Introduction to the Template for Subchronic Toxicity Study in Dogs

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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.       Body Weight And Feed Intake
   7.       Cage-Side Observations
   8.       Opthalmological Examination
   9.        Hematology
   10.       Clinical Chemistry
   11.       Urinalysis
   12.       Other Tests
   13.      Necropsy (Terminal)
   14.       Gross Pathology Observations
   15.       Histopathology Observations
   16.       Statistical Methods
5. Results
   1.       Dose Verification
   2.       Feed Consumption
   3.       Body Weight
   4.       Intake Of Test Substance
   5.       Feed Efficiency
   6.       Cage-Side Observations
   7.       Mortality
   8.       Ophthalmological Examination
   9.        Hematology
   10.       Clinical Chemistry
   11.       Urinalysis
   12.       Neurotoxicity (If Indicated)
   13.      Other Tests
   14.       Organ Weights
   15.       Gross Pathology Changes Observed
   16.       Histopathology Changes Observed
6. Evaluation and Comment 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.       Was There A Target Organ?
   4.       NOEL
8. References

Subchronic Toxicity Study in Dogs ¹

Date of Submission:

Title of Petition or Notification:                 

Name and Address of Petitioner or Notifier:         

I. Identification of Study² 

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 Practice³ 

A.    Good Laboratory Practice (GLP) Compliance?
B.    Quality Assurance (QA) Statement?
C.   Availability and Location of Original Data/Specimens/Test Substance:

 

III. Executive Summary

 

 

 

 

 

IV. Materials and Methods

A.   Test Substance⁴ 

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

B.   Test Substance As Administered⁶ 

1. Batch/Lot Number(s):
2.   Route:
3.   Vehicle used:
4.   Tested adequately for concentration? (See Part V-A for calculation)
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 Animals⁷ 

1.   Species/strain:
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:
9.   Comments:

 

E.   Experimental Design⁸ 

1.   Targeted dose levels:

 

Table # [Heading]

 

test group	conc. in diet (ppm or mg/kg)	dose to animals (mg/kg body-weight/day)	number of males	number of females
Control
Low
Mid
High

 

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

F.    Body Weight And Feed Intake⁹ 

  Parameter examined:

Table # [Heading]

 

Examined	Not Examined
	Feed Intake* Water Intake* Body Weight* Body Weight Changes*

*These parameters are recommended in REDBOOK for subchronic toxicity studies.

 

2. Comments: (e.g., list frequency)

 

G. Cage-Side Observations¹⁰ 

1. Parameter examined:

Table # [Heading]

 

Examined	Not Examined
	Appearance* Abnormal Stool* Morbidity* Mortality* Neurotoxicity Screening (Specify parameters)*,**

*These parameters are recommended in REDBOOK for subchronic 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.

2. Comments:

H.  Opthalmological Examination

1.   Parameter examined:
2.   Comments:

 

I.      Hematology¹¹ 

1. Fasting duration prior to blood collection:

2. When were the blood samples collected?

3. How were the blood samples drawn?

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 REDBOOK for subchronic toxicity studies.

6. Comments:

J.    Clinical Chemistry¹² 

1.  Fasting duration prior to blood collection:
2.  When in the study were the blood samples collected?
3.  How were the blood samples drawn?
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*,**
Carbohydrate Metabolism		Glucose*,**
Liver Function:   A) Hepatocellular       (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 REDBOOK for subchronic toxicity studies.

  ** These parameters should generally be given priority when adequate volumes of blood samples cannot be  obtained from test animals. 

6. Comments:

K.   Urinalysis¹³ 

1. When and how were urine samples collected?
2. Dose groups and number of animals tested:
3. 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 REDBOOK for subchronic toxicity studies.

