[Federal Register Volume 68, Number 33 (Wednesday, February 19, 2003)]
[Proposed Rules]
[Pages 7951-7956]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-3927]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 349

[Docket No. 80N-145B]
RIN 0910-AA01


Over-the-Counter Ophthalmic Drug Products for Emergency First Aid 
Use; Proposed Amendment of Final Monograph for Over-the-Counter 
Ophthalmic Drug Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
the final monograph for over-the-counter (OTC) ophthalmic drug products 
to include OTC emergency first aid eyewash drug products. These 
products are used to flush or irrigate the eye to remove acid and 
alkali chemicals or particulate contamination. This proposal is part of 
FDA's ongoing review of OTC drug products.

DATES: Submit written or electronic comments by May 20, 2003. Submit 
written or electronic comments on the agency's economic impact 
determination by May 20, 2003. Please see section IX of this document 
for the effective date of any final rule that may publish based on this 
proposal.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Submit electronic comments to http://www.fda.gov/
dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Marina Y. Chang, Center for Drug 
Evaluation and Research (HFD-560), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-2222.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of March 4, 1988 (53 FR 7076), FDA 
published a final monograph for OTC ophthalmic drug products in part 
349 (21 CFR part 349). The monograph provides for eyewash drug products 
in Sec.  349.20, but does not include emergency first aid eyewash drug 
products because there were no submissions or comments on these 
products during the rulemaking process.
    After the final monograph was published, the agency received a 
request for an advisory opinion (Ref. 1) concerning the status of a 
product used for emergency first aid treatment of chemical burns of the 
eyes and skin. This product was described as a sterile phosphate 
buffered solution containing sodium phosphate, USP and monobasic 
potassium phosphate, NF, preserved with edetate disodium, USP 1:2,000 
and benzalkonium chloride, USP 1:5,000, for use immediately following a 
chemical burn to thoroughly flush the eyes and skin for the express 
purpose of removing the chemical irritant, and to relieve the 
discomfort and burning caused by the irritating chemical prior to 
seeking medical treatment.
    As a result, the agency published a request for data and 
information on this category of drugs in the Federal Register of 
December 5, 1989 (54 FR 50240). The agency stated that it was unaware 
of sufficient data to make a determination as to the safety, 
effectiveness, and proper labeling of these ophthalmic drug products. 
Specifically, the agency noted that the majority of these products: (1) 
Are not intended to be marketed directly to individual consumers; (2) 
are often packaged in large volume containers not normally found at the 
retail level of distribution, especially for OTC ophthalmic drug 
products; (3) may be stored for long periods of time under different 
environmental conditions; (4) may be marketed in different types of 
containers and closure systems; and (5) may be used with plumbed, 
nonplumbed, self-contained emergency eyewash, or shower equipment/
stations. The agency noted it was not aware of all of the various 
labeling formats, labeling statements, and formulations of all the 
various emergency first aid eyewash products.
    In response to the request for data and information, three 
manufacturers and one manufacturer's association provided submissions 
(Refs. 2 through 7) that included several journal articles in support 
of the safety and effectiveness of products that provide immediate 
emergency care by neutralization and dilution to the most serious burns 
due to strong acids and alkalis. The submitted literature explained 
that acid burns cause instantaneous coagulation of protein and result 
in limited damage, whereas strong alkalis penetrate the ocular tissues 
rapidly and produce damage that is widespread, uncontrolled, and 
progressive (Ref. 8). The literature (Ref. 2) included a quote from the 
National Institute of Occupational Safety and Health occupational 
health guidelines which states: ``If (chemical) gets into the eyes, 
wash eyes immediately with large amounts of water, lifting the lower 
and upper lids occasionally. Get medical attention immediately.'' The 
comment included an excerpt from the regulations of the Occupational 
Safety and Health Administration (OSHA) entitled ``Requirements for 
Medical and First Aid'' (42 CFR 1910.151). This portion of the OSHA 
regulations assures that workers exposed to injurious corrosive 
materials be provided with ``suitable facilities for quick drenching or 
flushing of the eye.'' One manufacturer also provided sample labeling 
of several marketed products (Ref. 5).

