National Environmental Policy Act; Revision of Policies and Procedures

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

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United States for use in a drug product, either as a single ingredient

or as part of a combination product or as part of a mixture of

stereoisomers.'' FDA has decided not to include the definition of new

molecular entity in Sec. 25.5(b)(4). The term is currently defined in

guidance documents issued by the Center for Drug Evaluation and

Research (CDER). The agency does not find it necessary to include the

definition in its regulations. Parties interested in the definition of

new molecular entity should consult the information available from

CDER.

3. Proposed Sec. 25.10(c) describes when the environmental planning

process begins under NEPA: ``For actions initiated by applicants or

petitioners, NEPA planning begins when FDA receives a submission from

an applicant or petitioner seeking action by FDA.'' Proposed

Sec. 25.10(c) differs from current Sec. 25.10(a), which states that:

For actions initiated by applicants or petitioners, the process

begins when FDA receives from an applicant or petitioner an

environmental assessment (EA) or a claim that a categorical

exclusion applies, or when FDA personnel consult with applicants or

petitioners on the NEPA-related aspects of their requested actions.

One comment indicated that current Sec. 25.10(a) is consistent with

NEPA and CEQ regulations because it provides for consultation between

the agency and applicants or petitioners prior to Federal action.

However, the comment contended that proposed Sec. 25.10(c), as it

amends current Sec. 25.10(a), is inconsistent with NEPA and CEQ

regulations. The comment specifically cites an inconsistency between

proposed Sec. 25.10(c) and 40 CFR 1501.2(d), which states that in

``cases where actions are planned by private applicants or other non-

Federal entities before Federal involvement,'' agencies shall provide

policies or designated staff members ``to advise potential applicants

of studies or other information foreseeably required for later Federal

action,'' and shall begin the NEPA process ``at the earliest time

possible.''

FDA agrees with the comment. As explained in the preamble to the

proposal (61 FR 14922 at 14923, 61 FR 19476 at 19477), FDA intended to

eliminate unnecessary language by combining Sec. 25.5 (Policies) and

Sec. 25.10 (NEPA planning) into proposed Sec. 25.10 (Policies and NEPA

planning). FDA did not intend to change the timing of the initiation of

the agency's environmental planning process or to preclude early

consultation with FDA prior to Federal action when it proposed the

language in Sec. 25.10(c). Thus, because the proposed section does not

clearly express the agency's policy, the agency will incorporate the

current Sec. 25.10(a) language, and Sec. 25.10(c) will provide, in

relevant part:

For actions initiated by applicants or petitioners, NEPA

planning begins when FDA receives from an applicant or petitioner an

environmental assessment (EA) or a claim that a categorical

exclusion applies, or when FDA personnel consult with applicants or

petitioners on the NEPA-related aspects of their requested actions.

4. One comment stated that under CEQ regulations (40 CFR

1501.2(d)), FDA is required to ensure that potential applicants or

petitioners prepare an EA prior to the harvest of natural resources,

such as the Pacific yew tree, regardless of whether the drug sponsor

has filed an application or petition with the agency. The comment

requested that the proposed regulations be revised to specifically

address the issue of ``stockpiling'' harvested material prior to

submitting an application or petition.

The requirements and procedures of NEPA are triggered by a major

Federal action. Until FDA reviews an application or petition, initiates

an action, or is consulted regarding potential agency action, no action

exists to set the NEPA process in motion, and there is no regulatory

requirement for applicants or petitioners to inform FDA of their use of

natural resources prior to the submission of an application or petition

to FDA. Therefore, FDA cannot ensure that applicants or petitioners

prepare an EA prior to the harvest of natural resources. In accordance

with 40 CFR 1501.2(d), the agency makes staff available to advise

potential applicants or petitioners of studies or other information

foreseeably required for later Federal action and commences its NEPA

process at the earliest possible time (see Sec. 25.10(c) of this final

rule). FDA will request information about stockpiling and harvesting

once the NEPA process is triggered by a proposed action.

With regard to the comment's specific concerns about the Pacific

yew, the agency published a notice in the Federal Register of November

18, 1996 (61 FR 58694), clarifying the environmental information that

must be submitted to the agency with a new drug application (NDA),

abbreviated new drug application (ANDA), or investigational new drug

application (IND) involving paclitaxel derived from or otherwise

involving the Pacific yew.

5. One comment requested that proposed Sec. 25.10, which states

FDA's overall policy in implementing the NEPA requirements, be modified

to indicate that applicants should be involved in the development of

agency policies, procedures, and guidance documents that are designed

to interpret, clarify, or elaborate on the requirements placed on

applicants to satisfy FDA's statutory obligations under NEPA.

In a notice in the Federal Register of February 27, 1997 (62 FR

8961), FDA announced its ``Good Guidance Practices'' (GGP's), which

represents the agency's policy regarding the development and use of

guidance documents (hereinafter referred to as the GGP's notice). The

GGP's address public participation in the guidance document development

process generally. FDA does not believe that it is necessary or

appropriate to address public participation in the NEPA guidance

document development process specifically. Interested individuals are

encouraged to review the Federal Register notice and related comments

(Docket No. 95P-0110).

6. One comment requested that Sec. 25.10 be revised to provide that

a single center official be responsible for addressing and resolving

questions raised by reviewers and for mediating conflicts arising

between reviewers and sponsors regarding interpretations of the

regulatory requirements. The comment also requested that a provision be

included that establishes an appeal from the center's responsible

official to the Center Director, in the event that the center official

is unable to resolve questions raised by reviewers.

FDA does not believe it is necessary to revise proposed Sec. 25.10

as suggested by the comment. Individuals in each center with

specialized training and expertise oversee the NEPA review process,

resolve questions raised by reviewers, and mediate conflicts between

reviewers and sponsors. Actions by reviewers or other center officials

may be appealed through the appeals mechanisms already in place in each

center to the Center Director and, ultimately, to the Commissioner of

Food and Drugs (the Commissioner). Individuals who are interested in

obtaining copies of the appeals procedures established in each center

may contact the relevant center for such information.

B. Subpart B--Agency Actions Requiring Environmental Consideration

7. Proposed Sec. 25.15(a) states that the failure of an applicant

or petitioner to submit an ``adequate EA'' for a requested action that

is not categorically excluded is sufficient grounds for FDA to refuse

to file or approve the application or petition. One comment noted that

while FDA requires an ``adequate'' EA, the definition of that

[[Page 40572]]

term found in current Sec. 25.22(b) is not included in the proposed

regulations. The comment requested that the agency retain the

definition of adequate EA in its regulations.

The agency agrees that clarification of when an EA is adequate for

filing or approval is appropriate. Consequently, proposed Sec. 25.15(a)

has been revised to include the clarifying statements currently found

in Sec. 25.22(b):

An EA adequate for filing is one that addresses the relevant

environmental issues. An EA adequate for approval is one that

contains sufficient information to enable the agency to determine

whether the proposed action may significantly affect the quality of

the human environment.

8. Proposed Sec. 25.15(a) and (d) requires that applicants and

petitioners who claim that a categorical exclusion applies to a

proposed action certify that the action qualifies for a categorical

exclusion, citing the particular exclusion that is claimed, and certify

that to their knowledge no extraordinary circumstances exist. One

comment specifically welcomed and believed important to the success of

FDA's proposals the certification of compliance with the categorical

exclusion criteria required in Sec. 25.15(a) and (d). Another comment

requested clarification of the certification requirement in

Sec. 25.15(a) and (d), questioning whether the categorical exclusion

document needs to contain a separate certification indicating the

truthfulness and accuracy of the information provided in the

certification, or whether the categorical exclusion document alone is

sufficient.

Applications and petitions that are filed with the agency are

signed by a responsible agent or official of the sponsor, who attests

to the truth and accuracy of the information within the application or

petition. A separate, signed categorical exclusion document is not

needed. Under Sec. 25.15(a) and (d), FDA requires that an applicant or

petitioner requesting a categorical exclusion identify the categorical

exclusion being claimed, state that the action complies with the

categorical exclusion criteria, and state that to the applicant's

knowledge no extraordinary circumstances exist. For clarification,

Sec. 25.15(a) and (d) have been modified to indicate that a statement,

not a certification, is needed.

9. One comment contended that proposed Sec. 25.15(a) and (d) is

inconsistent with CEQ regulations in that the CEQ regulations require

that the agency use specific criteria to judge whether an action fits

within a categorical exclusion (40 CFR 1507.3(b)(2)(ii)) and

independently evaluate the information submitted and be responsible for

the accuracy of the information (40 CFR 1506.5). The comment also

asserted that proposed Sec. 25.15(a) and (d) departs from existing FDA

regulations, which require that applicants claiming a categorical

exclusion provide supporting information that the action meets the

criteria for the applicable exclusion.

Under current Sec. 25.23(c), a person who claims a categorical

exclusion provides information when appropriate that establishes to the

agency's satisfaction that the action meets the criteria for the

applicable exclusion (emphasis added). Proposed Sec. 25.15(a) and (d)

does not reflect a departure from current FDA regulations. In revising

its NEPA procedures, FDA has formulated its categorical exclusions to

include specific criteria, as required by CEQ's regulations (40 CFR

1507.3(b)(2)(ii)) that in most instances can either be facially

determined or confirmed by review of other information submitted as

part of the request for action. This approach is consistent with CEQ's

view that in most cases additional information should not be required.

In the limited instances when it may be necessary, FDA will request

additional information as needed to establish to the agency's

satisfaction that the criteria for a categorical exclusion have been

met.

10. One comment objected to the absence of information in the

proposal concerning the actions FDA may take in response to a

petitioner or applicant filing a false certification with the agency.

It is a violation of the criminal code (18 U.S.C. 1001) for anyone,

in any matter within the jurisdiction of any department or agency of

the United States, to knowingly and willfully make any false,

fictitious, or fraudulent statement or representation to such

department or agency. Enforcement decisions are generally a matter of

an agency's discretion. FDA will exercise its enforcement discretion

consistent with its statutory responsibilities under all applicable

statutes, including NEPA.

11. One comment recommended that the basic physical/chemical

characterization of a potential product be included in all EA documents

including claims for categorical exclusion.

In the event FDA determines that basic physical/chemical

characterization information is relevant to its environmental

consideration of a specific proposed action, FDA will request that such

information be provided in an EA. FDA intends to issue guidance

documents that will provide applicants with information about the

nature and scope of information that should be included in an EA. A

claim for categorical exclusion shall comply with Sec. 25.15(a) and (d)

and, as discussed in the response to comment 9, should not normally

include additional information.

12. Proposed Sec. 25.20 lists broad categories of agency actions

that require the preparation of an EA, unless the action qualifies for

exclusion. One comment noted that although FDA stated in the preamble

to the proposal that the types of actions requiring an EA remain

essentially the same as in current Sec. 25.22, the proposal did not

include the ``catch-all action'' in current Sec. 25.22(a)(19): ``Action

other than one listed in this subsection, unless subject to exclusion

under Secs. 25.23 and 25.24, that may significantly affect the quality

of the human environment.'' The comment recommended that a clause be

retained in new Sec. 25.20 providing that an ``EA must be prepared for

an action other than one listed in (Sec. 25.20) that may significantly

affect the quality of the human environment.''

The list of actions requiring preparation of an EA was not intended

to be all-inclusive. The list includes broad classes of actions that

require preparation of at least an EA, unless categorically excluded in

subpart C of part 25. Under NEPA and CEQ's implementing regulations,

FDA is required to consider the environmental impact of each of its

proposals for major Federal action that is not categorically excluded.

Therefore, it is not necessary for FDA to include the described catch-

all clause in the final rule.

13. Another comment noted that proposed Sec. 25.20(i) requires an

EA for actions on requests for exemptions for investigational use of

food additives, unless categorically excluded under proposed

Sec. 25.32(b), and questioned whether the agency expects a claim for

exclusion to be submitted for actions involving investigational food

additives. The comment asked FDA to clarify its intent.

The intent of the provision in proposed Sec. 25.20(i) is to

identify actions involving food additives that ordinarily require an

EA, unless the actions are in a specific class that qualifies for a

categorical exclusion. Similar to the agency's experience with actions

on investigational human and animal drugs, FDA expects that if action

were taken on an investigational food additive, such action would

qualify for the exclusion under Sec. 25.32(b) of the final rule.

14. Proposed Sec. 25.21 addresses ``extraordinary circumstances''

under which categories of actions that would

[[Page 40573]]

ordinarily be categorically excluded would require preparation of an

EA. One comment contended that this exception to categorical exclusions

will result in the potential for ``regulatory creep,'' that is, the

potential for FDA to implement the exception in a manner that results

in an expansion of the degree of FDA review, a lengthening of time for

review, and an increased cost of review. The comment expressed

particular concern about the opportunity for regulatory creep in

relation to applying the exception to categorical exclusions for

actions on new animal drug applications (NADA's). The comment suggested

that a primary safeguard against misuse of the extraordinary

circumstances exception is to ensure that decisions on exceptions are

reserved and delegated in part 5 (21 CFR part 5) to a truly responsible

official; in the case of actions on animal drugs, to the Director of

the Center for Veterinary Medicine.

As the comment recognizes, under CEQ regulations at 40 CFR 1508.4,

FDA is required to provide for extraordinary circumstances in which a

normally excluded action may have a significant effect on the

environment. Under proposed Sec. 25.21 (current Sec. 25.23(b)), FDA

requires an EA for any specific action that ordinarily would be

excluded if extraordinary circumstances indicate that the specific

proposed action may significantly affect the quality of the human

environment. CEQ regulations, in 40 CFR 1508.27, define

``significantly'' to require consideration of both the context and

intensity of an agency action. Proposed Sec. 25.21 cites Sec. 1508.27

to emphasize that, in implementing its regulations, FDA will rely on

the principles established by CEQ for determining whether an

extraordinary circumstance exists such that an action, ordinarily

excluded, may significantly affect the environment. By definition, a

categorical exclusion means a category of actions that has been found

not to have a significant effect on the human environment, therefore

application of the extraordinary circumstances provision should be

limited. Since 1985, in implementing its NEPA procedures, FDA has

invoked the extraordinary circumstance exception to categorical

exclusions in limited instances and in a manner consistent with CEQ

regulations. Section 25.21 lists two examples of extraordinary

circumstances where FDA may apply the exception.

FDA declines to modify part 5 to reflect that the authority to

determine the existence of extraordinary circumstances related to

animal drugs is reserved to the Director of the Center of Veterinary

Medicine. The agency's decision is described in the response to comment

60 below, which discusses the revision of part 5 with respect to all

FDA Center Directors.