4. Comments:

L.   Other Tests

1.   Observations:
2.   Comments:

 

M.  Necropsy (Terminal)

1. Organs weighed:

Table # [Heading]

 

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

* These parameters are recommended in REDBOOK for subchronic toxicity studies.                                                               

2. Comments:

N.   Gross Pathology Observations

1.   Organs/Tissues examined:
2.   Comments:

 

O. Histopathology Observations

1. Organs were collected from which dose groups?
2. Organs 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*, Liver (middle, left and triangular lobes)*, Pancreas*
Respiratory		Nasal Turbinates*, Trachea*, Lung (with main-stem bronchi)*
Cardiovascular		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*, Urinary Bladder*;  As applicable: fallopian tubes*, Corpus Uteri*, Cervix Uteri*, Vagina*, Prostate*, Seminal Vesicle*, Testes*
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*
Other		Bone (Femur)*, Eyes*, Skeletal Muscle*, Skin*, Epididymis*

    * These parameters are recommended in REDBOOK for subchronic toxicity studies.

5. Comments:

P. Statistical Methods

1. Methods of statistical analysis:

 

Table # [Heading]

Methods Of Statistical Analysis	Parameters Tested

 

2. Comments:

V. Results

A.   Dose Verification¹⁴ 

1. Were doses verified?    

We suggest using an Excel file to calculate the Means and Standard Deviations (SD).  (Optional): A sample Excel file (calculation.xls) is provided.

Table # [Heading]

 

Dose Groups	Targeted Daily Dose (Mg/Kg Body-Weight/Day)	Targeted Concentration In Feed (Ppm Or Mg/Kg)	Concentrations Found In Feed (Ppm Or Mg/Kg)	Standarddeviation	N*
Low
Mid
High

* Number of measurements (N)

2. Verified by:

3. Comments:

B.   Feed Consumption¹⁵ 

1. Observations:

Table # [Heading]

 

	Daily Feed Consumption (gram of feed consumed/day)
Sex	Males								Females
Targeted Daily Dose (mg/kg body-weight/day)	0 Control								0 Control
Number of Animals
	X	SD	X	SD	X	SD	X	SD	X	SD	X	SD	X	SD	X	SD
0 week
1st week
2nd week
3rd week
4th week
5th week
6th week
7th week
8th week
9th week
10th week
11th week
12th week
13th week

X: Mean, SD: Standard Deviation

2. Comments:

C.   Body Weight¹⁶ 

1. Observations:

Table # [Heading]

	Body Weights (kg body weight/day)
Sex	Males								Females
Targeted Daily Dose (mg/kg body-weight/day)	0 CONTROL								0 CONTROL
Number Of Animals
	X	SD	X	SD	X	SD	X	SD	X	SD	X	SD	X	SD	X	SD
0 week
1st week
2nd week
3rd week
4th week
5th week
6th week
7th week
8th week
9th week
10th week
11th week
12th week
13th week

X: Mean, SD: Standard Deviation

           

2. Comments:

D.   Intake Of Test Substance¹⁷ 

1. Observations:

            Table # [Heading]

	Daily Intake Of Test Material (mg/kg body-weight/day))
Sex	Males								Females
Targeted Daily Dose (mg/kg body-weight/day)	0 CONTROL								0 CONTROL
Number Of Animals
	X	SD	X	SD	X	SD	X	SD	X	SD	X	SD	X	SD	X	SD
0 week
1st week
2nd week
3rd week
4th week
5th week
6th week
7th week
8th week
9th week
10th week
11th week
12th week
13th week

X: Mean, SD: Standard Deviation

2. Comments:

E.   Feed Efficiency¹⁸ 

1.   Was feed efficiency calculated?
2.   Comments:

F.    Cage-Side Observations¹⁹ 

1.   Appearance
2.   Abnormal Stool
3.   Morbidity
4.   Signs of Neurotoxicity 
5.   Comments:

G.   Mortality²⁰ 

1.   Observations:
2.   Comments:

H.  Ophthalmological Examination

1.   Observations:
2.   Comments:

I. Hematology²¹ 

1. Observations:

Table # [Heading]

Sex		Males					Females
Daily Dose mg/kg body-weight/day)		0 Control				0 Control
Number Of Animals
Red Blood Cells
Hematocrit (Hct)	%
Hemoglobin Conc. (Hb)	g/L
Mean Corp. Hb. (MCH)
Mean Corp. Hb. Conc. (MCHC)
Mean Corp. Volume (MCV)	L/L
Total Erythrocyte Count (RBC)	1012/L
White Blood Cells
Basophils
Eosinophils
Lymphocytes	109/L
Macrophage/ Monocytes
Neutrophils	109/L
Total Leukocytes (WBC)	109/L
Clotting Potential
Activated Partial-Thromboplastin Time
Clotting Time
Platelet Count	109/L
Prothrombin Time
Others
Bone marrow cytology
Reticulocyte counts	1012/L

