CVM GFI #232 (VICH GL54) Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food: General Approach to Establish an Acute Reference Dose (ARfD)

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#232
S TUDIES TO EVALUATE THE S AFETY OF
RESIDUES OF VETERINARY
D RUGS IN H UMAN FOOD:
G ENERAL A PPROACH TO ESTABLISH AN
A CUTE REFERENCE D OSE (AR FD)
Guidance for Industry
VICH GL54
Submit comments on this guidance at any time. Submit electronic comments to
https://www.regulations.gov. Submit written comments to the Dockets Management Staff
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD
20852. Identify all comments with the Docket No. FDA-2015-D-1804.
For further information regarding this document, contact AskCVM@fda.hhs.gov.
Additional copies of this guidance document may be requested from the Policy and
Communications Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration,
7500 Standish Place, Rockville, MD 20855, and may be viewed on the Internet at either
https://www.fda.gov/AnimalVeterinary/default.htm or https://www.regulations.gov.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine
August 2017

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VICH GL54 (S AFETY) – ARfD
For Implementation at Step 7
STUDIES TO EVALUATE THE SAFETY OF
RESIDUES OF VETERINARY DRUGS IN
H UMAN FOOD:
G ENERAL APPROACH TO ESTABLISH
AN ACUTE REFERENCE DOSE (ARFD)
Adopted at Step 7 of the VICH Process by the VICH Steering Committee in November 2016
for implementation by November 2017.
This Guidance has been developed by the appropriate VICH Expert Working Group and has been
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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Table of Contents
1. 	Introduction......................................................................................................................... 4
1.1 	Objective ..................................................................................................................................................4
1.2 	Background.............................................................................................................................................4
1.3 	Scope of the current guidance ...........................................................................................................5
2. 	Guidance for an ARfD ........................................................................................................ 6
2.1 	Stepwise procedure ..............................................................................................................................6
2.2 	Information and studies to support an ARfD ................................................................................7
2.2.1 	Use of traditional repeat-dose toxicology studies .................................................. 7
2.2.2 	Acute studies ........................................................................................................... 8
2.3 	How to derive an ARfD .......................................................................................................................8
3. 	Glossary .............................................................................................................................. 9
4. 	References ......................................................................................................................... 11
5. 	Annex 1 - Procedure for the Derivation of an Appropriate ARfD .................................... 12

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S TUDIES TO EVALUATE THE S AFETY OF RESIDUES OF VETERINARY DRUGS IN H UMAN FOOD:
GENERAL APPROACH TO ESTABLISH AN ACUTE REFERENCE DOSE (ARFD)
GUIDANCE FOR INDUSTRY
This guidance represents the current thinking of the Food and Drug Administration (FDA or
Agency) on this topic. It does not establish any rights for any person and is not binding on FDA
or the public. You can use an alternative approach if it satisfies the requirements of the
applicable statutes and regulations. To discuss an alternative approach, contact the FDA office
responsible for this guidance as listed on the title page.
Introduction
1.1 	Objective
The current guidance addresses the nature and types of data that can be useful in determining a
toxicological acute reference dose (ARfD) for residues of veterinary drugs, the studies that may
generate such data, and how the ARfD may be calculated based on these data.
In general, FDA’s guidance documents 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 safety of residues of veterinary drugs in human food is most commonly addressed through
the conduct of toxicology studies in test animal species that provide for the determination of a
no-observed-adverse-effect level (NOAEL)1 and an acceptable daily intake (ADI) by application
of appropriate safety/uncertainty factors (UF(s)).2 The ADI, generally expressed as microgram
(μg) or milligram (mg)/kg body weight per day, is defined as the daily intake which, for up to an
entire lifetime, appears to be without adverse effects or harm to the health of the consumer (see
Glossary).
It has been recognized that there is the potential for some veterinary drug residues to cause
adverse effects in the human consumer following a single meal. The ADI may not be the
appropriate value in such cases for quantifying the level above which exposure after a single
1 Both the terms NOEL (no-observed-effect level) and NOAEL (no-observed-adverse-effect level) have historically
been used to establish an ADI. In practice, NOEL and NOAEL have had similar meanings when used for this
purpose.
2 While some regulatory authorities use the term “safety factor” and others use the term “uncertainty factor,” there is
a general agreement in the application of these terms to address variability between groups (e.g., from animal
models to humans) and within groups (e.g., animal to animal or human to human variability). For the purpose of
this document, UFs will be used to represent the use of either safety or uncertainty factors.

