CVM GFI #89 (VICH GL6) EIAs for Veterinary Medicinal Products - Phase I

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

89
Guidance for Industry
ENVIRONMENTAL I MPACT A SSESSMENTS (EIA' S )
FOR V ETERINARY M EDICINAL P RODUCTS (VMP' S )-
PHASE I
VICH GL6
Final Guidance
This 	final 	guidance 	is 	intended 	to 	harmonized 	methods 	used 	in 	conducting 	environmental
assessments for veterinary medicinal products in the European Union, Japan, and the United
States.
Comments and suggestions regarding the final document should be submitted to Division of
Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 	20852. 	Comments should be identified with the full title of the guidance document
and the Docket No. 99D-2975.
For questions regarding this guidance document, contact Charles E. Eirkson, Center for Veterinary
Medicine, (HFV-145), Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855,
240-276-8173, E-mail: charles.eirkson@fda.hhs.gov .
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Veterinary Medicine
March 7, 2001

VICH GL6 (ECOTOXICITY P HASE I)
June 2000
For implementation at Step 7
E NVIRONMENTAL 	I MPACT 	A SSESSMENTS
(EIA' S ) 	FOR 	V ETERINARY 	M EDICINAL
P RODUCTS 	(VMP' S ) 	- 	P HASE 	I
Recommended for Implementation
at Step 7 of the VICH Process
on 15 June 2000
by the VICH Steering Committee
THIS GUIDANCE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH E XPERT WORKING GROUP AND WAS
SUBJECT TO CONSULTATION BY THE PARTIES , IN ACCORDANCE WITH THE VICH P ROCESS. AT STEP 7 OF THE
P ROCESS THE FINAL DRAFT IS RECOMMENDED FOR ADOPTION TO THE REGULATORY BODIES OF THE EUROPEAN
UNION , JAPAN , AND USA.
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Guidance for Industry #89
ENVIRONMENTAL I MPACT ASSESSMENTS (EIA' S) FOR VETERINARY MEDICINAL
PRODUCTS (VMP'S) - PHASE I
This guidance represents FDA' s current thinking on this matter and does not create or confer any
rights for or on any person, and does not operate to bind FDA or the public. An alternate method may
be used as long as it satisfies the requirements of the applicable statutes and regulations.
Introduction
In 1996, the VICH Steering Committee (VICH SC) authorized formation of a working group to develop
harmonized 	guidance 	for 	conducting 	environmental 	impact 	assessments 	(EIA's) 	for 	veterinary
medicinal products (VMP's) in the European Union (EU), Japan (JP) and the United States (US). The
mandate of the VICH Ecotoxicity/Environmental Impact Assessment Working Group (VICH Ecotox
WG), 1 as set forth by the VICH SC, is as follows:
"To elaborate tripartite guidelines on the design of studies and the evaluation of the
environmental impact assessment of veterinary medicinal products. It is suggested to follow
a tiered approach based on the principle of risk analysis. 	Categories of products to be
covered by the different tiers of the guideline should be specified. Existing or draft guidelines
in the EU, Japan, and the US should be taken into account."
This document presents guidance on how to conduct Phase I EIA's for VMP's other than biological
products. Consistent with the mandate, two phases of EIA are recommended. In Phase I, the potential
for environmental exposure is assessed based on the intended use of the VMP. It is assumed that
VMP's with limited use and limited environmental exposure will have limited environmental effects and
thus stop in Phase I. 2 Phase I also identifies VMP's that may need a more extensive EIA under Phase
II. 3 Some VMP's that might otherwise stop in Phase I may need additional environmental information
to address particular concerns associated with their activity and use.4 These situations are expected
to be the exception rather than the rule and some evidence in support of the concern should be
1 Current working group members include Ms. Carol Aldridge (European Medicines Evaluation Agency), Dr. Yuuko
Endoh (Japanese Ministry of Agriculture, Forestry and Fisheries), Mr. Shuhei Ishihara (Japanese Veterinary
Pharmaceutical Association), Dr. Charles Eirkson (US/Food and Drug Administration/Center for Veterinary Medicine),
Dr. Joseph Robinson (Animal Health Institute) and Dr. Leo Van Leemput (European Federation of Animal Health).
