[Federal Register Volume 62, Number 145 (Tuesday, July 29, 1997)]
[Rules and Regulations]
[Pages 40570-40600]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19566]



[[Page 40569]]

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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



21 CFR Part 10, et al.



National Environmental Policy Act; Revision of Policies and Procedures; 
Final Rule

  Federal Register / Vol. 62, No. 145 / Tuesday July, 29, 1997 / Rules 
and Regulations  

[[Page 40570]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 10, 20, 25, 71, 101, 170, 171, 312, 314, 511, 514, 
570, 571, 601, 812, and 814

[Docket No. 96N-0057]


National Environmental Policy Act; Revision of Policies and 
Procedures

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its 
regulations governing compliance with the National Environmental Policy 
Act of 1969 (NEPA) as implemented by the regulations of the Council on 
Environmental Quality (CEQ). The primary purpose of this final rule is 
to increase the efficiency of FDA's implementation of NEPA and to 
reduce the number of NEPA evaluations by providing for categorical 
exclusions for additional classes of actions that do not individually 
or cumulatively have a significant effect on the human environment and 
for which, therefore, neither an environmental impact statement (EIS) 
nor an environmental assessment (EA) is required. FDA is also amending 
its regulations to make its NEPA procedures more concise and 
understandable to the public and to reflect current FDA policy with 
respect to environmental considerations. The amendments to FDA's 
regulations governing compliance with NEPA reflect FDA's continuing 
review of its policies and procedures to determine whether revisions 
are necessary to ensure full compliance with the purpose and provisions 
of NEPA and implement the President's reinventing Government 
initiatives announced in ``Reinventing Drug and Medical Device 
Regulations,'' April 1995, and ``Reinventing Food Regulations,'' 
January 1996.

DATES: The regulations are effective on August 28, 1997. For 
applications or petitions pending before the agency on August 28, 1997, 
for which the agency has not signed a finding of no significant impact 
(FONSI) on or before August 28, 1997, the applicant or petitioner may 
submit an amendment to the application or petition under 21 CFR 
10.30(g), 71.6(b), 171.6, 314.60, 514.6, 571.6, 601.2 or 814.37 
claiming a categorical exclusion in accordance with Sec. 25.15(d) of 
this final rule. The applicant or petitioner should state in the 
amendment that the applicant or petitioner waives the claim for 
categorical exclusion if a FONSI has been signed on or before August 
28, 1997.

FURTHER INFORMATION CONTACT:

For information regarding human drugs:
    Nancy B. Sager, Center for Drug Evaluation and Research (HFD-357), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-594-5629
For information regarding biologics:
    Daniel C. Kearns, Center for Biologics Evaluation and Research 
(HFM-208), Food and Drug Administration, 1401 Rockville Pike, 
Rockville, MD 20852, 301-827-3031
For information regarding veterinary medicines:
    Charles E. Eirkson, Center for Veterinary Medicine (HFV-150), Food 
and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-
594-1683
For information regarding foods:
    Buzz L. Hoffmann, Center for Food Safety and Applied Nutrition 
(HFS-246), Food and Drug Administration, 200 C St. SW., Washington, DC 
20204, 202-418-3005
For information regarding medical devices and radiological health:
    Mervin O. Parker, Center for Devices and Radiological Health (HFZ-
402), Food and Drug Administration, 9200 Corporate Blvd., Rockville, MD 
20850, 301-594-2186

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of April 3, 1996 (61 FR 14922) (republished 
May 1, 1996 (61 FR 19476)), FDA proposed to amend its regulations in 
part 25 (21 CFR part 25) governing compliance with NEPA as implemented 
by the regulations of CEQ. FDA provided 90 days for public comment on 
the proposed rule. In addition, in the Federal Register of October 22, 
1996 (61 FR 54746), FDA announced the placement in the administrative 
record of additional information and underlying data concerning the 
proposed rule, and granted a 30-day comment period permitting 
interested parties to submit comments relating to those categorical 
exclusions for which additional information was provided. The agency 
has revised portions of the final regulations in response to comments 
received on the proposal.
    This final rule amending FDA's NEPA procedures increases the 
efficiency of the agency's implementation of NEPA by substantially 
reducing the number of EA's required to be submitted by industry and 
reviewed by FDA and by providing for categorical exclusions for 
additional classes of actions that do not individually or cumulatively 
have a significant impact on the human environment. This final rule 
also makes the regulations more concise and useful to the public and 
regulated industry.

II. Comments on the Proposed Rule

    FDA received 17 letters, including letters from manufacturers, 
trade associations, environmental groups, academics, environmental 
consultants, and the U.S. Environmental Protection Agency (EPA), 
commenting on the proposed rule. In general, the comments supported 
FDA's proposed revisions to more efficiently implement NEPA. One 
manufacturer of human and veterinary pharmaceuticals projected that the 
final rule would reduce by 75 percent the number of its products that 
will require EA's, and a pharmaceutical industry trade association 
estimated that the rule will reduce by 90 percent the amount of 
environmental information submitted to the agency. FDA's analysis of 
the impacts of this final rule is included in section III of this 
document, ``Analysis of Impacts.''

A. Subpart A--General Provisions

    1. One comment stressed the need to have more interaction and 
greater alignment among the agencies involved in implementing NEPA in 
order to develop more consistent policies.
    CEQ regulations direct agencies with similar programs to consult 
with each other and with CEQ to coordinate their procedures (40 CFR 
1507.3). However, differences in Federal agencies' policies and 
procedures to implement NEPA are inevitable because each agency has its 
own distinct statutory mandates. Each agency needs to evaluate and 
prioritize different environmental risks based on the nature of the 
agency's actions. CEQ reviews the procedures of all agencies to ensure 
their conformity with NEPA and CEQ regulations. FDA consults and 
coordinates with other Federal agencies regarding the protection of the 
environment to the fullest extent possible.
    2. Proposed Sec. 25.5(b)(4) states that increased use of a drug or 
biologic product may occur if the drug may be administered at higher 
dosage levels, for longer duration or for different indications than 
were previously in effect, or if the drug is a new molecular entity. 
This section further defines new molecular entity as, ``a drug for 
which the active moiety * * * has not been previously approved or 
marketed in the

[[Page 40571]]

United States for use in a drug product, either as a single ingredient 
or as part of a combination product or as part of a mixture of 
stereoisomers.'' FDA has decided not to include the definition of new 
molecular entity in Sec. 25.5(b)(4). The term is currently defined in 
guidance documents issued by the Center for Drug Evaluation and 
Research (CDER). The agency does not find it necessary to include the 
definition in its regulations. Parties interested in the definition of 
new molecular entity should consult the information available from 
CDER.
    3. Proposed Sec. 25.10(c) describes when the environmental planning 
process begins under NEPA: ``For actions initiated by applicants or 
petitioners, NEPA planning begins when FDA receives a submission from 
an applicant or petitioner seeking action by FDA.'' Proposed 
Sec. 25.10(c) differs from current Sec. 25.10(a), which states that:

    For actions initiated by applicants or petitioners, the process 
begins when FDA receives from an applicant or petitioner an 
environmental assessment (EA) or a claim that a categorical 
exclusion applies, or when FDA personnel consult with applicants or 
petitioners on the NEPA-related aspects of their requested actions.

    One comment indicated that current Sec. 25.10(a) is consistent with 
NEPA and CEQ regulations because it provides for consultation between 
the agency and applicants or petitioners prior to Federal action. 
However, the comment contended that proposed Sec. 25.10(c), as it 
amends current Sec. 25.10(a), is inconsistent with NEPA and CEQ 
regulations. The comment specifically cites an inconsistency between 
proposed Sec. 25.10(c) and 40 CFR 1501.2(d), which states that in 
``cases where actions are planned by private applicants or other non-
Federal entities before Federal involvement,'' agencies shall provide 
policies or designated staff members ``to advise potential applicants 
of studies or other information foreseeably required for later Federal 
action,'' and shall begin the NEPA process ``at the earliest time 
possible.''
    FDA agrees with the comment. As explained in the preamble to the 
proposal (61 FR 14922 at 14923, 61 FR 19476 at 19477), FDA intended to 
eliminate unnecessary language by combining Sec. 25.5 (Policies) and 
Sec. 25.10 (NEPA planning) into proposed Sec. 25.10 (Policies and NEPA 
planning). FDA did not intend to change the timing of the initiation of 
the agency's environmental planning process or to preclude early 
consultation with FDA prior to Federal action when it proposed the 
language in Sec. 25.10(c). Thus, because the proposed section does not 
clearly express the agency's policy, the agency will incorporate the 
current Sec. 25.10(a) language, and Sec. 25.10(c) will provide, in 
relevant part:

    For actions initiated by applicants or petitioners, NEPA 
planning begins when FDA receives from an applicant or petitioner an 
environmental assessment (EA) or a claim that a categorical 
exclusion applies, or when FDA personnel consult with applicants or 
petitioners on the NEPA-related aspects of their requested actions.

    4. One comment stated that under CEQ regulations (40 CFR 
1501.2(d)), FDA is required to ensure that potential applicants or 
petitioners prepare an EA prior to the harvest of natural resources, 
such as the Pacific yew tree, regardless of whether the drug sponsor 
has filed an application or petition with the agency. The comment 
requested that the proposed regulations be revised to specifically 
address the issue of ``stockpiling'' harvested material prior to 
submitting an application or petition.
    The requirements and procedures of NEPA are triggered by a major 
Federal action. Until FDA reviews an application or petition, initiates 
an action, or is consulted regarding potential agency action, no action 
exists to set the NEPA process in motion, and there is no regulatory 
requirement for applicants or petitioners to inform FDA of their use of 
natural resources prior to the submission of an application or petition 
to FDA. Therefore, FDA cannot ensure that applicants or petitioners 
prepare an EA prior to the harvest of natural resources. In accordance 
with 40 CFR 1501.2(d), the agency makes staff available to advise 
potential applicants or petitioners of studies or other information 
foreseeably required for later Federal action and commences its NEPA 
process at the earliest possible time (see Sec. 25.10(c) of this final 
rule). FDA will request information about stockpiling and harvesting 
once the NEPA process is triggered by a proposed action.
    With regard to the comment's specific concerns about the Pacific 
yew, the agency published a notice in the Federal Register of November 
18, 1996 (61 FR 58694), clarifying the environmental information that 
must be submitted to the agency with a new drug application (NDA), 
abbreviated new drug application (ANDA), or investigational new drug 
application (IND) involving paclitaxel derived from or otherwise 
involving the Pacific yew.
    5. One comment requested that proposed Sec. 25.10, which states 
FDA's overall policy in implementing the NEPA requirements, be modified 
to indicate that applicants should be involved in the development of 
agency policies, procedures, and guidance documents that are designed 
to interpret, clarify, or elaborate on the requirements placed on 
applicants to satisfy FDA's statutory obligations under NEPA.
    In a notice in the Federal Register of February 27, 1997 (62 FR 
8961), FDA announced its ``Good Guidance Practices'' (GGP's), which 
represents the agency's policy regarding the development and use of 
guidance documents (hereinafter referred to as the GGP's notice). The 
GGP's address public participation in the guidance document development 
process generally. FDA does not believe that it is necessary or 
appropriate to address public participation in the NEPA guidance 
document development process specifically. Interested individuals are 
encouraged to review the Federal Register notice and related comments 
(Docket No. 95P-0110).
    6. One comment requested that Sec. 25.10 be revised to provide that 
a single center official be responsible for addressing and resolving 
questions raised by reviewers and for mediating conflicts arising 
between reviewers and sponsors regarding interpretations of the 
regulatory requirements. The comment also requested that a provision be 
included that establishes an appeal from the center's responsible 
official to the Center Director, in the event that the center official 
is unable to resolve questions raised by reviewers.
    FDA does not believe it is necessary to revise proposed Sec. 25.10 
as suggested by the comment. Individuals in each center with 
specialized training and expertise oversee the NEPA review process, 
resolve questions raised by reviewers, and mediate conflicts between 
reviewers and sponsors. Actions by reviewers or other center officials 
may be appealed through the appeals mechanisms already in place in each 
center to the Center Director and, ultimately, to the Commissioner of 
Food and Drugs (the Commissioner). Individuals who are interested in 
obtaining copies of the appeals procedures established in each center 
may contact the relevant center for such information.

B. Subpart B--Agency Actions Requiring Environmental Consideration

    7. Proposed Sec. 25.15(a) states that the failure of an applicant 
or petitioner to submit an ``adequate EA'' for a requested action that 
is not categorically excluded is sufficient grounds for FDA to refuse 
to file or approve the application or petition. One comment noted that 
while FDA requires an ``adequate'' EA, the definition of that

[[Page 40572]]

term found in current Sec. 25.22(b) is not included in the proposed 
regulations. The comment requested that the agency retain the 
definition of adequate EA in its regulations.
    The agency agrees that clarification of when an EA is adequate for 
filing or approval is appropriate. Consequently, proposed Sec. 25.15(a) 
has been revised to include the clarifying statements currently found 
in Sec. 25.22(b):

    An EA adequate for filing is one that addresses the relevant 
environmental issues. An EA adequate for approval is one that 
contains sufficient information to enable the agency to determine 
whether the proposed action may significantly affect the quality of 
the human environment.

    8. Proposed Sec. 25.15(a) and (d) requires that applicants and 
petitioners who claim that a categorical exclusion applies to a 
proposed action certify that the action qualifies for a categorical 
exclusion, citing the particular exclusion that is claimed, and certify 
that to their knowledge no extraordinary circumstances exist. One 
comment specifically welcomed and believed important to the success of 
FDA's proposals the certification of compliance with the categorical 
exclusion criteria required in Sec. 25.15(a) and (d). Another comment 
requested clarification of the certification requirement in 
Sec. 25.15(a) and (d), questioning whether the categorical exclusion 
document needs to contain a separate certification indicating the 
truthfulness and accuracy of the information provided in the 
certification, or whether the categorical exclusion document alone is 
sufficient.
    Applications and petitions that are filed with the agency are 
signed by a responsible agent or official of the sponsor, who attests 
to the truth and accuracy of the information within the application or 
petition. A separate, signed categorical exclusion document is not 
needed. Under Sec. 25.15(a) and (d), FDA requires that an applicant or 
petitioner requesting a categorical exclusion identify the categorical 
exclusion being claimed, state that the action complies with the 
categorical exclusion criteria, and state that to the applicant's 
knowledge no extraordinary circumstances exist. For clarification, 
Sec. 25.15(a) and (d) have been modified to indicate that a statement, 
not a certification, is needed.
    9. One comment contended that proposed Sec. 25.15(a) and (d) is 
inconsistent with CEQ regulations in that the CEQ regulations require 
that the agency use specific criteria to judge whether an action fits 
within a categorical exclusion (40 CFR 1507.3(b)(2)(ii)) and 
independently evaluate the information submitted and be responsible for 
the accuracy of the information (40 CFR 1506.5). The comment also 
asserted that proposed Sec. 25.15(a) and (d) departs from existing FDA 
regulations, which require that applicants claiming a categorical 
exclusion provide supporting information that the action meets the 
criteria for the applicable exclusion.
    Under current Sec. 25.23(c), a person who claims a categorical 
exclusion provides information when appropriate that establishes to the 
agency's satisfaction that the action meets the criteria for the 
applicable exclusion (emphasis added). Proposed Sec. 25.15(a) and (d) 
does not reflect a departure from current FDA regulations. In revising 
its NEPA procedures, FDA has formulated its categorical exclusions to 
include specific criteria, as required by CEQ's regulations (40 CFR 
1507.3(b)(2)(ii)) that in most instances can either be facially 
determined or confirmed by review of other information submitted as 
part of the request for action. This approach is consistent with CEQ's 
view that in most cases additional information should not be required. 
In the limited instances when it may be necessary, FDA will request 
additional information as needed to establish to the agency's 
satisfaction that the criteria for a categorical exclusion have been 
met.
    10. One comment objected to the absence of information in the 
proposal concerning the actions FDA may take in response to a 
petitioner or applicant filing a false certification with the agency.
    It is a violation of the criminal code (18 U.S.C. 1001) for anyone, 
in any matter within the jurisdiction of any department or agency of 
the United States, to knowingly and willfully make any false, 
fictitious, or fraudulent statement or representation to such 
department or agency. Enforcement decisions are generally a matter of 
an agency's discretion. FDA will exercise its enforcement discretion 
consistent with its statutory responsibilities under all applicable 
statutes, including NEPA.
    11. One comment recommended that the basic physical/chemical 
characterization of a potential product be included in all EA documents 
including claims for categorical exclusion.
    In the event FDA determines that basic physical/chemical 
characterization information is relevant to its environmental 
consideration of a specific proposed action, FDA will request that such 
information be provided in an EA. FDA intends to issue guidance 
documents that will provide applicants with information about the 
nature and scope of information that should be included in an EA. A 
claim for categorical exclusion shall comply with Sec. 25.15(a) and (d) 
and, as discussed in the response to comment 9, should not normally 
include additional information.
    12. Proposed Sec. 25.20 lists broad categories of agency actions 
that require the preparation of an EA, unless the action qualifies for 
exclusion. One comment noted that although FDA stated in the preamble 
to the proposal that the types of actions requiring an EA remain 
essentially the same as in current Sec. 25.22, the proposal did not 
include the ``catch-all action'' in current Sec. 25.22(a)(19): ``Action 
other than one listed in this subsection, unless subject to exclusion 
under Secs. 25.23 and 25.24, that may significantly affect the quality 
of the human environment.'' The comment recommended that a clause be 
retained in new Sec. 25.20 providing that an ``EA must be prepared for 
an action other than one listed in (Sec. 25.20) that may significantly 
affect the quality of the human environment.''
    The list of actions requiring preparation of an EA was not intended 
to be all-inclusive. The list includes broad classes of actions that 
require preparation of at least an EA, unless categorically excluded in 
subpart C of part 25. Under NEPA and CEQ's implementing regulations, 
FDA is required to consider the environmental impact of each of its 
proposals for major Federal action that is not categorically excluded. 
Therefore, it is not necessary for FDA to include the described catch-
all clause in the final rule.
    13. Another comment noted that proposed Sec. 25.20(i) requires an 
EA for actions on requests for exemptions for investigational use of 
food additives, unless categorically excluded under proposed 
Sec. 25.32(b), and questioned whether the agency expects a claim for 
exclusion to be submitted for actions involving investigational food 
additives. The comment asked FDA to clarify its intent.
    The intent of the provision in proposed Sec. 25.20(i) is to 
identify actions involving food additives that ordinarily require an 
EA, unless the actions are in a specific class that qualifies for a 
categorical exclusion. Similar to the agency's experience with actions 
on investigational human and animal drugs, FDA expects that if action 
were taken on an investigational food additive, such action would 
qualify for the exclusion under Sec. 25.32(b) of the final rule.
    14. Proposed Sec. 25.21 addresses ``extraordinary circumstances'' 
under which categories of actions that would

[[Page 40573]]

ordinarily be categorically excluded would require preparation of an 
EA. One comment contended that this exception to categorical exclusions 
will result in the potential for ``regulatory creep,'' that is, the 
potential for FDA to implement the exception in a manner that results 
in an expansion of the degree of FDA review, a lengthening of time for 
review, and an increased cost of review. The comment expressed 
particular concern about the opportunity for regulatory creep in 
relation to applying the exception to categorical exclusions for 
actions on new animal drug applications (NADA's). The comment suggested 
that a primary safeguard against misuse of the extraordinary 
circumstances exception is to ensure that decisions on exceptions are 
reserved and delegated in part 5 (21 CFR part 5) to a truly responsible 
official; in the case of actions on animal drugs, to the Director of 
the Center for Veterinary Medicine.
    As the comment recognizes, under CEQ regulations at 40 CFR 1508.4, 
FDA is required to provide for extraordinary circumstances in which a 
normally excluded action may have a significant effect on the 
environment. Under proposed Sec. 25.21 (current Sec. 25.23(b)), FDA 
requires an EA for any specific action that ordinarily would be 
excluded if extraordinary circumstances indicate that the specific 
proposed action may significantly affect the quality of the human 
environment. CEQ regulations, in 40 CFR 1508.27, define 
``significantly'' to require consideration of both the context and 
intensity of an agency action. Proposed Sec. 25.21 cites Sec. 1508.27 
to emphasize that, in implementing its regulations, FDA will rely on 
the principles established by CEQ for determining whether an 
extraordinary circumstance exists such that an action, ordinarily 
excluded, may significantly affect the environment. By definition, a 
categorical exclusion means a category of actions that has been found 
not to have a significant effect on the human environment, therefore 
application of the extraordinary circumstances provision should be 
limited. Since 1985, in implementing its NEPA procedures, FDA has 
invoked the extraordinary circumstance exception to categorical 
exclusions in limited instances and in a manner consistent with CEQ 
regulations. Section 25.21 lists two examples of extraordinary 
circumstances where FDA may apply the exception.
    FDA declines to modify part 5 to reflect that the authority to 
determine the existence of extraordinary circumstances related to 
animal drugs is reserved to the Director of the Center of Veterinary 
Medicine. The agency's decision is described in the response to comment 
60 below, which discusses the revision of part 5 with respect to all 
FDA Center Directors.
    15. One comment asserted that the extraordinary circumstances 
provision will not result in the preparation of EA's for applications 
involving paclitaxel that otherwise meet the criteria for categorical 
exclusion. The comment stated that the Pacific yew is not classified as 
an endangered or threatened species under the Endangered Species Act 
(ESA), nor is the species currently listed in any of the appendices to 
the Convention on International Trade in Endangered Species of Fauna 
and Flora (CITES) and expressed concern that agency actions regarding 
products containing paclitaxel would escape environmental consideration 
because they do not fall within FDA's examples of extraordinary 
circumstances. The comment also questioned the standard that the agency 
has proposed to use in determining whether an action involving wild 
flora and fauna falls within FDA's second example of extraordinary 
circumstances, citing FDA's statement in the preamble that the agency:

    (I)ntends to closely examine proposed actions that involve FDA-
regulated articles obtained from wild flora and fauna and will use 
the extraordinary circumstances provision to require at least an EA 
in any instance in which it appears from an examination of the 
proposed action that the action may cause a species to become 
endangered or threatened.

