IN THE NEUROLOGIC SYSTEM #
ORGAN/TISSUE
GROSS LESION