Environmental Assessment:  
Questions and Answers 
Regarding Drugs With 
Estrogenic, Androgenic, or 
  
Thyroid Activity
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2016 
Pharmaceutical Quality/CMC 
   
Environmental Assessment:  
Questions and Answers 
Regarding Drugs With 
Estrogenic, Androgenic, or 
  
Thyroid Activity
Guidance for Industry 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
March 2016 
Pharmaceutical Quality/CMC 
 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  QUESTIONS AND ANSWERS ....................................................................................... 3 
  Contains Nonbinding Recommendations 
Environmental Assessment:  Questions and Answers Regarding 
Drugs With Estrogenic, Androgenic, or Thyroid Activity  
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not create any rights for any person and is not binding on FDA or the public.  You can 
use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To 
discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title 
page.   
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to supplement FDAs guidance for industry on Environmental 
Assessment of Human Drug and Biologics Applications, issued July 1998 (the EA Guidance),2 
by addressing specific considerations for drugs that have potential estrogenic, androgenic, or 
thyroid hormone pathway activity (E, A, or T activity) in the environment.  It is intended to help 
sponsors of such drugs determine whether they should submit environmental assessments (EAs) 
for drug applications and certain supplements, and to clarify what information such sponsors 
should include if they submit a claim of categorical exclusion instead of an EA. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
II.  BACKGROUND 
 
The National Environmental Policy Act of 1969 (NEPA)3 requires all Federal agencies to assess 
the environmental impact of their actions and to ensure that the interested and affected public is 
informed of the environmental analyses.  To comply with NEPA, the Food and Drug 
Administration (FDA) considers the environmental impacts of its actions as an integral part of its 
regulatory process.  FDA regulations at 21 CFR part 25 specify that EAs must be submitted as 
part of certain NDAs, abbreviated new drug applications (ANDAs), biologic license applications 
(BLAs), supplements to such applications, and investigational new drug applications (INDs), as 
                                                 
1 This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and 
Research at the Food and Drug Administration.  
2 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance Web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
3 See http://www.nepa.gov. 
  1  Contains Nonbinding Recommendations 
well as for various other actions, unless the action qualifies for a categorical exclusion.  Failure 
to submit either an EA or a claim of categorical exclusion is sufficient grounds for FDA to refuse 
to file or approve an application (21 CFR 25.15(a), 314.101(d)(4), and 601.2(a) and (c)). 
 
Categorical exclusions for actions related to human drugs and biologics are listed at 21 CFR 
25.31.  This guidance focuses on the categorical exclusion for actions on NDAs and NDA 
supplements that would increase the use of an active moiety, but the estimated concentration of 
the substance at the point of entry into the aquatic environment would be below 1 part per billion 
(1 ppb) (21 CFR 25.31(b)).  Although an action that qualifies for this exclusion ordinarily does 
not require an EA, FDA will require at least an EA if extraordinary circumstances indicate 
that the specific proposed action (e.g., the approval of the NDA) may significantly affect the 
quality of the human environment (21 CFR 25.21).4  One example of extraordinary 
circumstances provided in FDAs regulations is an action for which available data establish that, 
at the expected level of exposure, there is the potential for serious harm to the environment (21 
CFR 25.21(a)). 
 
Consistent with these regulations, when the sponsor of an NDA or NDA supplement5 submits a 
claim of categorical exclusion under 21 CFR 25.31(b), FDA considers whether extraordinary 
circumstances exist under 21 CFR 25.21.  If extraordinary circumstances exist, FDA will require 
the sponsor to submit an EA.  If FDA needs more information to determine whether 
extraordinary circumstances exist, FDA may ask the sponsor to submit additional information 
concerning the potential environmental effects of approval of the sponsors application or 
supplement.  In light of research indicating that drugs with endocrine-related activity and, more 
specifically, drugs with E, A, or T activity, have the potential to cause developmental or 
reproductive effects in the aquatic environment at concentrations below 1 ppb,6 FDA has, on a 
case-by-case basis, requested additional information from sponsors to help it determine whether 
extraordinary circumstances exist.  However, late cycle requests for additional environmental 
information have the potential to delay approval of applications.  Accordingly, this guidance is 
intended to clarify that sponsors of drugs with potential E, A, or T activity should consult with 
the Agency early in product development concerning the information FDA may need to 
determine whether an EA will be required or whether a claim of categorical exclusion will be 
acceptable, and what information should be included in the EA or claim of categorical exclusion. 
 