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

2. Comments:

J.    Clinical Chemistry²² 

1. Observations:

Table # [Heading]

Sex		Males				Females
Daily Dose  (mg/kg body-weight/day)		0 Control				0 Control
Number Of Animals
Electrolyte Balance
Calcium	mmol/L
Chloride	mmol/L
Phosphorus	mmol/L
Potassium	mmol/L
Sodium	mmol/L
Carbohydrate Metabolism
Glucose	mmol/L
Liver Function:    A) Hepatocellular
Alanine Amino-transferase  (ALT or SGPT)	U/L
Aspartate Amino-transferase (AST or SGOT)	U/L
Glutamate Dehydrogenase	U/L
Sorbitol Dehydrogenase	U/L
Liver Function:    B) Hepatobiliary
Alkaline Phosphatase (ALP)	U/L
Gamma-Glutamyl Transferase (GGT)	U/L
Total Bile Acids	mmol/L
Total Bilirubin	mmol/L
5' Nucleotidase	U/L
Kidney Function
Creatinine	mmol/L
Urea Nitrogen	Mg/dL
Others
Albumin (A)	g/L
Globulin (G, calculated)	g/L
A/G Ratio
Total protein	g/L
Total Cholesterol	mmol/L
Fasting Triglycerides	mmol/L
Cholinesterase	U/L

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

2. Comments:

K.   Urinalysis²³ 

1. Observations:

Table # [Heading]

Sex		Males				Females
DAILY DOSE  (mg/kg body-weight/day)		0 CONTROL				0 CONTROL
NUMBER OF ANIMALS
Glucose	mmol/L
Microscopic evaluation for sediment and presence of blood/blood cells
pH
Protein	g/L
Specific Gravity
Volume	L/time

 

2. Comments:

L.    Neurotoxicity (If Indicated)²⁴ 

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
Non-Neoplastic Lesion
Non-Neoplastic Lesion
Non-Neoplastic Lesion
Neoplastic Lesions
Neoplastic Lesions
Neoplastic Lesions

+ See under section IV.G for the types of observation for nervous system toxicity: List noteworthy findings.  If additional parameters (other than those in the Template) showed noteworthy changes, these should be added to the tables.  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.  Footnotes should be used as needed to provide additional information about the tests or the results.  Note the severity of the abnormal observations using the following scales; + Mild, ++ Moderate, and +++ Marked or other scales, as appropriate.

# Organs/tissues listed under Section IV.O.

M.  Other Tests²⁵

1.   Observations:
2.   Comments:

 

N.   Organ Weights²⁶ 

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 Weight a	gram
Per Body Weight a	%
Adrenals
Absolute Weight a	gram
Per Body Weight a	%
Per Brain Weighta	%
Epididymides
Absolute Weight a	gram
Per Body Weight a	%
Per Brain Weighta	%
Heart
Absolute Weight a	gram
Per Body Weight a	%
Per Brain Weighta	%
Kidneys
Absolute Weight a	gram
Per Body Weight a	%
Per Brain Weighta	%
Liver
Absolute Weight a	gram
Per Body Weight a	%
Per Brain Weighta	%
Spleen
Absolute Weight a	gram
Per Body Weight a	%
Per Brain Weighta	%
Testes
Absolute Weight a	gram
Per Body Weight a	%
Per Brain Weighta	%
Thyroid and Parathyroid
Absolute Weight a	gram
Per Body Weight a	%
Per Brain Weighta	%
Thymus
Absolute Weight a	gram
Per Body Weight a	%
Per Brain Weighta	%
Ovaries
Absolute Weight A	gram
Per Body Weight a	%
Per Brain Weighta	%
Uterus
Absolute Weight a	gram
Per Body Weight a	%
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:

 

O.   Gross Pathology Changes Observed²⁷ 

1.   Observations:
2.   Comments:

P.   Histopathology Changes Observed²⁸ 

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
Neurologic System 29
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

^# See Section IV.O for the list of organs or tissues.