15. One comment asserted that the extraordinary circumstances

provision will not result in the preparation of EA's for applications

involving paclitaxel that otherwise meet the criteria for categorical

exclusion. The comment stated that the Pacific yew is not classified as

an endangered or threatened species under the Endangered Species Act

(ESA), nor is the species currently listed in any of the appendices to

the Convention on International Trade in Endangered Species of Fauna

and Flora (CITES) and expressed concern that agency actions regarding

products containing paclitaxel would escape environmental consideration

because they do not fall within FDA's examples of extraordinary

circumstances. The comment also questioned the standard that the agency

has proposed to use in determining whether an action involving wild

flora and fauna falls within FDA's second example of extraordinary

circumstances, citing FDA's statement in the preamble that the agency:

(I)ntends to closely examine proposed actions that involve FDA-

regulated articles obtained from wild flora and fauna and will use

the extraordinary circumstances provision to require at least an EA

in any instance in which it appears from an examination of the

proposed action that the action may cause a species to become

endangered or threatened.

Finally, the comment asserted that unlike the ESA, CITES does not speak

in terms of endangered or threatened species.

The examples provided by the agency in proposed Sec. 25.21 are

illustrative of the types of action that would require an EA despite

the fact that the action otherwise qualifies for a categorical

exclusion. The two examples are not intended to be an exhaustive list

of those actions.

FDA's extraordinary circumstances provision requires that an EA be

prepared if a normally excluded action may significantly affect the

quality of the human environment. FDA has specifically determined that

actions relating to applications involving paclitaxel derived from or

otherwise involving the Pacific yew tree fall within the CEQ definition

of ``significantly'' (40 CFR 1508.27) and has documented, in the

agreement filed in the U.S. District Court for the District of Columbia

in Oregon Natural Resources Council Action v. Shalala, No. 96-1449 PLF

(D.C.D.C. Oct. 4, 1996), its intent to require EA's for all actions on

applications, except some actions on IND's, involving paclitaxel

derived from or otherwise involving the Pacific yew tree. FDA also

published a notice in the Federal Register clarifying the environmental

information that must be submitted to the agency in marketing

applications for drug products containing paclitaxel (61 FR 58694).

FDA is clarifying that it will require an EA for an action,

including one involving wild flora and fauna, that is ordinarily

excluded if the action may have a significant effect on the

environment. Where a species of wild flora or fauna may become

endangered or threatened, the action may have a significant effect.

The comment is inaccurate in stating that CITES does not speak in

terms of endangered or threatened species. The regulations implementing

CITES (50 CFR 23.2) note that the appendices include endangered and

threatened species and a ``Facts'' sheet published by the Fish and

Wildlife Service explains that Appendix I includes species presently

threatened with extinction.

16. One comment expressed concern about the environmental effects

of synthetic estrogens in the aquatic environment, specifically those

synthetic estrogens in oral contraceptives and estrogenic replacement

therapy prescribed for post-menopausal women. The comment requested

that until research is available to determine a more accurate critical

concentration, FDA consider the use of synthetic estrogens in human

drugs to be an extraordinary circumstance so that actions involving

estrogen use would require an EA. The authors of the comment state that

they have observed significant alterations of gender ratios when

developing larval medaka (a fish) were exposed to 0.1 part per billion

(ppb) of 17-estradiol (naturally occurring) for 4 weeks.

Additionally, they cite from a published article that male rainbow

trout exposed to 0.002 ppb ethinyl estradiol (used in oral

contraceptives) for 3 weeks showed significantly elevated vitellogenin

levels and decreased testes weight and compromised spermatogenesis.

Concern was also expressed about the potential for higher

concentrations of these compounds in certain local areas.

FDA will require an EA for any specific action that ordinarily

would be excluded if available evidence establishes that, at the

expected level of exposure, a potential exists for a significant effect

on the environment.

[[Page 40574]]

The agency has considered the request that the use of synthetic

estrogens in human drugs be considered an extraordinary circumstance,

but has concluded that the available evidence does not support that, at

the expected level of exposure, a potential exists for significant

effect on the environment. FDA has considered many factors in arriving

at this conclusion including normal prescribing patterns for the drugs,

medical uses, pharmacological properties, waste water treatment

practices and expected introduction and environmental concentrations of

the substances. FDA provided its analysis to the EPA for review and EPA

agreed with FDA's position on this issue. Therefore, FDA will not

generally apply the extraordinary circumstances exception to actions

involving synthetic estrogens used in oral contraceptives and hormone

replacement therapy that otherwise meet the criteria for categorical

exclusion. A report explaining the basis of the agency's decision has

been placed in Docket No. 96N-0057. FDA will continue to investigate

this issue in general and assess each action on an individual basis to

determine whether an extraordinary circumstance exists.

17. Proposed Sec. 25.22 provides for the preparation of an EIS when

the responsible agency official finds, as a result of evaluating

relevant data and information, that a proposed action may significantly

affect the quality of the human environment. One comment recommended

that FDA establish specific criteria to determine the need to prepare

an EIS. The comment suggested that the agency base the criteria on the

number of potentially affected parties or on the formula used by the

European Union (EU) to trigger the EU equivalent of an EIS. The EU

criteria are based on annual tonnage.

An EIS is prepared when evaluation of data or information in an EA

or otherwise available to the agency leads to a finding that a proposed

action may significantly affect the quality of the human environment.

FDA does not believe it is necessary to further identify criteria for

preparing an EIS. CEQ regulations (40 CFR 1508.27) define

``significantly'' and provide guidance to FDA in its determination of

whether an action significantly affects the environment. Furthermore,

it is difficult to develop criteria that are more specific and that may

be applied with great frequency. Criteria relating to the amount of

material produced are not appropriate criteria for determining when an

EIS must be prepared. For example, an EIS may not be necessary for FDA-

regulated articles produced in large quantities if environmental

depletion mechanisms are identified and/or the material is relatively

nontoxic to environmental organisms at expected environmental

concentrations.

18. In the preamble to the proposal, FDA stated that it is

proposing to remove current Sec. 25.25 (Retroactive environmental

consideration) because any request by FDA to an applicant to submit

additional information to an existing FDA approval will be made under

authority granted to FDA by the Federal Food, Drug, and Cosmetic Act

(the act) or the Public Health Service Act (the PHS Act). One comment

contended that this proposed action is inconsistent with both CEQ

regulations and case law governing implementation of NEPA. The comment

stated that FDA was suggesting it could not comply with 40 CFR

1502.9(c)(1)(ii) because its authority to require additional

environmental information from applicants only stems from the act or

the PHS Act. The comment stated that the Federal court, in

Environmental Defense Fund v. Mathews, 410 F.Supp. 336, 338 (D.C.D.C.

1976), rejected similar claims when FDA issued its NEPA regulations in

the 1970's.

Because the comment misunderstands the agency's stated reasons for

proposing to remove current Sec. 25.25, FDA is clarifying them here.

Current Sec. 25.25 applies to agency consideration of the need to

prepare an EIS after the agency has already taken an action, e.g.,

promulgation of a regulation or action relating to an approval. NEPA

and CEQ regulations both require an agency to consider the

environmental impact of its actions before decisions are made and

before actions are taken. Thus, the agency must prepare an EIS for an

action it has found may significantly affect the environment before it

takes the action. NEPA does not apply retroactively; instead, however,

if an ongoing project undergoes changes which themselves amount to

``major Federal actions,'' the agency must then prepare an EIS (Upper

Snake River Chapter of Trout Unlimited v. Hodel, 921 F.2d 232, 234 (9th

Cir. 1990)). FDA is removing Sec. 25.25, which concerned retroactive

environmental consideration.

The comment cites Environmental Defense Fund v. Mathews, 410

F.Supp. 336, 338 (D.C.D.C. 1976), which relates to FDA's 1973

regulations implementing its obligations under NEPA. The case held

that, in addition to its other statutory mandates, FDA has a

nondiscretionary responsibility under NEPA to take environmental

considerations into account in its process of decisionmaking. For the

reasons stated above, elimination of current Sec. 25.25 does not affect

this responsibility and is not inconsistent with CEQ regulations or

case law.

The agency specifically acknowledges its responsibility to prepare

supplements in accord with Sec. 1502.9 in the new regulations (see

Sec. 25.42(c)). FDA's discussion in the preamble to the proposed rule

was intended to point out that CEQ regulations only discuss when a

supplement to a draft or final EIS is needed. CEQ regulations do not

specifically address or grant any authority to an agency to request

additional information under other circumstances. FDA also wanted to

make it clear that once FDA has taken an action, the agency has

authority under the act and the PHS Act to request that an applicant

submit additional information to an existing approval.

C. Subpart C--Categorical Exclusions

19. One comment found no major issues or problems with the policy

and procedure revisions, but expressed concern whether FDA had made

adequate analyses to substantiate the proposed categorical exclusions.

Another comment stated that the commenter was unable to evaluate the

proposed categorical exclusions, specifically the exclusion provided in

Sec. 25.31(b), because FDA had not made the information upon which it

based its conclusions available to the public.

To provide additional substantiation for its proposed categorical

exclusions, FDA supplemented the administrative record for the proposed

regulations with additional information. On October 22, 1996, the

agency published a notice in the Federal Register (61 FR 54746)

announcing the availability of specific information, including

underlying data, that along with the information in the preamble to the

proposed rule supports the categorical exclusions. FDA also reopened

the comment period for 30 days for the sole purpose of inviting public

comment on those categorical exclusions for which information had been

added to the administrative record. The agency received four comments

during this extended comment period, three of which addressed

categorical exclusions for drug and biologic products. FDA, therefore,

believes that it has provided adequate explanation of the categorical

exclusions and has provided adequate opportunity for comment on the

categorical exclusions by interested parties.

20. Proposed Sec. 25.30(j) revised the categorical exclusion for

issuance of certain types of regulations, including current good

manufacturing practice

[[Page 40575]]

(CGMP) regulations, to categorically exclude regulations based on the

hazard analysis critical control points (HACCP) principles. One comment

agreed with this change but recommended that HACCP programs incorporate

mandatory self audits and independent audits into their requirements.

This recommendation is outside the scope of this rulemaking.

1. Human Drugs and Biologics

21. Proposed Sec. 25.31(a) would categorically exclude FDA action

on an NDA, abbreviated application, or a supplement to such

applications, or action on an over-the-counter (OTC) monograph, if the

action does not increase the use of the active moiety of the drug. FDA

intended to include in this categorical exclusion applications for

marketing approval of a biologic product. As discussed in the preamble

to the proposed rule with regard to NDA's, abbreviated applications,

supplements, and OTC monographs, if an action, including action on a

marketing application for a biologic product, does not increase the use

of the product, there is no change in the level of substance in the

environment and, consequently, no increase in any environmental effects

associated with the use and disposal from use of the product.

Therefore, proposed Sec. 25.31(a) has been modified as follows:

Action on an NDA, abbreviated application, application for

marketing approval of a biologic product, or a supplement to such

applications, or action on an OTC monograph, if the action does not

increase the use of the active moiety.

22. Proposed Sec. 25.31(b) would categorically exclude FDA action

on a marketing application for a human drug, or supplement to such

application, or action on an OTC monograph, if the action increases the

use of the active moiety but the concentration of the substance in the

environment will be below 1 ppb. Several comments generally supported

the 1 ppb criterion, but sought minor revisions to or clarifications of

the criterion.

One comment suggested that the 1 ppb criterion be changed to 0.1

ppb using the predicted environmental concentration (PEC). PEC is

defined as the introduction concentration, corrected based on

metabolism/excretion data, on wastewater treatment facility fate

information, and on the use of an appropriate stream dilution factor of

10. Two comments suggested that proposed Sec. 25.31(b) be clarified to

indicate that the relevant concentration is at the point of entry into

the aquatic environment. One of these comments agreed that substances

entering the environment at less than or equal to 1 ppb will have an

insignificant environmental impact, but suggested that the standard be

an expected introduction concentration because this would give more

consideration to potential exposure to primary human receptors which

may come in contact with the substance before it degrades or enters a

wastewater treatment facility. Another comment suggested that because 1

ppb computes to a production rate of 40,700 kilograms (kg) per year

using the calculation method provided in FDA guidance, FDA should add

an exclusion for actions relating to human drugs for which the

production rate of the active moiety is less than 40,700 kg per year.

FDA agrees to clarify that the 1 ppb requirement is relevant at the

point of entry into the aquatic environment, that is, the environmental

introduction concentration (EIC). Under current part 25, FDA requires

EA's to initially provide an estimate of the quantity and concentration

of the substance that is expected to enter the environment. The

calculation method suggested by CDER is explained in its ``Guidance for

Industry for the Submission of an Environmental Assessment in Human

Drug Applications and Supplements'' (FDA, November 1995). If

environmental fate and effects information for a substance is required

in an EA, spatial and temporal concentration and depletion mechanisms

will, as appropriate, be used to adjust the EIC to estimate the

expected environmental concentration (EEC)/exposure concentration of

the product. PEC, as defined by the comment, is the same as the EEC/

exposure concentration. The comment's suggested use of a criterion of

0.1 ppb, calculated using a dilution factor of 10, is equivalent to the

agency's proposed criterion of 1 ppb calculated without using a

dilution factor, in that the same amount of the substance entering the

environment would qualify for categorical exclusion under each

proposal. It may be appropriate for FDA to consider a dilution factor

when estimating a substance's EEC/exposure concentration, based on

information provided in an EA, to evaluate the fate and effects of the

substance. For the purposes of a categorical exclusion criterion,

however, a conservative estimate of the concentration, EIC, will be

used.

As explained in the preamble to the proposed rule (61 FR 14922 at

14925, 61 FR 19476 at 19479), based on their method of entry into the

environment from use and their physical and chemical characteristics

(e.g., water solubility), human drugs would be expected predominantly

to enter the aquatic environment. The data submitted in EA's reviewed

by CDER have routinely supported this hypothesis. The data also have

routinely shown that in those cases in which an applicant has provided

toxicity results for terrestrial organisms in addition to acute

toxicity results for aquatic organisms, the drugs are toxic to aquatic

organisms at lower levels than they are to terrestrial organisms,

suggesting that the use of aquatic organisms is a conservative

approach. Proposed Sec. 25.31(b) has been revised to clarify that the

relevant concentration is at the point of entry into the aquatic

environment.

CEQ regulations require that localized (i.e., site-specific)

effects of a substance on the environment be considered, where

appropriate (40 CFR 1508.27(a)). Typically, the use of a drug product

is spread throughout the United States. However, in the rare instance

in which the use of a drug will be localized in one geographic area, a

categorical exclusion based on the concentration of a substance at the

point of entry into the aquatic environment, such as 1 ppb, provides

for an evaluation of the local environmental effect of that drug. The

suggestion to add a categorical exclusion based on a set quantity of

the drug product, such as 40,700 kg, ignores the possibility of

localized use that the agency is required to consider. Therefore, FDA

is not adding a categorical exclusion based on production rates.

Concerning potential exposure to primary human receptors, as

discussed in Calorie Control Council, Inc. v. U.S. Department of

Health, Education, and Welfare, No. 77-0776 (D.C.D.C. 1977), the

primary concern of NEPA is the impact of agency actions on physical

environmental resources, not the public health consequences of a

proposed action. Furthermore, NEPA authority is intended to supplement

other statutory responsibilities of a Federal agency. FDA already

addresses primary receptor issues as public health issues under the act

rather than through NEPA evaluation.