2 In the US, reference to a Phase I EIA is equivalent to either a categorical exclusion or an environmental assessment
(EA) conducted under the National Environmental Policy Act (NEPA). A VMP that may stop at Phase I is equivalent to
a categorical exclusion or an EA which leads to a finding of no significant impact (FONSI) under NEPA.
3 Phase II represents a second level of environmental analysis that may include testing. In the US, a Phase II EIA is
equivalent to an EA with more extensive data than would be required under the US equivalent of a Phase I EIA. A Phase
II EIA may lead to a FONSI or an Environmental Impact Statement under NEPA.
4 In the US, this is equivalent to an extraordinary circumstance under NEPA.
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available. In an effort to harmonize the EIA to the maximum extent possible, it is expected that the EU,
US, and JP will rely on this document for guidance on conducting Phase I EIA's for VMP's.
Phase I Guidance
The Phase I EIA for a VMP makes use of the decision tree in Figure 1. To use the Phase I decision tree,
the applicant5 works through the questions until they arrive at a question which allows them to conclude
that their product qualifies for a Phase I report. 	If there is no information on a particular question, the
question is ignored and the applicant continues to the next question. 	If while working through the
decision tree, an applicant determines that their VMP did not need an EIA, Question 1 still applies.
When an applicant determines that at least one of the Phase I criteria has been met, the applicant should
produce a Phase I EIA report discussing the basis for the decision. If the assessment determines that
the VMP has limited exposure for more than one reason, each reason may be discussed to strengthen
the Phase I EIA report. 	However, as suggested by the Phase I decision tree, the types of Phase II
studies needed will vary based upon the concerns identified in Phase I. In situations where clarification
is needed, it is important that the applicant contact the appropriate regulatory authorities.
Question 1: Is the VMP exempt from the need for an EIA by legislation and/or regulation? 6
This Phase I question takes into account the different statutory and regulatory requirements among the
EU, JP, and US. If the answer to Question 1 is yes, the applicant does not need to continue through the
Phase I decision tree but should comply with the region’s rules regarding submission of required
documentation.
Question 2: Is the VMP a natural substance, the use of which will not alter the concentration or
distribution of the substance in the environment? 7
It is assumed that many natural substances are already present in the environment or are rapidly
degraded upon entry into the environment, such that environmental exposure is not altered. VMP's likely
to stop at this question include electrolytes, peptides, proteins, vitamins, and other compounds that occur
naturally in the environment. 	In answering this question, the applicant documents and should give a
reasoned case that use of the VMP will not alter the concentration or distribution of the substance in the
environment.
Question 3: Will the VMP be used only in non-food animals? 7
5 In the US, the term “applicant” refers to the drug sponsor.
6 In the US, this includes products that are categorically excluded under NEPA. If a product is not categorically
excluded due to an extraordinary circumstance, however, the answer to this question is no – the VMP is not exempt from
the need for an EIA.
7 In the US, these VMPs are usually categorically excluded under NEPA. (21 CFR 25.33(c), 25.33(d)(1), 25.33(d)(2),
25.33(d)(3), 25.33(d)(4), 25.33(d)(5)).
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Generally, non-food animals are not intensively reared. Also, products used in these animals are usually
individual treatments. Approval of VMP's for use in non-food animals is likely to be associated with fewer
environmental concerns than approval of VMP's in food-producing animals simply because there is less
total amount of product used. The definition of non-food animals varies among the three regions.
Question 4: Is the VMP intended for use in a minor species that is reared and treated similarly to a
major species for which an EIA already exists? 7
VMP's intended for use in a minor species may stop in Phase I provided the VMP is already approved for
use in a major species, the minor species is reared under similar conditions as the major species, the
VMP is administered by the same route and the total dose administered to the minor species is no
greater than that used in the major species. In this case, it is assumed that use in the minor species will
have limited environmental impact. There are differences regarding what constitutes major versus minor
species among the EU, JP, and US.