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meal or over one day can produce acute adverse effects. Determining the ARfD is an
appropriate approach to address this concern.
The ARfD approach has been developed to provide a human health guidance value for pesticides
and other chemicals, including veterinary drugs, when their use can result in residues high
enough to cause adverse effects following acute or short-term exposures in people consuming
large portions of food containing the residue. This contrasts with the use of ADIs, which are
established to address potential adverse effects following chronic or long-term exposures to
residues in foods.
Various publications which describe the ARfD approach are available. In 2005, some members
of the United Nations Joint Food and Agriculture Organization (FAO)/World Health
Organization (WHO) Meeting on Pesticide Residues (JMPR) published a paper describing the
development of the ARfD for acute health risk assessment of agricultural pesticides (Solecki et
al., 2005). The Organization for Economic Co-Operation and Development (OECD) has
finalized Guidance No. 124, “Guidance for the Derivation of an Acute Reference Dose,” which
is primarily intended for pesticides, biocides, and veterinary drugs (IOMC, 2010). The OECD
Guidance No. 124 describes a tiered approach that is intended to maximize the use of available
data and minimize the need for studies specifically designed to derive an ARfD. This approach
is consistent with the 3-Rs (Replacement, Refinement and Reduction) minimizing the use of
animals in the development of veterinary drugs. In addition, the Joint FAO/WHO Expert
Committee on Food Additives (JECFA) has noted that “certain substances ….. e.g., some metals,
mycotoxins, or veterinary drug residues, could present an acute risk, i.e., could raise concern
regarding acute health effects in relation to short periods of intake at levels greater than the ADI
or TDI3.” JECFA agreed that, “building on the experience of and the guidance developed by
JMPR ….. the need to establish an ARfD should be considered on a case-by-case basis, and only
if the substance, on the basis of its toxicological profile and considering the pattern of its
occurrence and intake, is likely to present an acute health risk resulting from exposure in a period
of 24 h or less” (JECFA, 2005). JECFA and JMPR have contributed to the International
Program on Chemical Safety (IPCS) Environmental Health Criteria (EHC) 240 describing the
derivation of an ARfD in the application of a maximum residue limit (MRL), a tolerance, or
other national or regional tools used to establish an acceptable concentration of residues of the
veterinary drug in the edible tissues of treated animals (IPCS, 2009). In 2016, JECFA published
a draft guidance for monographers on the use and interpretation of the ARfD. This document
continues to be under development.
1.3 	Scope of the current guidance
This guidance can be used to address the nature and types of data that should be useful in
determining an ARfD, the studies that may generate such data, and how the ARfD can be
calculated based on these data. The current guidance is limited to the application of
toxicological and pharmacological endpoints and offers special consideration for residues of
veterinary drugs in contrast to the available guidances and guidances that address the derivation
and use of the ARfD for human exposure to pesticides, contaminants, and chemicals other than
veterinary drugs. The guidance provides internationally harmonized technical recommendations
3 TDI – tolerable daily intake.

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for an ARfD used in support of veterinary product registration/approval. Detailed guidance on
the derivation of an ARfD may be found in OECD Guidance 124 (IOMC, 2010).
This guidance does not, except in very broad terms, address
• 	When an ARfD would or would not be appropriate to address the concerns of a national
or regional regulatory authority.
• 	Evaluation of specific pharmacological or toxicological adverse effects that may lead to
the determination of an ARfD.
• 	Human dietary exposure data that may be appropriate for use with an ARfD in the
derivation of an MRL, a tolerance or other national or regional tools used to refine an
acceptable concentration of the veterinary drug residue in food.
• 	Refinement of the exposure calculation for the acute health risk assessment.
• 	Routes of human exposure to veterinary drugs other than the oral route.
Recognizing international efforts to address possible acute effects of residues of an antimicrobial
veterinary drug on the human intestinal microbiota following acute human exposure, the current
guidance only provides a harmonized approach to a toxicological ARfD at this time.
Finally, this guidance does not seek to limit the studies that can be performed to establish the
safety of residues in human food with respect to acute toxicity. Neither does it preclude the
possibility of alternative approaches that can offer an equivalent assurance of safety, including
scientifically-based reasons as to why such data are not warranted.
Guidance for an ARfD
2.1 	Stepwise procedure
Before examining the endpoints of acute pharmacological effects and toxicity, and before
designing studies, careful consideration should be given to the 3-Rs principles. Therefore, the
following stepwise approach is recommended before conducting an acute toxicity study:
• 	Step 1. Evaluate available pharmacological and toxicological data and information,
including data from repeated-dose toxicity studies, in order to establish whether or not
acute endpoints (attributable to the first 24 hours of dosing) have been adequately
addressed.
• 	Step 2. If additional acute toxicity information is needed, consideration to the 3-Rs
principle should be given, for example, by integrating observations/examinations related
to acute endpoints in planned standard toxicity studies.
• 	Step 3. If the two options in Steps 1 and 2 are insufficient to provide adequate
information on acute endpoints, then a new, specifically designed toxicity study(ies) can
be considered.
• 	See also the decision tree in Annex 1.