2. Comments:

 

VI. Evaluation and Comment on Study³⁰ 

 

 

 

 

 

VII. Summary and Conclusions³¹ 

A. Brief Summary Of Major Findings From The Study

 

 

 

B. Relationship Between Dose And Incidence/Severity Of Lesions Or Abnormalities

 

 

 

C. Was There A Target Organ?

 

 

 

D. NOEL

1.   Was there a no observed effect level?
2.   Comments:

 

VIII. References

 

End Notes

¹This Template is set up for typical 90-Day dog studies.  The sections are adjustable; if you find you need more space for a larger group of animals, you can add them to the section.  If you have a smaller group of animals, you can delete the unneeded sections.  The same applies to sections on feed mixtures and data for levels of test substances in feed.

 ²Make note of: Study location (Volume, pages), Study title/Report #, Testing facility, publication dates and comments, if needed.

 ³Indicate Yes or No for the Questions A and B.  However, you may want to elaborate on the type of GLP compliance (USFDA, OECD, etc.) or make other notations

 ⁴Description of the test substance should be given, including purity, any possible contaminants or impurities, any properties of the test substance that could affect its integrity. Are there factors that could affect the actual administered dose, as opposed to the intended dose?

 ⁵After you put a blinking cursor on the http address, (CTRL +) left-click once to follow the link and wait.  Enter a chemical name, CAS Number, or molecular formula inside the search window and click 'search' button.  Right-click inside the molecular structure and select 'copy' submenu.  Return to your document and put the cursor underneath item #4 (molecular structure).  Right click to open up the menu options and select 'paste' submenu.  You can drag the structure to any position you want and resize. If preferred, use other methods of depicting the molecular structure.

 ⁶Indicate how the test substance was given and whether any vehicle was used to dissolve or suspend the test substance (e.g., dissolved in corn oil and mixed into the feed).  Also note if there was adequate testing for concentration and homogeneity and whether stability tests were  done.  Was the strength of the test material checked over the period and under the conditions that the feed mix, test article in vehicle, etc., would be stored?  Note anything that was not normal or routine.

 ⁷Note anything that might have affected the study. Use the comments to indicate extremes or other factors that impacted the study.

 ⁸Provide adequate details. Use the comments to indicate additional information about the experimental design.  To change the table, place cursor in the row or column that you wish to modify, then from the "Table" menu, use "Select Row" or "Select Column" to highlight the row or column that you wish to change, and use the "delete" or "insert" functions to make your changes.

 ⁹Indicate the measurements that were made by highlighting the parameter and dragging the term into the "Examined" side.  Those parameters not examined will remain in the "Not Examined" side. Use the comments to indicate when observations were made and any other notable fact.

 ¹⁰Indicate the measurements or observations that were made by highlighting the parameter and dragging the term into the "Examined" side.  Those parameters not examined will remain in the "Not Examined" side. Use the comments to indicate when observations were made and any other notable fact.

 ¹¹Drag and drop to indicate the parameters that were examined.  Use comments to indicate other important information.

 ¹²Drag and drop to indicate parameters that were examined.  Use comments to indicate other important information.

 ¹³Note when urine was collected for testing, the groups that were tested, and drag and drop the parameters that were tested. Make comments on anything significant.

 ¹⁴Note here whether there was a check or verification of the doses being administered (by what analytical methodology and in which laboratory).  If the test substance was mixed in the feed, was there a statement in the study report verifying, for example, that a 100 ppm feed mixture was analyzed to contain 100 ± 5 ppm, or 100 ± 10 ppm of the test substance?  Was this done more than once? Were there adequate data to calculate the actual dose that was administered? 

We suggest using an Excel file to calculate the Means and Standard Deviations (SD).  (Optional): Download the Excel file named 'calculation.xls' to your computer.  This Excel file contains four sheets named: Dose verification, Body Wt, Feed Consumption, and Intake of test substance.  Each sheet can be accessed by clicking the name tab that appears on the lower left-hand side of the Excel file.