Question 5: Will the VMP be used to treat a small number of animals in a flock or herd? 7
This question may exempt VMP's from the need for a further assessment when the product is used to
treat an individual or a few animals in a flock or herd. It is assumed that the approval of VMP's captured
under this question will produce environmental exposures well below concentrations that impact the
environment. 	Products used to treat clinically mastitic cows, anesthetics used for surgical purposes,
ophthalmics, and hormones used as reproductive aids for individual animals may fall within the scope of
this question.
Question 6: Is the VMP extensively metabolized in the treated animal? 8
It is assumed that VMP's that are extensively metabolized in the treated animal do not enter the
environment. Demonstration of extensive metabolism may be accomplished through a radiolabeled
residue depletion and excretion study. 	A VMP may be defined as “extensively metabolized” when
analysis of excreta shows that it is converted into metabolites which have lost structural resemblance
with the parent drug, are common to basic biochemical pathways or when no single metabolite or the
parent drug exceeds 5% of the total radioactivity excreted.
Question 7: Is the VMP used to treat species reared in the aquatic or in the terrestrial environment?
The answer to this question defines the initial route by which the VMP enters the environment. 	For
VMP's intended for treatment of species reared in the aquatic environment, proceed to Questions 8-13.
For VMP's intended for treatment of species reared in the terrestrial environment, proceed to Questions
14-19.
8 In the US, information provided to respond to this question must be provided in an EA that includes documentation and
mitigations, as appropriate, to support a FONSI. (21 CFR 25.40)
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Aquatic Branch
Question 8: Is entry into the aquatic environment prevented by disposal of the aquatic waste matrix? 8
Some VMP's used in aquaculture do not enter the environment because the treatment waste is disposed
of by incineration or by other means which similarly preclude entry of the VMP to the environment.
These VMP's have no opportunity to impact the environment. Applicants answering yes to this question
should 	provide 	documentation 	to 	demonstrate 	that 	the 	VMP 	does 	not 	enter 	the 	environment.
Incineration of the waste matrix, containing the VMP, is an example of a means of disposal that may
permit stopping in Phase I, if the documentation described above can be provided.
Question 9: Are aquatic species reared in a confined facility? 8
A confined facility is defined as one in which the effluent can be treated and the discharge controlled.
This includes facilities such as tanks, lined ponds, and some raceways. VMP's introduced directly into
the aquatic environment have a greater potential to contaminate aquatic habitats. 	This is because the
aquaculture facility is contiguous with the aquatic environment, and there is no opportunity for processing
or treatment of effluents. Therefore, any VMP used to treat aquatic species, where the product is placed
directly into the environment, e.g., net pens, should not stop in Phase I.
Question 10: Is the VMP an ecto- and/or endoparasiticide?
The ecotoxicity database used to develop the quantitative value used in Question 11 included all classes
of pharmaceuticals used in human medicine (Reference 1). 	Very few parasiticides are used in human
therapy thus the human database is insufficient to establish a quantitative trigger value for these
compounds. 	The ecotoxicological potential of this class of compounds should be assessed by
conducting aquatic effects tests in Phase II.
Question 11: Is the environmental introduction concentration (EIC aquatic ) of the VMP released from
aquaculture facilities less than 1 μg/L? 8
The rationale for selecting 1 μg/L as the EIC aquatic is provided (Reference 1). This value is below
the level shown to have adverse effects in aquatic ecotoxicity studies with human drugs. 	The
EICaquatic applies only to VMP's that will be used to treat fish and other aquatic species in
confinement where the effluent can be treated and controlled prior to being discharged into the
environment. 	In order to apply this value, it is necessary to estimate the concentration of VMP
expected in the effluent from the aquaculture facility. For calculating the EIC aquatic a total residue
concept is adopted. This involves summing the parent drug and all related metabolites excreted
by the target species and entering the aquatic environment, as well as accounting for VMP in the
uneaten feed and VMP released to water. This assumes that 100% of the dose is excreted unless
there are data to support a value less than 100%. 	The EIC aquatic calculation may account for
current management and engineering practices provided appropriate documentation is supplied by
the applicant. 	The calculated value is compared against the 1 μg/L value. 	If the calculated
EICaquatic value for the VMP entering the environment is less than 1 μg/L, then the VMP may stop
at Phase I.