II. Comments Received and the Agency's Responses

A. Neutralization

    Three comments addressed the term ``neutralization.'' One comment 
stated that it removed this term from the principal display panel of 
its product's labeling and replaced it with ``Wash/Flush'' because the 
latter term better expressed the action of the product. Another comment 
considered the term ``neutralization'' to be relative and not absolute. 
The third comment believed that neutralizing was part of the action of 
the product and provided a chart demonstrating the buffering capacity 
of a neutralizer solution towards strong acids and bases versus 
purified water (Ref. 7).
    The agency reviewed available medical literature (Refs. 8 through 
15) and found the treatment of choice for acid and alkali burns listed 
in this literature to be copious and continuous irrigation of the area 
with water or a pH balanced solution for at least 20 to 30 minutes. 
According to the American Academy of Ophthalmology (Ref. 8), ``Specific 
neutralizing agents are not useful; simple dilution (with water or 
saline solution) is the most effective and practical way of 
neutralizing strong chemicals.'' Casarett and Doull's Toxicology: The 
Basic Science of Poisons (Ref. 9) states: ``Attempts to obtain some 
special buffered solution or

[[Page 7952]]

mildly alkaline wash will only delay the start of treatment. Washing 
should begin as close in time and place to the site of the accident as 
possible.'' Conn's Current Therapy 1990 (Ref. 10) states:
    The severity of the chemical burn is related directly to length 
of time that a given agent is exposed to the skin * * *. Exact 
identification of the burning chemical may suggest appropriate 
specific measures; but an acid should not be neutralized with a base 
or vice versa.
    The agency is concerned that attempts to adjust the pH of the 
affected area, such as by testing with litmus paper and then adding 
drops of neutralizing solution, would delay or, at a minimum, reduce 
the vigorous flushing needed to prevent further eye damage. Therefore, 
the agency tentatively concludes that initial treatment is best 
accomplished by copious and continuous amounts of water or saline 
solution. Any attempt to provide a corrective solution, if necessary, 
should be left to health care professionals following transport of the 
accident victim to the facility's first aid station or a hospital. 
Accordingly, the agency considers the term neutralization as 
inappropriate to describe the pharmacological action of these products.

B. Water Lavage

    Four comments emphasized the importance of immediate and continuous 
water lavage for emergency care of the eye following chemical burns. 
The Tulane University Research Report (Ref. 7) compared administration 
of 50 milliliters (mL) of distilled water and a test product, called 
``Neutralize'' (exact formulation not provided), to each eye 10 seconds 
after acid was dropped on the eye. The studies showed no significant 
difference in the rate of healing or in the final condition of both 
eyes.
    The agency agrees that the medical literature and the American 
Academy of Ophthalmology support the use of copious amounts of fluid as 
the best approach for emergency eyewash care. The agency also 
recognizes the value of providing a sterile and stable product in large 
quantities in an industrial setting where flowing water may not be 
available.

C. Container Size and Ease of Opening

    One comment referred to a 32-ounce (oz) container, intended for 
only one use, as having a closure that requires 1\1/4\ turns. The 
comment explained that a 38-millimeter unrestricted opening is 
approximately the diameter needed to cover an average adult eye. The 
comment added that this product is easily opened by a small stature 
adult under stress. The comment noted that a tamper evident plastic 
heat shrink seal that breaks away easily is used.
    All eyewash products must comply with the monograph standards in 
part 349. The products must also meet current good manufacturing 
practices (CGMPs) as stated in 21 CFR parts 210 and 211.
    The agency believes that emergency eyewash products must contain 
enough fluid to permit adequate flushing of the eye. While a maximum 
volume may depend on the configuration of the container or the plumbing 
system, the minimum volume should be no less than 16 oz (473 mL (500 mL 
or 1/2 liter is acceptable)). Because of concerns about sterility, the 
product should be for a single individual's use unless it is part of a 
plumbing system with a one-way valve.

D. pH Adjustment

    Several comments supported the pH range of 6.6 to 7.4 as 
appropriate for these products. One comment mentioned a lack of adverse 
event reports in the many years of use of these products as an 
indicator that the present pH is appropriate. Another comment stated it 
was unlikely that the pH of a product would have a clinically 
significant impact on the outcome of a chemical burn. One comment, 
however, felt that the agency should not require a specific range but 
define the requirement as ``needing to be at or near neutral pH, 6.6 to 
7.4.''
    The agency agrees that 6.6 to 7.4 is an appropriate pH range for 
emergency eyewash solutions. The agency believes this pH range provides 
sufficient flexibility for manufacturers to adjust agents to maintain 
stability, yet provides a solution that does not cause further harm or 
additional irritation to the accident victim. The agency, however, 
agrees that the pH within this range is not likely to impact on the 
outcome of a chemical burn. The agency believes that the inclusion of 
an antimicrobial preservative would aid the stability of the product.
    Accordingly, the agency is proposing the following in new Sec.  
349.22 Emergency first aid eyewashes: ``These products contain water, 
agents to achieve the pH within a range of 6.6 to 7.4, and a suitable 
antimicrobial preservative agent.''

