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Template For Subchronic Toxicity Study in Dogs

Introduction to the Template for a Subchronic Toxicity Study in Dogs

March 2004

Return to Toxicology Template Introduction

 


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 groupconc. in diet
(ppm or mg/kg)
dose to animals
(mg/kg body-weight/day)
number of malesnumber 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

This section includes some comments that are only relevant when using the Word template.

 

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.

 


Some of the internet links may have been changed in this document. Guidance documents can be found in the guidance area of the Food section of www.fda.gov

 

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