Finally, the comment asserted that unlike the ESA, CITES does not speak 
in terms of endangered or threatened species.
    The examples provided by the agency in proposed Sec. 25.21 are 
illustrative of the types of action that would require an EA despite 
the fact that the action otherwise qualifies for a categorical 
exclusion. The two examples are not intended to be an exhaustive list 
of those actions.
    FDA's extraordinary circumstances provision requires that an EA be 
prepared if a normally excluded action may significantly affect the 
quality of the human environment. FDA has specifically determined that 
actions relating to applications involving paclitaxel derived from or 
otherwise involving the Pacific yew tree fall within the CEQ definition 
of ``significantly'' (40 CFR 1508.27) and has documented, in the 
agreement filed in the U.S. District Court for the District of Columbia 
in Oregon Natural Resources Council Action v. Shalala, No. 96-1449 PLF 
(D.C.D.C. Oct. 4, 1996), its intent to require EA's for all actions on 
applications, except some actions on IND's, involving paclitaxel 
derived from or otherwise involving the Pacific yew tree. FDA also 
published a notice in the Federal Register clarifying the environmental 
information that must be submitted to the agency in marketing 
applications for drug products containing paclitaxel (61 FR 58694).
    FDA is clarifying that it will require an EA for an action, 
including one involving wild flora and fauna, that is ordinarily 
excluded if the action may have a significant effect on the 
environment. Where a species of wild flora or fauna may become 
endangered or threatened, the action may have a significant effect.
    The comment is inaccurate in stating that CITES does not speak in 
terms of endangered or threatened species. The regulations implementing 
CITES (50 CFR 23.2) note that the appendices include endangered and 
threatened species and a ``Facts'' sheet published by the Fish and 
Wildlife Service explains that Appendix I includes species presently 
threatened with extinction.
    16. One comment expressed concern about the environmental effects 
of synthetic estrogens in the aquatic environment, specifically those 
synthetic estrogens in oral contraceptives and estrogenic replacement 
therapy prescribed for post-menopausal women. The comment requested 
that until research is available to determine a more accurate critical 
concentration, FDA consider the use of synthetic estrogens in human 
drugs to be an extraordinary circumstance so that actions involving 
estrogen use would require an EA. The authors of the comment state that 
they have observed significant alterations of gender ratios when 
developing larval medaka (a fish) were exposed to 0.1 part per billion 
(ppb) of 17-estradiol (naturally occurring) for 4 weeks. 
Additionally, they cite from a published article that male rainbow 
trout exposed to 0.002 ppb ethinyl estradiol (used in oral 
contraceptives) for 3 weeks showed significantly elevated vitellogenin 
levels and decreased testes weight and compromised spermatogenesis. 
Concern was also expressed about the potential for higher 
concentrations of these compounds in certain local areas.
    FDA will require an EA for any specific action that ordinarily 
would be excluded if available evidence establishes that, at the 
expected level of exposure, a potential exists for a significant effect 
on the environment.

[[Page 40574]]

The agency has considered the request that the use of synthetic 
estrogens in human drugs be considered an extraordinary circumstance, 
but has concluded that the available evidence does not support that, at 
the expected level of exposure, a potential exists for significant 
effect on the environment. FDA has considered many factors in arriving 
at this conclusion including normal prescribing patterns for the drugs, 
medical uses, pharmacological properties, waste water treatment 
practices and expected introduction and environmental concentrations of 
the substances. FDA provided its analysis to the EPA for review and EPA 
agreed with FDA's position on this issue. Therefore, FDA will not 
generally apply the extraordinary circumstances exception to actions 
involving synthetic estrogens used in oral contraceptives and hormone 
replacement therapy that otherwise meet the criteria for categorical 
exclusion. A report explaining the basis of the agency's decision has 
been placed in Docket No. 96N-0057. FDA will continue to investigate 
this issue in general and assess each action on an individual basis to 
determine whether an extraordinary circumstance exists.
    17. Proposed Sec. 25.22 provides for the preparation of an EIS when 
the responsible agency official finds, as a result of evaluating 
relevant data and information, that a proposed action may significantly 
affect the quality of the human environment. One comment recommended 
that FDA establish specific criteria to determine the need to prepare 
an EIS. The comment suggested that the agency base the criteria on the 
number of potentially affected parties or on the formula used by the 
European Union (EU) to trigger the EU equivalent of an EIS. The EU 
criteria are based on annual tonnage.
    An EIS is prepared when evaluation of data or information in an EA 
or otherwise available to the agency leads to a finding that a proposed 
action may significantly affect the quality of the human environment. 
FDA does not believe it is necessary to further identify criteria for 
preparing an EIS. CEQ regulations (40 CFR 1508.27) define 
``significantly'' and provide guidance to FDA in its determination of 
whether an action significantly affects the environment. Furthermore, 
it is difficult to develop criteria that are more specific and that may 
be applied with great frequency. Criteria relating to the amount of 
material produced are not appropriate criteria for determining when an 
EIS must be prepared. For example, an EIS may not be necessary for FDA-
regulated articles produced in large quantities if environmental 
depletion mechanisms are identified and/or the material is relatively 
nontoxic to environmental organisms at expected environmental 
concentrations.
    18. In the preamble to the proposal, FDA stated that it is 
proposing to remove current Sec. 25.25 (Retroactive environmental 
consideration) because any request by FDA to an applicant to submit 
additional information to an existing FDA approval will be made under 
authority granted to FDA by the Federal Food, Drug, and Cosmetic Act 
(the act) or the Public Health Service Act (the PHS Act). One comment 
contended that this proposed action is inconsistent with both CEQ 
regulations and case law governing implementation of NEPA. The comment 
stated that FDA was suggesting it could not comply with 40 CFR 
1502.9(c)(1)(ii) because its authority to require additional 
environmental information from applicants only stems from the act or 
the PHS Act. The comment stated that the Federal court, in 
Environmental Defense Fund v. Mathews, 410 F.Supp. 336, 338 (D.C.D.C. 
1976), rejected similar claims when FDA issued its NEPA regulations in 
the 1970's.
    Because the comment misunderstands the agency's stated reasons for 
proposing to remove current Sec. 25.25, FDA is clarifying them here. 
Current Sec. 25.25 applies to agency consideration of the need to 
prepare an EIS after the agency has already taken an action, e.g., 
promulgation of a regulation or action relating to an approval. NEPA 
and CEQ regulations both require an agency to consider the 
environmental impact of its actions before decisions are made and 
before actions are taken. Thus, the agency must prepare an EIS for an 
action it has found may significantly affect the environment before it 
takes the action. NEPA does not apply retroactively; instead, however, 
if an ongoing project undergoes changes which themselves amount to 
``major Federal actions,'' the agency must then prepare an EIS (Upper 
Snake River Chapter of Trout Unlimited v. Hodel, 921 F.2d 232, 234 (9th 
Cir. 1990)). FDA is removing Sec. 25.25, which concerned retroactive 
environmental consideration.
    The comment cites Environmental Defense Fund v. Mathews, 410 
F.Supp. 336, 338 (D.C.D.C. 1976), which relates to FDA's 1973 
regulations implementing its obligations under NEPA. The case held 
that, in addition to its other statutory mandates, FDA has a 
nondiscretionary responsibility under NEPA to take environmental 
considerations into account in its process of decisionmaking. For the 
reasons stated above, elimination of current Sec. 25.25 does not affect 
this responsibility and is not inconsistent with CEQ regulations or 
case law.
    The agency specifically acknowledges its responsibility to prepare 
supplements in accord with Sec. 1502.9 in the new regulations (see 
Sec. 25.42(c)). FDA's discussion in the preamble to the proposed rule 
was intended to point out that CEQ regulations only discuss when a 
supplement to a draft or final EIS is needed. CEQ regulations do not 
specifically address or grant any authority to an agency to request 
additional information under other circumstances. FDA also wanted to 
make it clear that once FDA has taken an action, the agency has 
authority under the act and the PHS Act to request that an applicant 
submit additional information to an existing approval.

C. Subpart C--Categorical Exclusions

    19. One comment found no major issues or problems with the policy 
and procedure revisions, but expressed concern whether FDA had made 
adequate analyses to substantiate the proposed categorical exclusions. 
Another comment stated that the commenter was unable to evaluate the 
proposed categorical exclusions, specifically the exclusion provided in 
Sec. 25.31(b), because FDA had not made the information upon which it 
based its conclusions available to the public.
    To provide additional substantiation for its proposed categorical 
exclusions, FDA supplemented the administrative record for the proposed 
regulations with additional information. On October 22, 1996, the 
agency published a notice in the Federal Register (61 FR 54746) 
announcing the availability of specific information, including 
underlying data, that along with the information in the preamble to the 
proposed rule supports the categorical exclusions. FDA also reopened 
the comment period for 30 days for the sole purpose of inviting public 
comment on those categorical exclusions for which information had been 
added to the administrative record. The agency received four comments 
during this extended comment period, three of which addressed 
categorical exclusions for drug and biologic products. FDA, therefore, 
believes that it has provided adequate explanation of the categorical 
exclusions and has provided adequate opportunity for comment on the 
categorical exclusions by interested parties.
    20. Proposed Sec. 25.30(j) revised the categorical exclusion for 
issuance of certain types of regulations, including current good 
manufacturing practice

[[Page 40575]]

(CGMP) regulations, to categorically exclude regulations based on the 
hazard analysis critical control points (HACCP) principles. One comment 
agreed with this change but recommended that HACCP programs incorporate 
mandatory self audits and independent audits into their requirements.
    This recommendation is outside the scope of this rulemaking.
1. Human Drugs and Biologics
    21. Proposed Sec. 25.31(a) would categorically exclude FDA action 
on an NDA, abbreviated application, or a supplement to such 
applications, or action on an over-the-counter (OTC) monograph, if the 
action does not increase the use of the active moiety of the drug. FDA 
intended to include in this categorical exclusion applications for 
marketing approval of a biologic product. As discussed in the preamble 
to the proposed rule with regard to NDA's, abbreviated applications, 
supplements, and OTC monographs, if an action, including action on a 
marketing application for a biologic product, does not increase the use 
of the product, there is no change in the level of substance in the 
environment and, consequently, no increase in any environmental effects 
associated with the use and disposal from use of the product. 
Therefore, proposed Sec. 25.31(a) has been modified as follows:

    Action on an NDA, abbreviated application, application for 
marketing approval of a biologic product, or a supplement to such 
applications, or action on an OTC monograph, if the action does not 
increase the use of the active moiety.

    22. Proposed Sec. 25.31(b) would categorically exclude FDA action 
on a marketing application for a human drug, or supplement to such 
application, or action on an OTC monograph, if the action increases the 
use of the active moiety but the concentration of the substance in the 
environment will be below 1 ppb. Several comments generally supported 
the 1 ppb criterion, but sought minor revisions to or clarifications of 
the criterion.
    One comment suggested that the 1 ppb criterion be changed to 0.1 
ppb using the predicted environmental concentration (PEC). PEC is 
defined as the introduction concentration, corrected based on 
metabolism/excretion data, on wastewater treatment facility fate 
information, and on the use of an appropriate stream dilution factor of 
10. Two comments suggested that proposed Sec. 25.31(b) be clarified to 
indicate that the relevant concentration is at the point of entry into 
the aquatic environment. One of these comments agreed that substances 
entering the environment at less than or equal to 1 ppb will have an 
insignificant environmental impact, but suggested that the standard be 
an expected introduction concentration because this would give more 
consideration to potential exposure to primary human receptors which 
may come in contact with the substance before it degrades or enters a 
wastewater treatment facility. Another comment suggested that because 1 
ppb computes to a production rate of 40,700 kilograms (kg) per year 
using the calculation method provided in FDA guidance, FDA should add 
an exclusion for actions relating to human drugs for which the 
production rate of the active moiety is less than 40,700 kg per year.
    FDA agrees to clarify that the 1 ppb requirement is relevant at the 
point of entry into the aquatic environment, that is, the environmental 
introduction concentration (EIC). Under current part 25, FDA requires 
EA's to initially provide an estimate of the quantity and concentration 
of the substance that is expected to enter the environment. The 
calculation method suggested by CDER is explained in its ``Guidance for 
Industry for the Submission of an Environmental Assessment in Human 
Drug Applications and Supplements'' (FDA, November 1995). If 
environmental fate and effects information for a substance is required 
in an EA, spatial and temporal concentration and depletion mechanisms 
will, as appropriate, be used to adjust the EIC to estimate the 
expected environmental concentration (EEC)/exposure concentration of 
the product. PEC, as defined by the comment, is the same as the EEC/
exposure concentration. The comment's suggested use of a criterion of 
0.1 ppb, calculated using a dilution factor of 10, is equivalent to the 
agency's proposed criterion of 1 ppb calculated without using a 
dilution factor, in that the same amount of the substance entering the 
environment would qualify for categorical exclusion under each 
proposal. It may be appropriate for FDA to consider a dilution factor 
when estimating a substance's EEC/exposure concentration, based on 
information provided in an EA, to evaluate the fate and effects of the 
substance. For the purposes of a categorical exclusion criterion, 
however, a conservative estimate of the concentration, EIC, will be 
used.
    As explained in the preamble to the proposed rule (61 FR 14922 at 
14925, 61 FR 19476 at 19479), based on their method of entry into the 
environment from use and their physical and chemical characteristics 
(e.g., water solubility), human drugs would be expected predominantly 
to enter the aquatic environment. The data submitted in EA's reviewed 
by CDER have routinely supported this hypothesis. The data also have 
routinely shown that in those cases in which an applicant has provided 
toxicity results for terrestrial organisms in addition to acute 
toxicity results for aquatic organisms, the drugs are toxic to aquatic 
organisms at lower levels than they are to terrestrial organisms, 
suggesting that the use of aquatic organisms is a conservative 
approach. Proposed Sec. 25.31(b) has been revised to clarify that the 
relevant concentration is at the point of entry into the aquatic 
environment.
    CEQ regulations require that localized (i.e., site-specific) 
effects of a substance on the environment be considered, where 
appropriate (40 CFR 1508.27(a)). Typically, the use of a drug product 
is spread throughout the United States. However, in the rare instance 
in which the use of a drug will be localized in one geographic area, a 
categorical exclusion based on the concentration of a substance at the 
point of entry into the aquatic environment, such as 1 ppb, provides 
for an evaluation of the local environmental effect of that drug. The 
suggestion to add a categorical exclusion based on a set quantity of 
the drug product, such as 40,700 kg, ignores the possibility of 
localized use that the agency is required to consider. Therefore, FDA 
is not adding a categorical exclusion based on production rates.
    Concerning potential exposure to primary human receptors, as 
discussed in Calorie Control Council, Inc. v. U.S. Department of 
Health, Education, and Welfare, No. 77-0776 (D.C.D.C. 1977), the 
primary concern of NEPA is the impact of agency actions on physical 
environmental resources, not the public health consequences of a 
proposed action. Furthermore, NEPA authority is intended to supplement 
other statutory responsibilities of a Federal agency. FDA already 
addresses primary receptor issues as public health issues under the act 
rather than through NEPA evaluation.
    As a result of this discussion, proposed Sec. 25.31(b) has been 
revised to state:

    Action on a NDA, abbreviated application, or a supplement to 
such applications, or action on an OTC monograph, if the action 
increases 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 part per billion.

    CDER's document, ``Guidance for Industry for the Submission of an

[[Page 40576]]

Environmental Assessment in Human Drug Applications and Supplements,'' 
provides a method for calculating the estimated concentration of the 
substance at the point of entry into the aquatic environment. Other 
calculation methods may be appropriate. However, such alternative 
calculations will be reviewed by the agency on a case-by-case basis to 
determine whether they are appropriate for determining whether the 
categorical exclusion applies.
    23. One comment reiterated a comment made during the initial 
comment period that the agency needs to broaden ``extraordinary 
circumstances,'' especially as the provision relates to paclitaxel, and 
further noted ``troubling defects'' in the Toxicity Report the agency 
provided in the administrative record to support the 1 ppb categorical 
exclusion criterion in Sec. 25.31(b). The defects cited in the comment 
include: (1) The report is grounded in an evaluation of ecotoxicity in 
a few select laboratory species, not in wild organisms that may already 
be stressed by other pollutants; (2) the report appears to be based on 
EA's submitted by applicants to the agency, and no information is given 
about how the toxicity figures were obtained and whether certain 
assumptions were made in the studies; (3) the report does not consider 
cumulative impacts associated with disposal of the products in the 
environment, including the potential for bioaccumulation of pollutants 
over time; and (4) the report provides no scientific explanation, other 
than citing one article, for dividing the median effective 
concentration (EC50) or median lethal concentration (LC50) values by 
1,000 to arrive at a predicted no observed effect concentration (NOEC). 
The comment also stated that the Toxicity Report is based on toxicity 
tests that may be considered antiquated in light of recent efforts by 
the Organization for Economic Cooperation and Development (OECD) and 
EPA to revise such evaluations. The comment did not suggest any changes 
to the proposed regulations.
    FDA's extraordinary circumstances provision requires that at least 
an EA be prepared if a normally excluded action may significantly 
affect the quality of the human environment. The agency has 
specifically determined that most actions relating to paclitaxel 
derived from or otherwise involving the Pacific yew require the 
preparation of EA's, irrespective of the expected concentration of 
paclitaxel at its point of entry into the aquatic environment. (See the 
response to comment 15, above.)
    With respect to the alleged defects of the Toxicity Report, 
environmental risk assessment initially involves determining the toxic 
effect of a compound on a few select laboratory species. The test 
organisms used by the applicants to generate the data in the Toxicity 
Report are typically the same as those suggested by EPA (see 40 CFR 
797) and OECD for this initial screening. CDER evaluates the potential 
for significant environmental effects by relating the concentrations 
determined to have toxic effects on these test organisms to the level 
of the substance expected in the environment. Field studies (i.e., 
evaluation in actual environmental settings) are generally conducted 
only when initial evaluation and subsequent intermediate evaluations 
indicate that the potential for significant environmental harm may 
exist.
    FDA based the proposed 1 ppb categorical exclusion on toxicity data 
submitted to the agency in EA's. The agency's analysis of the toxicity 
data is explained in the Toxicity Report. Under 40 CFR 1506.5, the 
agency asks applicants to prepare an EA and FDA independently evaluates 
the information in the EA to determine its acceptability. The Toxicity 
Report provides summary information from the EA's, identifying the 
location of the detailed EA reports and FONSI's in the public docket. 
FDA reviewed the test reports provided in EA's and determined that the 
methodologies, assumptions, and conclusions of the reports were 
acceptable. Any interested party may obtain additional information 
regarding the test methods used for each EA from those reports in the 
public docket.
    Impacts on the environment which result from the incremental impact 
of an action when added to other past, present, and reasonably 
foreseeable future actions are known as cumulative impacts. 
Consideration of cumulative impacts is included in the proposed 
categorical exclusions for human drugs and biologics. Under 
Sec. 25.31(a), action on a marketing application for a human drug or 
biologic or action on an OTC monograph may be categorically excluded if 
the action does not increase the use of the active moiety. However, if 
an action increases the use of the active moiety, the impacts of that 
increased use will require environmental analysis unless the action 
meets other specific categorical exclusion criteria established in 
Sec. 25.31(b) and (c). The potential for cumulative effects is also 
considered in the calculation of the EIC of an active moiety of a drug 
because the applicant bases these estimates on the expected quantities 
that will be used 5 years in the future, including the use quantities 
associated with related FDA applications (see, e.g., Guidance for 
Industry for the Submission of an Environmental Assessment in Human 
Drug Applications and Supplements, Section III.D.6.e, November 1995).
    As stated in the preamble to the proposed rule (61 FR 14922 at 
14925, 61 FR 19476 at 19479), one of the criteria for determining that 
a drug is safe for human use is consideration of its potential to 
bioaccumulate in body tissue. The vast majority of drugs do not 
bioaccumulate because that characteristic would raise safety concerns 
for use of the drugs in humans. If a drug has characteristics that 
would allow it to bioaccumulate in tissue, the body must have a 
mechanism to metabolize the compound into a substance that has lower 
bioaccumulation potential so that it may be cleared from the body. In 
the EA's that the agency reviewed, bioaccumulation was not an issue.
    The practice of using assessment factors in environmental risk 
assessments is well established. FDA's use of an assessment factor of 
1,000 is consistent with EPA's approach (e.g., Zeeman, M., and J. 
Gilford, ``Ecological Hazard Evaluation and Risk Assessment Under EPA's 
Toxic Substances Control Act (TSCA): An Introduction,'' in 
Environmental Toxicology and Risk Assessment, ASTM STP 1179, edited by 
W. Landis, J. Hughes, and M. Lewis, pp. 7-21, American Society for 
Testing and Materials, Philadelphia, 1993.).
    The toxicity tests performed by FDA applicants and described in the 
Toxicity Report are consistent with contemporary practice and are based 
on current scientific thinking. Potential future revision of test 
methods does not render invalid current testing, data obtained as a 
result of that testing, or conclusions based on that data.
    24. One comment stated that under Sec. 25.31(b), FDA will now 
apparently permit companies seeking approval of metered dose inhalers 
to forgo preparation of EA's in connection with their marketing 
applications. The comment asked that the agency make clear in its final 
regulations that FDA will require EA's with all applications involving 
metered dose inhalers that release chlorofluorocarbons (CFC's) and that 
such EA's must thoroughly evaluate the cumulative impacts of CFC's on 
the Antarctic environment and alternatives that avoid such impacts.
    In 1978, FDA finalized a programmatic EIS regarding the use of 
fluorocarbons in products subject to regulation by the agency under the 
act (Final Environmental Impact Statement;

[[Page 40577]]

Fluorocarbons: Environmental and Health Implications, February, 1978, 
Docket No. 76N-0640) and announced the availability of the final EIS in 
the Federal Register (43 FR 11316, March 17, 1978). This EIS was used 
as the basis for prohibiting use of CFC's as propellants in self-
pressurized containers if the use of the CFC was not deemed to be 
essential. As stated in the EIS:

    The Commissioner of Food and Drugs has concluded that the 
continued use of chlorofluorocarbon propellants in self-pressurized 
containers in products subject to the Federal Food, Drug, and 
Cosmetic Act (FFD&C) poses an unreasonable risk of long-term 
biological and climatic impacts.
    Accordingly, the Food and Drug Administration is finalizing a 
prohibition of the nonessential use of chlorofluorocarbons as 
propellants in self-pressurized (aerosolized) containers in products 
subject to the FFD&C Act. The products to which the regulation 
applies are human food, food additives, human drugs, including 
biological products, animal food, animal drugs, cosmetics, and 
medical devices. (p. iii)

    The EIS further stated:

    The selection of fluorocarbon use(s) to be regulated requires a 
determination of whether or not a particular fluorocarbon use is 
essential. The Commissioner of Food and Drugs has defined 
essentiality to mean that there are no technically feasible aerosol 
or non-aerosol alternatives to using a fluorocarbon in a product and 
that a product provides a substantial public benefit such as a 
therapeutic medical benefit. The product need not be indispensable 
to life, but the benefit must be important and consist of more than 
added convenience. (p. 89)

