89 
  
Guidance for Industry 
 
E I A (EIA' )
NVIRONMENTAL  MPACT  SSESSMENTS  S  
V M P (VMP' )-
FOR  ETERINARY  EDICINAL  RODUCTS  S
P I 
HASE 
 
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 
 
 
 
 
 
E I A  
NVIRONMENTAL  MPACT  SSESSMENTS
(EIA' ) V M  
S  FOR  ETERINARY  EDICINAL
P (VMP' ) - P I 
RODUCTS  S     HASE 
 
 
 
 
 
 
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. 
 
Page 2 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.  
 
 
Page 3 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  regions  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)). 
 
 
 
 
 
 
Page 4 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) 
 
 
Page 5  
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 ) of the VMP released from 
aquatic
aquaculture facilities less than 1 g/L? 8 
 
The rationale for selecting 1 g/L as the EIC  is provided (Reference 1).  This value is below 
aquatic
the level shown to have adverse effects in aquatic ecotoxicity studies with human drugs.  The 
EIC   applies  only  to  VMP's  that  will  be  used  to  treat  fish  and  other  aquatic  species  in 
aquatic
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 a total residue 
aquatic 
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  calculation may account for 
aquatic
current management and engineering practices provided appropriate documentation is supplied by 
the applicant.  The calculated value is compared against the 1 g/L value.  If the calculated 
EIC  value for the VMP entering the environment is less than 1 g/L, then the VMP may stop 
aquatic
at Phase I. 
 
Question 12: Do data or mitigations exist that alter the EIC ? 8  
aquatic
 
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 
 
Page 6 specific example, the EIC  for an aquaculture facility may be reduced if additional volumes of 
aquatic
water are used during treatment.  In addition, UV/ozone treatments may be used to reduce the 
EIC if the VMP is known to be labile to these treatments.  When the applicant demonstrates a 
aquatic 
mitigation exists, it can be considered in the calculation of the EIC  
aquatic.
 
Question 13: Is recalculated EIC  less than 1 g/L? 8  
aquatic
 
 
This recalculated value is then compared against the 1 g/L value.  If the recalculated EIC  
aquatic
value for the VMP entering the environment is less than 1 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 ) less than 
soil
100 g/Kg? 8 
 
The rationale for selecting the PEC  value of 100 g/Kg is provided (Reference 2).  This value is 
soil
below the level shown to have effects in ecotoxicity studies conducted on earthworms, microbes, 
and plants, with VMPs currently registered in the US. 
  
 
Page 7 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 for VMP is provided (Reference 3).  
soil 
Other approaches for calculating PEC  should be used if they are more relevant for a particular 
soil
region.  For calculating PEC , a total residue concept is adopted.  This involves summing the 
soil
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 is compared against the value of 100 g/Kg.  If the PEC  for the VMP is less 
soil  soil
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  calculations may differ.  However, even in the pasture setting there is some 
soil
migration of the VMP into soil.  The PEC  estimate for a VMP excreted onto pasture assumes 
soil
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 PEC ? 8 
soil
 
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  may be reduced if there are legal requirements for a 
soil
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  less than 100 g/Kg? 8 
soil
 
The recalculated value is then compared against the 100 g/Kg value.  If the recalculated PEC  
soil
value for the VMP entering the environment is less than 100 g/Kg, then the VMP may stop at 
Phase I. 
 
 
 
(OMB Approval No. 0910-0332) 
 
Page 8  
 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  Trigger Value For Phase I (A retrospective review of ecotoxicity data from 
soil
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 Figure 1.  Phase I Decision Tree 
 
1. Is the VMP exempt from the  2. Is the VMP a natural substance,  
 
need for an EIA by legislation   No  the use of which will not alter the  
  and/or regulation?  concentration or distribution of the  
  Yes  Yes  substance in the environment? 
  
STOP  No 
4. Is the VMP intended for use in a  
minor species that is reared and  
No  3. Will the VMP be used only in  
treated similarly to a major species  
non-food animals? 
for which an EIA already exists? 
Yes  Yes 
No 
STOP 
Yes 
Yes 
5. Will the VMP  be used to 
6. Is the VMP extensively 
treat a small number of  No 
metabolized in the treated animal? 
animals in a flock or herd? 
No 
7. Is the VMP used to treat 
AQUATIC  TERRESTRIAL 
aquatic or terrestrial species? 
8. Is entry into the aquatic   Yes  14. Is entry to the terrestrial  
environment prevented by disposal   STOP  Yes  environment prevented through disposal 
of the aquatic waste matrix?  of the terrestrial waste matrix? 
No 
No 
9. Are aquatic species  
15. Are animals reared 
reared in a confined facility? 
on pasture? 
Yes 
No 
Yes 
16. Is the VMP 
an ecto- and/or 
endoparasiticide?  
Yes  10. Is the VMP an ecto-  No 
and/or endoparasiticide? 
No  Yes  
No 
11. Is the environmental  17. Is the predicted  
introduction concentration  Yes  Yes  environmental concentration  
(EICaquatic) of the VMP   STOP  of the VMP  in soil (PECsoil) 
released from aquaculture  < 100 g/Kg? 
facilities < 1 g/L?  No
Yes
Yes  18. Do any mitigations 
exist that alter the PEC ? 
soil
No  13. Is recalculated 
EIC  < 1 g/L?  Yes 
aquatic
 
Yes  No  19. Is recalculated 
No 
12. Do data or mitigations  PECsoil < 100 g/kg? 
exist that alter the EIC ? 
aquatic
No    Phase II  No 
 
Page 10
Tailored to address 
  issues of concern