Contains Non-Binding Recommendations 
 
 
160 

 
Guidance for Industry 

 
Studies to Evaluate the Safety of Residues of 

Veterinary Drugs in Human Food: 

Repeat-Dose (Chronic) Toxicity Testing 

VICH GL-37 

 
FINAL GUIDANCE 

(This version of the guidance replaces the version that was made available in February 4, 2005. 
This guidance document has been revised to correct the contact information in regard to this 
document.) 
 
 
 
Comments and suggestions regarding the document should be submitted to Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, 
MD  20852. Submit electronic comments to http://www.regulations.gov/.  All comments should be 
HTU UTH
identified with the Docket No. 2003D-0466. 
 
For questions regarding this document, contact the Division of Human Food Safety, Center for 
Veterinary Medicine, (HFV-150), Food and Drug Administration, 7500 Standish Place, Rockville,  
MD 20855, 240-276-8208. 
 
Additional copies of this guidance document may be requested from the Communications Staff 
(HFV-12), Center for Veterinary Medicine, Food and Drug Administration, 7519 Standish Place, 
Rockville, MD 20855, and may be viewed on the Internet at 
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm.  
HTU UTH
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Veterinary Medicine 

July 27, 2006 

   
VICH GL37 (SAFETY)   
May 2004 
For implementation at Step 7 - Final 
 
 
 
 
 
STUDIES TO EVALUATE THE SAFETY OF RESIDUES 
OF VETERINARY DRUGS IN HUMAN FOOD: 
REPEAT-DOSE CHRONIC TOXICITY TESTING  
 
 
 
 
 
 
 
Recommended for implementation by May 2005 
by the VICH SC at its meeting held in May 2004  
 
 
 
 
 
 
 
 
 
This Guidance has been developed by the appropriate VICH Expert Working Group and is subject to 
consultation by the parties, in accordance with the VICH Process.  At Step 7 of the Process the final draft is 
recommended for adoption to the regulatory bodies of the European Union, Japan and USA.  STUDIES TO EVALUATE THE SAFETY OF RESIDUES OF VETERINARY 

DRUGS IN HUMAN FOOD REPEAT-DOSE (CHRONIC)  

TOXICITY TESTING 

 
This final guidance represents the agencys current thinking on the safety of residues of veterinary drugs in  
human food.  It does not create or confer any rights for or on any person and does not operate to bind FDA or 
the public.  You can use an alternative approach if the approach satisfies the requirements of the applicable 
statutes  and regulations.  If you want to discuss an alternative  approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the  appropriate FDA staff, call the appropriate number listed 
on the title page of this guidance.   
 
 
1. INTRODUCTION 
 
1.1. Objective of the guidance 
 
A variety of toxicological evaluations are performed to establish the safety of veterinary 
drug residues in human food.  The objective of this guidance is to establish 
recommendations for internationally harmonized repeat-dose (chronic) toxicity testing. 
 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the Agencys current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory  or statutory  requirements are cited.   
The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
1.2. Background and scope of the guidance 
 
The current guidance is one of a series of guidances developed to facilitate the mutual 
acceptance of safety data necessary for the determination of acceptable daily intakes 
(ADIs) for veterinary drug residues in human food.  This guidance was developed after 
consideration of the current practices for evaluating veterinary drug residues in human 
food in the EU, Japan, USA, Australia, New Zealand, and Canada.  It also took account of 
available data from sub-chronic and chronic toxicity studies. 
 
While this guidance recommends  the framework for chronic toxicity testing of veterinary 
drugs, it is important that the design of the test remains flexible.  This guidance does not 
preclude the possibility of alternative approaches that may offer an equivalent assurance 
of safety, including scientifically based reasons as to why chronic toxicity testing may not 
need to be provided.  Within the context of this guidance, tests should be tailored to 
adequately establish the dose-response relationship and a no-observed adverse effect 
level (NOAEL) for toxicity seen following chronic treatment. 
 