A copy of the programmatic EIS has been placed in the administrative 
record for this rule (Docket No. 96N-0057).
    FDA regulations pertaining to the use of CFC propellants in self-
pressurized containers are described in Sec. 2.125. CFC's may be used 
as propellants in a self-pressurized container only if the drug is 
approved, a petition has been filed as described in Sec. 2.125(f), and 
Sec. 2.125(e) has been amended to specify the use as essential. The 
petition requesting an essential use designation must be supported by 
an adequate showing that: (1) No technically feasible alternatives 
exist to the use of a CFC in the product; (2) the product provides a 
substantial health benefit, environmental benefit, or other public 
benefit that would not be obtainable without the use of the CFC; and 
(3) the use does not involve a significant release of CFC's into the 
atmosphere or, in the alternative, the release is warranted in view of 
the consequences of the use not being permitted. The petition is a 
public document about which any interested party may comment before a 
final determination is made by the agency.
    FDA is in the process of establishing a policy for determining when 
uses of CFC's currently designated essential will no longer be deemed 
essential under the Clean Air Act due to the availability of safe and 
effective medical product technology that does not use CFC's. (See 
Docket No. 97N-0023.)
    The agency has, in the programmatic EIS, evaluated the individual 
and cumulative effects, including the effects on human health, 
stratospheric ozone, biological systems (nonhuman), and climate, of 
approvals of marketing applications that result in the release of 
CFC's. FDA has fulfilled its responsibilities and has adequately 
considered the environmental issues regarding CFC's. Therefore, a 
requirement that individual marketing applications for metered dose 
inhalers that release CFC's must include EA's is not necessary because 
the environmental information would already be under consideration by 
the agency in its decision whether to designate an essential use under 
Sec. 2.125(e). Resubmission of this information to the agency would not 
be consistent with CEQ goals of reducing excessive paperwork. NEPA 
supplements, but does not supersede, other statutory responsibilities. 
NEPA establishes requirements to ensure that an agency considers 
environmental information in its decisionmaking process. Thus, after a 
review of the relevant environmental information, FDA may, but is not 
required to, decline to take an action that may have a significant 
effect on the environment.
    25. Proposed Sec. 25.31 lists the general classes of agency actions 
relating to human drugs and biologics that are categorically excluded 
and, therefore, ordinarily do not require the preparation of EA's or 
EIS's. One comment requested that a categorical exclusion be added to 
the regulations for ``[a]ction on an NDA, abbreviated application, or a 
supplement to such application, or action on an OTC monograph, if the 
active moiety has been previously approved by FDA and the concentration 
in the environment will be above 1 part per billion.''
    The agency believes that providing a categorical exclusion in 
Sec. 25.31 for an active moiety that has been previously approved by 
the agency is inappropriate. FDA does not have any evidence that 
actions relating to the approval of a drug or biologic for which the 
active moiety has been previously approved do not individually or 
cumulatively have a significant effect on the environment. In some 
cases, the approval of a new indication or dosage form of a previously 
approved active moiety could substantially increase the use of the 
product. In such cases, an EA must be prepared unless the action meets 
one of the other criteria for a categorical exclusion.
    26. One comment requested that proposed Sec. 25.31 be revised to 
add a categorical exclusion for actions relating to drugs that involve 
substances that have an environmental concentration greater than 1 ppb 
(i.e., do not meet the criteria for categorical exclusion under 
Sec. 25.31(b)) but have a PEC to a predicted no effects concentration 
(PNEC) ratio equaling less than one.
    The agency declines to amend Sec. 25.31 as requested. A PEC/PNEC 
ratio is one of several commonly used approaches for evaluating 
environmental effects. To calculate the PEC/PNEC ratio, ecotoxicity 
studies are performed, results are compared to expected environmental 
concentrations, and a conclusion is drawn. The calculation also 
requires use of an assessment factor that will vary depending on the 
type of ecotoxicity data generated. The PEC/PNEC ratio constitutes an 
environmental analysis and, therefore, is not an appropriate criterion 
for a categorical exclusion. If FDA were to use a PEC/PNEC ratio as a 
criterion for categorical exclusion, FDA would need to review the 
underlying data that supports the PEC/PNEC ratio, including the 
assessment factor, and would, in essence, be requiring an EA. Thus, FDA 
will not add a categorical exclusion for actions relating to drugs 
based on the calculation of a PEC/PNEC ratio. An applicant is not 
precluded, however, from using a PEC/PNEC ratio to assess environmental 
effects in an EA or to aid in determining whether extraordinary 
circumstances exist such that a proposed action, which is normally 
excluded, may have an environmental effect.
    27. One comment recommended that the categorical exclusion 
described in proposed Sec. 25.31(c) for naturally occurring substances 
not include new steroid or hormone modulating drugs.
    As explained in the preamble to the proposal (61 FR 14922 at 14926, 
61 FR 19476 at 19480), FDA based the categorical exclusion in 
Sec. 25.31(c) on its finding, after reviewing abbreviated EA's for 
substances that are naturally occurring, that actions on submissions 
for these substances will not affect the environment if the action will 
not significantly alter the concentration or distribution of the 
natural substance in the environment. No information was provided in 
the comment to support the need for this change. The available

[[Page 40578]]

evidence does not support a finding that new steroid or hormone 
modulating drugs, at the expected level of exposure, have the potential 
to significantly affect the environment. Therefore FDA will not modify 
Sec. 25.31(c). The agency specifically addressed concerns regarding 
synthetic estrogens used in human drugs in comment 16 of this document. 
The agency will evaluate each proposed action on an individual basis to 
determine if extraordinary circumstances exist such that further 
environmental documentation is needed.
    28. One comment requested clarification regarding the definition of 
``substances that occur naturally in the environment'' as that phrase 
is used in proposed Sec. 25.31(c). The comment suggested that the 
categorical exclusion be revised to read ``substances that either occur 
naturally in the environment, or are derived from biological systems'' 
or, alternatively, that FDA provide a definition in the regulation.
    The agency declines to adopt the language suggested in the comment 
because the term ``or derived from biological systems'' is too broad. 
Not all substances produced by a biological system may be substances 
that occur naturally in the environment. The biological system, or the 
substance itself, may be modified such that the substance does not 
occur naturally in the environment. The comment provided no rationale 
as to why biologically-derived substances not occurring naturally in 
the environment should be subject to the categorical exclusion.
    FDA intends to clarify which type of actions would fall under this 
categorical exclusion in guidance documents prepared by each center. 
FDA-regulated articles may be considered for categorical exclusion 
under this provision whether they are obtained from natural sources, 
biological systems, or are chemically synthesized. The agency will 
consider the form in which the FDA-regulated article will exist in the 
environment when determining if an action will be eligible for this 
categorical exclusion. For example, a modified active moiety (e.g., 
salt) which does not occur naturally may be considered a naturally 
occurring substance if it is established that, in vivo and in the 
environment, the active moiety exists in a form that is found 
naturally. Biological and biotechnological products will be similarly 
evaluated. For example, a protein or DNA comprised of naturally 
occurring amino acids or nucleosides, but with a sequence different 
from that of a naturally occurring substance, will normally qualify for 
this categorical exclusion after consideration of metabolism. The same 
principle will apply to synthetic peptides and oligonucleotides. Living 
and dead cells and organisms regulated by the agency may also be 
considered for categorical exclusion under this provision if the action 
does not alter significantly the concentration or distribution of the 
substance, its metabolites, or degradation products in the environment. 
The agency will rely on the significant amount of information submitted 
by an applicant in support of a requested action (for example 
information about metabolism, excretion, and stability; viability (if 
applicable); and physical/chemical characteristics of the product) in 
determining whether categorical exclusion under Sec. 25.31(c) is 
appropriate.
    29. One comment requested that the phrase ``action on an OTC 
monograph,'' which is included in the categorical exclusions in 
Sec. 25.31 (a), (b), and (c), be changed to ``OTC activity'' and that 
the regulation define ``OTC activity'' as ``an action on an OTC 
monograph or a switch of a drug from prescription to OTC use that is 
submitted in an NDA or supplement, if the product is already marketed 
for the proposed use.'' The comment expressed a belief that the 
preamble to the proposed rule ``is clear on the intent for a 
prescription to an OTC switch to be considered as a categorical 
exclusion.''
    FDA does not believe it is necessary or appropriate to substitute 
``OTC activity'' for ``action on an OTC monograph'' in Sec. 25.31 (a), 
(b), and (c). Agency action on any request to switch a drug from 
prescription to OTC use is already covered in Sec. 25.31 (a), (b), and 
(c) by the language ``action on an NDA, abbreviated application, or a 
supplement to such application, or action on an OTC monograph.'' 
Depending on the circumstances and the applicant's preference, a 
prescription to OTC switch may be requested using any of these 
administrative filing mechanisms. As discussed in the preamble (61 FR 
14922 at 14925, 61 FR 19476 at 19479), the agency will not elevate form 
over substance and will treat like actions alike, regardless of the 
avenue through which the actions are requested. Thus, the same 
categorical exclusion criteria will apply to NDA's, abbreviated 
applications, supplements, and ``actions on OTC monographs.''
    Prescription to OTC switches have generally been, and will continue 
to be, considered by CDER to be actions that increase use because the 
potential patient population expands from only those persons who seek 
treatment under a physician's care to any person who enters a retail 
establishment that sells OTC products. Therefore, agency action on an 
OTC switch will be categorically excluded if the criteria of Sec. 25.31 
(b) or (c) apply to the action, specifically if the concentration of 
the substance at the point of entry into the aquatic environment will 
be below 1 ppb (Sec. 25.31(b)), or if it is a substance that occurs 
naturally in the environment and the action will not significantly 
alter the concentration of the substance in the environment 
(Sec. 25.31(c)).
    30. Proposed Sec. 25.31(e) would categorically exclude action on an 
IND from the requirement to prepare an EA. One comment suggested that 
this exclusion be limited by specifying in the exclusion a ceiling on 
the quantity (number of doses) to be released into the environment.
    As stated in the preamble to the proposed rule (61 FR 14922 at 
14926, 61 FR 19476 at 19480), FDA action on an IND in many cases does 
not significantly increase the use of the drug or the amount of the 
drug introduced into the environment because the drug is being 
administered to few patients or is already being marketed for another 
use. Consequently, no changes in the effect on the environment will 
occur due to agency action on the IND. In the event FDA action on an 
IND would increase the use of a drug, the agency's experience has 
demonstrated that significant environmental effects would not occur 
because the investigational use is limited and controlled. The dosing 
regimen for investigational drugs that would result in an environmental 
introduction concentration of 1 ppb (the concentration below which FDA 
has found no significant effect on the environment) is not expected for 
clinical trials held under an IND. Very large clinical trials are rare, 
but, cumulatively, they enroll approximately 8,000 patients. Those 
subjects would need to use 14 grams of the active moiety every day for 
an entire year to result in an environmental introduction concentration 
of approximately 1 ppb, the concentration below which CDER has 
routinely observed no significant effects on relevant standard test 
organisms in the aquatic environment. The level and duration of this 
dosing regimen, as described, are greater than is expected under 
clinical trials, thus the addition of a criterion limiting the number 
of doses is unnecessary.
    The preamble to the proposed rule (61 FR 14922 at 14923, 61 FR 
19476 at 19477) noted that categorical exclusion

[[Page 40579]]

criteria relating to toxicity, which includes current Sec. 25.24(c)(4), 
``if * * * waste will be controlled or the amount of waste expected to 
enter the environment may reasonably be expected to be nontoxic,'' have 
been incorporated into the extraordinary circumstances provision of 
Sec. 25.21(a). Therefore, the categorical exclusion for IND's remains 
essentially unchanged. In the event FDA has reason to believe its 
action on an IND may significantly affect the environment, FDA will 
invoke the provision relating to ``extraordinary circumstances'' and 
require an EA. Therefore, the agency declines the suggestion to modify 
the categorical exclusion in Sec. 25.31(e).
2. Foods, Food Additives, and Color Additives
    31. Proposed Sec. 25.32(b) provides for a categorical exclusion for 
FDA action on a request for exemption for investigational use of a food 
additive, if the food additive is intended to be used for clinical 
studies or research. One comment noted the absence of a discussion 
concerning the potential impact of the investigational use of food 
additives in the preamble to the proposal, despite the discussion about 
the potential environmental impact of investigational and clinical 
research for drugs. The comment recommended that FDA establish a 
maximum annual quantity for investigational uses of food additives 
allowed to be released to the environment.
    The agency declines to establish additional criteria for the 
application of the categorical exclusion of the investigational use of 
food additives. FDA has not required that a formal application be 
submitted to the agency for the investigational use of a food additive. 
The investigational use of food additives is expected to be limited to 
small amounts needed in studies with laboratory animals under 21 CFR 
170.17. Occasionally additives are tested in limited clinical trials 
under the control of institutional review boards. The program has 
functioned for 40 years with little investigational activity under 21 
U.S.C. 348(i). Thus, the agency is not aware of any need to revise this 
exclusion to include a ceiling on the yearly amount of a substance that 
may be released into the environment. Furthermore, the comment provided 
no information on which to conclude that such a ceiling is justified.
    32. One comment specifically supported the categorical exclusions 
in the proposed rule for food and color additives and generally 
recognized as safe (GRAS) substances. Another comment specifically 
supported the categorical exclusions set forth in proposed Sec. 25.32 
(i), (k), and (r), but raised issues regarding the need for reform of 
the review process for food additive and GRAS petitions.
    Reform of the review process for food additive and GRAS petitions 
is outside the scope of this rulemaking and will not be addressed here.
    33. One comment, while generally supporting the categorical 
exclusions in proposed Sec. 25.32 (i) and (j), requested that they be 
expanded to include all actions on components of food-contact 
materials, including actions on GRAS petitions, except where 
extraordinary circumstances exist. The comment asserted that compiling 
the information needed for EA's for food-packaging materials is 
unnecessary and unduly burdensome, that the costs of preparing EA's for 
these materials are significant, and that routine preparation of EA's 
for these actions results in an unnecessary expenditure of industry and 
agency resources. The comment requested that the agency not require 
EA's for actions on nonfunctional components of food-packaging 
materials because Federal, State, and local laws and regulations 
adequately control emissions to the environment at sites where these 
substances are used in the manufacture of food-packaging materials. The 
comment pointed out that the agency is proposing not to require 
information on the production of FDA-regulated substances based on its 
recognition that Federal, State, and local environmental laws and 
regulations adequately protect the environment at the production sites 
for those substances. The comment requested that the agency apply the 
same reasoning to conclude that EA's are no longer needed to assess the 
environmental impact of nonfunctional components of food-packaging 
materials that are used and enter the environment at the production 
sites of the packaging material. The comment also requested that EA's 
not be required for actions involving components of finished food-
packaging material present at greater than 5 percent-by-weight because: 
(1) Most of these additives will replace other similar, already 
regulated additives and will not have any meaningful impact on the 
potential uses of the finished food-packaging material; and (2) 
adequate Federal, State, and local laws and regulations are in place to 
protect environments that may be affected by disposal of food-packaging 
material. The comment pointed out that ``in certain rare situations, 
for example, in instances where the use of a new material may affect 
recycling streams, disposal of food-packaging materials prepared from a 
newly regulated polymer could potentially have some effect on the 
environment.'' The comment suggested that in these instances it may be 
appropriate for the agency to require an EA and that proposed 
Sec. 25.21 (Extraordinary circumstances) will provide the agency with 
the means to require EA's for these few situations.
    FDA agrees that the new categorical exclusions in proposed 
Sec. 25.32 (i) and (j) should be revised to include GRAS petitions. The 
agency also acknowledges that there are certain classes of 
nonfunctional components of food-packaging materials and certain 
classes of components of food-packaging material present at greater 
than 5 percent-by-weight of the finished food-packaging material that 
should be included under Sec. 25.32(i). However, FDA does not agree 
that all classes of actions on substances intended for use as 
components of food-contact materials warrant categorical exclusion. Nor 
does the agency agree that compiling the information needed for EA's 
for food-packaging materials is unnecessary, unduly burdensome, and 
costly. The basis for the agency's decision on these classes of actions 
is explained below.
    GRAS petitions: None of the petitions that the agency has reviewed 
while developing the categorical exclusions in Sec. 25.32 (i) and (j) 
(including those it has reviewed since the proposal issued) were GRAS 
affirmation petitions for components of food-packaging material or 
components of food-contact surfaces of equipment or other repeat use 
food-contact articles. But, because the environmental information that 
would be needed under part 25 for a GRAS petition for these types of 
food-contact substances is identical to the information required for a 
food additive petition, the agency believes that its experience with 
food additive petitions is relevant to GRAS affirmation petitions and 
that any future GRAS affirmation petitions for these classes of actions 
can also be excluded. Therefore, FDA has revised proposed Sec. 25.32(i) 
and (j) to include actions on GRAS affirmation petitions.
    Nonfunctional components of food-packaging material: The agency 
does not believe it is appropriate to categorically exclude all actions 
on nonfunctional components of food-packaging material, as requested by 
the comment. To evaluate the request that FDA revise Sec. 25.32(i) to 
further exclude from the requirements for EA actions on nonfunctional 
components of food-packaging materials, the agency reviewed 44 
petitions for nonfunctional components of food-packaging

[[Page 40580]]

materials.1 As a result of this review, the agency found 
that a number of these petitions warranted exclusion from the need for 
an EA, while others did not. The agency found that 13 of the petitions 
were for additives that remained with food-packaging materials used by 
consumers despite the fact that these additives did not function in the 
finished food-packaging material. As they pertained to use and disposal 
of nonfunctional components of food-packaging materials, the FONSI's 
for the agency's actions on these petitions were based on the following 
factors: (1) Only very small quantities, if any, of these additives 
were expected to enter the environment at sites where the additives 
were used in the manufacture of food-packaging materials; (2) only 
extremely low levels of substances, if any, could be expected to enter 
the environment as a result of disposal of food-packaging materials; 
and (3) virtually no change in the use of natural resources and energy 
would be expected because the additives would be replacing other, 
currently regulated, additives and would not affect the uses of the 
packaging materials to which they were added. These factors are the 
same as those upon which the agency bases its exclusion for actions on 
functional components of finished food-packaging materials. Therefore, 
the agency has decided that it is appropriate to revise proposed 
Sec. 25.32(i) to include all components of food-packaging materials 
that remain with finished packaging through use by consumers and are 
present at less than 5 percent-by-weight, regardless of whether they 
perform a function in the finished package.
---------------------------------------------------------------------------

    \1\ ``Index of Petitions for Nonfunctional Components of Food-
packaging Materials,'' (Docket No. 96N-0057).
---------------------------------------------------------------------------

    In its review of the remaining 31 petitions involving nonfunctional 
components of finished food-packaging material, the agency found that 5 
petitions were for antimicrobial substances that are also regulated by 
EPA under the Federal Insecticide, Fungicide, and Rodenticide Act 
(FIFRA) as pesticides. In Sec. 25.32(q) of the proposed rule, actions 
to approve a food additive petition or grant a request for exemption 
from regulation as a food additive under Sec. 170.39 are categorically 
excluded when the substance that is the subject of the petition or 
request is registered by EPA under FIFRA for the same use requested in 
the petition or in the request for exemption.
    Also among these 31 petitions were 6 petitions for substances that 
occur naturally in the environment. These petitions would be excluded 
from the requirement to prepare an EA under the categorical exclusion 
in Sec. 25.32(r) of the final rule.
    The 20 remaining petitions involving nonfunctional components of 
finished food-packaging material were for additives that were not 
expected to remain with the finished article, but instead were expected 
to enter the environment at sites where they were used as processing 
aids in the manufacture of food-packaging materials and were neither 
antimicrobial substances nor naturally occurring substances. These 
types of additives are not intended to remain with the finished food-
packaging materials which are used and disposed of by consumers 
throughout the United States. The results of environmental toxicity 
tests presented in some of these petitions showed that the additives 
had the potential to harm organisms in the environment present at or 
adjacent to the use sites. For 17 of these 20 petitions, FDA conducted 
an analysis of the environmental exposure levels of the additives at 
the use sites and compared these exposure levels to environmental 
toxicity information on the additives to determine the potential for 
significant impact. In some cases, the margin between environmental 
exposure levels and levels found to be toxic to organisms present in 
the receiving environment was very narrow. For the remaining three 
petitions, FDA relied upon adequate regulation of potential discharges 
to reach its environmental decision.
    Under current part 25, FDA has required specific information about 
Federal, State, and local laws and regulations that are applicable to 
emissions at the site of production of the subject substances where the 
manufacturing operations are designed to provide maximum yield of the 
FDA-regulated article for commercial sale. FDA reviewed hundreds of 
submissions with this information before deciding to eliminate the 
requirements for its inclusion. However, the formats for EA's in 
current Sec. 25.31a do not require information on emissions 
requirements at the sites where nonfunctional components of food-
packaging materials are used to produce the finished article. A review 
of FDA's experience with EA's for most nonfunctional components of 
finished food-packaging materials that are expected to enter the 
localized use site environment (i.e., the finished food-packaging 
manufacturing facility) has revealed that analysis of exposure and 
environmental toxicity is necessary to determine the potential for 
significant impact. Based on this experience, therefore, the agency 
does not agree with the comment that it can rely on other Federal, 
State, and local laws for protecting the environment to exclude actions 
on petitions for these nonfunctional components of food-packaging 
materials as was done to eliminate requirements for information on the 
sites of production of FDA-regulated articles.
    Thus, the agency cannot establish an additional categorical 
exclusion for petitions for nonfunctional components of food-packaging 
that do not remain with food-packaging through use by consumers. The 
agency will provide specific guidance to petitioners for preparing EA's 
for those categories of petitions that will require EA preparation. The 
guidance for EA's involving nonfunctional components of food-packaging 
materials will focus on the relevant issues surrounding a proposed 
action and will take into consideration whether other laws and 
regulations adequately control potential environmental impacts or 
whether an action may threaten a violation of such laws and regulations 
as required by CEQ regulations (40 CFR 1508.27(b)(10)).
    Components of Finished Food-packaging Material Present at Greater 
than 5 Percent-by-Weight: The comment requested a categorical exclusion 
for actions involving components of finished food-packaging material 
present at greater than 5 percent-by-weight, but did not provide any 
specific information showing that actions on petitions in this category 
do not individually or cumulatively have significant environmental 
effects. To evaluate this request, FDA reviewed 30 petitions for 
components of food-packaging materials present at greater than 5 
percent.2 The agency found that five of these petitions were 
for coatings or components of coatings for food-packaging materials. 
The FONSI's for the agency's actions on these petitions were based on 
the following factors: (1) Only extremely low levels of substances, if 
any, could be expected to enter the environment as a result of use and 
disposal of these coated food-packaging materials; and (2) virtually no 
change in the use of natural resources and energy would occur because 
the additives would be replacing other, currently regulated, additives 
and would not affect either the uses of the packaging materials to 
which they were added or the disposal technologies used for these 
materials. These factors are the same as those upon which the exclusion 
for actions on functional components of

[[Page 40581]]

finished food-packaging materials present at less than 5 percent are 
based even though the components of the coatings may be present in the 
finished food-packaging material at greater than 5 percent-by-weight. 
Therefore, the agency is revising the exclusion in proposed 
Sec. 25.32(i) to include actions on the components of coatings of 
finished food-packaging materials.
---------------------------------------------------------------------------

    \2\  ``Index of Petitions for Components of Food-packaging 
Materials Present at Greater than 5%,'' (Docket No. 96N-0057).
---------------------------------------------------------------------------

    The agency's findings for the remaining 25 petitions support FDA's 
position that significant environmental effects may result from agency 
actions on components of finished food-packaging material present at 
greater than 5 percent-by-weight. Examples of petitions that required 
extensive analysis to determine the potential impact of food-packaging 
materials on solid waste management strategies include food additive 
petition (FAP) 6B3948 (Docket No. 86F-0341); FAP 7B3979 (Docket No. 
86F-0508); FAP 8B4107 (Docket No. 88F-0404); FAP 1B4236 (Docket No. 
91F-0198); and FAP 8B4110 (Docket No. 88F-0339). In some cases, the 
agency and the petitioners decided to include mitigating measures in 
the food additive regulations to avoid potentially significant 
environmental effects. In addition, the agency has not acted on FAP 
7B3994, because it needs to consider further whether significant 
effects on solid waste management strategies may result (53 FR 47264 at 
47267, November 22, 1988). Evaluation of these potential effects is 
being conducted along with an evaluation of the agency's proposed 
action to provide for the safe use of vinyl chloride polymers (51 FR 
4177, February 3, 1986). The agency announced on November 22, 1988 (53 
FR 47264), its intent to prepare an EIS on its actions on vinyl 
chloride and other chlorinated polymers. FDA continues to work on this 
statement.
    This comment asserted that EA's are not needed for petitions for 
components of food-packaging materials because the effects of disposal 
of food-packaging materials by incineration or landfilling are subject 
to the control of laws, regulations, and government authorities 
directly concerned with the environment. FDA, based on its experience, 
agrees that the extremely low levels of substances that may leach from 
food-packaging materials disposed of in landfills are adequately 
controlled by EPA regulations in 40 CFR part 258. FDA is aware of laws 
and regulations governing the incineration of municipal solid waste, 
which include the incineration of food-packaging materials. However, 
there is potential for incineration of food-packaging materials to 
threaten a violation of these laws and regulations. FDA will consider 
this potential effect under 40 CFR 1508.27(b)(10). For example, in its 
decision to prepare an EIS on its actions on vinyl chloride and other 
chlorinated polymers (53 FR 47264 at 47265, November 22, 1988), the 
agency found that the expected increase in hydrogen chloride emissions 
from incinerators may affect the ability of incinerator operators to 
comply with existing and anticipated emissions standards. This issue is 
still under agency review.
    A number of the agency's actions on components of food-packaging 
materials present at greater than 5 percent-by-weight had potential for 
significant effects on the environment. The agency is unable, without 
specific information such as that provided in an EA, to distinguish 
which petitions for these actions may have potential for significant 
impact. Therefore, the agency will continue to require EA's for this 
category of petitions, with the exception of those petitions pertaining 
to components of coatings. The agency will develop and provide to 
petitioners specific guidance for preparing EA's for those categories 
of petitions that will require the preparation of EA's. The guidance 
for EA's involving components of packaging present at greater than 5 
percent-by-weight will focus on the relevant issues surrounding a 
proposed action, and will take into consideration the extent to which 
other laws and regulations adequately control potential environmental 
impacts.
    As a result of this analysis, proposed Sec. 25.32, categorical 
exclusions for foods, food additives, and color additives, will be 
revised at paragraphs (i) and (j) to read as follows:

    (i) Approval of a food additive petition, GRAS affirmation 
petition, or the granting of a request for exemption from regulation 
as a food additive under Sec. 170.39 of this chapter, when the 
substance is present in finished food-packaging material at not 
greater than 5 percent-by-weight and is expected to remain with 
finished food-packaging material through use by consumers or when 
the substance is a component of a coating of a finished food-
packaging material.
    (j) Approval of a food additive petition, GRAS affirmation 
petition, or the granting of a request for exemption from regulation 
as a food additive under Sec. 170.39 of this chapter, when the 
substance is to be used as a component of a food-contact surface of 
permanent or semipermanent equipment or of another food-contact 
article intended for repeated use.

