89 

 

Guidance for Industry 

ENVIRONMENTAL IMPACT ASSESSMENTS (EIA'S)

FOR VETERINARY MEDICINAL PRODUCTS (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 PHASE I) 

June 2000 

For implementation at Step 7 

ENVIRONMENTAL IMPACT ASSESSMENTS

(EIA'S) FOR VETERINARY MEDICINAL

PRODUCTS (VMP'S) - PHASE 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 EXPERT WORKING GROUP AND WAS 

SUBJECT TO CONSULTATION BY THE PARTIES, IN ACCORDANCE WITH THE VICH PROCESS. AT STEP 7 OF THE 

PROCESS THE FINAL DRAFT IS RECOMMENDED FOR ADOPTION TO THE REGULATORY BODIES OF THE EUROPEAN 

UNION, JAPAN, AND USA. 

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Guidance for Industry #89 

ENVIRONMENTAL IMPACT 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 (EICaquatic) of the VMP released from 

aquaculture 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 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 EICaquatic 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 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 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 PECsoil 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 PECsoil for VMP is provided (Reference 3). 

Other approaches for calculating PECsoil 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 PECsoil calculations may differ. However, even in the pasture setting there is some 

migration 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 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/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 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 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. 

(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. 

Page 9
 

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 ectoand/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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