VICH GL6 (ECOTOXICITY PHASE I)
June 2000
For implementation at Step 7

E NVIRONMENTAL I MPACT A SSESSMENT(EIA S ) FOR V ETERINARY M EDICINALP 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 GUIDELINE HAS BEEN DEVELOPED BY THE APPROPRIATE VICH EXPERT W ORKING 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.

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Secretariat : c/o COMISA, rue Defacqz, 1 - B - 1000 Bruxelles (Belgium) - Tel. +32-2-541.01.11, Fax +32-2-541.01.19
e-mail : vich@ comisa.org - Website : http://vich.eudra.org

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ENVIRONMENTAL IMPACT ASSESSMENT (EIAS) FOR VETERINARY MEDICINAL
PRODUCTS (VMPS) - PHASE I

Introduction
In 1996, the VICH Steering Committee (VICH SC) authorized formation of a working group to develop
harmonized guidance for conducting environmental impact assessments (EIAs) for veterinary
medicinal products (VMPs) 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 theenvironmental impact assessment of veterinary medicinal products. It is suggested to follow atiered approach based on the principle of risk analysis. Categories of products to be coveredby 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 EIAs for VMPs other than biologicalproducts. 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
VMPs with limited use and limited environmental exposure will have limited environmental effects andthus stop in Phase I. 2 Phase I also identifies VMPs that require a more extensive EIA under Phase II. 3
Some VMPs that might otherwise stop in Phase I may require additional environmental information toaddress particular concerns associated with their activity and use.4 These situations are expected tobe 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, andJP will rely on this document for guidance on conducting Phase I EIAs for VMPs.

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, thequestion is ignored and the applicant continues to the next question. If while working through the1

Current working group members include Ms. Carol Aldridge (EMEA), Dr. Yuuko Endoh (JMAFF), Mr. Shuhei Ishihara(JVPA), Dr. Charles Eirkson (US/FDA/CVM), Dr. Joseph Robinson (AHI) and Dr. Leo Van Leemput (FEDESA).
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 toa 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 isequivalent 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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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 clarificationis 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? 6This Phase I question takes into account the different statutory and regulatory requirements among theEU, JP, and US. If the answer to Question 1 is yes, the applicant does not need to continue through thePhase 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. VMPs 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 areasoned case that use of the VMP will not alter the concentration or distribution of the substance in theenvironment.
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 usuallyindividual treatments. Approval of VMPs for use in non-food animals is likely to be associated with fewer
environmental concerns than approval of VMPs in food-producing animals simply because there is lesstotal 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 amajor species for which an EIA already exists? 7
VMPs intended for use in a minor species may stop in Phase I provided the VMP is already approved foruse in a major species, the minor species is reared under similar conditions as the major species, theVMP 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 will5