    Burden of compiling the information for EA's for food-packaging 
materials: As discussed above, for certain actions involving food-
packaging materials, FDA will continue to require petitioners to submit 
an EA. FDA does not agree that the information it requires the 
petitioner to submit in these EA's is unnecessary, nor does the agency 
believe the effort to provide such information is unduly burdensome. As 
FDA has stated above, it will provide guidance to industry regarding 
the focus of environmental documents. In addition, FDA has limited in 
the past and will continue to limit its requests for information to 
only the amount needed to assess the potential environmental impact of 
its actions. FDA recognizes that in some cases the information needed 
for EA's is not readily available or is not yet known to a petitioner. 
In such cases, the agency in the past has asked the petitioner to 
provide a best possible forecast or to use a conservative approach to 
analyze environmental effects. FDA will continue this approach, 
recognizing that in some cases there may be uncertainty about the 
potential for significant environmental impact of food-packaging 
materials.
    In the preamble to the proposal (61 FR 14922 at 14935, 61 FR 19476 
at 19489), FDA noted its calculation that the proposed changes in the 
environmental regulations would reduce the costs for both the regulated 
industry and for the agency. These reduced costs will result from, 
among other things, providing for categorical exclusions for additional 
classes of actions. To this end, the agency proposed and is now making 
final two exclusions that will apply to actions on food-packaging 
materials (Sec. 25.32 (i) and (j)). As explained above, these 
exclusions have been expanded in the final rule to include additional 
classes of actions. These changes are expected to further reduce the 
costs of preparing and reviewing environmental documents for food-
packaging materials. The agency believes that the remaining actions on 
food-packaging materials that require EA's have the potential to result 
in significant environmental effects, and information in an EA is 
necessary for the agency to make decisions on these potential effects.
    34. Proposed Sec. 25.32(k) would categorically exclude actions to 
approve food additive, color additive, and GRAS affirmation petitions 
for substances added directly to food that are intended to remain in 
food through ingestion by consumers and that are not intended to 
replace macronutrients in foods. One comment claimed that FDA was 
proposing a 1 ppb environmental exposure threshold below which the 
exclusion applied, as was done for human drugs in proposed 
Sec. 25.31(b). The comment requested that FDA establish a maximum 
annual quantity of

[[Page 40582]]

the food additive allowed to be released to the environment under this 
exclusion.
    The agency declines to establish additional criteria for the 
exclusion under Sec. 25.32(k) covering substances that are intended to 
remain in food through ingestion by consumers and are not intended to 
replace macronutrients in food. As explained in the preamble to the 
proposal (61 FR 14922 at 14928, 61 FR 19476 at 19482), the basis for 
this exclusion is FDA's experience reviewing 21 petitions in this 
class, all of which resulted in a FONSI. The FONSI's relied on one or 
more of the following scenarios: (1) The approval of the petition 
resulted in very low levels of the substances in either effluents and/
or sewage sludge; (2) the substance was digested and/or metabolized by 
humans such that only the products of digestion and metabolism were 
expected to be excreted and those products were the same as (or very 
similar to) other products of digestion and metabolism resulting from 
human food; or (3) the substance was excreted largely intact but was 
rapidly degraded into nontoxic products. Based upon this review of 
petitions in this class, the agency found that it was not necessary to 
establish either an exposure threshold concentration or a maximum 
annual quantity of substances allowed to be released. Even in the three 
instances where it was necessary to compare the environmental exposure 
level of the substance with environmental toxicity data, there was a 
wide margin of safety. No information to support the establishment of 
either of these qualifying thresholds is provided in the comment. 
Therefore, the agency has no basis on which to revise Sec. 25.32(k) to 
incorporate either an exposure threshold concentration or a maximum 
annual quantity that may be released.
    35. An additional comment about the exclusion in proposed 
Sec. 25.32(k) expressed concern about the potential for significant 
impacts on energy and natural resources resulting from the use and 
disposal of nonnutritive oils. This comment recommended that the 
proposed exclusion be withdrawn or that a ceiling be added that would 
require an EA where such substances enter the environment above a 
certain annual level.
    The agency declines to amend the proposed exclusion as recommended. 
Actions on food additive petitions for nonnutritive oils or fat 
substitutes would not qualify for the categorical exclusion in 
Sec. 25.32(k), because such substances are considered to be 
replacements for macronutrients. An EA submitted for a fat substitute 
would include consideration of the impact on energy and natural 
resources resulting from the production (if appropriate), use, and 
disposal of such substances. Such considerations were part of FDA's 
action to approve the use of the fat substitute olestra (Docket No. 
87F-0179).
    36. Proposed Sec. 25.32(m) would categorically exclude actions to 
prohibit or otherwise restrict or reduce the use of asubstance in food, 
food packaging, or cosmetics. One comment supported this exclusion, but 
requested clarification regarding how FDA will consider under this 
exclusion impacts on the environment (to human well-being and on the 
environment itself) that are controversial.
    As discussed in the preamble to the proposal (61 FR 14922 at 14929, 
61 FR 19476 at 19483), the agency has found that this class of actions 
has not involved controversial issues with respect to potential impact 
on the physical environment. FDA's action to prohibit the use of CFC's 
is the only exception to this principle to date.
    In most instances, the purpose of actions to restrict or withdraw 
approval of foods, food packaging, or cosmetics is to protect the 
public health. Potential impacts on human health, and any controversy 
surrounding such impacts, are fully considered in Federal Register 
documents (e.g., a preamble to a proposed or final rule restricting or 
withdrawing approval) supporting the action. See the response to 
comment 22, above. The appropriateness of an exclusion for a proposed 
action to restrict or eliminate the use of a substance in food, food-
packaging, or cosmetics will depend on whether the action may involve 
extraordinary circumstances that would require evaluation through an EA 
or an EIS. Under proposed Sec. 25.21, extraordinary circumstances 
include the degree to which the possible effects on the human 
environment are likely to be highly controversial, as provided in 40 
CFR 1508.27(b)(4).
    37. Proposed Sec. 25.32(o) would categorically exclude actions to 
approve a food additive petition for the intended expression product(s) 
present in food derived from new plant varieties. One comment 
recommended that compounds that may be ``hormone modulators'' should 
not be included in this categorical exclusion.
    FDA is not aware of any specific substances derived from new plant 
varieties that could potentially affect the endocrine system of other 
organisms. It is unlikely that FDA would receive a food additive 
petition for a substance derived from new plant varieties that was 
intended to have a physiological effect on the human endocrine system. 
A substance derived from new plant varieties that is intended to have 
such an effect on the human endocrine system would be regulated by FDA 
as a drug. Thus, it is unlikely that a claim for categorical exclusion 
for a hormone modulator would be made under Sec. 25.32(o) and FDA 
declines to modify Sec. 25.32(o) to reflect such a scenario.
    In the event FDA receives a food additive petition for a substance 
derived from new plant varieties that is known or suspected to have 
potential for affecting the endocrine system in humans, aquatic life, 
and/or wildlife, agency action on such a petition would generally be 
excluded under Sec. 25.32(o). As described in the preamble to the 
proposed rule (61 FR 14922 at 14929-14930, 61 FR 19476 at 19483-19484), 
under Sec. 25.32(o) environmental review of new plant varieties would 
be performed by the United States Department of Agriculture (USDA). 
Therefore, if USDA has granted a categorical exclusion or conducted an 
environmental review, NEPA review by FDA would be redundant and 
therefore, unnecessary.
    38. In proposed Sec. 25.32(q), actions to approve a food additive 
petition or grant a request for exemption from regulation as a food 
additive under Sec. 170.39 are categorically excluded when the 
substance that is the subject of the petition or request is registered 
by EPA under FIFRA for the same use requested in the petition or in the 
request for exemption. One comment stated that the same information 
submitted to EPA for registration of pesticides under FIFRA should be 
encouraged for FDA submissions. The comment expressed concern about the 
lack of policy alignment between agencies regarding the level of risk 
and about the ability of FDA to meet deadlines due to its reliance on 
the review of data by another agency that may have different review 
priorities. The comment suggested that FDA ``handle this proposed 
exclusion as a guideline policy rather than a categorical exclusion,'' 
or align interagency risk determination policies before allowing this 
exclusion.
    FDA does not agree with the suggestion that the exclusion be 
handled as a guideline policy. As discussed in the preamble to the 
proposal (61 FR 14922 at 14930, 61 FR 19476 at 19484), FDA has found 
that the scope of EPA's review of the environmental risk of 
antimicrobial substances subject to pesticide registration under FIFRA 
encompasses FDA's review of the environmental risk

[[Page 40583]]

of these substances for food additive use under NEPA. In evaluating 
whether a food additive petition or request for exemption meets the 
categorical exclusion in Sec. 25.32(q), FDA will ensure that the 
substance for which a petitioner seeks approval is identical to the 
substance that is registered as a pesticide under FIFRA. If the 
substance is registered as part of a formulation under FIFRA, FDA will 
ensure that it is approving the substance for use as part of that 
formulation registered under FIFRA. By ``same use'' the agency means 
that in a comparison of the food additive use to the pesticide use, the 
purpose of the use, any components used with the substance for the 
petitioned use, and the amount of the substance and the amounts of any 
components used with it are substantially identical. FDA has found 
that, when these antimicrobial substances are intended for the same 
use, its assessment of the environmental risk of antimicrobial 
substances is the same as EPA's assessment of the environmental risk of 
pesticides and, therefore, the food additive use will be subsumed under 
EPA's environmental review of the substance as a pesticide registered 
under FIFRA.
    In addition to ensuring that the substance is identical to and for 
the same use as the registered pesticide, FDA will ensure that the 
label for the use of the substance as a food additive includes 
information related to the environmental effects, such as precautionary 
statements on environmental hazards, that is required on the label for 
the use of the substance as a registered pesticide under FIFRA. This 
will provide assurance that any adverse environmental effects from the 
use of the substance as a food additive have been addressed and are 
mitigated, as needed, to the same extent as any adverse environmental 
effects from the use of the substance as a pesticide registered under 
FIFRA.
    In response to the comment that FDA may not be able to meet its 
deadlines because of its reliance on review of data by another agency, 
nothing in this final rule precludes a petitioner or requester from 
submitting an environmental assessment to FDA for review, despite the 
fact that the action may be eligible for a categorical exclusion under 
Sec. 25.32(q). Moreover, establishing a categorical exclusion for an 
antimicrobial substance that is registered as a pesticide with EPA 
under FIFRA should not affect FDA's ability to meet its statutory 
deadlines for completing the review of food additive petitions that are 
eligible for an exclusion under Sec. 25.32(q). In order for a substance 
to be eligible for a Sec. 25.32(q) categorical exclusion, the substance 
must be registered by EPA as a pesticide under FIFRA for the same use 
requested in the petition at the time the food additive petition is 
submitted to FDA. Antimicrobial substances that are not registered by 
EPA under FIFRA for the same use at the time the food additive petition 
is submitted to FDA would not be eligible for a categorical exclusion 
under Sec. 25.32(q). Without the pesticide registration, FDA would not 
be able to determine whether the use is the same as that in the food 
additive petition or request for exemption and therefore eligible for a 
categorical exclusion.
    As previously mentioned, the scope of environmental review for a 
pesticide registration, based on the agency's review of previous 
petitions, encompasses FDA's environmental review for the use of the 
substance as a food additive. Therefore, the agency does not anticipate 
that any additional environmental review would be required for a 
petitioned food additive use of a substance that is registered as a 
pesticide under FIFRA. However, if the substance is not registered as a 
pesticide under FIFRA or the environmental impacts resulting from the 
petitioned food additive use or request for exemption are not within 
the scope of EPA's environmental assessment performed for the pesticide 
registration, FDA's action on the substance would not warrant 
categorical exclusion under Sec. 25.32(q), and instead, would require 
at least an EA under Sec. 25.20.
3. Veterinary Drugs and Feed Additives
    39. Proposed Sec. 25.33(a) would categorically exclude action on an 
NADA, abbreviated application, or supplement to such applications, if 
the action does not increase the use of the drug. One comment pointed 
out that, in its categorical exclusion relating to actions that do not 
increase use, FDA uses the term ``active moiety'' when referring to 
human drugs in proposed Sec. 25.31(a) and ``drug'' when referring to 
animal drugs in proposed Sec. 25.33(a). The comment stated that the 
reason for the use of different terms was not apparent, and recommended 
that the term active moiety also be used when referring both to human 
drugs and animal drugs.
    The agency does not agree that the term ``active moiety'' should be 
used in Sec. 25.33(a) to describe the actions on animal drugs that are 
categorically excluded because for many animal drugs an explicit active 
moiety cannot be defined. For example, an animal drug may consist of 
biomass which is the purified broth from fermentation manufacturing. In 
that case, the animal drug consists of a variety of components but an 
``active moiety'' is not explicitly defined. If there is no increase in 
the use of an animal drug, it follows that there is no increase in the 
level of the substance in the environment and, consequently, no 
increase in any associated environmental effects.
    40. One comment requested that proposed Sec. 25.33(a) be revised to 
categorically exclude actions that do not increase the use and the 
concentration of the drug. The comment reasoned that when an animal 
drug is administered, the concentration of that drug in the 
environment, rather than the fact of ``use,'' has the potential to 
raise environmental concerns.
    The agency agrees that an increase in concentration has the 
potential to raise environmental concern but does not agree that the 
addition of the term ``increase concentration'' to the exclusion is 
necessary. The primary purpose of the categorical exclusion is to 
provide a simple method to identify for drug sponsors which actions 
obviously have no significant environmental impacts. An increase in 
use, such as an increase in dosage level, an increase in the duration 
of use, or the addition of a new indication obviously results in an 
increase in the environmental concentration. To help clarify what 
actions are categorically excluded under proposed Sec. 25.33(a), the 
agency has defined in proposed Sec. 25.5(b)(4) that ``increased use'' 
may occur if the drug is administered at higher dosage levels, for 
longer duration, or for different indications than were previously in 
effect, and if the drug is a new molecular entity. The term ``use'' is 
further defined to encompass disposal of FDA-related articles. Section 
25.33(a) also lists specific examples of the actions that are excluded. 
Therefore, the agency believes that the use of the term ``increased 
use,'' as defined in Sec. 25.5(b)(4), along with the examples provided, 
best describes the criteria for categorical exclusion under proposed 
Sec. 25.33(a).
    41. In proposed Sec. 25.33(a), change in sponsor is included as one 
of the types of actions covered by the categorical exclusion 
(Sec. 25.33(a)(5)). One comment requested that FDA reconsider the 
inclusion of actions relating to changes in drug sponsors in this 
categorical exclusion because such a change may result in manufacturing 
or process changes that could cause a difference in end product 
chemical profiles. The comment argued that differences in manufacturing 
practices may warrant further environmental evaluation.

[[Page 40584]]

    The agency reconsidered the proposed categorical exclusion for 
changes in drug sponsor but decided to retain the exclusion in the 
final rule. A change in sponsor does not necessarily involve a change 
in the manufacturing or processing of a drug. In the event that a 
change in sponsor results in manufacturing or process changes, it is 
not likely that there will be a change in the end product that will 
affect the environmental impacts of the drug because a new sponsor must 
maintain the same quality, composition, and purity of the drug to 
assure that its safety and effectiveness are the same as the product 
approved for manufacture by a previous sponsor. Any change that would 
result in a change in the chemical profile of the end product would 
require a supplement to be filed with the agency. The need for 
environmental information would be evaluated by FDA in conjunction with 
agency action on that supplement. The exclusion in Sec. 25.33(a) has 
been changed to clarify that actions listed ``may'' be excluded if the 
actions meet the criteria in the categorical exclusion.
    42. In the preamble to FDA's proposed regulations (61 FR 14922 at 
14931, 61 FR 19476 at 19485), FDA stated that proposed Sec. 25.33(b) is 
being reserved for animal drugs ``not otherwise excluded in 
Sec. 25.33(a).'' One comment expressed concern that this statement 
regarding Sec. 25.33(b) may inadvertently create confusion about the 
actions on animal drugs exclusions in other paragraphs of proposed 
Sec. 25.33, especially in proposed Sec. 25.33(d)(5).
    FDA can understand how the wording in the preamble (61 FR 14922 at 
14931 and 14932, 61 FR 19476 at 19485 and 19486) could be confusing, 
but the regulations are explicit about what actions are categorically 
excluded. Actions that do not meet the criteria of Sec. 25.33(a) may 
still be categorically excluded under Sec. 25.33 (c) or (d), including 
Sec. 25.33(d)(5). If the agency adopts criteria for excluding actions 
under Sec. 25.33(b) as discussed in the preamble, this will add 
additional criteria for excluding actions, it will not restrict the 
application of other criteria to exclude actions.
    43. One comment suggested that reserved Sec. 25.33(b) should 
categorically exclude any action on an NADA, abbreviated application, 
or a supplement to such applications, that increases the use of a drug 
if the PEC in soil is less than the PNEC, based on a scientifically 
valid environmental test conducted with a representative soil organism. 
The comment noted that a relatively simple scientific explanation or 
calculation would be needed to determine whether an action qualifies 
for such an exclusion. The comment defended the use of a scientific 
threshold or screening test for a categorical exclusion as appropriate, 
citing regulations issued by the Bureau of Indian Affairs (BIA), EPA, 
and the Federal Highway Administration (FHWA).
    The agency declines to revise the proposed regulations as 
suggested. As explained above, the agency stated in the preamble to the 
proposal that it was reserving Sec. 25.33(b) to provide for actions 
that increase the use of an animal drug when the agency determines a 
level at or below which the concentration of the substance in the 
environment does not significantly affect the environment. Criteria for 
this categorical exclusion would require a relatively simple 
calculation using limited available information. The proposed PEC to 
PNEC comparison represents more than a simple calculation or 
explanation. Ecotoxicity studies are performed, results are compared to 
expected environmental concentrations, and a conclusion is drawn (see 
the response to comment 26). The agency considers this activity to be 
an environmental risk assessment that is more appropriately provided as 
part of an EA.
    The agency reviewed the BIA, EPA, and FHWA regulations cited in the 
comment. The BIA categorical exclusion refers to standards that are 
required by the Bureau of Land Management (BLM). To qualify for this 
categorical exclusion, an applicant merely states that it is in 
compliance with the BLM requirements. No scientific threshold or 
screening test is required. The EPA and FHWA citations refer to EPA and 
FHWA general categorical exclusion processes and do not include 
scientific explanations or calculations.
    44. One comment addressed its statements to FDA's description, in 
the preamble to the proposal (61 FR 14922 at 14931, 61 FR 19476 at 
19485), of the categorical exclusions established in proposed 
Sec. 25.33 (a) and (b). The comment stated that the EIC, rather than 
the EEC, should be used to determine potential environmental impacts of 
veterinary drugs and feed additives. The comment argued that this will 
give more weight in determining potential exposures to ``primary 
receptors'' before environmental degradation or waste treatment. The 
comment also recommended that the evaluation should include potential 
human exposure, such as the potential exposure to children assisting in 
animal care or living in close proximity to family farm feedlots, at 
the EIC.
    As explained above in response to comment 43 and in the preamble to 
the proposed rule (61 FR 14922 at 14931, 61 FR 19476 at 19485), 
Sec. 25.33(a) categorically excludes action on an NADA, abbreviated 
application, or supplement to such applications, if the action does not 
increase the use of the drug. Proposed Sec. 25.33(b) is reserved and 
would be for actions that increase the use of an animal drug if the 
agency determines a level at or below which the concentration of the 
substance in the environment does not significantly affect the 
environment.
    The EEC is an appropriate measure to use in evaluating information 
in an EA to determine whether an environmental impact is expected. The 
EEC provides the most accurate means of determining the concentration 
of a substance to which organisms may be exposed. Due to various 
factors in the environment, e.g., dilution, binding to particulate 
matter, and volatility, the concentration of an introduced compound may 
change significantly before it comes into contact with organisms that 
may be harmed.
    FDA addresses primary receptor issues, such as a child assisting in 
animal care or living in proximity to family farm animals, as public 
health issues under the act rather than through NEPA evaluation. See 
the response to comment 22, above.
    45. Proposed Sec. 25.33(d)(5) states that an action on a marketing 
application or supplement for an animal drug intended for therapeutic 
use under a prescription or veterinary order is categorically excluded 
and, therefore, ordinarily does not require an EA or an EIS. One 
comment contended that prescription animal drugs that are categorically 
excluded under proposed Sec. 25.33(d)(5) could subsequently require an 
EA if they become available OTC. The comment assumes this is an 
unintended result and that grandfathering would be appropriate. The 
comment recommended that proposed Sec. 25.33(d)(5) be revised to 
include a statement indicating that an animal drug that was once 
categorically excluded should not subsequently require an EA if it 
becomes available OTC.
    The comment is correct in its assertion that a categorically 
excluded prescription animal drug could require an EA when the agency 
acts on an application to switch the drug to OTC availability. However, 
the comment incorrectly concludes that such a result is anomalous and 
unintended. As discussed in the preamble to the proposal (61 FR 14922 
at 14932, 61 FR 19476 at 19486), the therapeutic use of an animal drug 
under a prescription by a veterinarian results in the drug being

[[Page 40585]]

administered to a limited number of animals for a limited amount of 
time. The agency's experience in reviewing EA's for these types of 
veterinary products indicates that this limited use results in no 
significant environmental impact. The limitations inherent in 
prescription use are not found in OTC use. Broader use and greater 
introduction of the drug into the environment may occur with OTC 
availability. Therefore, the agency believes that prescription to OTC 
switches of animal drugs warrant consideration through an EA. 
Grandfathering is not appropriate.
    46. One comment stressed the importance of interpreting the term 
``therapeutic use'' as it is used in the categorical exclusion for 
prescription veterinary drugs in proposed Sec. 25.33(d)(5) independent 
of the percentage of the herd treated. The comment indicated that if 
prescription use were limited to single animal treatment, the section 
would cease to be an important measure to reduce the number of EA's.
    Prescription animal drugs, by definition under the act, are limited 
to use under the professional supervision of a licensed veterinarian 
and, thus, are expected to be administered to a limited number of 
animals for a limited amount of time. Specifically, products intended 
for use by prescription require a veterinarian diagnosis of the disease 
or condition to be treated. The nature of this process limits the use 
of the prescription product and its introduction into the environment. 
Further, administration of the drug product by a veterinarian affords 
an added level of control over the use and disposal of the drug 
product. All veterinarians are trained on appropriate drug use 
procedures. Therefore, allowing a categorical exclusion under these 
circumstances is appropriate and the agency does not intend to 
interpret therapeutic use, as it pertains to proposed Sec. 25.33(d)(5), 
based on the number or percentage of animals treated.
    It is important to note that the agency's decision to propose this 
categorical exclusion of prescription animal drug products is primarily 
based upon its experience in reviewing EA's for these products. The 
EA's that comprise the bulk of agency experience in this area are for 
products used in terrestrial species. The agency has limited experience 
with reviewing drugs that will be used for the treatment of diseases in 
fish and other aquatic species. For this reason, the agency is revising 
proposed Sec. 25.33(d)(5) to clarify that it applies only to 
terrestrial species. The section has been revised to state, ``Drugs 
intended for use under prescription or veterinarian's order for 
therapeutic use in terrestrial species.''
    47. One comment noted that the same experience that led the agency 
to categorically exclude prescription animal drugs under 
Sec. 25.33(d)(5) could ultimately result in all animal drug products 
being excluded regardless of whether they are prescription or over the 
counter (OTC), subject to extraordinary circumstances.
    FDA will not speculate on future categorical exclusions. The agency 
based its decision to categorically exclude prescription animal drugs 
intended for therapeutic use on its extensive experience in reviewing 
EA's for those products. As the agency gains experience in reviewing 
other classes of drug products, additional categorical exclusions may 
be proposed. In all instances, FDA will require an EA to be prepared 
for products that would ordinarily be categorically excluded if there 
are extraordinary circumstances, see Sec. 25.21.
    48. Proposed Sec. 25.33(h) would categorically exclude the 
withdrawal of approval of a food additive petition that reduces or 
eliminates animal feed uses of a food additive. One comment questioned 
whether the disposal of nonnutritive oil in animal feed requires a food 
additive petition.
    The inclusion of nonnutritive oils in animal feeds requires the 
submission of a food additive petition and the preparation of an EA. 
(See the response to comment 35, above.) The categorical exclusion for 
the withdrawal of approval of a food additive petition has no bearing 
on whether a food additive petition, and corresponding EA for the 
petition, would be required for the nonnutritive oil.