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2.2 	Information and studies to support an ARfD
The first consideration should be to examine available data and information that describe the
physical, chemical, pharmacological, and toxicological characteristics of the veterinary drug.
This information can be available from data provided to support human food safety as per VICH
GL33 or through published peer reviewed literature. In addition the studies provided under
VICH GL33 to support safety may provide useful information for the evaluation of acute toxicity
endpoints that support the assessment of an ARfD. It is recommended that all information on a
specific veterinary drug be considered in the derivation of a chemical specific ARfD.
2.2.1 	Use of traditional repeat-dose toxicology studies
The following are key points for consideration when evaluating information regarding the
potential for acute toxicity:
• 	In the absence of data to the contrary, all relevant indications of acute adverse
pharmacological and toxicological effects observed in repeated-dose studies can be
considered as potentially relevant to setting an ARfD.
• 	Particular emphasis should be given to observations and investigations at the beginning
of repeated dose studies.
Examples of potential endpoints of acute toxicity in standard toxicity studies include those
described in OECD Guidance No. 124 (see paragraphs 36 through 59) and in EHC 240 (see
section 5.2.9.5). Endpoints could include, but are not limited to, haematoxicity, immunotoxicity,
neurotoxicity, hepatotoxicity, nephrotoxicity, developmental effects, reproductive effects,
pharmacological effects, and direct effects on the gastrointestinal tract as well as clinical
findings. In keeping with the goal of reducing the number of animals for testing, in some cases,
it may be possible to modify the standard toxicology study protocols to provide more relevant
information for the assessment of the ARfD without compromising the original objective of the
study. For example, a veterinary drug might be anticipated to cause acute haematological
changes; the protocol for a repeat-dose oral toxicity study in rats could be modified to include
satellite groups where blood is sampled from control and treated animals beginning on the first
day through the first two weeks of dosing to evaluate whether this endpoint occurs after one or
just a few doses. If no effects are observed in the high dose group then no further evaluation of
the collected samples would be warranted. Further, in this example a lower bound for potential
acute toxicity may be established based on the high dose group in the study. In addition to the
endpoints mentioned in EHC 240, adverse effects observed at the beginning of the study should
be taken into consideration.
Prior to modification of an existing protocol, consideration should be given to available data and
information that describe the physical, chemical, pharmacological, and toxicological
characteristics of the veterinary drug, including its possible mode of action (MOA). While the
relevant dosing for assessment of an ARfD is anticipated to be an acute dose (a single dose or up
to a single day’s dosing), the timing for measurement of effects should be based on an
understanding of available pharmacokinetics and pharmacodynamics of the veterinary drug.
Particular emphasis should be given to observations and investigations at the beginning of the

