148 
 
Guidance for Industry 
 
 
Studies to Evaluate the Safety of Residues of 
Veterinary Drugs in Human Food: 
Developmental Toxicity Testing  
VICH GL32 
 
FINAL GUIDANCE 
 
(This version of the guidance replaces the version that was made available in March 19, 2004. 
This guidance document has been revised to correct the contact information in regard to this document.)
 
This final guidance consolidates developmental toxicity testing recommendations 
of the EU, Japan, and the USA for establishing the safety of veterinary drug 
residues in human 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. 2002D-0369.  
 
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. 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine 
July 27, 2006 
  Contains Non-Binding Recommendations 
 
VICH GL32 (SAFETY: DEVELOPMENTAL TOXICITY) 
October 2002 
For implementation at Step 7 - Final 
 
 
 
 
 
S  
TUDIES TO EVALUATE 
 
THE SAFETY OF RESIDUES OF
V D H  
  ETERINARY  RUGS IN  UMAN
F : 
  OOD
D T  
EVELOPMENTAL  OXICITY 
T  
ESTING
 
 
 
 
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. 
 
Page 2 of 7  Contains Non-Binding Recommendations 
 
STUDIES TO EVALUATE THE SAFETY OF RESIDUES OF 
VETERINARY DRUGS IN HUMAN FOOD: 
DEVELOPMENTAL TOXICITY TESTING 
 
 
 
 
 
 
1.  INTRODUCTION........................................................................................................4 
1.1. Objective of the guidance.................................................................................4 
1.2. Background......................................................................................................4 
1.3. Scope of the guidance......................................................................................5 
1.4. General principles.............................................................................................5 
2. GUIDANCE..................................................................................................................6 
2.1. Number of species............................................................................................6 
2.2. Recommended test protocol.............................................................................7 
3. REFERENCES............................................................................................................7 
 
Page 3 of 7  Contains Non-Binding Recommendations 
 
Studies to Evaluate the Safety of Residues of Veterinary Drugs in 
Human Food:  Developmental Toxicity Testing  
 
This guidance represents the Food and Drug Administrations (FDAs) 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 
 
A number of toxicological evaluations are recommended to establish the safety of 
veterinary drug residues in human food, including the identification of any potential 
effects on human prenatal development. The objective of this guidance is to recommend 
that developmental toxicity assessment be performed according to an internationally 
harmonized approach. This guidance describes a test designed to provide information 
concerning the effects on the pregnant test animal and on the developing organism 
following prenatal exposure to this test animal. 
 
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 
 
The assessment of the potential for developmental toxicity has been identified as one of 
the key areas to be considered in the evaluation of the safety of residues of veterinary 
drugs in human food.  
 
The approach to reproductive and developmental toxicity testing of veterinary drugs 
differs from that adopted by the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH)1. The ICH 
guidance advocates a combination of three studies, in which dosing covers a number of 
stages that include, premating to conception, conception to implantation, implantation to 
closure of hard palate, closure of the hard palate to the end of pregnancy, birth to 
weaning and weaning to sexual maturity. While such an approach may be considered 
appropriate for most human drugs, exposure to veterinary drug residues in human food 
may be long-term, potentially throughout life. For this reason, the combination of the 
multi-generation, long-term VICH reproduction guideline (GL22), which addresses 
stages of exposure not addressed in developmental guidelines, and the current 
guideline (GL32) is believed to be more appropriate for assessing the safety of 
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veterinary drug residues in human food. This current guidance focuses on one stage of 
potential exposure, from implantation through the entire period of gestation to the day 
before caesarean section of the test animal. This guidance provides harmonized 
guidance on the conduct of a developmental toxicity study for the safety evaluation of 
veterinary drug residues in human food and is a core recommendation. 
 
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 should be read in 
conjunction with the guidance on the general approach for the safety evaluation of 
veterinary drug residues in human food (VICH GL33).  This guidance was developed 
after consideration of the existing ICH guidance for pharmaceuticals for human use on 
Detection of Toxicity to Reproduction for Medicinal Products 1, in conjunction with the 
current practices for evaluating veterinary drug residues in human food in the EU, Japan, 
USA, Australia, New Zealand, and Canada. 
 
1.3. Scope of the guidance 
 
This document provides guidance for developmental toxicity testing for those veterinary 
medicinal products used in food-producing animals. However, it does not limit the 
studies that may be performed to establish the safety of residues in human food with 
respect to developmental toxicity. The guidance does not preclude the possibility of 
alternative approaches that may offer an equivalent assurance of safety, including 
scientifically based reasons as to why developmental toxicity data may not need to be 
provided. 
 