D. Subpart D--Preparation of Environmental Documents

    49. Proposed part 25 regulations focus on the use and disposal from 
use of FDA-regulated articles, and do not routinely require submission 
of information regarding manufacturing sites or a certification of 
compliance with Federal, State, and local emission requirements. One 
comment recommended that manufacturing and production considerations 
continue to be included in the environmental evaluation process and 
suggested that FDA consider potential occupational exposures and worker 
safety. The comment also expressed concern that by basing some 
categorical exclusions, specifically Sec. 25.31(b), on presumed 
toxicity of a substance disposed of after use, the agency ``ignores the 
very substantial environmental impacts that may arise from 
manufacture'' of the product.
    Another comment by the same author expressed particular concern 
about secondary and tertiary manufacturing processes involving food 
additives that may result in uncontrolled end products. The comment 
cited as an example a nonnutritive food grade oil that may be 
synthesized by a primary producer who then sells it to a secondary 
manufacturer for ingredient use in food product processing. The comment 
recommended that production of food additives, color additives, and 
GRAS substances not be included as a categorical exclusion and that the 
environmental impact of secondary or tertiary manufacturing be 
considered in an EA. Several related comments recommended that the 
production, processing, and disposal of nonnutritive oils, including 
the impact of liquid and solid oil components, the effect of processing 
on the form of the food additive entering the environment, and the 
potential nutritional impact of nonnutritive oils on microorganisms and 
invertebrates be included in EA's.
    The agency has determined that its environmental evaluation process 
need not generally include a review of information on the manufacturing 
and production of FDA-regulated products, including food additives, 
color additives, and GRAS substances. This determination forms part of 
the basis for FDA's establishment of additional categorical exclusions 
for certain actions that currently require consideration of production 
sites in EA's and is the basis for FDA's decision that, for those 
actions requiring an EA, the EA will generally focus on potential 
impacts resulting from product use and disposal. Federal, State, and 
local environmental protection agencies are responsible for issuing 
regulations, permitting and licensing facilities, and enforcing 
compliance with those requirements that are necessary to ensure 
adequate protection of the environment from emissions resulting from 
production operations. Emergency response training and worker safety/
training are under the purview of these agencies and/or the 
Occupational Safety and Health Administration (OSHA).
    As discussed in the preamble to the proposed rule (61 FR 14922 at 
14933, 61 FR 19476 at 19487), after reviewing hundreds of EA's that 
contained information regarding manufacturing sites, the agency found 
that FDA-regulated articles produced in compliance with applicable 
emission and occupational safety requirements will not significantly 
affect the

[[Page 40586]]

environment. However, if information available to the agency or the 
applicant establishes that a general or specific emission requirement 
issued by Federal, State, or local environmental agencies does not 
adequately address unique emission circumstances, and the emission may 
harm the environment, there would be sufficient grounds for FDA to 
request manufacturing information in an EA. Likewise, in accordance 
with CEQ regulations (40 CFR 1508.27(b)(10)), any action that threatens 
to violate a Federal, State, or local law or other requirement imposed 
for the protection of the environment would fall under Sec. 25.21 
(Extraordinary circumstances), and an EA would be required for the 
proposed action. Thus, although manufacturing site information will not 
routinely be requested, there may be specific circumstances that would 
require the submission of such information.
    Concerning the comment about secondary and tertiary food additive 
production sites, FDA usually considers these facilities to be sites of 
use. The agency has found, with certain exceptions, that environmental 
introductions of food additives, color additives, and GRAS substances 
at secondary and tertiary production sites are minimal because these 
substances are typically meant to be incorporated into and function in 
food, food packaging, or food-contact equipment. Secondary direct food 
additives and nonfunctional components of food-packaging materials may, 
however, enter the environment at use sites because these additives are 
used as processing aids in the production of food and food-packaging 
materials, and are not intended to be present in the food or the 
finished packaging material. The agency did not propose a new 
categorical exclusion specifically for secondary direct additives, 
therefore, actions on these types of additives will generally require 
an EA. However, the agency notes that actions on certain secondary 
direct additives may qualify for exclusion under Sec. 25.32 (j), (q), 
or (r), as revised, because they are used as components of the food-
contact surface of permanent or semipermanent equipment or of another 
food-contact article intended for repeated use, are pesticides 
registered by EPA under FIFRA and subject to FDA's regulatory authority 
as food additives for the same use, or are substances that occur 
naturally in the environment. As discussed above in response to comment 
33, the agency will continue to require EA's for certain actions 
involving nonfunctional components of food-packaging materials. The 
agency will also require EA's for any normally excluded action if there 
are extraordinary circumstances suggesting that the action may have 
significant effects at use sites.
    Regarding the example in the comment of a nonnutritive food oil, 
these actions do not qualify for exclusion under Sec. 25.32(k), as 
revised, and require an EA because actions on these types of substances 
have the potential for significant environmental effects (see the 
responses to comments 35 and 48, above). The EA will take into 
consideration the potential effects raised in the comment, including 
introductions at all use and disposal sites (see, for example, the EA 
and FONSI for FDA's action on the fat substitute olestra (Docket No. 
87F0179)).
    50. Several comments suggested revisions to proposed Sec. 25.40(a), 
which states: ``The EA shall focus on relevant environmental issues and 
shall be a concise, objective, and well-balanced document that allows 
the public to understand the agency's decision.'' Two comments 
recommended the inclusion of a statement that the focus of the 
environmental review would be on the use and disposal of FDA-regulated 
articles, but not the manufacturing. One comment recommended 
substituting the following sentence: ``The EA shall focus on relevant 
environmental issues relating to the use and disposal from use of FDA 
regulated articles and shall be a concise, objective, and well balanced 
document,'' thus eliminating the phrase that the EA shall be ``a 
document that allows the public to understand the agency's decision.'' 
One comment requested additional language stating that manufacturing 
site information, including emission information, would not be 
required.
    The EA formats in current part 25, which have been eliminated in 
the proposed rule, focus on an analysis of the use and disposal of FDA-
regulated articles. To clarify the focus of EA's under the proposed 
regulations, FDA agrees with the suggestion to amend proposed 
Sec. 25.40(a) to state that ``The EA shall focus on relevant 
environmental issues relating to the use and disposal from use of FDA-
regulated articles * * * * '' Inclusion in the final regulation of a 
statement to the effect that emission information from production sites 
is not required in EA's would be contrary to FDA's position, as stated 
in the preamble to the proposed rule (61 FR 14922 at 14934, 61 FR 19476 
at 19487 and 19488), that when information establishes that emission 
requirements promulgated by Federal, State, or local environmental 
protection agencies do not address unique emission circumstances and 
the emissions may harm the environment, FDA will request manufacturing 
information in an EA.
    The phrase included in the proposed regulations that an EA should 
be ``a document that allows the public to understand the agency's 
decision'' is consistent with CEQ environmental policies and objectives 
and will not be deleted. NEPA procedures must ensure that environmental 
information is available to public officials and citizens (40 CFR 
1500.1(b)). Thus, among other things, environmental documents need to 
be written in plain language so that the public can readily understand 
them (see, e.g., Sec. 1502.8).
    51. Proposed Sec. 25.40(a) states that EA's shall include a brief 
discussion of alternatives to the proposed action as described by 
section 102(2)(E) of NEPA. Proposed Sec. 25.40(a) also states that if 
potentially adverse impacts on the environment are identified in the 
EA, the EA shall discuss any reasonable alternative course of action 
that offers less environmental risk or that is environmentally 
preferable to the proposed action. One comment stated that this 
requirement ``would only require applicants or petitioners to discuss 
`reasonable' alternatives where `potentially adverse environmental 
impacts are identified,' '' and, therefore, is inconsistent with 40 CFR 
1508.9.
    FDA does not believe there is an inconsistency between proposed 
Secs. 25.40(a) and 1508.9. EA's are to be concise public documents to 
determine whether a more detailed analysis, an EIS, is required 
(Sec. 1508.9). A discussion of alternatives other than those which are 
``reasonable'' is inconsistent with this overriding principle. 
Therefore, FDA is not amending Sec. 25.40(a) in response to this 
comment.
    52. One comment requested that proposed Sec. 25.40(a) include a 
maximum page limit for EA documents.
    Because the number or pages for any EA will vary in relation to the 
complexity of relevant environmental issues, and such flexibility 
should be permitted by the regulations, FDA declines to include in its 
regulation a page limit for EA's. CEQ regulations do not specify any 
limit on the number of pages in EA's. FDA suggested in the preamble (61 
FR 14922 at 14934, 61 FR 19476 at 19488) that, as a general rule, an EA 
should normally be no more than 30 pages, not including test reports 
and data.
    53. The last sentence of proposed Sec. 25.40(a) allows for a tiered 
environmental testing scheme that would result in test termination when

[[Page 40587]]

sufficient data are available to suggest that no significant 
environmental impact will occur as a result of the potential agency 
action. One comment suggested that this sentence be changed to state 
that when results of the initial tier of testing indicate that testing 
may be stopped, the EA need only contain a certification which states 
that a PEC/PNEC calculation has been completed and the ratio of the PEC 
to PNEC is less than one.
    The agency declines to include the suggested revision. Proposed 
Sec. 25.40(a) describes general EA requirements for all FDA-regulated 
articles. While a tiered testing approach may be adopted by applicants 
and petitioners of all products regulated by the agency, the language 
recommended in the comment is limited to human drugs, biologics, and 
animal drugs. Thus, the inclusion of the suggested language in 
Sec. 25.40(a) is not appropriate. Additionally, as discussed earlier in 
response to comment 26, if a PEC/PNEC ratio is used, FDA would need to 
review the underlying data that supports the PEC/PNEC ratio.
    54. FDA has proposed to remove the EA and abbreviated EA formats 
and any reference to the formats currently found in Sec. 25.31a and to 
provide appropriate formats in guidance documents. One comment 
emphasized that to the extent such guidance documents amend or revise 
informational requirements under NEPA, such requirements are 
impermissible unless the guidance documents are issued through notice 
and comment rulemaking under the Administrative Procedure Act (the APA) 
(5 U.S.C. 553), and the agency consults with CEQ to ensure that the FDA 
guidance is consistent with NEPA and CEQ requirements.
    The APA (5 U.S.C. 553) does not require notice of interpretive 
rules, general statements of policy, or rules of agency organization, 
procedure, or practice except when notice is required by other statute. 
Guidance documents are issued by FDA to provide assistance to the 
regulated industry and interested parties by interpreting and 
clarifying requirements that have been imposed by statute or 
regulation. They reflect the agency's current thinking on the 
implementation of its regulatory scheme, and because they are not 
binding on industry or on the agency, they do not create requirements. 
Consequently, guidance documents are not subject to the notice and 
comment rulemaking provisions of the APA.
    CEQ regulations (40 CFR 1507.3) encourage agencies to publish 
explanatory guidance for their own procedures and to revise them as 
necessary to ensure full compliance with the purposes and provisions of 
NEPA. Use of guidances provides the agency with greater flexibility to 
interpret requirements under its NEPA procedures in a manner that 
responds to the evolving nature of environmental science and the needs 
of industry and interested parties. In the Federal Register of February 
27, 1997, FDA announced its adoption of GGP's, which describes the 
agency's policies and procedures for the development, issuance, and use 
of guidance documents, including public input in the development of 
guidance and publication of a notice of availability. Any further 
development of guidance related to FDA's implementation of NEPA will be 
developed in accordance with these GGP's. Thus, although guidance 
documents that clarify the submission of environmental information to 
FDA are not required to undergo the notice and comment rulemaking 
procedures of the APA, such guidance documents are subject to public 
comment and input under the agency's GGP's. Until guidance documents 
are issued in accordance with the GGP's, applicants that need to submit 
an EA may follow the EA formats previously published by the agency or 
may contact the appropriate center for specific guidance on preparing 
the EA.
    In the Federal Register of January 11, 1996 (61 FR 1031), FDA 
announced the availability of a guidance document entitled, ``Guidance 
for Industry for the Submission of an Environmental Assessment in Human 
Drug Applications and Supplements.'' That guidance was intended to 
assist industry by providing guidance on how to prepare EA's for 
submission to CDER under current part 25 as part of NDA's, antibiotic 
applications, abbreviated applications, and IND's. In preparing the 
``Guidance for Industry for the Submission of an Environmental 
Assessment in Human Drug Applications and Supplements,'' CDER consulted 
with CEQ and gave CEQ an opportunity to review and comment on the 
guidance prior to its issuance. This guidance will be revised, as 
necessary, to ensure that the guidance is consistent with this final 
rule when it becomes effective. The agency intends to continue its 
working relationship with the CEQ in issuing additional guidance 
documents under the final rule.
    55. Two comments requested that a general format for EA's be 
incorporated into proposed Sec. 25.40(a). Both comments expressed 
concern that removal of the general format from part 25 may invite 
regulatory expansion, i.e., the opportunity for FDA to request more 
information.
    As explained above and in the preamble to the proposal (61 FR 14922 
at 14933, 61 FR 19476 at 19487), the agency, in consultation with CEQ, 
has decided that to the extent that EA formats are helpful, they are 
more appropriately placed in guidance documents. The formats included 
in former part 25 were developed to be applicable to all FDA-regulated 
articles. Due to the diverse nature of the products regulated by FDA, 
not all format items were relevant to each action. Consequently, some 
EA's contained unnecessary information and, in some instances, 
information needed to assess the environmental effects of an action was 
not initially submitted to the agency. Thus, the formats may be more 
appropriately included in guidance documents prepared by each center. 
Guidance documents will allow FDA to suggest EA formats that focus on 
important environmental issues relating to each type of product 
regulated by FDA and will assist the preparer in tailoring individual 
EA's to focus on environmental issues specific to the particular 
action.
    56. Current Sec. 25.31a establishes EA formats for proposed actions 
to approve food or color additives, drugs, biological products, animal 
drugs, and some medical devices, to affirm food substances as GRAS, and 
to grant requests for exemption from regulation as a food additive. One 
comment noted that in the prescribed EA format, an applicant or 
petitioner is required to identify the natural resources needed to 
produce, transport, use and/or dispose of a given amount of any product 
which is the subject of the action; to describe measures taken to avoid 
or mitigate potential adverse environmental impacts associated with the 
proposed action; and to describe in detail the environmental impact of 
all reasonable alternatives to the proposed action, including those 
that will enhance the quality of the environment and avoid some or all 
of the adverse environmental impacts of the proposed action 
(Sec. 25.31a(a)). The comment expressed concern that the proposed rule 
``completely eliminates'' those obligations as they apply to marketing 
applications for paclitaxel derived from the Pacific yew.
    Proposed Sec. 25.21 will require an EA for any action, including 
one involving natural resources, that is ordinarily excluded if the 
action may have a significant effect on the environment. Proposed 
Sec. 25.40(a) establishes that an EA shall include a brief discussion 
of the need for the proposed action,

[[Page 40588]]

alternatives to it, and environmental impacts of the proposed action 
and alternatives. If potentially adverse impacts on the environment are 
identified in the EA, the EA shall also discuss any alternative course 
of action that offers less environmental risk or that is 
environmentally preferable to the proposed action. The agency has 
determined that more specific information regarding the nature and 
scope of information that should be included in an EA will be provided 
in guidance documents rather than through regulatory requirements. Use 
of guidance documents will provide the agency with greater flexibility 
to implement NEPA in a manner that responds to the evolving nature of 
environmental science and the needs of industry and other interested 
parties. See the response to comment 54, above. As a result of this 
decision, topics to be analyzed in each EA will be discussed and 
clarified in guidance documents that will be issued by the center 
responsible for the underlying action. Such topics will include the use 
of natural resources in the proposed action (if relevant), and a 
description of measures that have been taken to avoid or mitigate 
adverse environmental impacts that may result from the proposed action.
    With regard to marketing applications for drugs involving 
paclitaxel derived from the Pacific yew, FDA published a notice in the 
Federal Register (61 FR 58694), explaining the extent of environmental 
documentation that needs to be submitted to the agency for drug 
products containing paclitaxel. See the response to comment 15, above. 
Persons interested in the agency's application of NEPA requirements 
with regard to paclitaxel and the Pacific yew are encouraged to review 
that notice.
    57. Proposed Sec. 25.40(d) states that EA's may incorporate by 
reference information presented in other documents that are available 
to FDA and to the public. One comment recommended that this section be 
revised to clarify that other EA's for approved FDA-regulated articles 
may be incorporated by reference into an EA.
    EA's that are available under the Freedom of Information Act are 
public information and therefore may be incorporated by reference into 
an EA to the extent that they are relevant to the action addressed in 
the EA. Information that is not publicly available but to which an 
applicant or petitioner has a right of reference or ownership may also 
be incorporated by that applicant or petitioner into an EA. In 
accordance with proposed Sec. 25.51(a), however, such confidential 
information shall be summarized in the EA to the extent possible. The 
agency does not find it necessary to revise the proposed regulation to 
further clarify this point.
    58. Proposed Sec. 25.40(e) states that the agency evaluates the 
information contained in an EA, along with any public input, to 
determine whether it is accurate and objective, whether the proposed 
action may significantly affect the quality of the human environment, 
and whether the agency should prepare a FONSI or EIS. One comment 
requested that this section be revised to define and restrict specific 
procedures in manufacturing and disposal to effectively prevent 
opportunities for some types of environmental release.
    Defining and restricting specific procedures in manufacturing and 
disposal to prevent pollution are more appropriately handled by 
Federal, State, or local environmental protection agencies that have 
regulatory authority and more expertise in those matters. However, as 
part of FDA's NEPA review process, alternatives and mitigation measures 
are considered by FDA.
    59. Proposed Sec. 25.43 states that in cases where EIS's are 
required, the agency will prepare, at the time of its decision, a 
concise public record of decision. One comment asserted that this 
section should explicitly address the CEQ provisions governing 
limitations on actions during the NEPA process. CEQ regulations (40 CFR 
1506.1(b)) require an agency to take appropriate action to ensure that 
the objectives and procedures of NEPA are achieved if the agency is 
aware that an applicant is about to take an action within the 
jurisdiction of the agency that will have adverse environmental impacts 
or will limit the choice of reasonable alternatives.
    FDA is not required under 40 CFR 1507.3(b), and does not see any 
need, to explicitly include in its procedures specific language to 
implement 40 CFR 1506.1(b). Because an agency's procedures must 
supplement CEQ regulations, all CEQ regulations in 40 CFR parts 1500 
through 1508 are incorporated by reference into FDA's policies and 
procedures implementing NEPA.
    60. Proposed Sec. 25.45 (Responsible agency official) states that 
the agency official identified in part 5 as being responsible for the 
underlying application or petition is responsible for preparing 
environmental documents. One comment suggested that Sec. 25.45 be 
revised to require the responsible agency official to be available to 
review any questions arising from the preparation of an EA. Two 
comments recommended that part 5 be amended to include a provision that 
establishes the Center Directors as the responsible officials for 
deciding the existence of extraordinary circumstances under proposed 
Sec. 25.21 and prohibits redelegation of such authority. One of these 
comments also requested revisions to make it clear that any decision by 
the Center Director on the question of extraordinary circumstances 
constitutes final agency action.
    FDA does not find it necessary to revise proposed Sec. 25.45 to 
require the responsible agency official to be available to review 
questions arising from the preparation of an EA. The FDA official 
responsible for preparing environmental documents is available to 
review questions concerning environmental issues and to meet with 
interested parties (see, e.g., Sec. 10.65 (21 CFR 10.65)). In proposed 
Sec. 25.40, FDA specifically encourages interaction between the 
responsible agency official and those submitting EA's during the 
preparation of the environmental documents.
    FDA also declines to amend part 5. Part 5 delegates to specific 
agency officials responsibility for taking particular actions on behalf 
of the agency. Responsibility for actions on petitions and applications 
is generally delegated to the Director or Deputy Director(s) of the 
center responsible for reviewing submissions relating to the FDA-
regulated product for which an action is requested. Consistent with 
CEQ's policy that the disciplines of those who prepare environmental 
documents be appropriate to the scope and issues of the document, see 
e.g., 40 CFR 1502.6, the Center Directors delegate responsibility 
(e.g., authority to determine extraordinary circumstances and to 
mediate conflicts between reviewers and sponsors) to individuals within 
their organization who have specialized training and expertise to 
evaluate all relevant issues. Individuals in each center who have 
training and experience in environmental science and in implementing 
environmental statutes are responsible for determining the adequacy of 
EA's and claims for categorical exclusion and the existence of 
extraordinary circumstances. These individuals are expected to consult 
with their supervisors and other management officials as needed. 
Specific delegations of responsibility are available to the public 
through each center office.
    Furthermore, each center has appeals procedures by which decisions 
of center personnel can be appealed to the Center Director. The Center 
Director's decision does not necessarily, however, constitute final 
agency action. A procedure for internal review of agency

[[Page 40589]]

decisions is established in Sec. 10.75(a) (21 CFR 10.75(a)), which 
states that a decision of any FDA employee, other than the 
Commissioner, is subject to review by the employee's supervisor. Thus, 
the proposal that a Center Director's decision necessarily constitutes 
final agency action is contrary to FDA regulations and FDA does not 
believe that its regulations should be modified.

