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141

Guidance for Industry 

Studies to Evaluate the Safety of Residues of Veterinary 

Drugs in Human Food: Carcinogenicity Testing 

VICH GL28 

FINAL GUIDANCE 

(This version of the guidance replaces the version that was made available in May 24, 

2004. This guidance document has been revised to correct the contact information in 

regard to this document.) 

This final guidance is to ensure that the assessment of carcinogenic potential is appropriate 

to human exposure through residues of veterinary drugs in food. 

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 identified with the Docket No. 2001D-0357. 

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, 240-276-8211. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Veterinary Medicine 

July 27, 2006 

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VICH GL28 (SAFETY: CARCINOGENITICY) 

October 2002 

For implementation at Step 7 - Final 

STUDIES TO EVALUATE 

THE SAFETY OF RESIDUES OF

VETERINARY DRUGS IN HUMAN

FOOD: 

CARCINOGENICITY TESTING

Recommended for Implementation 

on October 2002 

by the VICH Steering Committee 

THIS GUIDANCE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH EXPERT WORKING GROUP AND 

WAS 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. 

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Studies to Evaluate the Safety of Residues of Veterinary Drugs in 

Human Food: Carcinogenicity Testing 

1. INTRODUCTION ............................................................................................................4

1.1. Objective of the guidance................................................................ 4

1.2. Background ..................................................................................... 4

1.3. Scope of the guidance..................................................................... 4

2. CARCINOGENICITY ASSESSMENT ............................................................................4

2.1. Overall approach ............................................................................. 4

2.2. Genotoxic compounds..................................................................... 5

2.3. Non-genotoxic compounds.............................................................. 5

2.4. In vivo carcinogenicity testing.......................................................... 5

2.4.1. Existing relevant guidelines .......................................................................5

2.4.2. Species selection for long-term carcinogenicity testing .............................5

2.4.3. Number of animals and route of administration .........................................5

2.4.4. Dose selection for carcinogenicity testing..................................................6

2.5. In-life observations and pathological examination ........................... 6

3. REFERENCES ...............................................................................................................6

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Studies to Evaluate the Safety of Residues of Veterinary Drugs in 

Human Food: Carcinogenicity Testing 

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking for 

establishing the safety of veterinary drug residues 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 statute(s) and/or 

regulation(s). 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 

In order to establish the safety of veterinary drug residues in human food, a number of 

toxicological evaluations are recommended including the assessment of potential to 

induce neoplasia. The objective of this guidance is to ensure that the assessment of 

carcinogenic potential is appropriate for human exposure to veterinary drug residues in 

human food. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s 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 

The assessment of carcinogenic potential has been identified as one of the key areas to 

be considered in the evaluation of the safety of veterinary drug residues in human food. 

Exposure to residues of veterinary drugs will usually occur at extremely low levels, but 

potentially for long periods, possibly over a lifetime. To ensure that substances that could 

pose carcinogenic potential at relevant exposure levels are adequately assessed, a 

number of issues should be considered, including genotoxicity, metabolic fate, species 

differences, and cellular changes. 

1.3. Scope of the guidance 

This guidance sets out a recommended data-driven decision pathway to determine 

whether carcinogenicity studies should be conducted. It also provides guidance on the 

conduct of carcinogenicity studies. 

2. CARCINOGENICITY ASSESSMENT 

2.1. Overall approach 

The decision to undertake carcinogenicity testing should take into consideration, 1) the 

results of genotoxicity tests, 2) structure-activity relationships, and 3) findings in systemic 

toxicity tests that may be relevant to neoplasia in longer term studies. It should also take 

into consideration any known species specificity of the mechanism of toxicity. Any 

differences in metabolism between the test species, target animal species, and human 

beings should be taken into consideration. 

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2.2. Genotoxic compounds 

Many carcinogens have a genotoxic mode of action and it is prudent to regard 

genotoxicants as carcinogens unless there is convincing evidence that this is not the 

case. Clearly negative results for genotoxicity should usually be taken as sufficient 

evidence of a lack of carcinogenic potential via a genotoxic mechanism. 