As a result of this discussion, proposed Sec. 25.31(b) has been

revised to state:

Action on a NDA, abbreviated application, or a supplement to

such applications, or action on an OTC monograph, if the action

increases the use of the active moiety, but the estimated

concentration of the substance at the point of entry into the

aquatic environment will be below 1 part per billion.

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

[[Page 40576]]

Environmental Assessment in Human Drug Applications and Supplements,''

provides a method for calculating the estimated concentration of the

substance at the point of entry into the aquatic environment. Other

calculation methods may be appropriate. However, such alternative

calculations will be reviewed by the agency on a case-by-case basis to

determine whether they are appropriate for determining whether the

categorical exclusion applies.

23. One comment reiterated a comment made during the initial

comment period that the agency needs to broaden ``extraordinary

circumstances,'' especially as the provision relates to paclitaxel, and

further noted ``troubling defects'' in the Toxicity Report the agency

provided in the administrative record to support the 1 ppb categorical

exclusion criterion in Sec. 25.31(b). The defects cited in the comment

include: (1) The report is grounded in an evaluation of ecotoxicity in

a few select laboratory species, not in wild organisms that may already

be stressed by other pollutants; (2) the report appears to be based on

EA's submitted by applicants to the agency, and no information is given

about how the toxicity figures were obtained and whether certain

assumptions were made in the studies; (3) the report does not consider

cumulative impacts associated with disposal of the products in the

environment, including the potential for bioaccumulation of pollutants

over time; and (4) the report provides no scientific explanation, other

than citing one article, for dividing the median effective

concentration (EC50) or median lethal concentration (LC50) values by

1,000 to arrive at a predicted no observed effect concentration (NOEC).

The comment also stated that the Toxicity Report is based on toxicity

tests that may be considered antiquated in light of recent efforts by

the Organization for Economic Cooperation and Development (OECD) and

EPA to revise such evaluations. The comment did not suggest any changes

to the proposed regulations.

FDA's extraordinary circumstances provision requires that at least

an EA be prepared if a normally excluded action may significantly

affect the quality of the human environment. The agency has

specifically determined that most actions relating to paclitaxel

derived from or otherwise involving the Pacific yew require the

preparation of EA's, irrespective of the expected concentration of

paclitaxel at its point of entry into the aquatic environment. (See the

response to comment 15, above.)

With respect to the alleged defects of the Toxicity Report,

environmental risk assessment initially involves determining the toxic

effect of a compound on a few select laboratory species. The test

organisms used by the applicants to generate the data in the Toxicity

Report are typically the same as those suggested by EPA (see 40 CFR

797) and OECD for this initial screening. CDER evaluates the potential

for significant environmental effects by relating the concentrations

determined to have toxic effects on these test organisms to the level

of the substance expected in the environment. Field studies (i.e.,

evaluation in actual environmental settings) are generally conducted

only when initial evaluation and subsequent intermediate evaluations

indicate that the potential for significant environmental harm may

exist.

FDA based the proposed 1 ppb categorical exclusion on toxicity data

submitted to the agency in EA's. The agency's analysis of the toxicity

data is explained in the Toxicity Report. Under 40 CFR 1506.5, the

agency asks applicants to prepare an EA and FDA independently evaluates

the information in the EA to determine its acceptability. The Toxicity

Report provides summary information from the EA's, identifying the

location of the detailed EA reports and FONSI's in the public docket.

FDA reviewed the test reports provided in EA's and determined that the

methodologies, assumptions, and conclusions of the reports were

acceptable. Any interested party may obtain additional information

regarding the test methods used for each EA from those reports in the

public docket.

Impacts on the environment which result from the incremental impact

of an action when added to other past, present, and reasonably

foreseeable future actions are known as cumulative impacts.

Consideration of cumulative impacts is included in the proposed

categorical exclusions for human drugs and biologics. Under

Sec. 25.31(a), action on a marketing application for a human drug or

biologic or action on an OTC monograph may be categorically excluded if

the action does not increase the use of the active moiety. However, if

an action increases the use of the active moiety, the impacts of that

increased use will require environmental analysis unless the action

meets other specific categorical exclusion criteria established in

Sec. 25.31(b) and (c). The potential for cumulative effects is also

considered in the calculation of the EIC of an active moiety of a drug

because the applicant bases these estimates on the expected quantities

that will be used 5 years in the future, including the use quantities

associated with related FDA applications (see, e.g., Guidance for

Industry for the Submission of an Environmental Assessment in Human

Drug Applications and Supplements, Section III.D.6.e, November 1995).

As stated in the preamble to the proposed rule (61 FR 14922 at

14925, 61 FR 19476 at 19479), one of the criteria for determining that

a drug is safe for human use is consideration of its potential to

bioaccumulate in body tissue. The vast majority of drugs do not

bioaccumulate because that characteristic would raise safety concerns

for use of the drugs in humans. If a drug has characteristics that

would allow it to bioaccumulate in tissue, the body must have a

mechanism to metabolize the compound into a substance that has lower

bioaccumulation potential so that it may be cleared from the body. In

the EA's that the agency reviewed, bioaccumulation was not an issue.

The practice of using assessment factors in environmental risk

assessments is well established. FDA's use of an assessment factor of

1,000 is consistent with EPA's approach (e.g., Zeeman, M., and J.

Gilford, ``Ecological Hazard Evaluation and Risk Assessment Under EPA's

Toxic Substances Control Act (TSCA): An Introduction,'' in

Environmental Toxicology and Risk Assessment, ASTM STP 1179, edited by

W. Landis, J. Hughes, and M. Lewis, pp. 7-21, American Society for

Testing and Materials, Philadelphia, 1993.).

The toxicity tests performed by FDA applicants and described in the

Toxicity Report are consistent with contemporary practice and are based

on current scientific thinking. Potential future revision of test

methods does not render invalid current testing, data obtained as a

result of that testing, or conclusions based on that data.

24. One comment stated that under Sec. 25.31(b), FDA will now

apparently permit companies seeking approval of metered dose inhalers

to forgo preparation of EA's in connection with their marketing

applications. The comment asked that the agency make clear in its final

regulations that FDA will require EA's with all applications involving

metered dose inhalers that release chlorofluorocarbons (CFC's) and that

such EA's must thoroughly evaluate the cumulative impacts of CFC's on

the Antarctic environment and alternatives that avoid such impacts.

In 1978, FDA finalized a programmatic EIS regarding the use of

fluorocarbons in products subject to regulation by the agency under the

act (Final Environmental Impact Statement;

[[Page 40577]]

Fluorocarbons: Environmental and Health Implications, February, 1978,

Docket No. 76N-0640) and announced the availability of the final EIS in

the Federal Register (43 FR 11316, March 17, 1978). This EIS was used

as the basis for prohibiting use of CFC's as propellants in self-

pressurized containers if the use of the CFC was not deemed to be

essential. As stated in the EIS:

The Commissioner of Food and Drugs has concluded that the

continued use of chlorofluorocarbon propellants in self-pressurized

containers in products subject to the Federal Food, Drug, and

Cosmetic Act (FFD&C) poses an unreasonable risk of long-term

biological and climatic impacts.

Accordingly, the Food and Drug Administration is finalizing a

prohibition of the nonessential use of chlorofluorocarbons as

propellants in self-pressurized (aerosolized) containers in products

subject to the FFD&C Act. The products to which the regulation

applies are human food, food additives, human drugs, including

biological products, animal food, animal drugs, cosmetics, and

medical devices. (p. iii)

The EIS further stated:

The selection of fluorocarbon use(s) to be regulated requires a

determination of whether or not a particular fluorocarbon use is

essential. The Commissioner of Food and Drugs has defined

essentiality to mean that there are no technically feasible aerosol

or non-aerosol alternatives to using a fluorocarbon in a product and

that a product provides a substantial public benefit such as a

therapeutic medical benefit. The product need not be indispensable

to life, but the benefit must be important and consist of more than

added convenience. (p. 89)

A copy of the programmatic EIS has been placed in the administrative

record for this rule (Docket No. 96N-0057).

FDA regulations pertaining to the use of CFC propellants in self-

pressurized containers are described in Sec. 2.125. CFC's may be used

as propellants in a self-pressurized container only if the drug is

approved, a petition has been filed as described in Sec. 2.125(f), and

Sec. 2.125(e) has been amended to specify the use as essential. The

petition requesting an essential use designation must be supported by

an adequate showing that: (1) No technically feasible alternatives

exist to the use of a CFC in the product; (2) the product provides a

substantial health benefit, environmental benefit, or other public

benefit that would not be obtainable without the use of the CFC; and

(3) the use does not involve a significant release of CFC's into the

atmosphere or, in the alternative, the release is warranted in view of

the consequences of the use not being permitted. The petition is a

public document about which any interested party may comment before a

final determination is made by the agency.

FDA is in the process of establishing a policy for determining when

uses of CFC's currently designated essential will no longer be deemed

essential under the Clean Air Act due to the availability of safe and

effective medical product technology that does not use CFC's. (See

Docket No. 97N-0023.)

The agency has, in the programmatic EIS, evaluated the individual

and cumulative effects, including the effects on human health,

stratospheric ozone, biological systems (nonhuman), and climate, of

approvals of marketing applications that result in the release of

CFC's. FDA has fulfilled its responsibilities and has adequately

considered the environmental issues regarding CFC's. Therefore, a

requirement that individual marketing applications for metered dose

inhalers that release CFC's must include EA's is not necessary because

the environmental information would already be under consideration by

the agency in its decision whether to designate an essential use under

Sec. 2.125(e). Resubmission of this information to the agency would not

be consistent with CEQ goals of reducing excessive paperwork. NEPA

supplements, but does not supersede, other statutory responsibilities.

NEPA establishes requirements to ensure that an agency considers

environmental information in its decisionmaking process. Thus, after a

review of the relevant environmental information, FDA may, but is not

required to, decline to take an action that may have a significant

effect on the environment.

25. Proposed Sec. 25.31 lists the general classes of agency actions

relating to human drugs and biologics that are categorically excluded

and, therefore, ordinarily do not require the preparation of EA's or

EIS's. One comment requested that a categorical exclusion be added to

the regulations for ``[a]ction on an NDA, abbreviated application, or a

supplement to such application, or action on an OTC monograph, if the

active moiety has been previously approved by FDA and the concentration

in the environment will be above 1 part per billion.''

The agency believes that providing a categorical exclusion in

Sec. 25.31 for an active moiety that has been previously approved by

the agency is inappropriate. FDA does not have any evidence that

actions relating to the approval of a drug or biologic for which the

active moiety has been previously approved do not individually or

cumulatively have a significant effect on the environment. In some

cases, the approval of a new indication or dosage form of a previously

approved active moiety could substantially increase the use of the

product. In such cases, an EA must be prepared unless the action meets

one of the other criteria for a categorical exclusion.

26. One comment requested that proposed Sec. 25.31 be revised to

add a categorical exclusion for actions relating to drugs that involve

substances that have an environmental concentration greater than 1 ppb

(i.e., do not meet the criteria for categorical exclusion under

Sec. 25.31(b)) but have a PEC to a predicted no effects concentration

(PNEC) ratio equaling less than one.

The agency declines to amend Sec. 25.31 as requested. A PEC/PNEC

ratio is one of several commonly used approaches for evaluating

environmental effects. To calculate the PEC/PNEC ratio, ecotoxicity

studies are performed, results are compared to expected environmental

concentrations, and a conclusion is drawn. The calculation also

requires use of an assessment factor that will vary depending on the

type of ecotoxicity data generated. The PEC/PNEC ratio constitutes an

environmental analysis and, therefore, is not an appropriate criterion

for a categorical exclusion. If FDA were to use a PEC/PNEC ratio as a

criterion for categorical exclusion, FDA would need to review the

underlying data that supports the PEC/PNEC ratio, including the

assessment factor, and would, in essence, be requiring an EA. Thus, FDA

will not add a categorical exclusion for actions relating to drugs

based on the calculation of a PEC/PNEC ratio. An applicant is not

precluded, however, from using a PEC/PNEC ratio to assess environmental

effects in an EA or to aid in determining whether extraordinary

circumstances exist such that a proposed action, which is normally

excluded, may have an environmental effect.

27. One comment recommended that the categorical exclusion

described in proposed Sec. 25.31(c) for naturally occurring substances

not include new steroid or hormone modulating drugs.

As explained in the preamble to the proposal (61 FR 14922 at 14926,

61 FR 19476 at 19480), FDA based the categorical exclusion in

Sec. 25.31(c) on its finding, after reviewing abbreviated EA's for

substances that are naturally occurring, that actions on submissions

for these substances will not affect the environment if the action will

not significantly alter the concentration or distribution of the

natural substance in the environment. No information was provided in

the comment to support the need for this change. The available

[[Page 40578]]

evidence does not support a finding that new steroid or hormone

modulating drugs, at the expected level of exposure, have the potential

to significantly affect the environment. Therefore FDA will not modify

Sec. 25.31(c). The agency specifically addressed concerns regarding

synthetic estrogens used in human drugs in comment 16 of this document.

The agency will evaluate each proposed action on an individual basis to

determine if extraordinary circumstances exist such that further

environmental documentation is needed.

28. One comment requested clarification regarding the definition of

``substances that occur naturally in the environment'' as that phrase

is used in proposed Sec. 25.31(c). The comment suggested that the

categorical exclusion be revised to read ``substances that either occur

naturally in the environment, or are derived from biological systems''

or, alternatively, that FDA provide a definition in the regulation.

The agency declines to adopt the language suggested in the comment

because the term ``or derived from biological systems'' is too broad.

Not all substances produced by a biological system may be substances

that occur naturally in the environment. The biological system, or the

substance itself, may be modified such that the substance does not

occur naturally in the environment. The comment provided no rationale

as to why biologically-derived substances not occurring naturally in

the environment should be subject to the categorical exclusion.

FDA intends to clarify which type of actions would fall under this

categorical exclusion in guidance documents prepared by each center.

FDA-regulated articles may be considered for categorical exclusion

under this provision whether they are obtained from natural sources,

biological systems, or are chemically synthesized. The agency will

consider the form in which the FDA-regulated article will exist in the

environment when determining if an action will be eligible for this

categorical exclusion. For example, a modified active moiety (e.g.,

salt) which does not occur naturally may be considered a naturally

occurring substance if it is established that, in vivo and in the

environment, the active moiety exists in a form that is found

naturally. Biological and biotechnological products will be similarly

evaluated. For example, a protein or DNA comprised of naturally

occurring amino acids or nucleosides, but with a sequence different

from that of a naturally occurring substance, will normally qualify for

this categorical exclusion after consideration of metabolism. The same

principle will apply to synthetic peptides and oligonucleotides. Living

and dead cells and organisms regulated by the agency may also be

considered for categorical exclusion under this provision if the action

does not alter significantly the concentration or distribution of the

substance, its metabolites, or degradation products in the environment.

The agency will rely on the significant amount of information submitted

by an applicant in support of a requested action (for example

information about metabolism, excretion, and stability; viability (if

applicable); and physical/chemical characteristics of the product) in

determining whether categorical exclusion under Sec. 25.31(c) is

appropriate.