 ¹⁵Note any statistically or biologically significant feed consumption changes. Also note feed consumption changes that were not statistically significant (e.g., at low or mid dose) but could indicate a treatment-related trend. You may wish to insert graphs or use a table as provided in this section or delete it if not needed. To use the optional Excel file (calculation.xls) click the 'Feed Consumption' tab on the lower left-hand side of the file) to calculate the Means and Standard Deviations (SD).

 ¹⁶Note any statistically or biologically significant body weight changes. Also note body weight changes that were not statistically significant (e.g., at low or mid dose) but could indicate a treatment-related trend.  You may wish to insert graphs or use a table as provided in this section or delete it if not needed. To use the optional Excel file, (calculation.xls) click the 'Body Weight' tab on the lower left-hand side of the file) to calculate the Means and Standard Deviations (SD).

 ¹⁷Knowing what the intake of feed and the level of test substance in the feed was, what was the dose actually being delivered to the animals? You may wish to use the table as provided in this section or delete it if not needed. .  To use the optional Excel file (calculation.xls), click the 'Intake of Test Substance' tab on the lower left-hand side of the file to calculate the Means and Standard Deviations (SD).

 ¹⁸Note in this section if feed efficiency was determined; if any changes were observed; if feed efficiency was calculated for all groups or only selected groups; and if calculations were made per group or per animal.

 ¹⁹List significant, dose-related abnormal cage-side observations reported.  Also, use the Table in Section V. L. to note any significant, dose-related abnormal neurotoxicological observations (see Section IV. G for a list of neurotox  parameters).

 ²⁰For each animal with an unscheduled death, note the group, date of death, and any observations, including lesions observed at necropsy.

 ²¹Note findings that were statistically or biologically treatment-related.  Also note changes that were not statistically significant (e.g., at low or mid dose) but could indicate a treatment-related trend.  The comment section is available to explain data findings, if needed.

 ²²Note findings that were statistically or biologically treatment-related.  Also note changes that were not statistically significant (e.g., at low or mid dose) but could indicate a treatment-related trend.  The comment section is available to explain data findings, if needed.

 ²³Note findings that were statistically or biologically treatment-related.  Also note changes that were not statistically significant (e.g., at low or mid dose) but could indicate a treatment-related trend.  The comment section is available to explain data findings, if needed.

 ²⁴ If indicated, list treatment-related findings in the nervous system that were noted under results sections V. F: Abnormal cage-side observations, V. O: Gross pathological changes, and V.P: Histopathological changes.  Provide a statement whether or not the test substance presents a potential neurotoxicity hazard.  If no neurotoxicity was indicated, this section may be omitted or deleted.

 ²⁵ When other tests were conducted, make note of the tests and any significant treatment-related effects.

 ²⁶Note findings that were statistically or biologically treatment-related.  Also note changes that were not statistically significant (e.g., at low or mid dose) but could indicate a treatment-related trend.  The comment section is available to explain data findings, if needed.

 ²⁷Note findings that were statistically or biologically treatment-related.  Also note changes that were not statistically significant (e.g., at low or mid dose) but could indicate a treatment-related trend.  The type of lesion should be noted. The comment section is available to explain data findings, if needed. Also, use a Table at the next histopathology section to note any findings.

 ²⁸Note findings that were statistically or biologically treatment-related.  Also note changes that were not statistically significant (e.g., at low or mid dose) but could indicate a treatment-related trend.  Note treatment-related findings in the nervous system in this section, if not already noted in Section V. L.   The type of lesion should be noted.  The comment section is available to explain data findings, if needed. 

To change the table, place cursor in the row or column that you wish to modify, then from the "Table" menu, use "Select Row" or "Select Column" to highlight the row or column that you wish to change, and use the "delete" or "insert" functions to make your changes.

 ²⁹If this information has already been entered in section V.L.,  delete the relevant rows in this table to prevent duplication of neurologic system entries.

 ³⁰Give your evaluation of the study: what was done well; what the problems were; did the study accomplish what it was supposed to do?

 ³¹Summarize the key findings from the study. Was there a dose-effect relationship? Were target organs identified? Was a NOEL achieved for each significant effect/observation? What was the NOEL?  The whole study should be summarized in this section.

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