Guideline No. 147
Guidance for Industry 147 - Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food: Repeat-Dose (90-Day) Toxicity Testing - VICH GL31
Revised July 27, 2006
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR VETERINARY MEDICINE
Guidance for Industry
Studies to Evaluate the Safety of Residues of
Veterinary Drugs in Human Food:
Repeat-Dose (90-Day) Toxicity Testing
VICH GL31
(This version of the guidance replaces the version that was made available in November 12, 2003. This guidance document has been revised to correct the contact information in regard to this document.)
The objective of this guidance is to establish recommendations for an internationally harmonized 90-day repeat-dose testing
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.fda.gov/dockets/ecomments. All comments should be identified with the Docket No. 02D-0368.
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, 301-594-1626.
GL31 (SAFETY: REPEAT-DOSE (90-DAY) TOXICITY)
October 2002
For implementation at Step 7 - Final
STUDIES TO EVALUATE
THE SAFETY OF RESIDUES OF
VETERINARY DRUGS IN HUMAN
FOOD:
REPEAT-DOSE (90-DAY)
TOXICITY 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.
REPEAT-DOSE (90-DAY) TOXICITY TESTING
TABLE OF CONTENTS
1. INTRODUCTION
1.1. Objective of the guidance
1.2. Background and scope of the guidance
1.3. General principles
2. GUIDANCE
1.1.1. Purpose
2.1.2. Experimental design for a 90-day toxicity test
2.1.2.1.Pathological examination
3. REFERENCES
REPEAT-DOSE (90-DAY) TOXICITY TESTING
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This guidance represents the agency’s current thinking on 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. |
1.1. 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 90-day repeat-dose testing.
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 and scope of the guidance
The current guidance is one of a series of guidances developed to facilitate the mutual acceptance of safety data 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 European Union, Japan, United States, Australia, New Zealand, and Canada.
Although this guidance recommends a framework for 90-day toxicity testing of veterinary drugs, it is important that the design of the tests remain flexible. It is recommended that tests be tailored to adequately establish the dose-response and a no-observed adverse effect level (NOAEL) for toxicity following 90-day compound treatment.
1.3. General principles
Adequate toxicity testing should include an assessment of the effects of repeated exposure to a parent compound and/or metabolites. It should also ascertain a dose that does not produce toxicity. As with other types of toxicity testing it is recommended that available information on the compound be utilized in designing the test. Repeat-dose toxicity tests should be performed in sensitive/appropriate species. While species selection should take account of relevance to human metabolism, pharmacokinetics and pharmacodynamics, the generally accepted default species recommended are the rat and the dog. It is recommended that exposure begin early enough in life to encompass the growth phase of the test animals. In general, the highest dose should be sufficient to produce toxicity. The data obtained from this test may be used to establish a NOAEL for a veterinary drug.
2. GUIDANCE
2.1. Repeat-dose (90-day) toxicity test
2.1.1. Purpose
It is recommended that repeat-dose (90-day) toxicity testing be performed in a rodent and a non-rodent species in order to (1) identify target organs and toxicological endpoints, (2) provide information that will help the setting of dose levels to be used in repeat-dose (chronic) toxicity testing, and (3) identify the most appropriate species for subsequent repeat-dose (chronic) toxicity testing. A NOAEL should be identified from the results of each repeat-dose (90-day) toxicity test.
2.1.2. Experimental design for a 90-day toxicity test
It is recommended that repeat-dose (90-day) toxicity tests be conducted in accordance with OECD Test Guidelines 408 “Repeated Dose 90-day Oral Toxicity Study in Rodents”1 and 409 “Repeated Dose 90-day Oral Toxicity Study in Non-rodents.”2
2.1.2.1. Pathological examination
It is recommended that gross necropsy and histopathological examination be performed in accordance with Organization for Economic Cooperation and Development (OECD)Test Guidelines 4081 and 4092 with the following exception: for non-rodents, histopathological evaluations should be made on a standardized set of tissues plus gross lesions from all animals in all groups.
3. REFERENCES
1. OECD. 1998. Test Guideline 408. Repeated Dose 90-day Oral Toxicity Study in Rodents. In: OECD Guidelines for the Testing of Chemicals. Organisation for Economic Cooperation & Development, Paris.
2. OECD. 1998. Test Guideline 409. Repeated Dose 90-day Oral Toxicity Study in Non-rodents. In: OECD Guidelines for the Testing of Chemicals. Organisation for Economic Cooperation & Development, Paris.
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