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repeat-dose study in the determination of potential acute toxicity. The inclusion of selected
endpoints for the evaluation of acute toxicity beyond those described in the guidance documents
should be considered on a case-by-case basis.
Consideration should be given to dose selection, numbers of animals, and the use of satellite
groups. A high dose group within the repeat-dose toxicity study protocol that is relevant to
concerns related to acute exposure to the human consumer could inform an ARfD evaluation.
Elements of study design described in OECD Guidance No. 124, Annex 2, can be incorporated
into modifications of an existing repeat-dose toxicity study. Dose selection is also critical when
developing a point of departure (POD) for the derivation of the ARfD. The POD from the most
sensitive endpoint relevant to human food safety in the most appropriate species should be used.
2.2.2 	Acute studies
In some cases, an appropriate POD to determine an ARfD is not available from existing
information. Studies intended to address chronic toxicity may not provide sufficient information
to allow a robust estimate of the ARfD. In such cases, a single exposure study specifically
designed to support an ARfD for a given veterinary drug may be warranted. In all cases, it is
recommended that the design of an acute effect study specifically to derive an ARfD include
consideration of all available relevant physical, chemical, pharmacological, and toxicological
information, and also consider the MOA (particularly of the pharmacologically active substance)
where relevant.
Specific guidance on the conduct of a single exposure toxicity study can be found in Annex 2 of
OECD Guidance No. 124.
2.3 	How to derive an ARfD
The basic approach for the derivation of an ARfD is based on the identification of an appropriate
POD, or threshold, for the pharmacological or toxicological endpoint of concern. This is
typically identified as a NOAEL dose or benchmark dose lower confidence limit (BMDL). The
ARfD is determined by dividing this POD by an appropriate UF(s). The ARfD can be reported
as an amount of the substance expressed on a per person or body weight basis (e.g., mg/person or
mg/kg body weight)
UF
POD
=	ARfD
Where:
POD is the point of departure or threshold for pharmacological or toxicological effects of
concern (see Glossary).
UF is an uncertainty or safety factor, or series of factors that typically account for considerations
such as animal to animal variability, interspecies extrapolation, quality of data, severity of
response, etc. (see Glossary). Additional recommendations on the selection of an appropriate

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uncertainty factor (described as a chemical specific assessment factor) are provided in Step One
of the Tiered-Approach for the Derivation of an appropriate ARfD in OECD Guidance No 124
(IOMC, 2010).
Consideration should be given to the discussion of uncertainty factors in OECD Guidance No.
124 (see page 21) and EHC 240 (see section 5.2.3). The selection of appropriate UFs for inter-
species and human inter-individual variabilities should be considered based on available data.
To provide for the quantitative incorporation of differences in the toxicokinetic/toxicodynamics
for a chemical, the default 10-fold factor for inter-species variability and the default 10-fold
factor for human inter-individual variability can be used. When available, chemical-specific UFs
on one or more specific sources of variability could replace the default values to adjust sub-
factors for inter-species and human inter-individual variabilities. If chemical specific
toxicokinetic and toxicodynamic data are inadequate to justify data based UFs, consider any
information (e.g., quantitative structure-activity relationship (QSAR) or MOA, of closely related
compounds) that would indicate reduced or increased uncertainty.
When an ARfD could be determined based on toxicological and/or pharmacological endpoints,
the ARfD should be based on the endpoint that is most relevant for protecting public health.
Glossary
The following definitions apply for purposes of this guidance:
3-Rs 	Replacement, Refinement, Reduction. VICH is committed to approaches that
reduce, refine or replace the use of laboratory animals (the 3Rs) while maintaining appropriate
scientific standards. The 3Rs principles were first introduced in Russell and Burch's 1959 book,
'The principles of humane experimental technique'.
ADI 	Acceptable Daily Intake is the daily intake which, during up to an entire life of a
human, appears to be without adverse effects or harm to the health of the consumer. The ADI
most often will be set on the basis of the drug’s toxicological, microbiological, or
pharmacological properties. It is usually expressed in micrograms or milligrams of the chemical
per kilogram of body weight per day.
ARfD 	Acute Reference Dose. An estimate of the amount of residues expressed on a
body weight basis that can be ingested in a period of 24 h or less without adverse effects or harm
to the health of the human consumer.
BMD 	Benchmark Dose. A dose of a substance associated with a specified low
incidence of response, generally in the range of 1 to 10%, of a health effect, or a dose associated
with a specified measure or change of a biological effect. See Benchmark Dose Software
(BMDS) (US Environmental Protection Agency, 2015), and PROAST (National Institute for
Public Health and the Environment (RIVM), 2014).
BMDL 	Benchmark Dose Lower Confidence Limit. A dose producing an appropriate,
low, and measurable response at a defined lower bound response level based on the lower one-