E. Subpart E--Public Participation and Notification of Environmental 
Documents

    61. Proposed Sec. 25.50(b) states that many actions performed by 
FDA are protected from disclosure by the act, the Trade Secret Act (the 
TSA) (18 U.S.C. 1905), and FDA regulations and ``unless the existence 
of an application for human drugs * * * has been made publicly 
available, the release of the environmental document before approval of 
human drugs * * * is inconsistent with statutory requirements imposed 
on FDA.'' One comment stated that this provision conflicts with the 
requirements of NEPA and CEQ that mandate public involvement at the 
earliest possible time. The comment stated that FDA may not completely 
abandon NEPA's public participation provisions by broadly invoking 
protection under the TSA. The comment stated that at least for NDA's 
and ANDA's, FDA clearly has authority to release environmental 
documents following issuance of an approvable letter to the applicant. 
The comment cited two Federal court cases, Flint Ridge Development Co. 
v. Scenic Rivers Association of Oklahoma et al., 426 U.S. 776 (1976) 
and Concerned About Trident v. Rumsfeld, 555 F.2d 817 (D.C. Cir. 1977), 
to support the proposition that exceptions to NEPA's requirements have 
been construed narrowly.
    Proposed Sec. 25.50(b) is consistent with NEPA and CEQ regulations. 
Section 102 of NEPA (42 U.S.C. 4332)

    (D)irects that, to the fullest extent possible: (1) The 
policies, regulations, and public laws of the United States shall be 
interpreted and administered in accordance with the policies set 
forth in [NEPA], and (2) all agencies of the Federal government 
shall-- * * * (C) include in every recommendation * * * for * * * 
major Federal action significantly affecting the quality of the 
human environment, a detailed statement by the responsible official 
on--(i) the environmental impact of the proposed action (emphasis 
added).

Section 102 of NEPA further requires copies of any such detailed 
statement and the comments and views of the appropriate Federal, State, 
and local agencies, which are authorized to develop and enforce 
environmental standards, to be made available to the President, CEQ, 
and to the public as provided in 5 U.S.C. 552. CEQ regulations (40 CFR 
1500.6) state that ``the phrase `to the fullest extent possible' in 
section 102 means that each agency of the Federal Government shall 
comply with that section unless existing law applicable to the agency's 
operations expressly prohibits or makes compliance impossible.''
    The TSA expressly prohibits any officer or employee of the United 
States from publishing, divulging, disclosing, or making known in any 
manner or to any extent not authorized by law any information which 
concerns or relates to trade secrets, processes, operations, styles of 
work, or apparatus, or to the identity, confidential statistical data, 
amount or source of any income, profits, losses, or expenditures of any 
person, firm, partnership, corporation, or association. The TSA covers 
trade secrets as well as confidential commercial or financial 
information. Therefore, FDA is prohibited from disclosing trade secrets 
and confidential commercial information except to the extent authorized 
by law.
    Under section 301(j) of the act (21 U.S.C. 331(j)), FDA is 
authorized to disclose trade secret information only to the Secretary 
of the Department of Health and Human Services or officers or employees 
of the Department, courts when relevant in any judicial proceeding 
under the act, either House of Congress, or, to the extent of matter 
within its jurisdiction, any committee or its subcommittee or any joint 
committee of Congress or its subcommittee. FDA is not authorized to 
disclose trade secrets to any other parties.
    The comment cited two cases. Flint Ridge stands for the proposition 
that the only time that a Federal agency can avoid compliance with NEPA 
under the ``to the fullest extent possible'' caveat is when a clear and 
unavoidable conflict in statutory authority exists, in which case NEPA 
must give way. In Concerned about Trident, the Court rejected the 
Department of Defense-Navy's attempt to exempt from the mandate of NEPA 
strategic military decisions made by the Department of Defense-Navy 
because the Navy pointed to no existing specific statutory authority 
prohibiting compliance with NEPA in that case or making such compliance 
impossible.
    Proposed Sec. 25.50(b) is consistent with NEPA's direction to 
implement its policies ``to the fullest extent possible,'' as the case 
law has interpreted that phrase. In those instances in which the TSA 
and section 301(j) of the act prohibit FDA from disclosing 
environmental information to the public, compliance with NEPA is 
impossible and NEPA must give way. FDA cannot disclose to the public 
environmental information prior to taking action to approve certain 
marketing applications. Thus, FDA does not contravene NEPA when it 
refuses to disclose information in such circumstances.
    Furthermore, FDA's procedures comply with NEPA's requirements to 
implement NEPA to the fullest extent possible because the procedures 
require FDA to review and/or prepare environmental documentation for 
any major Federal action before taking the action unless the action 
meets criteria for categorical exclusion. Moreover, FDA's procedures 
specifically provide that information will be released to the public in 
accordance with NEPA when, and to the extent, permitted by the TSA and 
other laws governing FDA's operations. Clearly, FDA is not completely 
abandoning NEPA's public participation provisions. If FDA is not 
prohibited under the TSA and the act from disclosing specific 
environmental information before FDA takes action, FDA will disclose 
that environmental information at the earliest possible time before 
action is taken. To the extent that compliance with the TSA and the act 
make impossible disclosure of environmental information before action 
is taken, FDA will disclose environmental information after the action 
is taken to the extent permitted under the TSA and the act.
    Finally, Sec. 25.50 is also consistent with the requirement that 
environmental information be made available to the public as provided 
in the Freedom of Information Act (the FOIA) (5 U.S.C. 552). Although 
the FOIA requires an agency to make available to the public most 
information available to the agency, certain matters are exempt from 
disclosure. Specifically, the FOIA exempts from disclosure trade 
secrets and commercial or financial information that is obtained from a 
person and is privileged or confidential.
    62. Proposed Sec. 25.52(a) states that if an EIS is prepared for a 
drug, animal drug, biologic product, or device, it will become 
available to the public only at the time of the approval of the 
product. One comment asserted that this provision ``cuts back 
significantly on one of the most fundamental requirements of NEPA and 
the CEQ regulations--the ability of the public to review and comment on 
proposed agency decisions.'' The comment stated that the proposal 
``constitutes a complete repeal of the agency's current NEPA 
regulations providing for public

[[Page 40590]]

involvement in the EIS process and, as such, it must be rejected.''
    The agency disagrees. Proposed Sec. 25.52 does not repeal the 
agency's regulations providing for public involvement in the EIS 
process but merely clarifies that when there is a clear and unavoidable 
conflict between NEPA's public disclosure goals and other laws 
governing FDA's disclosure of information, FDA must follow the 
disclosure laws that govern its operations. As discussed in response 61 
above, the agency is limited in its ability to disclose to the public 
information contained within certain marketing applications. The agency 
will generally make an EIS available to the public at the time of 
approval of the relevant drug, animal drug, biological product, or 
device (Sec. 25.52(a)) but, in instances where disclosure of an 
application has occurred, the agency will abide by its responsibility 
to make a diligent effort to involve the public while concurrently 
complying with its own disclosure requirements (Sec. 25.52(c)).

F. Subpart F--Other Requirements

    63. Section 25.60 states that in accordance with Executive Order 
12114, ``Environmental Effects Abroad of Major Federal Actions,'' 
January 4, 1979, FDA will consider the environmental effects abroad of 
its potential actions. One comment claimed that under this provision, 
Executive Order 12114, not NEPA, would govern environmental impacts 
that may occur abroad as a result of FDA action. The comment stated 
that as a result, FDA's proposal would not govern environmental impacts 
associated with harvest of Pacific yew trees in Canada for paclitaxel 
marketed in the United States. The comment cited Environmental Defense 
Fund v. Massey, 986 F.2d 528 (D.C. Cir. 1993), stating that the Court 
of Appeals for the D.C. Circuit rejected the notion that NEPA only 
governs activities within the United States.
    Executive Order 12114 and proposed Sec. 25.60 (current Sec. 25.50) 
have not changed since 1985. Executive Order 12114, ``Environmental 
Effects Abroad of Major Federal Actions,'' represents the U.S. 
Government's ``exclusive and complete determination of * * * actions to 
be taken by Federal agencies to further the purpose of the National 
Environmental Policy Act with respect to the environment outside the 
United States, its territories, and possessions.'' The agency issued 
current Sec. 25.50 to implement this executive order. FDA requirements 
include the consideration of potential environmental effects of an 
action on a foreign nation, current Sec. 25.50(a)(2) (proposed 
Sec. 25.60(a)(2)). In the event the agency action would have a 
significant environmental effect on the foreign nation, the agency 
official will require additional environmental documentation, current 
Sec. 25.50(c) (proposed Sec. 25.60(c)).
    In the case cited in the comment, Environmental Defense Fund v. 
Massey, 986 F.2d 528, 532 (D.C. Cir. 1993), the court held that the 
National Science Foundation must comply with NEPA before going forward 
with plans to incinerate food waste in Antarctica. The court expressly 
limited its decision to the unique circumstances of Antarctica, 
stating, ``we do not decide today how NEPA might apply to actions in a 
case involving an actual sovereign.'' (Massey, at 537.) The court did 
not rule on the applicability of Executive Order 12114.
    The comment's allegation that FDA's proposal would not govern the 
environmental impacts associated with the harvest of the Pacific yew in 
Canada for paclitaxel marketed in the United States is without basis. 
FDA is required to consider the environmental impacts of its actions 
either under NEPA or the Executive Order. Executive Order 12114 states 
if the responsible official determines that an action may have a 
significant environmental effect abroad, the responsible official shall 
prepare appropriate environmental documents. Additionally, as discussed 
in the response to comment 15, above, FDA issued a notice in the 
November 18, 1996, Federal Register explaining the environmental 
information to be submitted with marketing applications for drug 
products containing paclitaxel.

III. Conforming Amendments

    The environmental regulations in part 25 are cited throughout FDA's 
regulations. Because FDA is revising part 25, the agency is taking this 
opportunity to make conforming amendments to 21 CFR parts 10, 20, 71, 
101,170, 171, 312, 314, 315, 511, 514, 570, 571, 601, 812, 813, and 814 
to reflect revised part 25. These conforming amendments will ensure the 
accuracy and consistency of the regulations.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612), 
and under the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The Regulatory 
Flexibility Act requires agencies to analyze regulatory options that 
would minimize any significant impact of a rule on small entities 
unless the rule is not expected to have a significant economic impact 
on a substantial number of small entities. The Unfunded Mandates Reform 
Act (Pub. L. 104-4) requires that agencies prepare an assessment of 
anticipated costs and benefits before proposing any rule that may 
result in an annual expenditure by State, local, and tribal 
governments, in the aggregate, or by the private sector, of 
$100,000,000 or more (adjusted annually for inflation). The following 
analysis demonstrates that this final rule is consistent with the 
principles set forth in the Executive Order and in these two statutes. 
The final rule is a significant but not an economically significant 
regulatory action under Executive Order 12866 and the rule does not 
impose any mandates on State, local, or tribal governments, or the 
private sector, that will result in an annual expenditure of 
$100,000,000 or more.
    Based on the approximate number of EA's that FDA currently receives 
each year and the resources needed to prepare them, the agency 
estimates that the reduced requirements for submitting EA's will result 
in an annual cost savings to industry of approximately $15.7 million. 
Two letters received by FDA in response to the proposed rule commented 
that the rule would eliminate a majority of EA's that the respondents, 
or their members, have been required to submit in the past. These 
comments are consistent with the estimate presented here. The basis for 
this estimate is as follows:

Human Pharmaceuticals

    Approximately 125 EA's related to human pharmaceuticals will be 
eliminated annually under the final rule. About one-half of these are 
abbreviated EA's; the remainder are full assessments. Based on industry 
estimates, FDA assumes that the average cost of preparing an 
abbreviated assessment was approximately $40,000, while the average 
cost of a full assessment was approximately $200,000. These assumptions 
yield a cost savings of about $2.5 million for abbreviated EA's and 
$12.5 million for full EA's, for a total savings to industry from the 
reduced requirements of EA's relating to human pharmaceuticals of 
approximately $15 million per year.

[[Page 40591]]

Veterinary Products

    The changes eliminate approximately 37 abbreviated EA's for 
veterinary products each year, at an industry-estimated average cost of 
approximately $5,000 each. About 77 brief submissions, which currently 
require categorical exclusion criteria review, are also eliminated; 
these cost an industry-estimated $300 each to prepare. Total cost 
savings to the veterinary products industry under the proposal are thus 
approximately $208,000 per year.

Food Products

    About 39 EA's per year received by the Center for Food Safety and 
Applied Nutrition (CFSAN) will be eliminated under the final rule. 
Approximately 30 of these would have been abbreviated EA's and 9 would 
have been full assessments under current rules. Based on industry 
estimates, FDA projects that the cost of producing most abbreviated 
EA's for CFSAN is approximately $2,500 and the average cost of 
producing a full EA is approximately $50,000. These assumptions imply 
an annual cost savings of approximately $75,000 for abbreviated EA's 
and $450,000 for full EA's, for a total annual savings to the foods 
industry of approximately $525,000.
    In addition to these savings to industry, the final rule will 
improve FDA efficiency by eliminating agency review costs of 
approximately $1 million per year.
    As these regulations will not impose significant new costs on any 
firms, under the Regulatory Flexibility Act, 5 U.S.C. 605(b), the 
Commissioner certifies that the final rule will not have a significant 
economic impact on a substantial number of small entities. Therefore, 
under the Regulatory Flexibility Act, no further analysis is required.

V. The Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). A 
description of these provisions is given below with an estimate of the 
annual reporting burden. Included in the estimate is the time for 
reviewing instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: National Environmental Policy Act; Reporting Provisions.
    Description: FDA has previously issued regulations that implement 
NEPA (part 25). This final rule calls for applicants and petitioners to 
submit environmental information to FDA, in the form of EIS's, EA's, or 
claims for categorical exclusion, where appropriate. NEPA requires such 
reporting to enable FDA to take into account in its decisionmaking 
process the potential impact of agency actions on the environment.
    This final rule will reduce the number of NEPA evaluations by 
providing for categorical exclusions for additional classes of actions 
that do not individually or cumulatively have a significant effect on 
the human environment and for which, therefore, neither an EIS nor an 
EA is required. FDA is also amending these regulations to ensure that 
the NEPA procedures are more concise and understandable to the public, 
and to reflect current FDA policy with respect to environmental 
considerations.
    Individuals and organizations may submit comments on these burden 
estimates or on any other aspect of these information collection 
provisions, including suggestions for reducing the burden, and should 
direct them to the appropriate contact person listed at the beginning 
of this document.
    Description of Respondents: Persons and businesses, including small 
businesses.

                                        Estimated Annual Reporting Burden                                       
----------------------------------------------------------------------------------------------------------------
                                                                 Annual                                         
                                                    No. of     frequency      Total      Hours per              
                  CFR section                    respondents      per         annual     Responses   Total hours
                                                                response    responses                           
----------------------------------------------------------------------------------------------------------------
25.15(a), (d)..................................          455        11.82        5,376         7.94       42,685
25.40(a), (c)..................................          455          .13           58      2832.93      164,310
                                                ----------------------------------------------------------------
    Total......................................  ...........  ...........  ...........  ...........      206,995
----------------------------------------------------------------------------------------------------------------

    This estimate represents the total reporting burden for the amended 
regulations. The total reporting burden for the regulations in part 25 
before the amendments was 710,987 hours; thus, the amended regulations 
will result in an estimated net decrease in burden of 503,992 hours, a 
reduction of more than 70 percent.
    The information collection provisions in this final rule have been 
approved under OMB Control No. 0910-0332. This approval expires June 
30, 1999. An agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

List of Subjects

21 CFR Part 10

    Administrative practice and procedure, News media.

21 CFR Part 20

    Confidential business information, Courts, Freedom of information, 
Government employees.

21 CFR Part 25

    Environmental impact statements, Foreign relations, Reporting and 
recordkeeping requirements.

21 CFR Part 71

    Administrative practice and procedure, Color additives, 
Confidential business information, Cosmetics, Drugs, Reporting and 
recordkeeping requirements.

21 CFR Part 101

    Food labeling, Nutrition, Reporting and recordkeeping requirements.

21 CFR Part 170

    Administrative practice and procedure, Food additives, Reporting 
and recordkeeping requirements.

21 CFR Part 171

    Administrative practice and procedure, Food additives.

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 314

    Administrative practice and procedure, Confidential business

[[Page 40592]]

information, Drugs, Reporting and recordkeeping requirements.

21 CFR Part 511

    Animal drugs, Medical research, Reporting and recordkeeping 
requirements.

21 CFR Part 514

    Administrative practice and procedure, Animal drugs, Confidential 
business information, Reporting and recordkeeping requirements.

21 CFR Part 570

    Animal feeds, Animal foods, Food additives.

21 CFR Part 571

    Administrative practice and procedure, Animal feeds, Animal foods, 
Food additives.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.

21 CFR Part 812

    Health records, Medical devices, Medical research, Reporting and 
recordkeeping requirements.

21 CFR Part 814

    Administrative practice and procedure, Confidential business 
information, Medical devices, Medical research, Reporting and 
recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and authority delegated to the Commissioner 
of Food and Drugs, 21 CFR parts 10, 20, 25, 71, 101, 170, 171, 312, 
314, 511, 514, 570, 571, 601, 812, and 814 are amended as follows:

PART 10--ADMINISTRATIVE PRACTICES AND PROCEDURES

    1. The authority citation for 21 CFR part 10 continues to read as 
follows:

    Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 321-394); 21 U.S.C. 41-50, 141-149, 467f, 679, 821, 
1034; secs. 2, 351, 354, 361 of the Public Health Service Act (42 
U.S.C. 201, 262, 263b, 264); secs. 2-12 of the Fair Packaging and 
Labeling Act (15 U.S.C. 1451-1461); 5 U.S.C. 551-558, 701-721; 28 
U.S.C. 2112.

    2. Section 10.30 is amended in paragraph (b) by revising item C to 
read as follows:


Sec. 10.30  Citizen petition.

* * * * *
    (b) * * *
    C. Environmental impact.
    (A) claim for categorical exclusion under Secs. 25.30, 25.31, 
25.32, 25.33, or Sec. 25.34 of this chapter or an environmental 
assessment under Sec. 25.40 of this chapter.)
* * * * *
    3. Section 10.40 is amended by revising paragraph (b)(1)(ix) to 
read as follows:


Sec. 10.40  Promulgation of regulations for the efficient enforcement 
of the law.

* * * * *
    (b) * * *
    (1) * * *
    (ix) a reference to the existence or lack of need for an 
environmental impact statement under Sec. 25.52 of this chapter; and
* * * * *

PART 20--PUBLIC INFORMATION

    4. The authority citation for 21 CFR part 20 continues to read as 
follows:

    Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 321-393); secs. 301, 302, 303, 307, 310, 311, 351, 
352, 354-360F, 361, 362, 1701-1706, 2101 of the Public Health 
Service Act (42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263, 
263b-263n, 264, 265, 300u-5, 300aa-1); 5 U.S.C. 552; 18 U.S.C. 190; 
19 U.S.C. 2531-2582; 21 U.S.C. 1401-1403.

    5. Section 20.100 is amended by revising paragraph (c)(3) to read 
as follows:


Sec. 20.100  Applicability; cross-reference to other regulations.

* * * * *
    (c) * * *
    (3) Environmental assessments; finding of no significant impact, in 
Sec. 25.51 of this chapter, or draft and final environmental impact 
statements, in Sec. 25.52 of this chapter.
    6. Part 25 is revised to read as follows:

PART 25--ENVIRONMENTAL IMPACT CONSIDERATIONS

Subpart A--General Provisions

Sec.
25.1  Purpose.
25.5  Terminology.
25.10  Policies and NEPA planning.

Subpart B--Agency Actions Requiring Environmental Consideration

25.15  General procedures.
25.16  Public health and safety emergencies.
25.20  Actions requiring preparation of an environmental assessment.
25.21  Extraordinary circumstances.
25.22  Actions requiring the preparation of an environmental impact 
statement.

Subpart C--Categorical Exclusions

25.30  General.
25.31  Human drugs and biologics.
25.32  Foods, food additives, and color additives.
25.33  Animal drugs.
25.34  Devices and electronic products.

Subpart D--Preparation of Environmental Documents

25.40  Environmental assessments.
25.41  Findings of no significant impact.
25.42  Environmental impact statements.
25.43  Records of decision.
25.44  Lead and cooperating agencies.
25.45  Responsible agency official.
Subpart E--Public Participation and Notification of Environmental 
Documents
25.50  General information.
25.51  Environmental assessments and findings of no significant 
impact.
25.52  Environmental impact statements.

Subpart F--Other Requirements

25.60  Environmental effects abroad of major agency actions.

    Authority: Secs. 201-903 of the Federal Food, Drug, and Cosmetic 
Act (21 U.S.C. 321-393); secs. 351, 354-361 of the Public Health 
Service Act (42 U.S.C. 262, 263b-264); 42 U.S.C. 4321, 4331-4335; 40 
CFR parts 1500-1508; E.O. 11514, 3 CFR 1966-1970, Comp., p. 902, as 
amended by E.O. 11991, 3 CFR 1977 Comp., p. 123. E.O. 12114, 3 CFR 
1977 Comp., p. 123.

PART 25--ENVIRONMENTAL IMPACT CONSIDERATIONS

Subpart A--General Provisions


Sec. 25.1  Purpose.

    The National Environmental Policy Act of 1969 (NEPA), as amended, 
directs that, to the fullest extent possible, the policies, 
regulations, and public laws of the United States shall be interpreted 
and administered in accordance with the policies set forth in NEPA. All 
agencies of the Federal Government shall comply with the procedures in 
section 102(2) of NEPA except where compliance would be inconsistent 
with other statutory requirements. The regulations in this part 
implement section 102(2) of NEPA in a manner that is consistent with 
FDA's authority under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act. This part also supplements the regulations 
for implementing the procedural provisions of NEPA that were published 
by the Council on Environmental Quality (CEQ) in 40 CFR parts 1500 
through 1508 and the procedures included in the ``HHS General 
Administration Manual, part 30: Environmental Protection'' (45 FR 76519 
to 76534, November 19, 1980).


Sec. 25.5  Terminology.