29. One comment requested that the phrase ``action on an OTC

monograph,'' which is included in the categorical exclusions in

Sec. 25.31 (a), (b), and (c), be changed to ``OTC activity'' and that

the regulation define ``OTC activity'' as ``an action on an OTC

monograph or a switch of a drug from prescription to OTC use that is

submitted in an NDA or supplement, if the product is already marketed

for the proposed use.'' The comment expressed a belief that the

preamble to the proposed rule ``is clear on the intent for a

prescription to an OTC switch to be considered as a categorical

exclusion.''

FDA does not believe it is necessary or appropriate to substitute

``OTC activity'' for ``action on an OTC monograph'' in Sec. 25.31 (a),

(b), and (c). Agency action on any request to switch a drug from

prescription to OTC use is already covered in Sec. 25.31 (a), (b), and

(c) by the language ``action on an NDA, abbreviated application, or a

supplement to such application, or action on an OTC monograph.''

Depending on the circumstances and the applicant's preference, a

prescription to OTC switch may be requested using any of these

administrative filing mechanisms. As discussed in the preamble (61 FR

14922 at 14925, 61 FR 19476 at 19479), the agency will not elevate form

over substance and will treat like actions alike, regardless of the

avenue through which the actions are requested. Thus, the same

categorical exclusion criteria will apply to NDA's, abbreviated

applications, supplements, and ``actions on OTC monographs.''

Prescription to OTC switches have generally been, and will continue

to be, considered by CDER to be actions that increase use because the

potential patient population expands from only those persons who seek

treatment under a physician's care to any person who enters a retail

establishment that sells OTC products. Therefore, agency action on an

OTC switch will be categorically excluded if the criteria of Sec. 25.31

(b) or (c) apply to the action, specifically if the concentration of

the substance at the point of entry into the aquatic environment will

be below 1 ppb (Sec. 25.31(b)), or if it is a substance that occurs

naturally in the environment and the action will not significantly

alter the concentration of the substance in the environment

(Sec. 25.31(c)).

30. Proposed Sec. 25.31(e) would categorically exclude action on an

IND from the requirement to prepare an EA. One comment suggested that

this exclusion be limited by specifying in the exclusion a ceiling on

the quantity (number of doses) to be released into the environment.

As stated in the preamble to the proposed rule (61 FR 14922 at

14926, 61 FR 19476 at 19480), FDA action on an IND in many cases does

not significantly increase the use of the drug or the amount of the

drug introduced into the environment because the drug is being

administered to few patients or is already being marketed for another

use. Consequently, no changes in the effect on the environment will

occur due to agency action on the IND. In the event FDA action on an

IND would increase the use of a drug, the agency's experience has

demonstrated that significant environmental effects would not occur

because the investigational use is limited and controlled. The dosing

regimen for investigational drugs that would result in an environmental

introduction concentration of 1 ppb (the concentration below which FDA

has found no significant effect on the environment) is not expected for

clinical trials held under an IND. Very large clinical trials are rare,

but, cumulatively, they enroll approximately 8,000 patients. Those

subjects would need to use 14 grams of the active moiety every day for

an entire year to result in an environmental introduction concentration

of approximately 1 ppb, the concentration below which CDER has

routinely observed no significant effects on relevant standard test

organisms in the aquatic environment. The level and duration of this

dosing regimen, as described, are greater than is expected under

clinical trials, thus the addition of a criterion limiting the number

of doses is unnecessary.

The preamble to the proposed rule (61 FR 14922 at 14923, 61 FR

19476 at 19477) noted that categorical exclusion

[[Page 40579]]

criteria relating to toxicity, which includes current Sec. 25.24(c)(4),

``if * * * waste will be controlled or the amount of waste expected to

enter the environment may reasonably be expected to be nontoxic,'' have

been incorporated into the extraordinary circumstances provision of

Sec. 25.21(a). Therefore, the categorical exclusion for IND's remains

essentially unchanged. In the event FDA has reason to believe its

action on an IND may significantly affect the environment, FDA will

invoke the provision relating to ``extraordinary circumstances'' and

require an EA. Therefore, the agency declines the suggestion to modify

the categorical exclusion in Sec. 25.31(e).

2. Foods, Food Additives, and Color Additives

31. Proposed Sec. 25.32(b) provides for a categorical exclusion for

FDA action on a request for exemption for investigational use of a food

additive, if the food additive is intended to be used for clinical

studies or research. One comment noted the absence of a discussion

concerning the potential impact of the investigational use of food

additives in the preamble to the proposal, despite the discussion about

the potential environmental impact of investigational and clinical

research for drugs. The comment recommended that FDA establish a

maximum annual quantity for investigational uses of food additives

allowed to be released to the environment.

The agency declines to establish additional criteria for the

application of the categorical exclusion of the investigational use of

food additives. FDA has not required that a formal application be

submitted to the agency for the investigational use of a food additive.

The investigational use of food additives is expected to be limited to

small amounts needed in studies with laboratory animals under 21 CFR

170.17. Occasionally additives are tested in limited clinical trials

under the control of institutional review boards. The program has

functioned for 40 years with little investigational activity under 21

U.S.C. 348(i). Thus, the agency is not aware of any need to revise this

exclusion to include a ceiling on the yearly amount of a substance that

may be released into the environment. Furthermore, the comment provided

no information on which to conclude that such a ceiling is justified.

32. One comment specifically supported the categorical exclusions

in the proposed rule for food and color additives and generally

recognized as safe (GRAS) substances. Another comment specifically

supported the categorical exclusions set forth in proposed Sec. 25.32

(i), (k), and (r), but raised issues regarding the need for reform of

the review process for food additive and GRAS petitions.

Reform of the review process for food additive and GRAS petitions

is outside the scope of this rulemaking and will not be addressed here.

33. One comment, while generally supporting the categorical

exclusions in proposed Sec. 25.32 (i) and (j), requested that they be

expanded to include all actions on components of food-contact

materials, including actions on GRAS petitions, except where

extraordinary circumstances exist. The comment asserted that compiling

the information needed for EA's for food-packaging materials is

unnecessary and unduly burdensome, that the costs of preparing EA's for

these materials are significant, and that routine preparation of EA's

for these actions results in an unnecessary expenditure of industry and

agency resources. The comment requested that the agency not require

EA's for actions on nonfunctional components of food-packaging

materials because Federal, State, and local laws and regulations

adequately control emissions to the environment at sites where these

substances are used in the manufacture of food-packaging materials. The

comment pointed out that the agency is proposing not to require

information on the production of FDA-regulated substances based on its

recognition that Federal, State, and local environmental laws and

regulations adequately protect the environment at the production sites

for those substances. The comment requested that the agency apply the

same reasoning to conclude that EA's are no longer needed to assess the

environmental impact of nonfunctional components of food-packaging

materials that are used and enter the environment at the production

sites of the packaging material. The comment also requested that EA's

not be required for actions involving components of finished food-

packaging material present at greater than 5 percent-by-weight because:

(1) Most of these additives will replace other similar, already

regulated additives and will not have any meaningful impact on the

potential uses of the finished food-packaging material; and (2)

adequate Federal, State, and local laws and regulations are in place to

protect environments that may be affected by disposal of food-packaging

material. The comment pointed out that ``in certain rare situations,

for example, in instances where the use of a new material may affect

recycling streams, disposal of food-packaging materials prepared from a

newly regulated polymer could potentially have some effect on the

environment.'' The comment suggested that in these instances it may be

appropriate for the agency to require an EA and that proposed

Sec. 25.21 (Extraordinary circumstances) will provide the agency with

the means to require EA's for these few situations.

FDA agrees that the new categorical exclusions in proposed

Sec. 25.32 (i) and (j) should be revised to include GRAS petitions. The

agency also acknowledges that there are certain classes of

nonfunctional components of food-packaging materials and certain

classes of components of food-packaging material present at greater

than 5 percent-by-weight of the finished food-packaging material that

should be included under Sec. 25.32(i). However, FDA does not agree

that all classes of actions on substances intended for use as

components of food-contact materials warrant categorical exclusion. Nor

does the agency agree that compiling the information needed for EA's

for food-packaging materials is unnecessary, unduly burdensome, and

costly. The basis for the agency's decision on these classes of actions

is explained below.

GRAS petitions: None of the petitions that the agency has reviewed

while developing the categorical exclusions in Sec. 25.32 (i) and (j)

(including those it has reviewed since the proposal issued) were GRAS

affirmation petitions for components of food-packaging material or

components of food-contact surfaces of equipment or other repeat use

food-contact articles. But, because the environmental information that

would be needed under part 25 for a GRAS petition for these types of

food-contact substances is identical to the information required for a

food additive petition, the agency believes that its experience with

food additive petitions is relevant to GRAS affirmation petitions and

that any future GRAS affirmation petitions for these classes of actions

can also be excluded. Therefore, FDA has revised proposed Sec. 25.32(i)

and (j) to include actions on GRAS affirmation petitions.

Nonfunctional components of food-packaging material: The agency

does not believe it is appropriate to categorically exclude all actions

on nonfunctional components of food-packaging material, as requested by

the comment. To evaluate the request that FDA revise Sec. 25.32(i) to

further exclude from the requirements for EA actions on nonfunctional

components of food-packaging materials, the agency reviewed 44

petitions for nonfunctional components of food-packaging

[[Page 40580]]

materials.1 As a result of this review, the agency found

that a number of these petitions warranted exclusion from the need for

an EA, while others did not. The agency found that 13 of the petitions

were for additives that remained with food-packaging materials used by

consumers despite the fact that these additives did not function in the

finished food-packaging material. As they pertained to use and disposal

of nonfunctional components of food-packaging materials, the FONSI's

for the agency's actions on these petitions were based on the following

factors: (1) Only very small quantities, if any, of these additives

were expected to enter the environment at sites where the additives

were used in the manufacture of food-packaging materials; (2) only

extremely low levels of substances, if any, could be expected to enter

the environment as a result of disposal of food-packaging materials;

and (3) virtually no change in the use of natural resources and energy

would be expected because the additives would be replacing other,

currently regulated, additives and would not affect the uses of the

packaging materials to which they were added. These factors are the

same as those upon which the agency bases its exclusion for actions on

functional components of finished food-packaging materials. Therefore,

the agency has decided that it is appropriate to revise proposed

Sec. 25.32(i) to include all components of food-packaging materials

that remain with finished packaging through use by consumers and are

present at less than 5 percent-by-weight, regardless of whether they

perform a function in the finished package.

---------------------------------------------------------------------------

\1\ ``Index of Petitions for Nonfunctional Components of Food-

packaging Materials,'' (Docket No. 96N-0057).

---------------------------------------------------------------------------

In its review of the remaining 31 petitions involving nonfunctional

components of finished food-packaging material, the agency found that 5

petitions were for antimicrobial substances that are also regulated by

EPA under the Federal Insecticide, Fungicide, and Rodenticide Act

(FIFRA) as pesticides. In Sec. 25.32(q) of the proposed rule, actions

to approve a food additive petition or grant a request for exemption

from regulation as a food additive under Sec. 170.39 are categorically

excluded when the substance that is the subject of the petition or

request is registered by EPA under FIFRA for the same use requested in

the petition or in the request for exemption.

Also among these 31 petitions were 6 petitions for substances that

occur naturally in the environment. These petitions would be excluded

from the requirement to prepare an EA under the categorical exclusion

in Sec. 25.32(r) of the final rule.

The 20 remaining petitions involving nonfunctional components of

finished food-packaging material were for additives that were not

expected to remain with the finished article, but instead were expected

to enter the environment at sites where they were used as processing

aids in the manufacture of food-packaging materials and were neither

antimicrobial substances nor naturally occurring substances. These

types of additives are not intended to remain with the finished food-

packaging materials which are used and disposed of by consumers

throughout the United States. The results of environmental toxicity

tests presented in some of these petitions showed that the additives

had the potential to harm organisms in the environment present at or

adjacent to the use sites. For 17 of these 20 petitions, FDA conducted

an analysis of the environmental exposure levels of the additives at

the use sites and compared these exposure levels to environmental

toxicity information on the additives to determine the potential for

significant impact. In some cases, the margin between environmental

exposure levels and levels found to be toxic to organisms present in

the receiving environment was very narrow. For the remaining three

petitions, FDA relied upon adequate regulation of potential discharges

to reach its environmental decision.

Under current part 25, FDA has required specific information about

Federal, State, and local laws and regulations that are applicable to

emissions at the site of production of the subject substances where the

manufacturing operations are designed to provide maximum yield of the

FDA-regulated article for commercial sale. FDA reviewed hundreds of

submissions with this information before deciding to eliminate the

requirements for its inclusion. However, the formats for EA's in

current Sec. 25.31a do not require information on emissions

requirements at the sites where nonfunctional components of food-

packaging materials are used to produce the finished article. A review

of FDA's experience with EA's for most nonfunctional components of

finished food-packaging materials that are expected to enter the

localized use site environment (i.e., the finished food-packaging

manufacturing facility) has revealed that analysis of exposure and

environmental toxicity is necessary to determine the potential for

significant impact. Based on this experience, therefore, the agency

does not agree with the comment that it can rely on other Federal,

State, and local laws for protecting the environment to exclude actions

on petitions for these nonfunctional components of food-packaging

materials as was done to eliminate requirements for information on the

sites of production of FDA-regulated articles.

Thus, the agency cannot establish an additional categorical

exclusion for petitions for nonfunctional components of food-packaging

that do not remain with food-packaging through use by consumers. The

agency will provide specific guidance to petitioners for preparing EA's

for those categories of petitions that will require EA preparation. The

guidance for EA's involving nonfunctional components of food-packaging

materials will focus on the relevant issues surrounding a proposed

action and will take into consideration whether other laws and

regulations adequately control potential environmental impacts or

whether an action may threaten a violation of such laws and regulations

as required by CEQ regulations (40 CFR 1508.27(b)(10)).

Components of Finished Food-packaging Material Present at Greater

than 5 Percent-by-Weight: The comment requested a categorical exclusion

for actions involving components of finished food-packaging material

present at greater than 5 percent-by-weight, but did not provide any

specific information showing that actions on petitions in this category

do not individually or cumulatively have significant environmental

effects. To evaluate this request, FDA reviewed 30 petitions for

components of food-packaging materials present at greater than 5

percent.2 The agency found that five of these petitions were

for coatings or components of coatings for food-packaging materials.

The FONSI's for the agency's actions on these petitions were based on

the following factors: (1) Only extremely low levels of substances, if

any, could be expected to enter the environment as a result of use and

disposal of these coated food-packaging materials; and (2) virtually no

change in the use of natural resources and energy would occur because

the additives would be replacing other, currently regulated, additives

and would not affect either the uses of the packaging materials to

which they were added or the disposal technologies used for these

materials. These factors are the same as those upon which the exclusion

for actions on functional components of

[[Page 40581]]

finished food-packaging materials present at less than 5 percent are

based even though the components of the coatings may be present in the

finished food-packaging material at greater than 5 percent-by-weight.

Therefore, the agency is revising the exclusion in proposed

Sec. 25.32(i) to include actions on the components of coatings of

finished food-packaging materials.