 
   
                                                 
4 FDA evaluates the information in a sponsors EA, along with relevant, additional information, in making the 
determination whether to prepare an environmental impact statement (21 CFR 25.22(b)). 
5 Unless extraordinary circumstances exist, INDs are categorically excluded from the requirement to submit an EA 
(21 CFR 25.31(e)). 
6 For example, see Section II.C (pp. 7-13) of USFDA, 2013, Response to Citizen Petition to the FDA 
Commissioner under the National Environmental Policy Act and Administrative Procedure Act Requesting an 
Amendment to an FDA Rule Regarding Human Drugs and Biologics, Docket No. FDA-2010-P-0377; U.S. 
Environmental Protection Agency (USEPA), Endocrine Disruptor Screening Program (EDSP), last accessed 
February 17, 2015, at http://www.epa.gov/endo; and Organisation for Economic Co-operation and Development 
(OECD), OECD Work Related to Endocrine Disrupters, last accessed February 17, 2015, at 
http://www.oecd.org/env/ehs/testing/oecdworkrelatedtoendocrinedisrupters.htm. 
  2  Contains Nonbinding Recommendations 
III.  QUESTIONS AND ANSWERS 
 
Q1.  What is a categorical exclusion? 
 
A.  Certain classes of Agency actions are subject to categorical exclusion and, 
therefore, ordinarily do not require the preparation of an EA because, as a class, these 
actions, individually or cumulatively, do not significantly affect the quality of the human 
environment (21 CFR 25.15(c), 40 CFR 1508.4).  The categorical exclusions for CDER 
regulated products are listed at 21 CFR 25.31.  To claim a categorical exclusion the 
applicant must provide:  (1) a statement that the action requested qualifies for a specific 
categorical exclusion, citing the particular categorical exclusion that is claimed; and (2) a 
statement that, to the applicants knowledge, no extraordinary circumstances exist (21 
CFR 25.15(d)). 
 
Q2.  What are extraordinary circumstances? 
 
A.  Extraordinary circumstances are conditions under which a specific proposed action 
may significantly affect the quality of the human environment, including actions that 
ordinarily would fall under a categorical exclusion.  If such extraordinary circumstances 
exist, FDA will require at least an EA (21 CFR 25.21).  Several examples of 
extraordinary circumstances for FDA actions are listed at 21 CFR 25.21 and in Section 
III.C of the EA guidance.  The Agency can also determine on a case-by-case basis 
whether extraordinary circumstances exist for a specific action, such that the submission 
of additional environmental information may be necessary. 
 
Q3.  What drugs are addressed by this guidance? 
 
A.  This guidance addresses drugs with potential E, A, or T activity.  Such drugs include 
(1) estrogenic, androgenic, or thyroid hormones, (2) drugs that are based on these 
hormones (e.g., estrogen derivatives), and (3) drugs that are not based on these hormones 
but that have the potential to interact with E, A, or T hormone pathways (e.g., aromatase 
inhibitors, which block a key enzyme from converting androgens into estrogens). 
 
Q4.  Which categorical exclusions are addressed by this guidance? 
 
A.  This guidance focuses on the categorical exclusion for actions on NDAs and NDA 
supplements if approval of the application would increase the use of the active moiety, 
but the estimated concentration of the substance at the point of entry into the aquatic 
environment will be below 1 ppb (21 CFR 25.31(b)).7 
 
                                                 
7 See 21 CFR 25.5(b)(4) for the definition of increased use and Attachment B of the EA Guidance for examples of 
increased use applications.  In general, abbreviated applications (ANDAs) are not considered to result in increased 
use of an active moiety if approved by the Agency (EA Guidance, Attachment A). 
  3  Contains Nonbinding Recommendations 
Q5.  What extraordinary circumstances does this guidance address? 
 
A.  One example of extraordinary circumstances provided in the regulations is an action 
for which available data establish that, at the expected level of exposure, there is the 
potential for serious harm to the environment (21 CFR 25.21(a)).  Accordingly, in 
determining whether extraordinary circumstances exist for an Agency action on an NDA 
or NDA supplement for a drug with E, A, or T activity that falls within the categorical 
exclusion under 21 CFR 25.31(b), FDA intends to consider available scientific research 
concerning the potential for such drugs to produce developmental or reproductive effects 
in the aquatic environment at expected levels of exposure below 1 ppb.  FDA also intends 
to consider any information provided by the sponsor in support of the sponsors statement 
that no extraordinary circumstances exist. 
 
