**89**

**Guidance for Industry**

[Environmental Impact Assessments (EIA\'s) for Veterinary Medicinal
Products (VMP\'s)-Phase I]{.smallcaps}

###### 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 Dockets Management Branch (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, 301-827-6958,
E-mail: <ceirkson@cvm.fda.gov>.

######### U.S. Department of Health and Human Services

######### Food and Drug Administration

**Center for Veterinary Medicine**

**March 7, 2001**

**VICH GL6 [(Ecotoxicity Phase I)]{.smallcaps}**

**June 2000**

**For implementation at Step 7**

[Environmental Impact Assessments]{.smallcaps}

[(EIA\'s) for Veterinary Medicinal]{.smallcaps}

[Products (VMP\'s) - Phase I]{.smallcaps}

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 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]{.smallcaps} USA.

**Guidance for Industry #89**

**[Environmental Impact Assessments (EIA\'s) for veterinary medicinal
Products (VMP\'s) - Phase I]{.smallcaps}**

***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 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 applicant**^5^** 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? [^5]

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? [^6]

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]

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**.**

# 

# 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 **μ**g/L? **^8^**

The rationale for selecting 1 **μ**g/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
EIC~aquatic~ 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 **μ**g/L value. If the calculated EIC~aquatic~
value for the VMP entering the environment is less than 1 **μ**g/L, then
the VMP may stop at Phase I.

**Question 12:** Do data or mitigations exist that alter the
EIC~aquatic~? **^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 EIC~aquatic~ 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 EIC~aquatic~ 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 EIC~aquatic.~

**Question 13:** Is recalculated EIC~aquatic~ less than 1 **μ**g/L?
**^8^**

This recalculated value is then compared against the 1 **μ**g/L value.
If the recalculated EIC~aquatic~ value for the VMP entering the
environment is less than 1 **μ**g/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 (PEC~soil~) less than 100 **μ**g/Kg? **^8^**

The rationale for selecting the PEC~soil~ value of 100 **μ**g/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.

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 PEC~soil~, 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 PEC~soil~ is compared against the value of 100
**μ**g/Kg. If the PEC~soil~ 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 PEC~soil~?
**^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 PEC~soil~ 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 PEC~soil~.

**Question 19:** Is the recalculated PEC~soil~ less than 100 **μ**g/Kg?
**^8^**

The recalculated value is then compared against the 100 **μ**g/Kg value.
If the recalculated PEC~soil~ value for the VMP entering the environment
is less than 100 **μ**g/Kg, then the VMP may stop at Phase I.

(OMB Approval No. 0910-0332)

# 

#  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 PEC~soil~ 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.

[^1]: 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]: 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]: 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]: 4 In the US, this is equivalent to an extraordinary circumstance
    under NEPA.

[^5]: 6^5^ 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)).

[^6]: 7

[^7]: 7

[^8]:
    # 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)