---------------------------------------------------------------------------

\2\ ``Index of Petitions for Components of Food-packaging

Materials Present at Greater than 5%,'' (Docket No. 96N-0057).

---------------------------------------------------------------------------

The agency's findings for the remaining 25 petitions support FDA's

position that significant environmental effects may result from agency

actions on components of finished food-packaging material present at

greater than 5 percent-by-weight. Examples of petitions that required

extensive analysis to determine the potential impact of food-packaging

materials on solid waste management strategies include food additive

petition (FAP) 6B3948 (Docket No. 86F-0341); FAP 7B3979 (Docket No.

86F-0508); FAP 8B4107 (Docket No. 88F-0404); FAP 1B4236 (Docket No.

91F-0198); and FAP 8B4110 (Docket No. 88F-0339). In some cases, the

agency and the petitioners decided to include mitigating measures in

the food additive regulations to avoid potentially significant

environmental effects. In addition, the agency has not acted on FAP

7B3994, because it needs to consider further whether significant

effects on solid waste management strategies may result (53 FR 47264 at

47267, November 22, 1988). Evaluation of these potential effects is

being conducted along with an evaluation of the agency's proposed

action to provide for the safe use of vinyl chloride polymers (51 FR

4177, February 3, 1986). The agency announced on November 22, 1988 (53

FR 47264), its intent to prepare an EIS on its actions on vinyl

chloride and other chlorinated polymers. FDA continues to work on this

statement.

This comment asserted that EA's are not needed for petitions for

components of food-packaging materials because the effects of disposal

of food-packaging materials by incineration or landfilling are subject

to the control of laws, regulations, and government authorities

directly concerned with the environment. FDA, based on its experience,

agrees that the extremely low levels of substances that may leach from

food-packaging materials disposed of in landfills are adequately

controlled by EPA regulations in 40 CFR part 258. FDA is aware of laws

and regulations governing the incineration of municipal solid waste,

which include the incineration of food-packaging materials. However,

there is potential for incineration of food-packaging materials to

threaten a violation of these laws and regulations. FDA will consider

this potential effect under 40 CFR 1508.27(b)(10). For example, in its

decision to prepare an EIS on its actions on vinyl chloride and other

chlorinated polymers (53 FR 47264 at 47265, November 22, 1988), the

agency found that the expected increase in hydrogen chloride emissions

from incinerators may affect the ability of incinerator operators to

comply with existing and anticipated emissions standards. This issue is

still under agency review.

A number of the agency's actions on components of food-packaging

materials present at greater than 5 percent-by-weight had potential for

significant effects on the environment. The agency is unable, without

specific information such as that provided in an EA, to distinguish

which petitions for these actions may have potential for significant

impact. Therefore, the agency will continue to require EA's for this

category of petitions, with the exception of those petitions pertaining

to components of coatings. The agency will develop and provide to

petitioners specific guidance for preparing EA's for those categories

of petitions that will require the preparation of EA's. The guidance

for EA's involving components of packaging present at greater than 5

percent-by-weight will focus on the relevant issues surrounding a

proposed action, and will take into consideration the extent to which

other laws and regulations adequately control potential environmental

impacts.

As a result of this analysis, proposed Sec. 25.32, categorical

exclusions for foods, food additives, and color additives, will be

revised at paragraphs (i) and (j) to read as follows:

(i) Approval of a food additive petition, GRAS affirmation

petition, or the granting of a request for exemption from regulation

as a food additive under Sec. 170.39 of this chapter, when the

substance is present in finished food-packaging material at not

greater than 5 percent-by-weight and is expected to remain with

finished food-packaging material through use by consumers or when

the substance is a component of a coating of a finished food-

packaging material.

(j) Approval of a food additive petition, GRAS affirmation

petition, or the granting of a request for exemption from regulation

as a food additive under Sec. 170.39 of this chapter, when the

substance is to be used as a component of a food-contact surface of

permanent or semipermanent equipment or of another food-contact

article intended for repeated use.

Burden of compiling the information for EA's for food-packaging

materials: As discussed above, for certain actions involving food-

packaging materials, FDA will continue to require petitioners to submit

an EA. FDA does not agree that the information it requires the

petitioner to submit in these EA's is unnecessary, nor does the agency

believe the effort to provide such information is unduly burdensome. As

FDA has stated above, it will provide guidance to industry regarding

the focus of environmental documents. In addition, FDA has limited in

the past and will continue to limit its requests for information to

only the amount needed to assess the potential environmental impact of

its actions. FDA recognizes that in some cases the information needed

for EA's is not readily available or is not yet known to a petitioner.

In such cases, the agency in the past has asked the petitioner to

provide a best possible forecast or to use a conservative approach to

analyze environmental effects. FDA will continue this approach,

recognizing that in some cases there may be uncertainty about the

potential for significant environmental impact of food-packaging

materials.

In the preamble to the proposal (61 FR 14922 at 14935, 61 FR 19476

at 19489), FDA noted its calculation that the proposed changes in the

environmental regulations would reduce the costs for both the regulated

industry and for the agency. These reduced costs will result from,

among other things, providing for categorical exclusions for additional

classes of actions. To this end, the agency proposed and is now making

final two exclusions that will apply to actions on food-packaging

materials (Sec. 25.32 (i) and (j)). As explained above, these

exclusions have been expanded in the final rule to include additional

classes of actions. These changes are expected to further reduce the

costs of preparing and reviewing environmental documents for food-

packaging materials. The agency believes that the remaining actions on

food-packaging materials that require EA's have the potential to result

in significant environmental effects, and information in an EA is

necessary for the agency to make decisions on these potential effects.

34. Proposed Sec. 25.32(k) would categorically exclude actions to

approve food additive, color additive, and GRAS affirmation petitions

for substances added directly to food that are intended to remain in

food through ingestion by consumers and that are not intended to

replace macronutrients in foods. One comment claimed that FDA was

proposing a 1 ppb environmental exposure threshold below which the

exclusion applied, as was done for human drugs in proposed

Sec. 25.31(b). The comment requested that FDA establish a maximum

annual quantity of

[[Page 40582]]

the food additive allowed to be released to the environment under this

exclusion.

The agency declines to establish additional criteria for the

exclusion under Sec. 25.32(k) covering substances that are intended to

remain in food through ingestion by consumers and are not intended to

replace macronutrients in food. As explained in the preamble to the

proposal (61 FR 14922 at 14928, 61 FR 19476 at 19482), the basis for

this exclusion is FDA's experience reviewing 21 petitions in this

class, all of which resulted in a FONSI. The FONSI's relied on one or

more of the following scenarios: (1) The approval of the petition

resulted in very low levels of the substances in either effluents and/

or sewage sludge; (2) the substance was digested and/or metabolized by

humans such that only the products of digestion and metabolism were

expected to be excreted and those products were the same as (or very

similar to) other products of digestion and metabolism resulting from

human food; or (3) the substance was excreted largely intact but was

rapidly degraded into nontoxic products. Based upon this review of

petitions in this class, the agency found that it was not necessary to

establish either an exposure threshold concentration or a maximum

annual quantity of substances allowed to be released. Even in the three

instances where it was necessary to compare the environmental exposure

level of the substance with environmental toxicity data, there was a

wide margin of safety. No information to support the establishment of

either of these qualifying thresholds is provided in the comment.

Therefore, the agency has no basis on which to revise Sec. 25.32(k) to

incorporate either an exposure threshold concentration or a maximum

annual quantity that may be released.

35. An additional comment about the exclusion in proposed

Sec. 25.32(k) expressed concern about the potential for significant

impacts on energy and natural resources resulting from the use and

disposal of nonnutritive oils. This comment recommended that the

proposed exclusion be withdrawn or that a ceiling be added that would

require an EA where such substances enter the environment above a

certain annual level.

The agency declines to amend the proposed exclusion as recommended.

Actions on food additive petitions for nonnutritive oils or fat

substitutes would not qualify for the categorical exclusion in

Sec. 25.32(k), because such substances are considered to be

replacements for macronutrients. An EA submitted for a fat substitute

would include consideration of the impact on energy and natural

resources resulting from the production (if appropriate), use, and

disposal of such substances. Such considerations were part of FDA's

action to approve the use of the fat substitute olestra (Docket No.

87F-0179).

36. Proposed Sec. 25.32(m) would categorically exclude actions to

prohibit or otherwise restrict or reduce the use of asubstance in food,

food packaging, or cosmetics. One comment supported this exclusion, but

requested clarification regarding how FDA will consider under this

exclusion impacts on the environment (to human well-being and on the

environment itself) that are controversial.

As discussed in the preamble to the proposal (61 FR 14922 at 14929,

61 FR 19476 at 19483), the agency has found that this class of actions

has not involved controversial issues with respect to potential impact

on the physical environment. FDA's action to prohibit the use of CFC's

is the only exception to this principle to date.

In most instances, the purpose of actions to restrict or withdraw

approval of foods, food packaging, or cosmetics is to protect the

public health. Potential impacts on human health, and any controversy

surrounding such impacts, are fully considered in Federal Register

documents (e.g., a preamble to a proposed or final rule restricting or

withdrawing approval) supporting the action. See the response to

comment 22, above. The appropriateness of an exclusion for a proposed

action to restrict or eliminate the use of a substance in food, food-

packaging, or cosmetics will depend on whether the action may involve

extraordinary circumstances that would require evaluation through an EA

or an EIS. Under proposed Sec. 25.21, extraordinary circumstances

include the degree to which the possible effects on the human

environment are likely to be highly controversial, as provided in 40

CFR 1508.27(b)(4).

37. Proposed Sec. 25.32(o) would categorically exclude actions to

approve a food additive petition for the intended expression product(s)

present in food derived from new plant varieties. One comment

recommended that compounds that may be ``hormone modulators'' should

not be included in this categorical exclusion.

FDA is not aware of any specific substances derived from new plant

varieties that could potentially affect the endocrine system of other

organisms. It is unlikely that FDA would receive a food additive

petition for a substance derived from new plant varieties that was

intended to have a physiological effect on the human endocrine system.

A substance derived from new plant varieties that is intended to have

such an effect on the human endocrine system would be regulated by FDA

as a drug. Thus, it is unlikely that a claim for categorical exclusion

for a hormone modulator would be made under Sec. 25.32(o) and FDA

declines to modify Sec. 25.32(o) to reflect such a scenario.

In the event FDA receives a food additive petition for a substance

derived from new plant varieties that is known or suspected to have

potential for affecting the endocrine system in humans, aquatic life,

and/or wildlife, agency action on such a petition would generally be

excluded under Sec. 25.32(o). As described in the preamble to the

proposed rule (61 FR 14922 at 14929-14930, 61 FR 19476 at 19483-19484),

under Sec. 25.32(o) environmental review of new plant varieties would

be performed by the United States Department of Agriculture (USDA).

Therefore, if USDA has granted a categorical exclusion or conducted an

environmental review, NEPA review by FDA would be redundant and

therefore, unnecessary.

38. In proposed Sec. 25.32(q), actions to approve a food additive

petition or grant a request for exemption from regulation as a food

additive under Sec. 170.39 are categorically excluded when the

substance that is the subject of the petition or request is registered

by EPA under FIFRA for the same use requested in the petition or in the

request for exemption. One comment stated that the same information

submitted to EPA for registration of pesticides under FIFRA should be

encouraged for FDA submissions. The comment expressed concern about the

lack of policy alignment between agencies regarding the level of risk

and about the ability of FDA to meet deadlines due to its reliance on

the review of data by another agency that may have different review

priorities. The comment suggested that FDA ``handle this proposed

exclusion as a guideline policy rather than a categorical exclusion,''

or align interagency risk determination policies before allowing this

exclusion.

FDA does not agree with the suggestion that the exclusion be

handled as a guideline policy. As discussed in the preamble to the

proposal (61 FR 14922 at 14930, 61 FR 19476 at 19484), FDA has found

that the scope of EPA's review of the environmental risk of

antimicrobial substances subject to pesticide registration under FIFRA

encompasses FDA's review of the environmental risk

[[Page 40583]]

of these substances for food additive use under NEPA. In evaluating

whether a food additive petition or request for exemption meets the

categorical exclusion in Sec. 25.32(q), FDA will ensure that the

substance for which a petitioner seeks approval is identical to the

substance that is registered as a pesticide under FIFRA. If the

substance is registered as part of a formulation under FIFRA, FDA will

ensure that it is approving the substance for use as part of that

formulation registered under FIFRA. By ``same use'' the agency means

that in a comparison of the food additive use to the pesticide use, the

purpose of the use, any components used with the substance for the

petitioned use, and the amount of the substance and the amounts of any

components used with it are substantially identical. FDA has found

that, when these antimicrobial substances are intended for the same

use, its assessment of the environmental risk of antimicrobial

substances is the same as EPA's assessment of the environmental risk of

pesticides and, therefore, the food additive use will be subsumed under

EPA's environmental review of the substance as a pesticide registered

under FIFRA.

In addition to ensuring that the substance is identical to and for

the same use as the registered pesticide, FDA will ensure that the

label for the use of the substance as a food additive includes

information related to the environmental effects, such as precautionary

statements on environmental hazards, that is required on the label for

the use of the substance as a registered pesticide under FIFRA. This

will provide assurance that any adverse environmental effects from the

use of the substance as a food additive have been addressed and are

mitigated, as needed, to the same extent as any adverse environmental

effects from the use of the substance as a pesticide registered under

FIFRA.

In response to the comment that FDA may not be able to meet its

deadlines because of its reliance on review of data by another agency,

nothing in this final rule precludes a petitioner or requester from

submitting an environmental assessment to FDA for review, despite the

fact that the action may be eligible for a categorical exclusion under

Sec. 25.32(q). Moreover, establishing a categorical exclusion for an

antimicrobial substance that is registered as a pesticide with EPA

under FIFRA should not affect FDA's ability to meet its statutory

deadlines for completing the review of food additive petitions that are

eligible for an exclusion under Sec. 25.32(q). In order for a substance

to be eligible for a Sec. 25.32(q) categorical exclusion, the substance

must be registered by EPA as a pesticide under FIFRA for the same use

requested in the petition at the time the food additive petition is

submitted to FDA. Antimicrobial substances that are not registered by

EPA under FIFRA for the same use at the time the food additive petition

is submitted to FDA would not be eligible for a categorical exclusion

under Sec. 25.32(q). Without the pesticide registration, FDA would not

be able to determine whether the use is the same as that in the food

additive petition or request for exemption and therefore eligible for a

categorical exclusion.

As previously mentioned, the scope of environmental review for a

pesticide registration, based on the agency's review of previous

petitions, encompasses FDA's environmental review for the use of the

substance as a food additive. Therefore, the agency does not anticipate

that any additional environmental review would be required for a

petitioned food additive use of a substance that is registered as a

pesticide under FIFRA. However, if the substance is not registered as a

pesticide under FIFRA or the environmental impacts resulting from the

petitioned food additive use or request for exemption are not within

the scope of EPA's environmental assessment performed for the pesticide

registration, FDA's action on the substance would not warrant

categorical exclusion under Sec. 25.32(q), and instead, would require

at least an EA under Sec. 25.20.