Question 12: Do data or mitigations exist that alter the EICaquatic? 8
The concentration of the VMP in the effluent may be decreased by filtration, settlement, dilution, or
other mitigations. 	Other mitigations (both natural degradation and management practices) may
reduce the concentration of the VMP in water and hence reduce environmental exposure. 	As a

specific example, the EICaquatic for an aquaculture facility may be reduced if additional volumes of
water are used during treatment. 	In addition, UV/ozone treatments may be used to reduce the
EICaquatic if the VMP is known to be labile to these treatments. When the applicant demonstrates a
mitigation exists, it can be considered in the calculation of the EICaquatic.
Question 13: Is recalculated EICaquatic less than 1 μg/L? 8
This recalculated value is then compared against the 1 μg/L value. 	If the recalculated EICaquatic
value for the VMP entering the environment is less than 1 μg/L, then the VMP may stop at Phase I.
Terrestrial Branch
Question 14: Is entry to the terrestrial environment prevented through disposal of the terrestrial
waste matrix? 8
Some VMPs used in intensive livestock production do not enter the environment because the
treatment waste is disposed of by incineration or by other means which similarly preclude entry of
the VMP to the environment. 	These VMP's have no opportunity to impact the environment.
Applicants answering yes to this question should provide documentation to demonstrate that the
VMP does not enter the environment. Incineration of the waste matrix, containing the VMP, is an
example of a means of disposal that may permit stopping in Phase I, if the documentation
described above can be provided.
Question 15: Are animals reared on pasture?
For intensively-reared animals that are housed or raised in feedlots, excreta is collected in the form
of manure and slurries, stored, and then spread onto agricultural land, with or without ploughing.
For these VMP's, advance directly to Question 17. This is in contrast to animals raised on pasture,
where excretion is directly into the environment. For these VMPs advance directly to Question 16.
For animals reared on pasture, there are specific concerns for certain types of products related to
their direct entry into the environment. For some products both Question 16 and Question 17 will
be applicable.
Question 16: Is the VMP an ecto- and/or endoparasiticide?
Ecto- and endoparasiticides have specific ecotoxicity concerns especially when used in animals
reared on pasture. These VMP's are pharmacologically active against organisms that are
biologically related to pasture invertebrates. 	Because protozoa are not biologically related to
pasture invertebrates, products used to treat protozoa are not captured in this question. 	VMPs
that are ecto- and/or endoparasiticides used in pasture should advance directly to Phase II to
address specific areas of concern, e.g., dung fauna. Other VMPs used in pasture animals should
advance to Question 17.
Question 17: Is the predicted environmental concentration of the VMP in soil (PECsoil ) less than
100 μg/Kg? 8
The rationale for selecting the PEC soil value of 100 μg/Kg is provided (Reference 2). This value is
below the level shown to have effects in ecotoxicity studies conducted on earthworms, microbes,
and plants, with VMPs currently registered in the US.
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In order to apply this value, it is necessary to estimate the concentration of the VMP in terrestrial
ecosystems. 	An example on how to calculate the PEC soil for VMP is provided (Reference 3).
Other approaches for calculating PEC soil should be used if they are more relevant for a particular
region. 	For calculating PECsoil , a total residue concept is adopted. 	This involves summing the
parent drug with all related metabolites excreted by the treated animal. This assumes that 100%
of the dose is excreted unless residue depletion data support a value less than 100%. The total
residue approach is considered to be conservative in assessing effects in that it combines parent
plus metabolites in calculating environmental concentrations, and metabolites generally have less
biological activity than the parent compound. 	Results from degradation studies in manure and
soils may be used to refine the estimate of the concentration of the VMP in soil (Reference 3). The
calculated PECsoil is compared against the value of 100 μg/Kg. If the PECsoil for the VMP is less
than the value, then the EIA for the VMP may stop in Phase I.