 
 
  1.3. General principles 
 
Adequate toxicity testing should include the administration of repeated doses to assess 
the effects of prolonged exposure to a parent compound and/or metabolites, to define the 
toxic effects of compounds following chronic exposure, and to ascertain the highest dose  
that does not produce toxicity.  All available information on the compound should be 
utilized in designing the chronic toxicity test.  The data obtained in this test may be used to 
establish a NOAEL for a veterinary drug. 
 
2. GUIDANCE 
 
2.1. Repeat-dose (chronic) toxicity testing  
 
2.1.1. Purpose 
 
Chronic toxicity testing is recommended to (1) define toxic effects based on long-term 
exposures to the compound and/or its metabolites, (2) identify target organs and 
toxicological endpoints in relation to dose and/or duration of exposure, (3) determine 
dosages associated with toxic and biological responses, and (4) establish a NOAEL. 
 
2.1.2. Selection of test species 
 
Species selection should consider the relevance to human metabolism, pharmacokinetics 
and pharmacodynamics.  If testing in two species is to be conducted, one should be a 
rodent and the other a non-rodent.  Generally, the default rodent species recommended is 
the rat, and the default non-rodent species recommended is the dog. 
 
A review of available data on a large number of chemicals resulted in differing but equally 
valid interpretations as to whether one or two species should be used for chronic toxicity  
testing in the EU, USA, and Japan.  Future data may clarify this issue.  In Japan, chronic 
studies are required in two species.  However, with appropriate scientific justification, 
chronic toxicity testing may be performed in only one species (see Appendix A).  In the EU 
and the USA, chronic testing should be performed in the most appropriate species chosen 
on the basis of all available scientific data, including 90-day studies.  The default species 
recommended is the rat. 
 
2.1.3. Experimental design 
 
Chronic toxicity tests should be conducted in accordance with OECD Test Guideline 452 
Chronic Toxicity Studies. 1   
P P 
 
2.1.4. Pathological examination 
 
Gross necropsy and histopathological examination should be performed in accordance 
with OECD Test Guidelines 408 (Repeated Dose 90-day Oral Toxicity Study in Rodents 
P  2) and 409 (Repeated Dose 90-day Oral Toxicity Study in Non-rodents 3) with the 
P	 P P
following amendments: 
o 	  the following tissues also should be examined: bone (sternum, femur and joint), 
clitoral or preputial gland (rodents only), Harderian gland, lachrymal gland, larynx, 
nasal cavity, optic nerves, pharynx, and Zymbal gland (rodents only). 
o 	  for non-rodents, histopathological evaluations should be made on all prescribed 
tissues plus gross lesions from all animals. 
 
 
 
 
 
 
 
 
3. REFERENCES 
 
1. OECD. 1981. Test Guideline 452. Chronic Toxicity Studies. In: OECD Guidelines for 
the testing of chemicals Organization for Economic Cooperation & Development, Paris.   
 
2. OECD. 1998. Test Guideline 408. Repeated Dose 90-day Oral Toxicity Study in 
Rodents. In: OECD Guidelines for the testing of chemicals. Organization for Economic 
Cooperation & Development, Paris. 
 
3. OECD. 1998. Test Guideline 409. Repeated Dose 90-day Oral Toxicity Study in Non-
rodents. In: OECD Guidelines for the testing of chemicals. Organization for Economic 
Cooperation & Development, Paris. 
 
 
  APPENDIX A 
 
 
In Japan, Justifications for Performing Chronic Toxicity Studies in Only  
One Species When two are Normally Required 
 
Some criteria for eliminating one species: 
 
1. When it is shown that the mechanism/mode of action that is responsible for the 
occurrence of toxicity of the test substance in one species cannot be extrapolated to 
humans. 
 
2. When it is demonstrated that the metabolism of the test substance in one species is not 
applicable to humans. 
 
If these are unknown, then: 
 
3. When it is demonstrated that the absorption rate from the gastrointestinal tract is 
extremely low in one species, as compared to the other species.