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sided confidence limit of a 95% confidence interval extrapolated from a line fitted to available
data for an appropriate endpoint.
EHC 	Environmental Health Criteria. International Program on Chemical Safety (IPCS)
documents that provide international critical reviews on the effects on human health and the
environment of chemicals or combinations of chemicals, including veterinary drugs, as well as
physical and biological agents.
IPCS 	International Program on Chemical Safety. A joint program of the World Health
Organization, International Labor Organization and the United Nations Environment
Programme.
MOA 	Mode of Action. A biologically plausible sequence of key events leading to an
observed effect supported by robust experimental observations and mechanistic data. A mode of
action describes key cytological and biochemical events, that is, those that are both measurable
and necessary to the observed effect in a logical framework.
NOEL 	No Observed Effect Level. The highest administered dose that was observed not
to cause an effect in a particular study.
NOAEL 	No Observed Adverse Effect Level. The highest administered dose that was
observed not to cause an adverse effect in a particular study.
OECD 	Organization for Economic Co-operation and Development brings together the
governments of various countries to support sustainable economic growth, boost employment,
raise living standards, maintain financial stability, assist other countries’ economic development
and contribute to world trade.
POD 	Point of Departure. A reference point for hazard characterization; typically a
point on a dose-response curve at which the response first becomes apparent, and represents
toxicological or pharmacological effects of concern; often classified as a NOEL, NOAEL, or
BMDL.
QSAR 	Quantitative Structure Activity Relationship. A quantitative relationship between
a biological activity (e.g., toxicity) and one or more molecular descriptions that are used to
predict activity.
Satellite Groups 	Additional groups of animals typically treated following all or some of the
study treatment protocol and then examined for endpoints that differ from the main study group
or are in other ways treated differently. For example, a satellite group of rats receiving all
treatments but limited to a few animals per treatment group can be used for
pharmacokinetic/toxicokinetic measurements, or a satellite group containing all treatment groups
but only receiving a single dose can be used to examine acute effects in a subchronic repeat dose
study.

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UF 	Uncertainty Factors. Typically UFs are intended to account for uncertainty in
extrapolating animal data to humans (inter-species variability), the variation in sensitivity among
humans (inter-individual variability), quality of data, severity of response, or other concerns,
where available sources of variability can be replaced with chemical specific information to
refine the UF, such as toxicokinetics, toxicodynamics, QSAR, MOA, and information on closely
related compounds.
References
US Environmental Protection Agency (EPA). Benchmark dose software (BMDS) and User’s
Manual. Available from: https://www.epa.gov/bmds.
European Food Safety Agency (EFSA). Guidance of the Scientific Committee on a request from
EFSA on the use of the benchmark dose approach in risk assessment. The EFSA Journal. 2009.
1150:1-72.
Inter-Organization Programme for the Sound Management of Chemicals (IOMC). 2010. OECD
Environment Directorate Joint Meeting of the Chemicals Committee and the Working Party on
Chemicals, Pesticides and Biotechnology. Series on Testing and Assessment. No. 124. Guidance
for the Derivation of an Acute Reference Dose. Env/JM/MONO(2010)15.
Joint FAO/WHO Expert Committee on Food Additives. Sixty-fourth meeting. Rome, 8-17
February 2005. Summary and Conclusions. Available from:
ftp://ftp.fao.org/es/esn/jecfa/jecfa64_summary.pdf.
International Programme on Chemical Safety. 2009. Environmental Health Criteria 240.
Principles and Methods for the Risk Assessment of Chemicals in Food. Food and Agriculture
Organization of the United Nations and World Health Organization.
Solecki, R, Davies L, Dellarco V, Dewhurst I, van Raaij M, and Tritscher A. 2005. Guidance on
setting of acute reference dose (ARfD) for pesticides. Food and Chemical Toxicology 43:1569-
1593.
VICH. 2009. VICH Guidance 33, Safety Studies for Veterinary Drug Residues in Human Food:
General Approach to Testing.

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Annex 1 - Procedure for the Derivation of an Appropriate ARfD
Select the Appropriate Point of Departure
Select an Uncertainty Factor
Is the
Available
Information
Adequate?
Evaluate Existing Database
Calculate ARfD
Need more information
No
Yes
Select the Appropriate Endpoints Incorporate Appropriate Endpoints
into Repeat-Dose Study, or
Conduct Acute Toxicity Study
When ARfD is appropriate