# National Environmental Policy Act; Revision of Policies and Procedures

> Briefs, arguments, decisions, and more.

URL: https://www.frixlaw.com/law-library/documents/fr%3A97-19566

## Record

- **Collection:** Federal Register
- **Document type:** Rule
- **Published:** July 29, 1997
- **Citation:** 62 FR 40570

## Text

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 Healt

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/fr%3A97-19566. Public record. Not legal advice.