Q6.  How can the sponsor determine whether the drug has E, A, or T activity? 
 
A.  The sponsor can evaluate existing information such as nonclinical studies (e.g., 
receptor-binding and enzyme assays, pharmacology studies, repeat-dose toxicity studies, 
developmental and reproductive toxicity studies, carcinogenicity studies), ecological 
toxicity studies (fish and invertebrate short-term and life cycle studies), Endocrine 
Disruptor Screening Program (EDSP) studies,8 existing literature on the same or related 
compounds, modeling (including computational toxicology assessments reviewed with 
the use of expert knowledge), structural elements, or other scientific data.  Based on a 
thorough evaluation of the totality of this information, the sponsor should assess whether 
the data are adequate for a determination of E, A, or T activity or whether additional 
studies should be conducted to further characterize the drugs potential E, A, or T 
activity.9 
 
Q7.  If the sponsor has information indicating that the drug has or may have E, A, or T 
activity, and the proposed Agency action would fall within the categorical exclusion 
under 21 CFR 25.31(b), what should the sponsor submit with the application? 
 
A.  The sponsor should submit either an EA or a claim of categorical exclusion that is 
accompanied by information supporting the sponsors statement that no extraordinary 
circumstances exist under 21 CFR 25.21.  Such information should support the 
conclusion that approval of the application would not, at the expected level of exposure, 
significantly affect the quality of the human environment despite the drugs E, A, or T 
activity.  For example, the sponsor could provide information demonstrating negligible 
introductions of the active moiety, metabolites, or degradation products into the 
environment, or information demonstrating that the active moiety, metabolites, or 
degradation products would not be expected to produce developmental or reproductive 
toxicity in the aquatic environment at expected levels of exposure.  In either case, the 
                                                 
8 USEPA, Endocrine Disruptor Screening Program (EDSP), last accessed February 17, 2015, at 
http://www.epa.gov/endo. 
9 A similar approach is described in greater detail in FDAs guidance for industry on Nonclinical Evaluation of 
Endocrine-Related Drug Toxicity. 
  4  Contains Nonbinding Recommendations 
sponsor should consult with the Agency as needed prior to the submission of the NDA as 
described below. 
 
Q8.  When and how should the sponsor consult with the Agency? 
 
A.  If the sponsor has information indicating that the drug has or may have E, A, or T 
activity, the sponsor should consult with the Agency early in product development and 
preferably before initiation of clinical trials.  The sponsor can submit a Type C meeting 
request and include the relevant E, A, or T information in the pre-meeting package.  By 
consulting early with the Agency, the sponsor may learn whether specific studies are 
needed and whether to submit a claim of categorical exclusion or an EA with the NDA.  
Such knowledge can help the sponsor avoid late cycle information requests that could 
delay approval of the application and is especially important in the context of expedited 
drug development. 
 
Q9.  How does the tiered approach to ecotoxicity testing recommended in the EA guidance 
apply to drugs with E, A, or T activity? 
 
A.  Tier 1 and Tier 2 studies described in section IV.B.1 of the EA Guidance are used 
both to assess a drugs acute toxicity and to determine whether Tier 3 chronic and life-
cycle studies (e.g., fish reproduction assays) should be conducted.  For drugs with E, A, 
or T activity, however, sponsors generally should conduct Tier 3 studies, regardless of the 
outcome of Tier 1 and Tier 2 studies.  The sponsor of a drug with E, A, or T activity 
should consult with the Agency as needed during drug development for guidance on 
study recommendations. 
 
Q10.  How will the Agency determine when extraordinary circumstances exist with respect to 
actions involving other types of drugs? 
 
A.  FDA intends to continue monitoring new research and data with respect to other types 
of drugs and to continue exercising its authority to determine on a case-by-case basis 
whether extraordinary circumstances exist and an EA will be required for an Agency 
action that falls within a categorical exclusion under Part 25.  If FDA concludes that it 
needs more information to determine whether extraordinary circumstances exist for a 
proposed action involving another type of drug (e.g., approval of an application), FDA 
may ask the sponsor to submit additional information concerning the potential 
environmental effects of the action.  FDA also may issue additional guidance on EA 
considerations for other types of drugs. 
 
 
  5