Some products used in intensively-reared livestock may also be used in pasture animals. In such
cases, the PEC soil calculations may differ. 	However, even in the pasture setting there is some
migration of the VMP into soil. 	The PEC soil estimate for a VMP excreted onto pasture assumes
direct entry into soil with even distribution in the upper 5 cm of soil. 	This estimate for whole
herd/flock treatments is based upon: (1) dose/animal based on mg/kg and body-weight of animal;
(2) percentage of dose excreted by the treated animals (use 100% if no excretion data are
available); (3) stocking density of treated animals (animals/hectare); (4) excreted VMP is
distributed in soil to 5 cm; and (5) bulk density of soil. Effectively, this means that for a soil bulk
density of 1,500 kg/m 3
, the total dose/hectare is distributed in 750,000 Kg of soil.
Question 18: Do any mitigations exist that alter the PECsoil ? 8
The concentration of the VMP in soil may be decreased by standard animal husbandry practices,
manure management, or other mitigations. 	Other mitigations (both natural and management
practices) may reduce the concentration of the VMP in soil and hence reduce the environmental
exposure. As a specific example, the PECsoil may be reduced if there are legal requirements for a
minimum storage period for manure and there are data to show that degradation during storage
occurs. 	When the applicant demonstrates a mitigation exists, it can be considered in the
calculation of the PECsoil .
Question 19: Is the recalculated PEC soil less than 100 μg/Kg? 8
The recalculated value is then compared against the 100 μg/Kg value. If the recalculated PECsoil
value for the VMP entering the environment is less than 100 μg/Kg, then the VMP may stop at
Phase I.
(OMB Approval No. 0910-0332)
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REFERENCES
1. 	Center for Drug Evaluation and Research (CDER), US Food and Drug Administration, 1997.
Retrospective review of ecotoxicity data submitted in environmental assessments for public
display. Docket No. 96N-0057.
2. 	AHI Environmental Risk Assessment Working Group, 1997, Analysis Of Data And Information
To Support A PECsoil Trigger Value For Phase I (A retrospective review of ecotoxicity data from
environmental assessments submitted to FDA/CVM to support the approval of veterinary drug
products in the United States from 1973-1997).
3. 	Spaepen, K. R. I., L. J. J. Van Leemput, P. G. Wislocki and C. Verschueren, 1997. A uniform
procedure to estimate the predicted environmental concentration of the residues of veterinary
medicines in soil. Environmental Toxicology and Chemistry 16: 1977-1982.
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No
Yes
Yes
9. Are aquatic species
reared in a confined facility?
11. Is the environmental
introduction concentration
(EICaquatic) of the VMP
released from aquaculture
facilities < 1 μg/L?
17. Is the predicted
environmental concentration
of the VMP in soil (PECsoil )
< 100 μ 	?
No
g/Kg
10. Is the VMP an ecto-
and/or endoparasiticide?
No
15. Are animals reared
on pasture?
No
No
16. Is the VMP
an ecto- and/or
endoparasiticide?
Yes
STOP
Yes 	Yes
Yes
No
Yes
AQUATIC 	TERRESTRIAL
7. Is the VMP used to treat
aquatic or terrestrial species?
8. Is entry into the aquatic
environment prevented by disposal
of the aquatic waste matrix?
14. Is entry to the terrestrial
environment prevented through disposal
of the terrestrial waste matrix?
STOP
Yes Yes
5. Will the VMP be used to
treat a small number of
animals in a flock or herd?
6. Is the VMP extensively
metabolized in the treated animal?
No
No
Yes
2. Is the VMP a natural substance,
the use of which will not alter the
concentration or distribution of the
substance in the environment?
3. Will the VMP be used only in
non-food animals?
4. Is the VMP intended for use in a
minor species that is reared and
treated similarly to a major species
for which an EIA already exists?
Figure 1. Phase I Decision Tree
1. Is the VMP exempt from the
need for an EIA by legislation
and/or regulation?
No
STOP
Yes 	Yes
No
No
STOP
Yes 	Yes
Yes
No
Phase II
Tailored to address
issues of concern
12. Do data or mitigations
exist that alter the EICaquatic?
13. Is recalculated
EICaquatic < 1 μg/L?
Yes
No
No
No
18. Do an 	itigations
exist that alter the PECsoil?
y m
No
Yes
Yes
19. Is recalculated
PECsoil < 100 μg/kg? 	No
No
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