3. Veterinary Drugs and Feed Additives

39. Proposed Sec. 25.33(a) would categorically exclude action on an

NADA, abbreviated application, or supplement to such applications, if

the action does not increase the use of the drug. One comment pointed

out that, in its categorical exclusion relating to actions that do not

increase use, FDA uses the term ``active moiety'' when referring to

human drugs in proposed Sec. 25.31(a) and ``drug'' when referring to

animal drugs in proposed Sec. 25.33(a). The comment stated that the

reason for the use of different terms was not apparent, and recommended

that the term active moiety also be used when referring both to human

drugs and animal drugs.

The agency does not agree that the term ``active moiety'' should be

used in Sec. 25.33(a) to describe the actions on animal drugs that are

categorically excluded because for many animal drugs an explicit active

moiety cannot be defined. For example, an animal drug may consist of

biomass which is the purified broth from fermentation manufacturing. In

that case, the animal drug consists of a variety of components but an

``active moiety'' is not explicitly defined. If there is no increase in

the use of an animal drug, it follows that there is no increase in the

level of the substance in the environment and, consequently, no

increase in any associated environmental effects.

40. One comment requested that proposed Sec. 25.33(a) be revised to

categorically exclude actions that do not increase the use and the

concentration of the drug. The comment reasoned that when an animal

drug is administered, the concentration of that drug in the

environment, rather than the fact of ``use,'' has the potential to

raise environmental concerns.

The agency agrees that an increase in concentration has the

potential to raise environmental concern but does not agree that the

addition of the term ``increase concentration'' to the exclusion is

necessary. The primary purpose of the categorical exclusion is to

provide a simple method to identify for drug sponsors which actions

obviously have no significant environmental impacts. An increase in

use, such as an increase in dosage level, an increase in the duration

of use, or the addition of a new indication obviously results in an

increase in the environmental concentration. To help clarify what

actions are categorically excluded under proposed Sec. 25.33(a), the

agency has defined in proposed Sec. 25.5(b)(4) that ``increased use''

may occur if the drug is administered at higher dosage levels, for

longer duration, or for different indications than were previously in

effect, and if the drug is a new molecular entity. The term ``use'' is

further defined to encompass disposal of FDA-related articles. Section

25.33(a) also lists specific examples of the actions that are excluded.

Therefore, the agency believes that the use of the term ``increased

use,'' as defined in Sec. 25.5(b)(4), along with the examples provided,

best describes the criteria for categorical exclusion under proposed

Sec. 25.33(a).

41. In proposed Sec. 25.33(a), change in sponsor is included as one

of the types of actions covered by the categorical exclusion

(Sec. 25.33(a)(5)). One comment requested that FDA reconsider the

inclusion of actions relating to changes in drug sponsors in this

categorical exclusion because such a change may result in manufacturing

or process changes that could cause a difference in end product

chemical profiles. The comment argued that differences in manufacturing

practices may warrant further environmental evaluation.

[[Page 40584]]

The agency reconsidered the proposed categorical exclusion for

changes in drug sponsor but decided to retain the exclusion in the

final rule. A change in sponsor does not necessarily involve a change

in the manufacturing or processing of a drug. In the event that a

change in sponsor results in manufacturing or process changes, it is

not likely that there will be a change in the end product that will

affect the environmental impacts of the drug because a new sponsor must

maintain the same quality, composition, and purity of the drug to

assure that its safety and effectiveness are the same as the product

approved for manufacture by a previous sponsor. Any change that would

result in a change in the chemical profile of the end product would

require a supplement to be filed with the agency. The need for

environmental information would be evaluated by FDA in conjunction with

agency action on that supplement. The exclusion in Sec. 25.33(a) has

been changed to clarify that actions listed ``may'' be excluded if the

actions meet the criteria in the categorical exclusion.

42. In the preamble to FDA's proposed regulations (61 FR 14922 at

14931, 61 FR 19476 at 19485), FDA stated that proposed Sec. 25.33(b) is

being reserved for animal drugs ``not otherwise excluded in

Sec. 25.33(a).'' One comment expressed concern that this statement

regarding Sec. 25.33(b) may inadvertently create confusion about the

actions on animal drugs exclusions in other paragraphs of proposed

Sec. 25.33, especially in proposed Sec. 25.33(d)(5).

FDA can understand how the wording in the preamble (61 FR 14922 at

14931 and 14932, 61 FR 19476 at 19485 and 19486) could be confusing,

but the regulations are explicit about what actions are categorically

excluded. Actions that do not meet the criteria of Sec. 25.33(a) may

still be categorically excluded under Sec. 25.33 (c) or (d), including

Sec. 25.33(d)(5). If the agency adopts criteria for excluding actions

under Sec. 25.33(b) as discussed in the preamble, this will add

additional criteria for excluding actions, it will not restrict the

application of other criteria to exclude actions.

43. One comment suggested that reserved Sec. 25.33(b) should

categorically exclude any action on an NADA, abbreviated application,

or a supplement to such applications, that increases the use of a drug

if the PEC in soil is less than the PNEC, based on a scientifically

valid environmental test conducted with a representative soil organism.

The comment noted that a relatively simple scientific explanation or

calculation would be needed to determine whether an action qualifies

for such an exclusion. The comment defended the use of a scientific

threshold or screening test for a categorical exclusion as appropriate,

citing regulations issued by the Bureau of Indian Affairs (BIA), EPA,

and the Federal Highway Administration (FHWA).

The agency declines to revise the proposed regulations as

suggested. As explained above, the agency stated in the preamble to the

proposal that it was reserving Sec. 25.33(b) to provide for actions

that increase the use of an animal drug when the agency determines a

level at or below which the concentration of the substance in the

environment does not significantly affect the environment. Criteria for

this categorical exclusion would require a relatively simple

calculation using limited available information. The proposed PEC to

PNEC comparison represents more than a simple calculation or

explanation. Ecotoxicity studies are performed, results are compared to

expected environmental concentrations, and a conclusion is drawn (see

the response to comment 26). The agency considers this activity to be

an environmental risk assessment that is more appropriately provided as

part of an EA.

The agency reviewed the BIA, EPA, and FHWA regulations cited in the

comment. The BIA categorical exclusion refers to standards that are

required by the Bureau of Land Management (BLM). To qualify for this

categorical exclusion, an applicant merely states that it is in

compliance with the BLM requirements. No scientific threshold or

screening test is required. The EPA and FHWA citations refer to EPA and

FHWA general categorical exclusion processes and do not include

scientific explanations or calculations.

44. One comment addressed its statements to FDA's description, in

the preamble to the proposal (61 FR 14922 at 14931, 61 FR 19476 at

19485), of the categorical exclusions established in proposed

Sec. 25.33 (a) and (b). The comment stated that the EIC, rather than

the EEC, should be used to determine potential environmental impacts of

veterinary drugs and feed additives. The comment argued that this will

give more weight in determining potential exposures to ``primary

receptors'' before environmental degradation or waste treatment. The

comment also recommended that the evaluation should include potential

human exposure, such as the potential exposure to children assisting in

animal care or living in close proximity to family farm feedlots, at

the EIC.

As explained above in response to comment 43 and in the preamble to

the proposed rule (61 FR 14922 at 14931, 61 FR 19476 at 19485),

Sec. 25.33(a) categorically excludes action on an NADA, abbreviated

application, or supplement to such applications, if the action does not

increase the use of the drug. Proposed Sec. 25.33(b) is reserved and

would be for actions that increase the use of an animal drug if the

agency determines a level at or below which the concentration of the

substance in the environment does not significantly affect the

environment.

The EEC is an appropriate measure to use in evaluating information

in an EA to determine whether an environmental impact is expected. The

EEC provides the most accurate means of determining the concentration

of a substance to which organisms may be exposed. Due to various

factors in the environment, e.g., dilution, binding to particulate

matter, and volatility, the concentration of an introduced compound may

change significantly before it comes into contact with organisms that

may be harmed.

FDA addresses primary receptor issues, such as a child assisting in

animal care or living in proximity to family farm animals, as public

health issues under the act rather than through NEPA evaluation. See

the response to comment 22, above.

45. Proposed Sec. 25.33(d)(5) states that an action on a marketing

application or supplement for an animal drug intended for therapeutic

use under a prescription or veterinary order is categorically excluded

and, therefore, ordinarily does not require an EA or an EIS. One

comment contended that prescription animal drugs that are categorically

excluded under proposed Sec. 25.33(d)(5) could subsequently require an

EA if they become available OTC. The comment assumes this is an

unintended result and that grandfathering would be appropriate. The

comment recommended that proposed Sec. 25.33(d)(5) be revised to

include a statement indicating that an animal drug that was once

categorically excluded should not subsequently require an EA if it

becomes available OTC.

The comment is correct in its assertion that a categorically

excluded prescription animal drug could require an EA when the agency

acts on an application to switch the drug to OTC availability. However,

the comment incorrectly concludes that such a result is anomalous and

unintended. As discussed in the preamble to the proposal (61 FR 14922

at 14932, 61 FR 19476 at 19486), the therapeutic use of an animal drug

under a prescription by a veterinarian results in the drug being

[[Page 40585]]

administered to a limited number of animals for a limited amount of

time. The agency's experience in reviewing EA's for these types of

veterinary products indicates that this limited use results in no

significant environmental impact. The limitations inherent in

prescription use are not found in OTC use. Broader use and greater

introduction of the drug into the environment may occur with OTC

availability. Therefore, the agency believes that prescription to OTC

switches of animal drugs warrant consideration through an EA.

Grandfathering is not appropriate.

46. One comment stressed the importance of interpreting the term

``therapeutic use'' as it is used in the categorical exclusion for

prescription veterinary drugs in proposed Sec. 25.33(d)(5) independent

of the percentage of the herd treated. The comment indicated that if

prescription use were limited to single animal treatment, the section

would cease to be an important measure to reduce the number of EA's.

Prescription animal drugs, by definition under the act, are limited

to use under the professional supervision of a licensed veterinarian

and, thus, are expected to be administered to a limited number of

animals for a limited amount of time. Specifically, products intended

for use by prescription require a veterinarian diagnosis of the disease

or condition to be treated. The nature of this process limits the use

of the prescription product and its introduction into the environment.

Further, administration of the drug product by a veterinarian affords

an added level of control over the use and disposal of the drug

product. All veterinarians are trained on appropriate drug use

procedures. Therefore, allowing a categorical exclusion under these

circumstances is appropriate and the agency does not intend to

interpret therapeutic use, as it pertains to proposed Sec. 25.33(d)(5),

based on the number or percentage of animals treated.

It is important to note that the agency's decision to propose this

categorical exclusion of prescription animal drug products is primarily

based upon its experience in reviewing EA's for these products. The

EA's that comprise the bulk of agency experience in this area are for

products used in terrestrial species. The agency has limited experience

with reviewing drugs that will be used for the treatment of diseases in

fish and other aquatic species. For this reason, the agency is revising

proposed Sec. 25.33(d)(5) to clarify that it applies only to

terrestrial species. The section has been revised to state, ``Drugs

intended for use under prescription or veterinarian's order for

therapeutic use in terrestrial species.''

47. One comment noted that the same experience that led the agency

to categorically exclude prescription animal drugs under

Sec. 25.33(d)(5) could ultimately result in all animal drug products

being excluded regardless of whether they are prescription or over the

counter (OTC), subject to extraordinary circumstances.

FDA will not speculate on future categorical exclusions. The agency

based its decision to categorically exclude prescription animal drugs

intended for therapeutic use on its extensive experience in reviewing

EA's for those products. As the agency gains experience in reviewing

other classes of drug products, additional categorical exclusions may

be proposed. In all instances, FDA will require an EA to be prepared

for products that would ordinarily be categorically excluded if there

are extraordinary circumstances, see Sec. 25.21.

48. Proposed Sec. 25.33(h) would categorically exclude the

withdrawal of approval of a food additive petition that reduces or

eliminates animal feed uses of a food additive. One comment questioned

whether the disposal of nonnutritive oil in animal feed requires a food

additive petition.

The inclusion of nonnutritive oils in animal feeds requires the

submission of a food additive petition and the preparation of an EA.

(See the response to comment 35, above.) The categorical exclusion for

the withdrawal of approval of a food additive petition has no bearing

on whether a food additive petition, and corresponding EA for the

petition, would be required for the nonnutritive oil.

D. Subpart D--Preparation of Environmental Documents

49. Proposed part 25 regulations focus on the use and disposal from

use of FDA-regulated articles, and do not routinely require submission

of information regarding manufacturing sites or a certification of

compliance with Federal, State, and local emission requirements. One

comment recommended that manufacturing and production considerations

continue to be included in the environmental evaluation process and

suggested that FDA consider potential occupational exposures and worker

safety. The comment also expressed concern that by basing some

categorical exclusions, specifically Sec. 25.31(b), on presumed

toxicity of a substance disposed of after use, the agency ``ignores the

very substantial environmental impacts that may arise from

manufacture'' of the product.

Another comment by the same author expressed particular concern

about secondary and tertiary manufacturing processes involving food

additives that may result in uncontrolled end products. The comment

cited as an example a nonnutritive food grade oil that may be

synthesized by a primary producer who then sells it to a secondary

manufacturer for ingredient use in food product processing. The comment

recommended that production of food additives, color additives, and

GRAS substances not be included as a categorical exclusion and that the

environmental impact of secondary or tertiary manufacturing be

considered in an EA. Several related comments recommended that the

production, processing, and disposal of nonnutritive oils, including

the impact of liquid and solid oil components, the effect of processing

on the form of the food additive entering the environment, and the

potential nutritional impact of nonnutritive oils on microorganisms and

invertebrates be included in EA's.

The agency has determined that its environmental evaluation process

need not generally include a review of information on the manufacturing

and production of FDA-regulated products, including food additives,

color additives, and GRAS substances. This determination forms part of

the basis for FDA's establishment of additional categorical exclusions

for certain actions that currently require consideration of production

sites in EA's and is the basis for FDA's decision that, for those

actions requiring an EA, the EA will generally focus on potential

impacts resulting from product use and disposal. Federal, State, and

local environmental protection agencies are responsible for issuing

regulations, permitting and licensing facilities, and enforcing

compliance with those requirements that are necessary to ensure

adequate protection of the environment from emissions resulting from

production operations. Emergency response training and worker safety/

training are under the purview of these agencies and/or the

Occupational Safety and Health Administration (OSHA).

As discussed in the preamble to the proposed rule (61 FR 14922 at

14933, 61 FR 19476 at 19487), after reviewing hundreds of EA's that

contained information regarding manufacturing sites, the agency found

that FDA-regulated articles produced in compliance with applicable

emission and occupational safety requirements will not significantly

affect the

[[Page 40586]]

environment. However, if information available to the agency or the

applicant establishes that a general or specific emission requirement

issued by Federal, State, or local environmental agencies does not

adequately address unique emission circumstances, and the emission may

harm the environment, there would be sufficient grounds for FDA to

request manufacturing information in an EA. Likewise, in accordance

with CEQ regulations (40 CFR 1508.27(b)(10)), any action that threatens

to violate a Federal, State, or local law or other requirement imposed

for the protection of the environment would fall under Sec. 25.21

(Extraordinary circumstances), and an EA would be required for the

proposed action. Thus, although manufacturing site information will not

routinely be requested, there may be specific circumstances that would

require the submission of such information.