1.4. General principles 
 
The aim of developmental toxicity testing is to detect any adverse effects on the 
pregnant female test animal and development of the embryo and fetus consequent to 
exposure of the female from implantation through the entire period of gestation to the 
day before caesarean section. Such adverse effects may include enhanced toxicity 
relative to that observed in non-pregnant female test animals, embryo-fetal death, 
altered fetal growth, and structural changes in the fetus of the test animal. For the 
purpose of this guidance, teratogenicity is defined as the capability of producing a 
structural change in the fetus considered detrimental to the animal, which may or may 
not be compatible with life. 
 
The design of the test should be such that if any adverse effects on development are 
detected, the dose(s) at which they occur and the dose(s) producing no adverse effects 
are clearly identified. Some observations may suggest further study to fully characterize 
the nature of the response or of the dose-response relationship. 
 
Traditionally, two species, one rodent and one non-rodent have been used for 
developmental toxicity testing. Two species are still recommended under the ICH testing 
guidance for developmental toxicity testing for human drugs.   
 
However, a review of an extensive database for veterinary products indicated that a 
tiered approach would provide sufficient data to evaluate veterinary drugs for 
developmental toxicity while reducing the number of animals used in testing2.  The 
recommended tiered strategy for developmental toxicity testing of veterinary products for 
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food animals was developed based on an evaluation of positive and negative teratogenic 
findings from the published Summary Reports of the EU Committee for Veterinary 
Medicinal Products and Joint FAO/WHO Expert Committee of Additives (JECFA) reports 
on veterinary drug residues in food. The data showed: (1) considerable concordance 
between test species; (2) no single test species was consistently more sensitive; and (3) 
in cases where the rabbit was more sensitive than the rat, the difference in sensitivity 
was well within the 10-fold safety factor used to account for interspecies variability.   
 
This recommended approach is described below. 
 
 
2. GUIDANCE 
 
2.1. Number of species 
 
The tiered approach (see Figure 1) should begin with developmental toxicity testing in 
the rat. If clear evidence of teratogenicity is observed, regardless of maternal toxicity, 
testing in a second species would not be recommended, except under the 
circumstances described in the next paragraph. If a negative or an equivocal result for 
teratogenicity is observed in the rat, a developmental test in a second species, 
preferably the rabbit, should be conducted. In the absence of teratogenicity in the rat, a 
developmental toxicity test in a second species would be recommended even if there 
were other signs of developmental toxicity in the rat (i.e. fetotoxicity or embryolethality). 
 
If, upon review of all the core studies, it is apparent that the ADI would be based on 
teratogenicity occurring in the rat, a developmental toxicity study should be conducted in 
another species in order to determine whether the second species shows greater 
sensitivity for developmental effects. It is therefore recommended that a tiered approach 
beginning with a test in the rat be conducted.  The outcome of this initial test should 
indicate whether a developmental test in a second species should be conducted.   
 
 
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Figure 1 
 
 
 
Rat Developmental 
 
  Toxicity Test 
 
 
+ Teratogenicity   
 
- Teratogenicity or 
 
equivocal result  Teratogenicity 
 
    sets ADI ? 
 
     Yes 
 
  No 
 
 
 
Performance of a  Stop 
 
developmental toxicity  Development of toxicity 
 
test in a second species is  test in second species is 
 
recommended  not recommended 
 
 
 
2.2. Recommended test protocol 
 
One appropriate reference method for a developmental toxicity test to establish the 
safety of veterinary drugs used in food-producing animals is the OECD Test Guideline 
414 Prenatal Developmental Toxicity Study. 3 This test guidance includes discussion of 
the number of the test animals, administration period, selection of doses, observations of 
the dams, examination of the fetuses and reporting of results.  
 
 
3. REFERENCES 
 
1.  ICH. 1993. ICH Harmonised Tripartite Guidance S5A. Detection of Toxicity to 
Reproduction for Medicinal Products. International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use. 
 
2.  Hurtt, M.E., Cappon, G.D., and Browning, A.  (2003). Proposal for a tiered approach 
to developmental toxicity testing for veterinary pharmaceutical products for food 
producing animals. Food Chem. Toxicol. 41(5), 611-619. 
 
3.  OECD. 2001. Test Guideline 414. Prenatal Developmental Toxicity Study. In: OECD 
Guidances for the Testing of Chemicals. Organisation for Economic Cooperation & 
Development, Paris. 
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