    (a) Definitions that apply to the terms used in this part are set 
forth in the CEQ regulations under 40 CFR part 1508. The terms and the 
sections of 40 CFR part 1508 in which they are defined follow:

[[Page 40593]]

    (1) Categorical exclusion (40 CFR 1508.4).
    (2) Cooperating agency (40 CFR 1508.5).
    (3) Cumulative impact (40 CFR 1508.7).
    (4) Effects (40 CFR 1508.8).
    (5) Environmental assessment (EA) (40 CFR 1508.9).
    (6) Environmental document (40 CFR 1508.10).
    (7) Environmental impact statement (EIS) (40 CFR 1508.11).
    (8) Federal agency (40 CFR 1508.12).
    (9) Finding of no significant impact (40 CFR 1508.13).
    (10) Human environment (40 CFR 1508.14).
    (11) Lead agency (40 CFR 1508.16).
    (12) Legislation (40 CFR 1508.17).
    (13) Major Federal action (40 CFR 1508.18).
    (14) Mitigation (40 CFR 1508.20).
    (15) NEPA process (40 CFR 1508.21).
    (16) Notice of intent (40 CFR 1508.22).
    (17) Proposal (40 CFR 1508.23).
    (18) Scope (40 CFR 1508.25).
    (19) Significantly (40 CFR 1508.27).
    (b) The following terms are defined solely for the purpose of 
implementing the supplemental procedures provided by this part and are 
not necessarily applicable to any other statutory or regulatory 
requirements:
    (1) Abbreviated application applies to an abbreviated new drug 
application, an abbreviated antibiotic application, and an abbreviated 
new animal drug application.
    (2) Active moiety means the molecule or ion, excluding those 
appended portions of the molecule that cause the drug to be an ester, 
salt (including a salt with hydrogen or coordination bonds), or other 
noncovalent derivative (such as a complex chelate or clathrate) of the 
molecule responsible for the physiological or pharmacological action of 
the drug substance.
    (3) Agency means the Food and Drug Administration (FDA).
    (4) Increased use of a drug or biologic product may occur if the 
drug will be administered at higher dosage levels, for longer duration 
or for different indications than were previously in effect, or if the 
drug is a new molecular entity. The term ``use'' also encompasses 
disposal of FDA-regulated articles by consumers.
    (5) Responsible agency official means the agency decisionmaker 
designated in part 5 of this chapter.
    (c) The following acronyms are used in this part:
    (1) CEQ--Council on Environmental Quality.
    (2) CGMP--Current good manufacturing practice.
    (3) EA--Environmental assessment.
    (4) EIS--Environmental impact statement.
    (5) The act--Federal Food, Drug, and Cosmetic Act.
    (6) FIFRA--Federal Insecticide, Fungicide, and Rodenticide Act.
    (7) FONSI--Finding of no significant impact.
    (8) GLP--Good laboratory practice.
    (9) GRAS--Generally recognized as safe.
    (10) HACCP--Hazard analysis critical control point.
    (11) IDE--Investigational device exemption.
    (12) IND--Investigational new drug application.
    (13) INAD--Investigational new animal drug application.
    (14) NADA--New animal drug application.
    (15) NDA--New drug application.
    (16) NEPA--National Environmental Policy Act of 1969.
    (17) OTC--Over-the-counter.
    (18) PDP--Product development protocol.
    (19) PMA--Premarket approval application.


Sec. 25.10  Policies and NEPA planning.

    (a) All FDA's policies and programs will be planned, developed, and 
implemented to achieve the policies declared by NEPA and required by 
CEQ's regulations to ensure responsible stewardship of the environment 
for present and future generations.
    (b) Assessment of environmental factors continues throughout 
planning and is integrated with other program planning at the earliest 
possible time to ensure that planning and decisions reflect 
environmental values, to avoid delays later in the process, and to 
avoid potential conflicts.
    (c) For actions initiated by the agency, the NEPA process will 
begin when the agency action under consideration is first identified. 
For actions initiated by applicants or petitioners, NEPA planning 
begins when FDA receives from an applicant or petitioner an EA or a 
claim that a categorical exclusion applies, or when FDA personnel 
consult with applicants or petitioners on the NEPA-related aspects of 
their requested actions. FDA may issue a public call for environmental 
data or otherwise consult with affected individuals or groups when a 
contemplated action in which it is or may be involved poses potential 
significant environmental effects.
    (d) Environmental documents shall concentrate on timely and 
significant issues, not amass needless detail.
    (e) If a proposed action for which an EIS will be prepared involves 
possible environmental effects that are required to be considered under 
statutes or Executive Orders other than those referred to under 
``Authority'' in this part, these effects shall be considered in the 
NEPA review, consistent with 40 CFR 1502.25 and the HHS General 
Administration Manual, part 30: Environmental Protection.

Subpart B--Agency Actions Requiring Environmental Consideration


Sec. 25.15  General procedures.

    (a) All applications or petitions requesting agency action require 
the submission of an EA or a claim of categorical exclusion. A claim of 
categorical exclusion shall include a statement of compliance with the 
categorical exclusion criteria and shall state that to the applicant's 
knowledge, no extraordinary circumstances exist. Failure to submit an 
adequate EA for an application or petition requesting action by the 
agency of a type specified in Sec. 25.20, unless the agency can 
determine that the action qualifies for exclusion under Secs. 25.30, 
25.31, 25.32, 25.33, or 25.34, is sufficient grounds for FDA to refuse 
to file or approve the application or petition. An EA adequate for 
filing is one that addresses the relevant environmental issues. An EA 
adequate for approval is one that contains sufficient information to 
enable the agency to determine whether the proposed action may 
significantly affect the quality of the human environment.
    (b) The responsible agency officials will evaluate the information 
contained in the EA to determine whether it is accurate and objective, 
whether the proposed action may significantly affect the quality of the 
human environment, and whether an EIS will be prepared. If significant 
effects requiring the preparation of an EIS are identified, FDA will 
prepare an EIS for the action in accordance with the procedures in 
subparts D and E of this part. If significant effects requiring the 
preparation of an EIS are not identified, resulting in a decision not 
to prepare an EIS, the responsible agency official will prepare a FONSI 
in accordance with Sec. 25.41.
    (c) Classes of actions that individually or cumulatively do not 
significantly affect the quality of the human environment ordinarily 
are excluded from the requirement to prepare an EA or an EIS. The 
classes of actions that qualify as categorical exclusions are set forth 
in Secs. 25.30, 25.31, 25.32, 25.33, or 25.34.
    (d) A person submitting an application or petition of a type 
subject to categorical exclusion under Secs. 25.30,

[[Page 40594]]

25.31, 25.32, 25.33, or 25.34, or proposing to dispose of an article as 
provided in Sec. 25.30(d) or 25.32(h), is not required to submit an EA 
if the person states that the action requested qualifies for a 
categorical exclusion, citing the particular categorical exclusion that 
is claimed, and states that to the applicant's knowledge, no 
extraordinary circumstances exist.


Sec. 25.16  Public health and safety emergencies.

    There are certain regulatory actions that, because of their 
immediate importance to the public health or safety, may make full 
adherence to the procedural provisions of NEPA and CEQ's regulations 
impossible. For such actions, the responsible agency official shall 
consult with CEQ about alternative arrangements before the action is 
taken, or after the action is taken, if time does not permit prior 
consultation with CEQ.


Sec. 25.20  Actions requiring preparation of an environmental 
assessment.

    Any proposed action of a type specified in this section ordinarily 
requires at least the preparation of an EA, unless it is an action in a 
specific class that qualifies for exclusion under Secs. 25.30, 25.31, 
25.32, 25.33, or 25.34:
    (a) Major recommendations or reports made to Congress on proposals 
for legislation in instances where the agency has primary 
responsibility for the subject matter involved.
    (b) Destruction or other disposition of articles condemned after 
seizure or whose distribution or use has been enjoined, unless 
categorically excluded in Secs. 25.30(d) or 25.32(h).
    (c) Destruction or other disposition of articles following 
detention or recall at agency request, unless categorically excluded in 
Secs. 25.30(d) or 25.32(h).
    (d) Disposition of FDA laboratory waste materials, unless 
categorically excluded in Sec. 25.30(m).
    (e) Intramural and extramural research supported in whole or in 
part through contracts, other agreements, or grants, unless 
categorically excluded in Sec. 25.30 (e) or (f).
    (f) Establishment by regulation of labeling requirements, a 
standard, or a monograph, unless categorically excluded in 
Secs. 25.30(k) or 25.31 (a), (b), (c), (h), (i), or (j), or 25.32 (a) 
or (p).
    (g) Issuance, amendment, and enforcement of FDA regulations, or an 
exemption or variance from FDA regulations, unless categorically 
excluded in Sec. 25.30 (h), (i), or (j), or Sec. 25.32 (e), (g), (n), 
or (p).
    (h) Withdrawal of existing approvals of FDA-approved articles, 
unless categorically excluded in Secs. 25.31 (d) or (k), 25.32(m), or 
25.33 (g) or (h).
    (i) Approval of food additive petitions and color additive 
petitions, approval of requests for exemptions for investigational use 
of food additives, and granting of requests for exemption from 
regulation as a food additive, unless categorically excluded in 
Sec. 25.32 (b), (c), (i), (j), (k), (l), (o), (q), or (r).
    (j) Establishment of a tolerance for unavoidable poisonous or 
deleterious substances in food or in packaging materials to be used for 
food.
    (k) Affirmation of a food substance as GRAS for humans or animals, 
on FDA's initiative or in response to a petition, under parts 182, 184, 
186, or 582 of this chapter and establishment or amendment of a 
regulation for a prior-sanctioned food ingredient, as defined in 
Secs. 170.3(l) and 181.5(a) of this chapter, unless categorically 
excluded in Sec. 25.32 (f), (k), or (r).
    (l) Approval of NDA's, abbreviated applications, applications for 
marketing approval of a biologic product, supplements to such 
applications, and actions on IND's, unless categorically excluded in 
Sec. 25.31 (a), (b), (c), (e), or (l).
    (m) Approval of NADA's, abbreviated applications, supplements, and 
actions on INAD's, unless categorically excluded under Sec. 25.33 (a), 
(c), (d), or (e).
    (n) Approval of PMA's for medical devices, notices of completion of 
PDP's for medical devices, authorizations to commence clinical 
investigation under an approved PDP, or applications for an IDE, unless 
categorically excluded in Sec. 25.34.


Sec. 25.21  Extraordinary circumstances.

    As required under 40 CFR 1508.4, FDA will require at least an EA 
for any specific action that ordinarily would be excluded if 
extraordinary circumstances indicate that the specific proposed action 
may significantly affect the quality of the human environment (see 40 
CFR 1508.27 for examples of significant impacts). Examples of such 
extraordinary circumstances include:
    (a) Actions for which available data establish that, at the 
expected level of exposure, there is the potential for serious harm to 
the environment; and
    (b) Actions that adversely affect a species or the critical habitat 
of a species determined under the Endangered Species Act or the 
Convention on International Trade in Endangered Species of Wild Flora 
and Fauna to be endangered or threatened or wild flora or fauna that 
are entitled to special protection under some other Federal law.


Sec. 25.22  Actions requiring the preparation of an environmental 
impact statement.

    (a) There are no categories of agency actions that routinely 
significantly affect the quality of the human environment and that 
therefore ordinarily require the preparation of an EIS.
    (b) EIS's are prepared for agency actions when evaluation of data 
or information in an EA or otherwise available to the agency leads to a 
finding by the responsible agency official that a proposed action may 
significantly affect the quality of the human environment.

Subpart C--Categorical Exclusions


Sec. 25.30  General.

    The classes of actions listed in this section and Secs. 25.31 
through 25.34 are categorically excluded and, therefore, ordinarily do 
not require the preparation of an EA or an EIS:
    (a) Routine administrative and management activities, including 
inspections, and issuance of field compliance programs, program 
circulars, or field investigative assignments.
    (b) Recommendation for an enforcement action to be initiated in a 
Federal court.
    (c) Agency requests for initiation of recalls.
    (d) Destruction or disposition of any FDA-regulated article 
condemned after seizure or the distribution or use of which has been 
enjoined or following detention or recall at agency request if the 
method of destruction or disposition of the article, including 
packaging material, is in compliance with all Federal, State, and local 
requirements.
    (e) Extramural contracts, other agreements, or grants for 
statistical and epidemiological studies, surveys and inventories, 
literature searches, and report and manual preparation, or any other 
studies that will not result in the production or distribution of any 
substance and, therefore, will not result in the introduction of any 
substance into the environment.
    (f) Extramural contracts, other agreements, and grants for research 
for such purposes as to develop analytical methods or other test 
methodologies.
    (g) Activities of voluntary Federal-State cooperative programs, 
including issuance of model regulations proposed for State adoption.
    (h) Issuance, amendment, or revocation of procedural or 
administrative regulations and guidelines, including procedures for 
submission of applications for product development, testing and 
investigational use, and approval.
    (i) Corrections and technical changes in regulations.

[[Page 40595]]

    (j) Issuance of CGMP regulations, HACCP regulations, establishment 
standards, emergency permit control regulations, GLP regulations, and 
issuance or denial of permits, exemptions, variances, or stays under 
these regulations.
    (k) Establishment or repeal by regulation of labeling requirements 
for marketed articles if there will be no increase in the existing 
levels of use or change in the intended uses of the product or its 
substitutes.
    (l) Routine maintenance and minor construction activities such as:
    (1) Repair to or replacement of equipment or structural components 
(e.g., door, roof, or window) of facilities controlled by FDA;
    (2) Lease extensions, renewals, or succeeding leases;
    (3) Construction or lease construction of 10,000 square feet or 
less of occupiable space;
    (4) Relocation of employees into existing owned or currently leased 
space;
    (5) Acquisition of 20,000 square feet or less of occupiable space 
in a structure that was substantially completed before the issuance of 
solicitation for offers; and
    (6) Acquisition of between 20,000 square feet and 40,000 square 
feet of occupiable space if it constitutes less than 40 percent of the 
occupiable space in a structure that was substantially completed before 
the solicitation for offers.
    (m) Disposal of low-level radioactive waste materials (as defined 
in the Nuclear Regulatory Commission regulations at 10 CFR 61.2) and 
chemical waste materials generated in the laboratories serviced by the 
contracts administered by FDA, if the waste is disposed of in 
compliance with all applicable Federal, State, and local requirements.


Sec. 25.31  Human drugs and biologics.

    The classes of actions listed in this section are categorically 
excluded and, therefore, ordinarily do not require the preparation of 
an EA or an EIS:
    (a) Action on an NDA, abbreviated application, application for 
marketing approval of a biologic product, or a supplement to such 
applications, or action on an OTC monograph, if the action does not 
increase the use of the active moiety.
    (b) Action on an NDA, abbreviated application, or a supplement to 
such applications, or action on an OTC monograph, if the action 
increases 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 part per billion.
    (c) Action on an NDA, abbreviated application, application for 
marketing approval of a biologic product, or a supplement to such 
applications, or action on an OTC monograph, for substances that occur 
naturally in the environment when the action does not alter 
significantly the concentration or distribution of the substance, its 
metabolites, or degradation products in the environment.
    (d) Withdrawal of approval of an NDA or an abbreviated application.
    (e) Action on an IND.
    (f) Testing and certification of batches of an antibiotic or 
insulin.
    (g) Testing and release by the Center for Biologics Evaluation and 
Research of lots or batches of a licensed biologic product.
    (h) Issuance, revocation, or amendment of a monograph for an 
antibiotic drug.
    (i) Establishment of bioequivalence requirements for a human drug 
or a comparability determination for a biologic product subject to 
licensing.
    (j) Issuance, revocation, or amendment of a standard for a biologic 
product.
    (k) Revocation of a license for a biologic product.
    (l) Action on an application for marketing approval for marketing 
of a biologic product for transfusable human blood or blood components 
and plasma.


Sec. 25.32  Foods, food additives, and color additives.

    The classes of actions listed in this section are categorically 
excluded and, therefore, ordinarily do not require the preparation of 
an EA or an EIS:
    (a) Issuance, amendment, or repeal of a food standard.
    (b) Action on a request for exemption for investigational use of a 
food additive if the food additive to be shipped under the request is 
intended to be used for clinical studies or research.
    (c) Approval of a color additive petition to change a provisionally 
listed color additive to permanent listing for use in food, drugs, 
devices, or cosmetics.
    (d) Testing and certification of batches of a color additive.
    (e) Issuance of an interim food additive regulation.
    (f) Affirmation of a food substance as GRAS for humans or animals 
on FDA's initiative or in response to a petition, under parts 182, 184, 
186, or 582 of this chapter, and establishment or amendment of a 
regulation for a prior-sanctioned food ingredient, as defined in 
Secs. 170.3(l) and 181.5(a) of this chapter, if the substance or food 
ingredient is already marketed in the United States for the proposed 
use.
    (g) Issuance and enforcement of regulations relating to the control 
of communicable diseases or to interstate conveyance sanitation under 
parts 1240 and 1250 of this chapter.
    (h) Approval of a request for diversion of adulterated or 
misbranded food for humans or animals to use as animal feeds.
    (i) Approval of a food additive petition, GRAS affirmation 
petition, or the granting of a request for exemption from regulation as 
a food additive under Sec. 170.39 of this chapter, when the substance 
is present in finished food-packaging material at not greater than 5 
percent-by-weight and is expected to remain with finished food-
packaging material through use by consumers or when the substance is a 
component of a coating of a finished food-packaging material.
    (j) Approval of a food additive petition, GRAS affirmation 
petition, or the granting of a request for exemption from regulation as 
a food additive under Sec. 170.39 of this chapter, when the substance 
is to be used as a component of a food-contact surface of permanent or 
semipermanent equipment or of another food-contact article intended for 
repeated use.
    (k) Approval of a food additive, color additive, or GRAS petition 
for substances added directly to food that are intended to remain in 
food through ingestion by consumers and that are not intended to 
replace macronutrients in food.
    (l) Approval of a petition for color additives used in contact 
lenses, sutures, filaments used as supporting haptics in intraocular 
lenses, bone cement, and in other FDA-regulated products having 
similarly low levels of use.
    (m) Action to prohibit or otherwise restrict or reduce the use of a 
substance in food, food packaging, or cosmetics.
    (n) Issuance, amendment, or revocation of a regulation pertaining 
to infant formulas.
    (o) Approval of a food additive petition for the intended 
expression product(s) present in food derived from new plant varieties.
    (p) Issuance, amendment, or revocation of a regulation in response 
to a reference amount petition as described in Sec. 101.12(h) of this 
chapter, a nutrient content claim petition as described in Sec. 101.69 
of this chapter, a health claim petition as described in Sec. 101.70 of 
this chapter, or a petition pertaining to the label declaration of 
ingredients as described in Sec. 101.103 of this chapter.

[[Page 40596]]

    (q) Approval of a food additive petition or the granting of a 
request for an exemption from regulation as a food additive under 
Sec. 170.39 of this chapter for a substance registered by the 
Environmental Protection Agency under FIFRA for the same use requested 
in the petition.
    (r) Approval of a food additive, color additive, or GRAS 
affirmation petition for a substance that occurs naturally in the 
environment, when the action does not alter significantly the 
concentration or distribution of the substance, its metabolites, or 
degradation products in the environment.


Sec. 25.33  Animal drugs.

    The classes of actions listed in this section are categorically 
excluded and, therefore, ordinarily do not require the preparation of 
an EA or an EIS:
    (a) Action on an NADA, abbreviated application, or a supplement to 
such applications, if the action does not increase the use of the drug. 
Actions to which this categorical exclusion applies may include:
    (1) An animal drug to be marketed under the same conditions of 
approval as a previously approved animal drug;
    (2) A combination of previously approved animal drugs;
    (3) A new premix or other formulation of a previously approved 
animal drug;
    (4) Changes specified in Sec. 514.8 (a)(5), (a)(6), or (d) of this 
chapter;
    (5) A change of sponsor;
    (6) A previously approved animal drug to be contained in medicated 
feed blocks under Sec. 510.455 of this chapter or as a liquid feed 
supplement under Sec. 558.5 of this chapter; or
    (7) Approval of a drug for use in animal feeds if such drug has 
been approved under Sec. 514.2 or 514.9 of this chapter for other uses.
    (b) [Reserved]
    (c) Action on an NADA, abbreviated application, or a supplement to 
such applications, for substances that occur naturally in the 
environment when the action does not alter significantly the 
concentration or distribution of the substance, its metabolites, or 
degradation products in the environment.
    (d) Action on an NADA, abbreviated application, or a supplement to 
such applications, for:
    (1) Drugs intended for use in nonfood animals;
    (2) Anesthetics, both local and general, that are individually 
administered;
    (3) Nonsystemic topical and ophthalmic animal drugs;
    (4) Drugs for minor species, including wildlife and endangered 
species, when the drug has been previously approved for use in another 
or the same species where similar animal management practices are used; 
and
    (5) Drugs intended for use under prescription or veterinarian's 
order for therapeutic use in terrestrial species.
    (e) Action on an INAD.
    (f) Action on an application submitted under section 512(m) of the 
act.
    (g) Withdrawal of approval of an NADA or an abbreviated NADA.
    (h) Withdrawal of approval of a food additive petition that reduces 
or eliminates animal feed uses of a food additive.


Sec. 25.34  Devices and electronic products.

    The classes of actions listed in this section are categorically 
excluded and, therefore, ordinarily do not require the preparation of 
an EA or an EIS:
    (a) Action on a device premarket notification submission under 
subpart E of part 807 of this chapter.
    (b) Classification or reclassification of a device under part 860 
of this chapter.
    (c) Issuance, amendment, or repeal of a standard for a class II 
medical device or an electronic product, and issuance of exemptions or 
variances from such a standard.
    (d) Approval of a PMA or a notice of completion of a PDP or amended 
or supplemental applications or notices for a class III medical device 
if the device is of the same type and for the same use as a previously 
approved device.
    (e) Changes in the PMA or a notice of completion of a PDP for a 
class III medical device that do not require submission of an amended 
or supplemental application or notice.
    (f) Issuance of a restricted device regulation if it will not 
result in increases in the existing levels of use or changes in the 
intended uses of the product or its substitutes.
    (g) Action on an application for an IDE or an authorization to 
commence a clinical investigation under an approved PDP.
    (h) Issuance of a regulation exempting from preemption a 
requirement of a State or political subdivision concerning a device, or 
a denial of an application for such exemption.

Subpart D--Preparation of Environmental Documents


Sec. 25.40  Environmental assessments.

    (a) As defined by CEQ in 40 CFR 1508.9, an EA is a concise public 
document that serves to provide sufficient evidence and analysis for an 
agency to determine whether to prepare an EIS or a FONSI. The EA shall 
include brief discussions of the need for the proposal, of alternatives 
as required by section 102(2)(E) of NEPA, of the environmental impacts 
of the proposed action and alternatives, and a listing of agencies and 
persons consulted. An EA shall be prepared for each action not 
categorically excluded in Secs. 25.30, 25.31, 25.32, 25.33, or 25.34. 
The EA shall focus on relevant environmental issues relating to the use 
and disposal from use of FDA-regulated articles and shall be a concise, 
objective, and well-balanced document that allows the public to 
understand the agency's decision. If potentially adverse environmental 
impacts are identified for an action or a group of related actions, the 
EA shall discuss any reasonable alternative course of action that 
offers less environmental risk or that is environmentally preferable to 
the proposed action. The use of a scientifically justified tiered 
testing approach, in which testing may be stopped when the results 
suggest that no significant impact will occur, is an acceptable 
approach.
    (b) Generally, FDA requires an applicant to prepare an EA and make 
necessary corrections to it. Ultimately, FDA is responsible for the 
scope and content of EA's and may include additional information in 
environmental documents when warranted.
    (c) Information concerning the nature and scope of information that 
an applicant or petitioner shall submit in an EA may be obtained from 
the center or other office of the agency having responsibility for the 
action that is the subject of the environmental evaluation. Applicants 
and petitioners are encouraged to submit proposed protocols for 
environmental studies for technical review by agency staff. Applicants 
and petitioners also are encouraged to consult applicable FDA EA 
guidance documents, which provide additional advice on how to comply 
with FDA regulations.
    (d) Consistent with 40 CFR 1500.4(j) and 1502.21, EA's may 
incorporate by reference information presented in other documents that 
are available to FDA and to the public.
    (e) The agency evaluates the information contained in an EA and any 
public input to determine whether it is accurate and objective, whether 
the proposed action may significantly affect the quality of the human 
environment, and whether an EIS or a FONSI will be prepared. The 
responsible agency official designated in part 5 of this chapter as 
responsible for the underlying action examines the environmental risks 
of the proposed action and the alternative courses of action, selects a 
course of action, and

[[Page 40597]]

ensures that any necessary mitigating measures are implemented as a 
condition for approving the selected course of action.