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 fromthe 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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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 VMPs from the need for a further assessment when the product is used totreat an individual or a few animals in a flock or herd. It is assumed that the approval of VMPs captured
under this question will produce environmental exposures well below concentrations that impact theenvironment. 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 VMPs that are extensively metabolized in the treated animal do not enter theenvironment. Demonstration of extensive metabolism may be accomplished through a radiolabeledresidue depletion and excretion study. A VMP may be defined as “extensively metabolized” whenanalysis of excreta shows that it is converted into metabolites which have lost structural resemblancewith the parent drug, are common to basic biochemical pathways or when no single metabolite or theparent 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
VMPs intended for treatment of species reared in the aquatic environment, proceed to Questions 8-13.
For VMPs 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 andmitigations, as appropriate, to support a FONSI.
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Aquatic Branch
Question 8: Is entry into the aquatic environment prevented by disposal of the aquatic waste matrix? 8Some VMPs used in aquaculture do not enter the environment because the treatment waste is disposedof by incineration or by other means which similarly preclude entry of the VMP to the environment.
These VMPs 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. VMPs introduced directly into
the aquatic environment have a greater potential to contaminate aquatic habitats. This is because theaquaculture 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, does not stopin 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 allclasses of pharmaceuticals used in human medicine (Reference 1). Very few parasiticides are used inhuman therapy thus the human database is insufficient to establish a quantitative trigger value for thesecompounds. The ecotoxicological potential of this class of compounds needs to be assessed byconducting aquatic effects tests in Phase II.
Question 11: Is the environmental introduction concentration (EICaquatic) of the VMP released fromaquaculture facilities less than 1 µg/L? 8
The rationale for selecting 1 µg/L as the EICaquatic 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 VMPs 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 theenvironment. 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 EICaquatic a total residue
concept is adopted. This involves summing the parent drug and all related metabolites excretedby the target species and entering the aquatic environment; as well as accounting for VMP in theuneaten feed and VMP released to water. This assumes that 100% of the dose is excreted unlessthere are data to support a value less than 100%. The EICaquatic 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 stopat 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, orother mitigations. Other mitigations (both natural degradation and management practices) may
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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 ofwater 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? 8This 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? 8Some VMP’s used in intensive livestock production do not enter the environment because thetreatment waste is disposed of by incineration, or by other means which similarly preclude entry of
the VMP to the environment. These VMPs 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 formof 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 VMP’s advance directly to Question 16.
For animals reared on pasture, there are specific concerns for certain types of products related totheir 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 VMPs 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. VMP’s
that are ecto- and/or endoparasiticides used in pasture should advance directly to Phase II toaddress specific areas of concern, e.g. dung fauna. Other VMP’s 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 PECsoil value of 100 µg/Kg is provided (Reference 2). This value isbelow the level shown to have effects in ecotoxicity studies conducted on earthworms, microbes,
and plants, with VMP’s currently registered in the USA.
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Page 6 of 9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 PECsoil for VMP is provided (Reference 3).
Other approaches for calculating PECsoil should be used if they are more relevant for a particularregion. For calculating PECsoil, a total residue concept is adopted. This involves summing theparent 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 lessbiological activity than the parent compound. Results from degradation studies in manure andsoils 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 lessthan 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 suchcases, the PECsoil calculations may differ. However, even in the pasture setting there is somemigration of the VMP into soil. The PECsoil 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 wholeherd/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/m3, 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 aminimum 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 thecalculation of the PECsoil.
Question 19: Is the recalculated PECsoil 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.

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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 fromenvironmental 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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Figure 1. Phase I Decision Tree
1. Is the VMP exempt from theneed for an EIA by legislation
and/or regulation?

2. Is the VMP a natural substance,
the use of which will not alter theconcentration or distribution of thesubstance in the environment?

No
Yes

Yes

No

STOP
4. Is the VMP intended for use in aminor species that is reared andtreated similarly to a major species
for which an EIA already exists?

3. Will the VMP be used only in
non-food animals?

No
Yes

No

Yes

STOP

Yes

Yes

5. Will the VMP be used totreat a small number ofanimals in a flock or herd?

6. Is the VMP extensively
metabolized in the treated animal?

NoNo

7. Is the VMP used to treat
aquatic or terrestrial species?

AQUATIC

8. Is entry into the aquatic
environment prevented by disposalof the aquatic waste matrix?

Yes

STOP

TERRESTRIAL

Yes

14. Is entry to the terrestrial
environment prevented through disposalof the terrestrial waste matrix?

NoNo

9. Are aquatic species
reared in a confined facility?

15. Are animals rearedon pasture?
Yes

No

Yes

Yes

10. Is the VMP an ectoand/or endoparasiticide?

No

No

No

11. Is the environmental
introduction concentration(EICaquatic) of the VMP
released from aquaculture
facilities < 1 µg/L?

Yes

Yes

STOP
Yes

No

13. Is recalculated
EICaquatic < 1 µg/L?
Yes

No

12. Do data or mitigations
exist that alter the EICaquatic?
No

16. Is the VMP
an ecto- and/or
endoparasiticide?

Phase II

Yes

17. Is the predictedenvironmental concentrationof the VMP in soil (PECsoil)< 100 µg/Kg?
No
18. Do any mitigations
exist that alter the PECsoil?
Yes
19. Is recalculated
PECsoil < 100 µg/kg?

No

No

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Tailored to address
issues of concern

Yes

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