2.3. Non-genotoxic compounds 

Because it is generally believed that non-genotoxic compounds exhibit a threshold dose 

for carcinogenicity and human exposure to residues of veterinary drugs is low, nongenotoxic compounds should not be routinely tested for carcinogenicity. Such tests may 

however be recommended if, for example, 1) the compound is a member of a chemical 

class known to be animal or human carcinogens, 2) available systemic toxicity studies 

with the compound identify potentially preneoplastic lesions or findings indicative of 

neoplasia, or 3) systemic toxicity studies indicate that the compound may be associated 

with effects known to be linked with epigenetic mechanisms of carcinogenicity that are 

relevant to humans. 

2.4. In vivo carcinogenicity testing 

2.4.1. Existing relevant guidelines 

The OECD Test Guideline 451 “Carcinogenicity Studies” Ref 1 contains study protocol 

guidelines and approaches for testing chemicals for carcinogenicity using experimental 

animals. OECD Test Guideline serves as the basis for carcinogenicity testing of 

veterinary drugs with clarifications outlined in the following paragraphs. 

Note: Information derived from a combined assay for carcinogenicity and chronic toxicity 

(OECD Test Guideline 453 “Combined Chronic Toxicity/Carcinogenicity Studies”Ref 2 ) 

would also be acceptable. 

2.4.2. Species selection for long-term carcinogenicity testing 

Carcinogenicity bioassays consisting of a two-year rat study and an 18-month mouse 

study are generally recommended. With appropriate scientific justification, carcinogenicity 

studies may be carried out in one rodent species, preferably the rat. A positive response 

in either test species should be considered indicative of carcinogenic potential. 

2.4.3. Number of animals and route of administration 

Consistent with OECD Test Guideline 4511

and common practice, a minimum of 50 rats 

and/or mice per dose (including concurrent controls) per sex is recommended for 

carcinogenicity testing. The route of administration for carcinogenicity testing of 

veterinary drug residues in human food should be oral, preferably dietary. Other routes of 

administration are not generally recommended for risk assessment of veterinary drug 

residues in human food. 

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2.4.4. Dose selection for carcinogenicity testing 

2.4.4.1. General 

It is recommended that at least three dose levels, in addition to a concurrent control 

group(s), be used for typical rodent carcinogenicity studies. 

2.4.4.2. Dose selection 

The high dose should be set to demonstrate a minimum toxic effect without affecting 

survivability due to effects other than carcinogenicity. Demonstration of a toxic effect in 

the carcinogenicity study, without compromising survivability or physiological 

homeostasis, ensures that the animals were sufficiently challenged and provides 

confidence in the reliability of a negative outcome. 

Factors recommended to be considered in establishing other doses include linearity of 

pharmacokinetics, saturation of metabolic pathways, anticipated human exposure levels, 

pharmacodynamics in the test species, the potential for threshold effects in the test 

species, available mechanistic information, and the unpredictability of the progression of 

toxicity observed in short-term rodent studies. It is recommended to set the lowest dose 

at a level that does not induce significant toxicity and is not lower than 10% of the highest 

dose.

2.5. In-life observations and pathological examination 

In-life observations and pathological examination, consistent with OECD Test Guideline 

451Ref 1, are recommended for carcinogenicity studies of veterinary drugs. Clinical 

pathology (hematology, urinalysis, and clinical chemistry) is not considered necessary or 

contributory to the assessment of neoplastic endpoints. 

3. REFERENCES 

1. OECD. 1981. Test Guideline 451. Carcinogenicity Studies. In: OECD Guideline for the 

Testing of Chemicals. Organization for Economic Cooperation & Development, Paris. 

2. OECD. 1981. Test Guideline 453. Combined ChronicToxicity/Carcinogenicity Studies. 

In: OECD Guideline for the Testing of Chemicals. Organization for Economic Cooperation 

& 

Development, Paris.