Concerning the comment about secondary and tertiary food additive

production sites, FDA usually considers these facilities to be sites of

use. The agency has found, with certain exceptions, that environmental

introductions of food additives, color additives, and GRAS substances

at secondary and tertiary production sites are minimal because these

substances are typically meant to be incorporated into and function in

food, food packaging, or food-contact equipment. Secondary direct food

additives and nonfunctional components of food-packaging materials may,

however, enter the environment at use sites because these additives are

used as processing aids in the production of food and food-packaging

materials, and are not intended to be present in the food or the

finished packaging material. The agency did not propose a new

categorical exclusion specifically for secondary direct additives,

therefore, actions on these types of additives will generally require

an EA. However, the agency notes that actions on certain secondary

direct additives may qualify for exclusion under Sec. 25.32 (j), (q),

or (r), as revised, because they are used as components of the food-

contact surface of permanent or semipermanent equipment or of another

food-contact article intended for repeated use, are pesticides

registered by EPA under FIFRA and subject to FDA's regulatory authority

as food additives for the same use, or are substances that occur

naturally in the environment. As discussed above in response to comment

33, the agency will continue to require EA's for certain actions

involving nonfunctional components of food-packaging materials. The

agency will also require EA's for any normally excluded action if there

are extraordinary circumstances suggesting that the action may have

significant effects at use sites.

Regarding the example in the comment of a nonnutritive food oil,

these actions do not qualify for exclusion under Sec. 25.32(k), as

revised, and require an EA because actions on these types of substances

have the potential for significant environmental effects (see the

responses to comments 35 and 48, above). The EA will take into

consideration the potential effects raised in the comment, including

introductions at all use and disposal sites (see, for example, the EA

and FONSI for FDA's action on the fat substitute olestra (Docket No.

87F0179)).

50. Several comments suggested revisions to proposed Sec. 25.40(a),

which states: ``The EA shall focus on relevant environmental issues and

shall be a concise, objective, and well-balanced document that allows

the public to understand the agency's decision.'' Two comments

recommended the inclusion of a statement that the focus of the

environmental review would be on the use and disposal of FDA-regulated

articles, but not the manufacturing. One comment recommended

substituting the following sentence: ``The EA shall focus on relevant

environmental issues relating to the use and disposal from use of FDA

regulated articles and shall be a concise, objective, and well balanced

document,'' thus eliminating the phrase that the EA shall be ``a

document that allows the public to understand the agency's decision.''

One comment requested additional language stating that manufacturing

site information, including emission information, would not be

required.

The EA formats in current part 25, which have been eliminated in

the proposed rule, focus on an analysis of the use and disposal of FDA-

regulated articles. To clarify the focus of EA's under the proposed

regulations, FDA agrees with the suggestion to amend proposed

Sec. 25.40(a) to state that ``The EA shall focus on relevant

environmental issues relating to the use and disposal from use of FDA-

regulated articles * * * * '' Inclusion in the final regulation of a

statement to the effect that emission information from production sites

is not required in EA's would be contrary to FDA's position, as stated

in the preamble to the proposed rule (61 FR 14922 at 14934, 61 FR 19476

at 19487 and 19488), that when information establishes that emission

requirements promulgated by Federal, State, or local environmental

protection agencies do not address unique emission circumstances and

the emissions may harm the environment, FDA will request manufacturing

information in an EA.

The phrase included in the proposed regulations that an EA should

be ``a document that allows the public to understand the agency's

decision'' is consistent with CEQ environmental policies and objectives

and will not be deleted. NEPA procedures must ensure that environmental

information is available to public officials and citizens (40 CFR

1500.1(b)). Thus, among other things, environmental documents need to

be written in plain language so that the public can readily understand

them (see, e.g., Sec. 1502.8).

51. Proposed Sec. 25.40(a) states that EA's shall include a brief

discussion of alternatives to the proposed action as described by

section 102(2)(E) of NEPA. Proposed Sec. 25.40(a) also states that if

potentially adverse impacts on the environment are identified in the

EA, the EA shall discuss any reasonable alternative course of action

that offers less environmental risk or that is environmentally

preferable to the proposed action. One comment stated that this

requirement ``would only require applicants or petitioners to discuss

`reasonable' alternatives where `potentially adverse environmental

impacts are identified,' '' and, therefore, is inconsistent with 40 CFR

1508.9.

FDA does not believe there is an inconsistency between proposed

Secs. 25.40(a) and 1508.9. EA's are to be concise public documents to

determine whether a more detailed analysis, an EIS, is required

(Sec. 1508.9). A discussion of alternatives other than those which are

``reasonable'' is inconsistent with this overriding principle.

Therefore, FDA is not amending Sec. 25.40(a) in response to this

comment.

52. One comment requested that proposed Sec. 25.40(a) include a

maximum page limit for EA documents.

Because the number or pages for any EA will vary in relation to the

complexity of relevant environmental issues, and such flexibility

should be permitted by the regulations, FDA declines to include in its

regulation a page limit for EA's. CEQ regulations do not specify any

limit on the number of pages in EA's. FDA suggested in the preamble (61

FR 14922 at 14934, 61 FR 19476 at 19488) that, as a general rule, an EA

should normally be no more than 30 pages, not including test reports

and data.

53. The last sentence of proposed Sec. 25.40(a) allows for a tiered

environmental testing scheme that would result in test termination when

[[Page 40587]]

sufficient data are available to suggest that no significant

environmental impact will occur as a result of the potential agency

action. One comment suggested that this sentence be changed to state

that when results of the initial tier of testing indicate that testing

may be stopped, the EA need only contain a certification which states

that a PEC/PNEC calculation has been completed and the ratio of the PEC

to PNEC is less than one.

The agency declines to include the suggested revision. Proposed

Sec. 25.40(a) describes general EA requirements for all FDA-regulated

articles. While a tiered testing approach may be adopted by applicants

and petitioners of all products regulated by the agency, the language

recommended in the comment is limited to human drugs, biologics, and

animal drugs. Thus, the inclusion of the suggested language in

Sec. 25.40(a) is not appropriate. Additionally, as discussed earlier in

response to comment 26, if a PEC/PNEC ratio is used, FDA would need to

review the underlying data that supports the PEC/PNEC ratio.

54. FDA has proposed to remove the EA and abbreviated EA formats

and any reference to the formats currently found in Sec. 25.31a and to

provide appropriate formats in guidance documents. One comment

emphasized that to the extent such guidance documents amend or revise

informational requirements under NEPA, such requirements are

impermissible unless the guidance documents are issued through notice

and comment rulemaking under the Administrative Procedure Act (the APA)

(5 U.S.C. 553), and the agency consults with CEQ to ensure that the FDA

guidance is consistent with NEPA and CEQ requirements.

The APA (5 U.S.C. 553) does not require notice of interpretive

rules, general statements of policy, or rules of agency organization,

procedure, or practice except when notice is required by other statute.

Guidance documents are issued by FDA to provide assistance to the

regulated industry and interested parties by interpreting and

clarifying requirements that have been imposed by statute or

regulation. They reflect the agency's current thinking on the

implementation of its regulatory scheme, and because they are not

binding on industry or on the agency, they do not create requirements.

Consequently, guidance documents are not subject to the notice and

comment rulemaking provisions of the APA.

CEQ regulations (40 CFR 1507.3) encourage agencies to publish

explanatory guidance for their own procedures and to revise them as

necessary to ensure full compliance with the purposes and provisions of

NEPA. Use of guidances provides the agency with greater flexibility to

interpret requirements under its NEPA procedures in a manner that

responds to the evolving nature of environmental science and the needs

of industry and interested parties. In the Federal Register of February

27, 1997, FDA announced its adoption of GGP's, which describes the

agency's policies and procedures for the development, issuance, and use

of guidance documents, including public input in the development of

guidance and publication of a notice of availability. Any further

development of guidance related to FDA's implementation of NEPA will be

developed in accordance with these GGP's. Thus, although guidance

documents that clarify the submission of environmental information to

FDA are not required to undergo the notice and comment rulemaking

procedures of the APA, such guidance documents are subject to public

comment and input under the agency's GGP's. Until guidance documents

are issued in accordance with the GGP's, applicants that need to submit

an EA may follow the EA formats previously published by the agency or

may contact the appropriate center for specific guidance on preparing

the EA.

In the Federal Register of January 11, 1996 (61 FR 1031), FDA

announced the availability of a guidance document entitled, ``Guidance

for Industry for the Submission of an Environmental Assessment in Human

Drug Applications and Supplements.'' That guidance was intended to

assist industry by providing guidance on how to prepare EA's for

submission to CDER under current part 25 as part of NDA's, antibiotic

applications, abbreviated applications, and IND's. In preparing the

``Guidance for Industry for the Submission of an Environmental

Assessment in Human Drug Applications and Supplements,'' CDER consulted

with CEQ and gave CEQ an opportunity to review and comment on the

guidance prior to its issuance. This guidance will be revised, as

necessary, to ensure that the guidance is consistent with this final

rule when it becomes effective. The agency intends to continue its

working relationship with the CEQ in issuing additional guidance

documents under the final rule.

55. Two comments requested that a general format for EA's be

incorporated into proposed Sec. 25.40(a). Both comments expressed

concern that removal of the general format from part 25 may invite

regulatory expansion, i.e., the opportunity for FDA to request more

information.

As explained above and in the preamble to the proposal (61 FR 14922

at 14933, 61 FR 19476 at 19487), the agency, in consultation with CEQ,

has decided that to the extent that EA formats are helpful, they are

more appropriately placed in guidance documents. The formats included

in former part 25 were developed to be applicable to all FDA-regulated

articles. Due to the diverse nature of the products regulated by FDA,

not all format items were relevant to each action. Consequently, some

EA's contained unnecessary information and, in some instances,

information needed to assess the environmental effects of an action was

not initially submitted to the agency. Thus, the formats may be more

appropriately included in guidance documents prepared by each center.

Guidance documents will allow FDA to suggest EA formats that focus on

important environmental issues relating to each type of product

regulated by FDA and will assist the preparer in tailoring individual

EA's to focus on environmental issues specific to the particular

action.

56. Current Sec. 25.31a establishes EA formats for proposed actions

to approve food or color additives, drugs, biological products, animal

drugs, and some medical devices, to affirm food substances as GRAS, and

to grant requests for exemption from regulation as a food additive. One

comment noted that in the prescribed EA format, an applicant or

petitioner is required to identify the natural resources needed to

produce, transport, use and/or dispose of a given amount of any product

which is the subject of the action; to describe measures taken to avoid

or mitigate potential adverse environmental impacts associated with the

proposed action; and to describe in detail the environmental impact of

all reasonable alternatives to the proposed action, including those

that will enhance the quality of the environment and avoid some or all

of the adverse environmental impacts of the proposed action

(Sec. 25.31a(a)). The comment expressed concern that the proposed rule

``completely eliminates'' those obligations as they apply to marketing

applications for paclitaxel derived from the Pacific yew.

Proposed Sec. 25.21 will require an EA for any action, including

one involving natural resources, that is ordinarily excluded if the

action may have a significant effect on the environment. Proposed

Sec. 25.40(a) establishes that an EA shall include a brief discussion

of the need for the proposed action,

[[Page 40588]]

alternatives to it, and environmental impacts of the proposed action

and alternatives. If potentially adverse impacts on the environment are

identified in the EA, the EA shall also discuss any alternative course

of action that offers less environmental risk or that is

environmentally preferable to the proposed action. The agency has

determined that more specific information regarding the nature and

scope of information that should be included in an EA will be provided

in guidance documents rather than through regulatory requirements. Use

of guidance documents will provide the agency with greater flexibility

to implement NEPA in a manner that responds to the evolving nature of

environmental science and the needs of industry and other interested

parties. See the response to comment 54, above. As a result of this

decision, topics to be analyzed in each EA will be discussed and

clarified in guidance documents that will be issued by the center

responsible for the underlying action. Such topics will include the use

of natural resources in the proposed action (if relevant), and a

description of measures that have been taken to avoid or mitigate

adverse environmental impacts that may result from the proposed action.

With regard to marketing applications for drugs involving

paclitaxel derived from the Pacific yew, FDA published a notice in the

Federal Register (61 FR 58694), explaining the extent of environmental

documentation that needs to be submitted to the agency for drug

products containing paclitaxel. See the response to comment 15, above.

Persons interested in the agency's application of NEPA requirements

with regard to paclitaxel and the Pacific yew are encouraged to review

that notice.

57. Proposed Sec. 25.40(d) states that EA's may incorporate by

reference information presented in other documents that are available

to FDA and to the public. One comment recommended that this section be

revised to clarify that other EA's for approved FDA-regulated articles

may be incorporated by reference into an EA.

EA's that are available under the Freedom of Information Act are

public information and therefore may be incorporated by reference into

an EA to the extent that they are relevant to the action addressed in

the EA. Information that is not publicly available but to which an

applicant or petitioner has a right of reference or ownership may also

be incorporated by that applicant or petitioner into an EA. In

accordance with proposed Sec. 25.51(a), however, such confidential

information shall be summarized in the EA to the extent possible. The

agency does not find it necessary to revise the proposed regulation to

further clarify this point.

58. Proposed Sec. 25.40(e) states that the agency evaluates the

information contained in an EA, along with any public input, to

determine whether it is accurate and objective, whether the proposed

action may significantly affect the quality of the human environment,

and whether the agency should prepare a FONSI or EIS. One comment

requested that this section be revised to define and restrict specific

procedures in manufacturing and disposal to effectively prevent

opportunities for some types of environmental release.

Defining and restricting specific procedures in manufacturing and

disposal to prevent pollution are more appropriately handled by

Federal, State, or local environmental protection agencies that have

regulatory authority and more expertise in those matters. However, as

part of FDA's NEPA review process, alternatives and mitigation measures

are considered by FDA.

59. Proposed Sec. 25.43 states that in cases where EIS's are

required, the agency will prepare, at the time of its decision, a

concise public record of decision. One comment asserted that this

section should explicitly address the CEQ provisions governing

limitations on actions during the NEPA process. CEQ regulations (40 CFR

1506.1(b)) require an agency to take appropriate action to ensure that

the objectives and procedures of NEPA are achieved if the agency is

aware that an applicant is about to take an action within the

jurisdiction of the agency that will have adverse environmental impacts

or will limit the choice of reasonable alternatives.

FDA is not required under 40 CFR 1507.3(b), and does not see any

need, to explicitly include in its procedures specific language to

implement 40 CFR 1506.1(b). Because an agency's procedures must

supplement CEQ regulations, all CEQ regulations in 40 CFR parts 1500

through 1508 are incorporated by reference into FDA's policies and

procedures implementing NEPA.