Sec. 25.41  Findings of no significant impact.

    (a) As defined by the CEQ regulations (40 CFR 1508.13), a FONSI is 
a document prepared by a Federal agency stating briefly why an action, 
not otherwise excluded, will not significantly affect the human 
environment and for which, therefore, an EIS will not be prepared. A 
FONSI includes the EA or a summary of it and a reference to any other 
related environmental documents.
    (b) The agency official(s) responsible for approving the FONSI will 
sign the document, thereby establishing that the official(s) approve(s) 
the conclusion not to prepare an EIS for the action under 
consideration.


Sec. 25.42  Environmental impact statements.

    (a) As defined by CEQ regulations (40 CFR 1508.11) and section 
102(2)(C) of NEPA, an EIS should be a clear, concise, and detailed 
written statement describing:
    (1) The environmental impacts of a proposed action;
    (2) Any adverse effects that cannot be avoided if the action is 
implemented;
    (3) Alternatives to the action;
    (4) The relationship between local short-term uses of the 
environment and the maintenance and enhancement of long-term 
productivity; and
    (5) Any irreversible and irretrievable commitments of resources 
that would be involved in the proposed action should it be implemented.
    (b) The CEQ regulations (40 CFR 1501.7 and part 1502) describe the 
process for determining the scope of an EIS and provide detailed 
requirements for the preparation of draft and final EIS's. CEQ format 
and procedures for preparing EIS shall be followed.
    (c) Under the conditions prescribed in 40 CFR 1502.9, the agency 
will prepare a supplement for a draft or final EIS and introduce the 
supplement into the administrative record.


Sec. 25.43  Records of decision.

    (a) In cases requiring environmental impact statements, at the time 
of its decision, the agency shall prepare a concise public record of 
decision.
    (b) The record of decision shall:
    (1) State what the decision was;
    (2) Identify and discuss alternatives considered by the agency in 
reaching its decision;
    (3) State whether all practicable means to avoid or minimize 
environmental harm have been adopted, and if not, why not; and
    (4) Summarize the program for monitoring and enforcing the 
practicable means adopted to avoid or minimize the environmental harm.


Sec. 25.44  Lead and cooperating agencies.

    For actions requiring the preparation of an EIS, FDA and other 
affected Federal agencies will agree which will be the lead agency and 
which will be the cooperating agencies. The responsibilities of lead 
agencies and cooperating agencies are described in the CEQ regulations 
(40 CFR 1501.5 and 1501.6, respectively). If an action affects more 
than one center within FDA, the Commissioner of Food and Drugs will 
designate one of these units to be responsible for coordinating the 
preparation of any required environmental documentation.


Sec. 25.45  Responsible agency official.

    (a) The person designated in part 5 of this chapter as the 
responsible agency official for the underlying action is responsible 
for preparing environmental documents or ensuring that they are 
prepared.
    (b) The responsible agency official will weigh any environmental 
impacts of each alternative course of action, including possible 
mitigation measures, and will balance environmental impacts with the 
agency's objectives in choosing an appropriate course of action. The 
weighing of any environmental impacts of alternatives in selecting a 
final course of action will be reflected in the agency's record of 
formal decisionmaking as required by 40 CFR 1505.2.

Subpart E--Public Participation and Notification of Environmental 
Documents


Sec. 25.50  General information.

    (a) To the extent actions are not protected from disclosure by 
existing law applicable to the agency's operation, FDA will involve the 
public in preparing and implementing its NEPA procedures and will 
provide public notice of NEPA-related hearings, public meetings, and 
the availability of environmental documents.
    (b) Many FDA actions involving investigations, review, and approval 
of applications, and premarket notifications for human drugs, animal 
drugs, biologic products, and devices are protected from disclosure 
under the Trade Secret Act, 18 U.S.C. 1905, and 301(j) of the act. 
These actions are also protected from disclosure under FDA's 
regulations including part 20, Secs. 312.130(a), 314.430(b), 514.11(b), 
514.12(a), 601.50(a), 601.51(a), 807.95(b), 812.38(a), and 814.9(b) of 
this chapter. Even the existence of applications for human drugs, 
animal drugs, biologic products, and devices is protected from 
disclosure under these regulations. Therefore, unless the existence of 
applications for human drugs, animal drugs, biologic products, or 
premarket notification for devices has been made publicly available, 
the release of the environmental document before approval of human 
drugs, animal drugs, biologic products, and devices is inconsistent 
with statutory requirements imposed on FDA. Appropriate environmental 
documents, comments, and responses will be included in the 
administrative record to the extent allowed by applicable laws.


Sec. 25.51  Environmental assessments and findings of no significant 
impact.

    (a) Data and information that are protected from disclosure by 18 
U.S.C. 1905 or 21 U.S.C. 331(j) or 360j(c) shall not be included in the 
portion of environmental documents that is made public. When such data 
and information are pertinent to the environmental review of a proposed 
action, an applicant or petitioner shall submit such data and 
information separately in a confidential section and shall summarize 
the confidential data and information in the EA to the extent possible.
    (b) FONSI's and EA's will be available to the public in accordance 
with 40 CFR 1506.6 as follows:
    (1) When the proposed action is the subject of a notice of proposed 
rulemaking or a notice of filing published in the Federal Register, the 
notice shall state that no EIS is necessary and that the FONSI and the 
EA are available for public inspection at FDA's Dockets Management 
Branch. If the responsible agency official is unable to complete 
environmental consideration of the proposed action before a notice of 
filing of a food or color additive petition is required to be published 
under the act, and if the subsequent environmental analysis leads to 
the conclusion that no EIS is necessary, the final regulation rather 
than the notice of filing shall state that no EIS is necessary and that 
the FONSI and the EA are available upon request and filed in FDA's 
Dockets Management Branch.
    (2) For actions for which notice is not published in the Federal 
Register, the FONSI and the EA shall be made available to the public 
upon request according to the procedures in 40 CFR 1506.6.
    (3) For a limited number of actions, the agency may make the FONSI 
and EA

[[Page 40598]]

available for public review (including review by State and areawide 
information clearinghouses) for 30 days before the agency makes its 
final determination whether to prepare an EIS and before the action may 
begin, as described in 40 CFR 1501.4(e). This procedure will be 
followed when the proposed action is, or is closely similar to, one 
that normally requires an EIS or when the proposed action is one 
without precedent.


Sec. 25.52  Environmental impact statements.

    (a) If FDA determines that an EIS is necessary for an action 
involving investigations or approvals for drugs, animal drugs, biologic 
products, or devices, an EIS will be prepared but will become available 
only at the time of the approval of the product. Disclosure will be 
made in accordance with 40 CFR 1506.6 and part 20 of this chapter. The 
EIS will in all other respects conform to the requirements for EIS's as 
specified in 40 CFR part 1502 and 1506.6(f).
    (b) Comments on the EIS may be submitted after the approval of the 
drug, animal drug, biologic product, or device. Those comments can form 
the basis for the agency to consider beginning an action to withdraw 
the approval of applications for a drug, animal drug, or biologic 
product, or to withdraw premarket notifications or premarket approval 
applications for devices.
    (c) In those cases where the existence of applications and 
premarket notifications for drugs, animal drugs, biologic products, or 
devices has already been disclosed before the agency approves the 
action, the agency will make diligent effort (40 CFR 1506.6) to involve 
the public in preparing and implementing the NEPA procedures for EIS's 
while following its own disclosure requirements including those listed 
in part 20, Secs. 312.130(b), 314.430(d), 514.11(d), 514.12(b), 
601.51(d), 807.95(e), 812.38(b), and 814.9(d) of this chapter.
    (d) Draft and final EIS's, comments, and responses will be included 
in the administrative record and will be available from the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857.

Subpart F--Other Requirements


Sec. 25.60  Environmental effects abroad of major agency actions.

    (a) In accordance with Executive Order 12114, ``Environmental 
Effects Abroad of Major Federal Actions'' of January 4, 1979 (44 FR 
1957, January 9, 1979), the responsible agency official, in analyzing 
actions under his or her program, shall consider the environmental 
effects abroad, including whether the actions involve:
    (1) Potential environmental effects on the global commons and areas 
outside the jurisdiction of any nation, e.g., oceans and the upper 
atmosphere.
    (2) Potential environmental effects on a foreign nation not 
participating with or otherwise involved in an FDA activity.
    (3) The export of products (or emissions) that in the United States 
are prohibited or strictly regulated because their effects on the 
environment create a serious public health risk.
    (4) Potential environmental effects on natural and ecological 
resources of global importance designated under the Executive Order.
    (b) Before deciding on any action falling into the categories 
specified in paragraph (a) of this section, the responsible agency 
official shall determine, in accordance with section 2-3 of the 
Executive Order, whether such actions may have a significant 
environmental effect abroad.
    (c) If the responsible agency official determines that an action 
may have a significant environmental effect abroad, the responsible 
agency official shall determine, in accordance with section 2-4(a) and 
(b) of the Executive Order, whether the subject action calls for:
    (1) An EIS;
    (2) A bilateral or multilateral environmental study; or
    (3) A concise environmental review.
    (d) In preparing environmental documents under this subpart, the 
responsible official shall:
    (1) Determine, as provided in section 2-5 of the Executive Order, 
whether proposed actions are subject to the exemptions, exclusions, and 
modification in contents, timing, and availability of documents.
    (2) Coordinate all communications with foreign governments 
concerning environmental agreements and other arrangements in 
implementing the Executive Order.

PART 71--COLOR ADDITIVE PETITIONS

    7. The authority citation for 21 CFR part 71 continues to read as 
follows:

    Authority: Secs. 201, 402, 409, 501, 505, 506, 507, 510, 512-
516, 518-520, 601, 701, 721, 801 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 342, 348, 351, 355, 356, 357, 360, 
360b-360f, 360h-360j, 361, 371, 379e, 381); secs. 215, 351 of the 
Public Health Service Act (42 U.S.C. 216, 262).

    8. Section 71.1 is amended in paragraph (c) by revising item J to 
read as follows:


Sec. 71.1  Petitions.

* * * * *
    (c) * * *
    J. The petitioner is required to submit either a claim for 
categorical exclusion under Sec. 25.30 or 25.32 of this chapter or an 
environmental assessment under Sec. 25.40 of this chapter.
* * * * *

PART 101--FOOD LABELING

    9. The authority citation for 21 CFR part 101 continues to read as 
follows:

    Authority: Secs. 4, 5, 6 of the Fair Packaging and Labeling Act 
(15 U.S.C. 1453, 1454, 1455); secs. 201, 301, 402, 403, 409, 701 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 342, 
343, 348, 371).

    10. Section 101.12 is amended by revising paragraph (h)(12) to read 
as follows:


Sec. 101.12  Reference amounts customarily consumed per eating 
occasion.

* * * * *
    (h) * * *
    (12) A claim for categorical exclusion under Sec. 25.30 or 25.32 of 
this chapter or an environmental assessment under Sec. 25.40 of this 
chapter; and
* * * * *
    11. Section 101.69 is amended by revising paragraph (h), item E of 
paragraph (m)(1), item C of paragraph (n)(1), and item C of paragraph 
(o)(1) to read as follows:


Sec. 101.69  Petitions for nutrient content claims.

* * * * *
    (h) All petitions submitted under this section shall include either 
a claim for a categorical exclusion under Sec. 25.30 or 25.32 of this 
chapter or an environmental assessment under Sec. 25.40 of this 
chapter.
* * * * *
    (m) * * *
    (1) * * *

    E. The petitioner is required to submit either a claim for 
categorical exclusion under Sec. 25.30 or Sec. 25.32 of this chapter 
or an environmental assessment under Sec. 25.40 of this chapter.
* * * * *
    (n) * * *
    (1) * * *

    C. The petitioner is required to submit either a claim for 
categorical exclusion under Sec. 25.30 or Sec. 25.32 of this chapter 
or an environmental assessment under Sec. 25.40 of this chapter.
* * * * *
    (o) * * *

[[Page 40599]]

    (1) * * *

    C. The petitioner is required to submit either a claim for 
categorical exclusion under Sec. 25.30 or Sec. 25.32 of this chapter 
or an environmental assessment under Sec. 25.40 of this chapter.
* * * * *
    12. Section 101.70 is amended in paragraph (f) by revising item F 
to read as follows:


Sec. 101.70  Petitions for health claims.

* * * * *
    (f) * * *

    F. The petitioner is required to submit either a claim for 
categorical exclusion under Sec. 25.30 or Sec. 25.32 of this chapter 
or an environmental assessment under Sec. 25.40 of this chapter.
* * * * *

PART 170--FOOD ADDITIVES

    13. The authority citation for 21 CFR part 170 continues to read as 
follows:

    Authority: Secs. 201, 401, 402, 408, 409, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 346a, 348, 
371).

    14. Section 170.35 is amended by revising paragraph (c)(1)(viii) to 
read as follows:


Sec. 170.35  Affirmation of generally recognized as safe (GRAS) status.

* * * * *
    (c) * * *
    (1) * * *
    (viii) A claim for categorical exclusion under Sec. 25.30 or 
Sec. 25.32 of this chapter or an environmental assessment under 
Sec. 25.40 of this chapter.
* * * * *
    15. Section 170.39 is amended by revising the second sentence in 
paragraph (c)(6) and the seventh sentence in paragraph (e) to read as 
follows:


Sec. 170.39  Threshold of regulation for substances used in food-
contact articles.

* * * * *
    (c) * * *
    (6) * * * The request should contain either a claim for categorical 
exclusion as specified in Sec. 25.32 of this chapter or an 
environmental assessment as specified in Sec. 25.40 of this chapter.
* * * * *
    (e) * * * For actions requiring an environmental assessment, the 
agency's finding of no significant impact and the evidence supporting 
that finding, contained in the petitioner's environmental assessment, 
also will be available for public inspection at the Dockets Management 
Branch in accordance with Sec. 25.51(b)(2) of this chapter. * * *
* * * * *

PART 171--FOOD ADDITIVE PETITIONS

    16. The authority citation for 21 CFR part 171 continues to read as 
follows:

    Authority: Secs. 201, 402, 409, 701 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 321, 342, 348, 371).

    17. Section 171.1 is amended in paragraph (c) by revising item H to 
read as follows:


Sec. 171.1  Petitions.

* * * * *
    (c) * * *

    H. The petitioner is required to submit either a claim for 
categorical exclusion under Sec. 25.30 or 25.32 of this chapter or 
an environmental assessment under Sec. 25.40 of this chapter.
* * * * *

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

    18. The authority citation for 21 CFR part 312 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 
352, 353, 355, 356, 357, 371); sec. 351 of the Public Health Service 
Act (42 U.S.C. 262).

    19. Section 312.23 is amended by revising paragraph (a)(7)(iv)(e) 
to read as follows:


Sec. 312.23  IND content and format.

    (a) * * *
    (7) * * *
    (iv) * * *
    (E) Environmental analysis requirements. A claim for categorical 
exclusion under Sec. 25.30 or 25.31 or an environmental assessment 
under Sec. 25.40.
* * * * *

PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN 
ANTIBIOTIC DRUG

    20. The authority citation for 21 CFR part 314 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 701, 
704, 721 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 
331, 351, 352, 353, 355, 356, 357, 371, 374, 379e).

    21. Section 314.50 is amended by revising paragraph (d)(1)(iii) to 
read as follows:


Sec. 314.50  Content and format of an application.

* * * * *
    (d) * * *
    (1) * * *
    (iii) Environmental impact. The application is required to contain 
either a claim for categorical exclusion under Sec. 25.30 or 25.31 of 
this chapter or an environmental assessment under Sec. 25.40 of this 
chapter.
    22. Section 314.101 is amended by revising paragraph (d)(4) to read 
as follows:


Sec. 314.101  Filing an application and an abbreviated antibiotic 
application and receiving an abbreviated new drug application.

* * * * *
    (d) * * *
    (4) The applicant fails to submit a complete environmental 
assessment, which addresses each of the items specified in the 
applicable format under Sec. 25.40 of this chapter or fails to provide 
sufficient information to establish that the requested action is 
subject to categorical exclusion under Sec. 25.30 or Sec. 25.31 of this 
chapter.
* * * * *

PART 511--NEW ANIMAL DRUGS FOR INVESTIGATIONAL USE

    23. The authority citation for 21 CFR part 511 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 512, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 360b, 
371).

    24. Section 511.1 is amended by revising paragraph (b)(10) to read 
as follows:


Sec. 511.1  New animal drugs for investigational use exempt from 
section 512(a) of the act.

* * * * *
    (b) * * *
    (10) The sponsor shall submit either a claim for categorical 
exclusion under Sec. 25.30 or Sec. 25.33 of this chapter or an 
environmental assessment under Sec. 25.40 of this chapter.
* * * * *

PART 514--NEW ANIMAL DRUG APPLICATIONS

    25. The authority citation for 21 CFR part 514 continues to read as 
follows:

    Authority: Secs. 501, 502, 512, 701, 721, 801 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 351, 352, 360b, 371, 379e, 
381).

    26. Section 514.1 is amended by revising paragraph (b)(14) to read 
as follows:


Sec. 514.1  Applications.

* * * * *
    (b) * * *
    (14) Environmental assessment. The applicant is required to submit 
either a claim for categorical exclusion under Sec. 25.30 or Sec. 25.33 
of this chapter or an

[[Page 40600]]

environmental assessment under Sec. 25.40 of this chapter.
* * * * *
    27. Section 514.8 is amended by revising the fourth sentence of 
paragraph (a)(1) to read as follows:


Sec. 514.8  Supplemental new animal drug applications.

    (a)(1) * * * A supplemental application shall be accompanied by 
either a claim for categorical exclusion under Sec. 25.30 or Sec. 25.33 
of this chapter or an environmental assessment under Sec. 25.40 of this 
chapter.
* * * * *
    28. Section 514.110 is amended by revising paragraph (b)(10) to 
read as follows:


Sec. 514.110  Reasons for refusing to file applications.

* * * * *
    (b) * * *
    (10) The applicant fails to submit a complete environmental 
assessment under Sec. 25.40 of this chapter or fails to provide 
sufficient information to establish that the requested action is 
subject to categorical exclusion under Sec. 25.30 or Sec. 25.33 of this 
chapter.
* * * * *
    29. Section 514.111 is amended by revising paragraph (a)(9) to read 
as follows:


Sec. 514.111  Refusal to approve an application.

    (a) * * *
    (9) The applicant fails to submit an adequate environmental 
assessment under Sec. 25.40 of this chapter or fails to provide 
sufficient information to establish that the requested action is 
subject to categorical exclusion under Sec. 25.30 or Sec. 25.33 of this 
chapter.
* * * * *

PART 570--FOOD ADDITIVES

    30. The authority citation for 21 CFR part 570 continues to read as 
follows:

    Authority: Secs. 201, 401, 402, 408, 409, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 346a, 348, 
371).

    31. Section 570.35 is amended by revising paragraph (c)(1)(viii) to 
read as follows:


Sec. 570.35  Affirmation of generally recognized as safe (GRAS) status.

* * * * *
    (c) * * *
    (viii) A claim for categorical exclusion under Sec. 25.30 or 25.32 
of this chapter or an environmental assessment under Sec. 25.40 of this 
chapter.
* * * * *

PART 571--FOOD ADDITIVE PETITIONS

    32. The authority citation for 21 CFR part 571 continues to read as 
follows:

    Authority: Secs. 201, 402, 409, 701 of the Federal Food, Drug, 
and Cosmetic Act (21 U.S.C. 321, 342, 348, 371); sec. 301 of the 
Public Health Service Act (42 U.S.C. 241).

    33. Section 571.1 is amended in paragraph (c) by revising item H to 
read as follows:


Sec. 571.1  Petitions.

* * * * *
    (c) * * *

    H. The petitioner is required to submit either a claim for 
categorical exclusion under Sec. 25.30 or Sec. 25.32 of this chapter 
or an environmental assessment under Sec. 25.40 of this chapter.
* * * * *

PART 601--LICENSING

    34. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520, 
701, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374, 
379e, 381); secs. 215, 301, 351, 352 of the Public Health Service 
Act (42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging 
and Labeling Act (15 U.S.C. 1451-1461).

    35. Section 601.2 is amended by revising the third sentence in 
paragraph (a) and the second sentence in paragraph (c)(2) to read as 
follows:


Sec. 601.2  Applications for establishment and product licenses; 
procedures for filing.

    (a) * * * The applicant shall also include either a claim for 
categorical exclusion under Sec. 25.30 or 25.31 of this chapter or an 
environmental assessment under Sec. 25.40 of this chapter.
* * * * *
    (c) * * *
    (2) * * * The applicant shall also include either a claim for 
categorical exclusion under Sec. 25.30 or 25.31 of this chapter or an 
environmental assessment under Sec. 25.40 of this chapter.
* * * * *

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

    36. The authority citation for 21 CFR part 812 continues to read as 
follows:

    Authority: Secs. 301, 501, 502, 503, 505, 506, 507, 510, 513-
516, 518-520, 701, 702, 704, 721, 801 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 331, 351, 352, 353, 355, 356, 357, 360, 
360c-360f, 360h-360j, 371, 372, 374, 379e, 381); secs. 215, 301, 
351, 354-360F of the Public Health Service Act (42 U.S.C. 216, 241, 
262, 263b-263n).

    37. Section 812.20 is amended by revising paragraph (b)(9) to read 
as follows:


Sec. 812.20  Application.

* * * * *
    (b) * * *
    (9) A claim for categorical exclusion under Sec. 25.30 or 25.34 or 
an environmental assessment under Sec. 25.40.
* * * * *

PART 814--PREMARKET APPROVAL OF MEDICAL DEVICES

    38. The authority citation for 21 CFR part 814 continues to read as 
follows:

    Authority: Secs. 501, 502, 503, 510, 513-520, 701, 702, 703, 
704, 705, 721, 708, 801 of the Federal Food, Drug, and Cosmetic Act 
(21 U.S.C. 351, 352, 353, 360, 360c-360j, 371, 372, 373, 374, 375, 
379e, 381).
    39. Section 814.20 is amended by revising paragraph (b)(11) to read 
as follows:


Sec. 814.20  Application.

* * * * *
    (b) * * *
    (11) An environmental assessment under Sec. 25.20(n) prepared in 
the applicable format in Sec. 25.40, unless the action qualifies for 
exclusion under Sec. 25.30 or Sec. 25.34. If the applicant believes 
that the action qualifies for exclusion, the PMA shall under 
Sec. 25.15(a) and (d) provide information that establishes to FDA's 
satisfaction that the action requested is included within the excluded 
category and meets the criteria for the applicable exclusion.
* * * * *
    Dated: May 9, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-19566 Filed 7-28-97; 8:45 am]
BILLING CODE 4160-01-P