60. Proposed Sec. 25.45 (Responsible agency official) states that

the agency official identified in part 5 as being responsible for the

underlying application or petition is responsible for preparing

environmental documents. One comment suggested that Sec. 25.45 be

revised to require the responsible agency official to be available to

review any questions arising from the preparation of an EA. Two

comments recommended that part 5 be amended to include a provision that

establishes the Center Directors as the responsible officials for

deciding the existence of extraordinary circumstances under proposed

Sec. 25.21 and prohibits redelegation of such authority. One of these

comments also requested revisions to make it clear that any decision by

the Center Director on the question of extraordinary circumstances

constitutes final agency action.

FDA does not find it necessary to revise proposed Sec. 25.45 to

require the responsible agency official to be available to review

questions arising from the preparation of an EA. The FDA official

responsible for preparing environmental documents is available to

review questions concerning environmental issues and to meet with

interested parties (see, e.g., Sec. 10.65 (21 CFR 10.65)). In proposed

Sec. 25.40, FDA specifically encourages interaction between the

responsible agency official and those submitting EA's during the

preparation of the environmental documents.

FDA also declines to amend part 5. Part 5 delegates to specific

agency officials responsibility for taking particular actions on behalf

of the agency. Responsibility for actions on petitions and applications

is generally delegated to the Director or Deputy Director(s) of the

center responsible for reviewing submissions relating to the FDA-

regulated product for which an action is requested. Consistent with

CEQ's policy that the disciplines of those who prepare environmental

documents be appropriate to the scope and issues of the document, see

e.g., 40 CFR 1502.6, the Center Directors delegate responsibility

(e.g., authority to determine extraordinary circumstances and to

mediate conflicts between reviewers and sponsors) to individuals within

their organization who have specialized training and expertise to

evaluate all relevant issues. Individuals in each center who have

training and experience in environmental science and in implementing

environmental statutes are responsible for determining the adequacy of

EA's and claims for categorical exclusion and the existence of

extraordinary circumstances. These individuals are expected to consult

with their supervisors and other management officials as needed.

Specific delegations of responsibility are available to the public

through each center office.

Furthermore, each center has appeals procedures by which decisions

of center personnel can be appealed to the Center Director. The Center

Director's decision does not necessarily, however, constitute final

agency action. A procedure for internal review of agency

[[Page 40589]]

decisions is established in Sec. 10.75(a) (21 CFR 10.75(a)), which

states that a decision of any FDA employee, other than the

Commissioner, is subject to review by the employee's supervisor. Thus,

the proposal that a Center Director's decision necessarily constitutes

final agency action is contrary to FDA regulations and FDA does not

believe that its regulations should be modified.

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

Documents

61. Proposed Sec. 25.50(b) states that many actions performed by

FDA are protected from disclosure by the act, the Trade Secret Act (the

TSA) (18 U.S.C. 1905), and FDA regulations and ``unless the existence

of an application for human drugs * * * has been made publicly

available, the release of the environmental document before approval of

human drugs * * * is inconsistent with statutory requirements imposed

on FDA.'' One comment stated that this provision conflicts with the

requirements of NEPA and CEQ that mandate public involvement at the

earliest possible time. The comment stated that FDA may not completely

abandon NEPA's public participation provisions by broadly invoking

protection under the TSA. The comment stated that at least for NDA's

and ANDA's, FDA clearly has authority to release environmental

documents following issuance of an approvable letter to the applicant.

The comment cited two Federal court cases, Flint Ridge Development Co.

v. Scenic Rivers Association of Oklahoma et al., 426 U.S. 776 (1976)

and Concerned About Trident v. Rumsfeld, 555 F.2d 817 (D.C. Cir. 1977),

to support the proposition that exceptions to NEPA's requirements have

been construed narrowly.

Proposed Sec. 25.50(b) is consistent with NEPA and CEQ regulations.

Section 102 of NEPA (42 U.S.C. 4332)

(D)irects that, to the fullest extent possible: (1) The

policies, regulations, and public laws of the United States shall be

interpreted and administered in accordance with the policies set

forth in [NEPA], and (2) all agencies of the Federal government

shall-- * * * (C) include in every recommendation * * * for * * *

major Federal action significantly affecting the quality of the

human environment, a detailed statement by the responsible official

on--(i) the environmental impact of the proposed action (emphasis

added).

Section 102 of NEPA further requires copies of any such detailed

statement and the comments and views of the appropriate Federal, State,

and local agencies, which are authorized to develop and enforce

environmental standards, to be made available to the President, CEQ,

and to the public as provided in 5 U.S.C. 552. CEQ regulations (40 CFR

1500.6) state that ``the phrase `to the fullest extent possible' in

section 102 means that each agency of the Federal Government shall

comply with that section unless existing law applicable to the agency's

operations expressly prohibits or makes compliance impossible.''

The TSA expressly prohibits any officer or employee of the United

States from publishing, divulging, disclosing, or making known in any

manner or to any extent not authorized by law any information which

concerns or relates to trade secrets, processes, operations, styles of

work, or apparatus, or to the identity, confidential statistical data,

amount or source of any income, profits, losses, or expenditures of any

person, firm, partnership, corporation, or association. The TSA covers

trade secrets as well as confidential commercial or financial

information. Therefore, FDA is prohibited from disclosing trade secrets

and confidential commercial information except to the extent authorized

by law.

Under section 301(j) of the act (21 U.S.C. 331(j)), FDA is

authorized to disclose trade secret information only to the Secretary

of the Department of Health and Human Services or officers or employees

of the Department, courts when relevant in any judicial proceeding

under the act, either House of Congress, or, to the extent of matter

within its jurisdiction, any committee or its subcommittee or any joint

committee of Congress or its subcommittee. FDA is not authorized to

disclose trade secrets to any other parties.

The comment cited two cases. Flint Ridge stands for the proposition

that the only time that a Federal agency can avoid compliance with NEPA

under the ``to the fullest extent possible'' caveat is when a clear and

unavoidable conflict in statutory authority exists, in which case NEPA

must give way. In Concerned about Trident, the Court rejected the

Department of Defense-Navy's attempt to exempt from the mandate of NEPA

strategic military decisions made by the Department of Defense-Navy

because the Navy pointed to no existing specific statutory authority

prohibiting compliance with NEPA in that case or making such compliance

impossible.

Proposed Sec. 25.50(b) is consistent with NEPA's direction to

implement its policies ``to the fullest extent possible,'' as the case

law has interpreted that phrase. In those instances in which the TSA

and section 301(j) of the act prohibit FDA from disclosing

environmental information to the public, compliance with NEPA is

impossible and NEPA must give way. FDA cannot disclose to the public

environmental information prior to taking action to approve certain

marketing applications. Thus, FDA does not contravene NEPA when it

refuses to disclose information in such circumstances.

Furthermore, FDA's procedures comply with NEPA's requirements to

implement NEPA to the fullest extent possible because the procedures

require FDA to review and/or prepare environmental documentation for

any major Federal action before taking the action unless the action

meets criteria for categorical exclusion. Moreover, FDA's procedures

specifically provide that information will be released to the public in

accordance with NEPA when, and to the extent, permitted by the TSA and

other laws governing FDA's operations. Clearly, FDA is not completely

abandoning NEPA's public participation provisions. If FDA is not

prohibited under the TSA and the act from disclosing specific

environmental information before FDA takes action, FDA will disclose

that environmental information at the earliest possible time before

action is taken. To the extent that compliance with the TSA and the act

make impossible disclosure of environmental information before action

is taken, FDA will disclose environmental information after the action

is taken to the extent permitted under the TSA and the act.

Finally, Sec. 25.50 is also consistent with the requirement that

environmental information be made available to the public as provided

in the Freedom of Information Act (the FOIA) (5 U.S.C. 552). Although

the FOIA requires an agency to make available to the public most

information available to the agency, certain matters are exempt from

disclosure. Specifically, the FOIA exempts from disclosure trade

secrets and commercial or financial information that is obtained from a

person and is privileged or confidential.

62. Proposed Sec. 25.52(a) states that if an EIS is prepared for a

drug, animal drug, biologic product, or device, it will become

available to the public only at the time of the approval of the

product. One comment asserted that this provision ``cuts back

significantly on one of the most fundamental requirements of NEPA and

the CEQ regulations--the ability of the public to review and comment on

proposed agency decisions.'' The comment stated that the proposal

``constitutes a complete repeal of the agency's current NEPA

regulations providing for public

[[Page 40590]]

involvement in the EIS process and, as such, it must be rejected.''

The agency disagrees. Proposed Sec. 25.52 does not repeal the

agency's regulations providing for public involvement in the EIS

process but merely clarifies that when there is a clear and unavoidable

conflict between NEPA's public disclosure goals and other laws

governing FDA's disclosure of information, FDA must follow the

disclosure laws that govern its operations. As discussed in response 61

above, the agency is limited in its ability to disclose to the public

information contained within certain marketing applications. The agency

will generally make an EIS available to the public at the time of

approval of the relevant drug, animal drug, biological product, or

device (Sec. 25.52(a)) but, in instances where disclosure of an

application has occurred, the agency will abide by its responsibility

to make a diligent effort to involve the public while concurrently

complying with its own disclosure requirements (Sec. 25.52(c)).

F. Subpart F--Other Requirements

63. Section 25.60 states that in accordance with Executive Order

12114, ``Environmental Effects Abroad of Major Federal Actions,''

January 4, 1979, FDA will consider the environmental effects abroad of

its potential actions. One comment claimed that under this provision,

Executive Order 12114, not NEPA, would govern environmental impacts

that may occur abroad as a result of FDA action. The comment stated

that as a result, FDA's proposal would not govern environmental impacts

associated with harvest of Pacific yew trees in Canada for paclitaxel

marketed in the United States. The comment cited Environmental Defense

Fund v. Massey, 986 F.2d 528 (D.C. Cir. 1993), stating that the Court

of Appeals for the D.C. Circuit rejected the notion that NEPA only

governs activities within the United States.

Executive Order 12114 and proposed Sec. 25.60 (current Sec. 25.50)

have not changed since 1985. Executive Order 12114, ``Environmental

Effects Abroad of Major Federal Actions,'' represents the U.S.

Government's ``exclusive and complete determination of * * * actions to

be taken by Federal agencies to further the purpose of the National

Environmental Policy Act with respect to the environment outside the

United States, its territories, and possessions.'' The agency issued

current Sec. 25.50 to implement this executive order. FDA requirements

include the consideration of potential environmental effects of an

action on a foreign nation, current Sec. 25.50(a)(2) (proposed

Sec. 25.60(a)(2)). In the event the agency action would have a

significant environmental effect on the foreign nation, the agency

official will require additional environmental documentation, current

Sec. 25.50(c) (proposed Sec. 25.60(c)).

In the case cited in the comment, Environmental Defense Fund v.

Massey, 986 F.2d 528, 532 (D.C. Cir. 1993), the court held that the

National Science Foundation must comply with NEPA before going forward

with plans to incinerate food waste in Antarctica. The court expressly

limited its decision to the unique circumstances of Antarctica,

stating, ``we do not decide today how NEPA might apply to actions in a

case involving an actual sovereign.'' (Massey, at 537.) The court did

not rule on the applicability of Executive Order 12114.

The comment's allegation that FDA's proposal would not govern the

environmental impacts associated with the harvest of the Pacific yew in

Canada for paclitaxel marketed in the United States is without basis.

FDA is required to consider the environmental impacts of its actions

either under NEPA or the Executive Order. Executive Order 12114 states

if the responsible official determines that an action may have a

significant environmental effect abroad, the responsible official shall

prepare appropriate environmental documents. Additionally, as discussed

in the response to comment 15, above, FDA issued a notice in the

November 18, 1996, Federal Register explaining the environmental

information to be submitted with marketing applications for drug

products containing paclitaxel.

III. Conforming Amendments

The environmental regulations in part 25 are cited throughout FDA's

regulations. Because FDA is revising part 25, the agency is taking this

opportunity to make conforming amendments to 21 CFR parts 10, 20, 71,

101,170, 171, 312, 314, 315, 511, 514, 570, 571, 601, 812, 813, and 814

to reflect revised part 25. These conforming amendments will ensure the

accuracy and consistency of the regulations.

IV. Analysis of Impacts

FDA has examined the impacts of the final rule under Executive

Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),

and under the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). The Regulatory

Flexibility Act requires agencies to analyze regulatory options that

would minimize any significant impact of a rule on small entities

unless the rule is not expected to have a significant economic impact

on a substantial number of small entities. The Unfunded Mandates Reform

Act (Pub. L. 104-4) requires that agencies prepare an assessment of

anticipated costs and benefits before proposing any rule that may

result in an annual expenditure by State, local, and tribal

governments, in the aggregate, or by the private sector, of

$100,000,000 or more (adjusted annually for inflation). The following

analysis demonstrates that this final rule is consistent with the

principles set forth in the Executive Order and in these two statutes.

The final rule is a significant but not an economically significant

regulatory action under Executive Order 12866 and the rule does not

impose any mandates on State, local, or tribal governments, or the

private sector, that will result in an annual expenditure of

$100,000,000 or more.

Based on the approximate number of EA's that FDA currently receives

each year and the resources needed to prepare them, the agency

estimates that the reduced requirements for submitting EA's will result

in an annual cost savings to industry of approximately $15.7 million.

Two letters received by FDA in response to the proposed rule commented

that the rule would eliminate a majority of EA's that the respondents,

or their members, have been required to submit in the past. These

comments are consistent with the estimate presented here. The basis for

this estimate is as follows:

Human Pharmaceuticals

Approximately 125 EA's related to human pharmaceuticals will be

eliminated annually under the final rule. About one-half of these are

abbreviated EA's; the remainder are full assessments. Based on industry

estimates, FDA assumes that the average cost of preparing an

abbreviated assessment was approximately $40,000, while the average

cost of a full assessment was approximately $200,000. These assumptions

yield a cost savings of about $2.5 million for abbreviated EA's and

$12.5 million for full EA's, for a total savings to industry from the

reduced requirements of EA's relating to human pharmaceuticals of

approximately $15 million per year.

[[Page 40591]]

Veterinary Products

The changes eliminate approximately 37 abbreviated EA's for

veterinary products each year, at an industry-estimated average cost of

approximately $5,000 each. About 77 brief submissions, which currently

require categorical exclusion criteria review, are also eliminated;

these cost an industry-estimated $300 each to prepare. Total cost

savings to the veterinary products industry under the proposal are thus

approximately $208,000 per year.

Food Products

About 39 EA's per year received by the Center for Food Safety and

Applied Nutrition (CFSAN) will be eliminated under the final rule.

Approximately 30 of these would have been abbreviated EA's and 9 would

have been full assessments under current rules. Based on industry

estimates, FDA projects that the cost of producing most abbreviated

EA's for CFSAN is approximately $2,500 and the average cost of

producing a full EA is approximately $50,000. These assumptions imply

an annual cost savings of approximately $75,000 for abbreviated EA's

and $450,000 for full EA's, for a total annual savings to the foods

industry of approximately $525,000.

In addition to these savings to industry, the final rule will

improve FDA efficiency

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