E. Buffering

    One comment noted that buffering is an added feature to help 
neutralize the chemical burn but that both buffered and unbuffered 
solutions can be extremely beneficial to achieve dilution and 
neutralization because the main treatment is by dilution. Another 
comment added that buffers help ensure product integrity during storage 
in an industrial setting, while another comment was unaware of any 
superiority of either buffering or not buffering.
    The product that led to the request for data was described as a 
sterile phosphate buffered solution (Ref. 1) for use immediately 
following a chemical burn to thoroughly flush the eyes and skin for the 
express purpose of removing the chemical irritant, and to relieve the 
discomfort and burning caused by the irritating chemical prior to 
seeking medical treatment. The comment provided excerpts from studies 
presented in a Tulane University Research Report (Ref. 7) to 
demonstrate the superiority of its product when compared to water as an 
emergency first aid eyewash to treat a caustic acid splash.
    The agency notes that a medical dictionary (Ref. 16) defines 
``buffering'' as ``a chemical system that prevents change in 
concentration of another chemical substance, e.g., proton donor and 
acceptor systems serve as buffers preventing marked changes in hydrogen 
ion concentration (pH).'' The agency acknowledges the buffer system 
contributes to the tonicity of the ophthalmic product but adds that the 
tonicity of the entire formulation should approximate lacrimal fluids.
    The agency agrees with the comment that stated it was unaware of 
any superiority of either buffering or not buffering these products. 
Accordingly, the agency is proposing in Sec.  349.22 that emergency 
first aid eyewash products may contain agents for buffering the pH.

F. Phosphate Treatment of Chemical Burns

    One comment provided references to support ``phosphate therapy'' to 
treat burns caused by acidic or basic substances (Ref. 1). The 
references reported a phosphate buffer is prepared by dissolving 70 
grams (g) of monobasic potassium phosphate 
(KH2PO4) and 180g of dibasic sodium phosphate 
(Na2HPO4.12 H2O) in 850 mL of water. 
The concentration of the solution is molar with respect to phosphate, 
but as the phosphates are physiologically occurring substances they can 
be safely employed in such high concentrations and provide prompt 
neutralization. The comment contended that some antidotes are too 
acidic or alkaline; that burns caused by acids or bases require 
different treatment; and that the phosphate buffer is neutral in its 
reaction, and thus is well suited for the treatment of injuries caused 
by acidic or basic chemicals.

[[Page 7953]]

    At this time, the agency considers a phosphate buffered solution 
acceptable for emergency first aid eyewash products. The increased 
concentration of phosphates would not alter the pH range but could be 
more effective against an acid or alkali burn.

G. Industrial Glare

    One comment briefly referred to emergency first aid eyewash 
solutions to treat industrial glare (i.e., from welder's arc) but did 
not provide any data to support this use. At this time, the agency is 
not including this use as an indication for these products without 
adequate supporting documentation. The agency requests interested 
parties to provide supporting data.

H. Five to 15-gallon Container Plus Preservative Concentrate

    One comment explained that a 15-minute emergency eyewash requires 
14 gallons (gal) of potable water and a 5-minute eyewash requires 9 1/2 
gal of potable water. The comment stated that the unit would be filled 
with potable water and the preservative concentrate added. The comment 
offered that a concentrate will preserve 5 to 20 gal of potable water 
for up to 180 days. The comment further stated that potable eyewash 
units should be flushed and cleaned and the water and concentrate 
replaced every 60 days.
    All emergency eyewash products must be able to meet monograph 
requirements, which include safety and effectiveness, a pH range of 6.6 
to 7.4, and compliance with CGMPs. The agency is aware that there are 
preservative concentrates in the marketplace for use in potable eyewash 
units, as the comment noted. Under Sec.  349.82(d)(3), the agency is 
proposing that the labeling contain the word ``concentrate'' in bold 
type. The labeling must provide adequate directions for adding the 
concentrate to potable water to obtain a solution that meets the 
requirements of Sec.  349.22. The directions should also state that the 
concentrate should be added to potable water to have a fully 
constituted solution available in advance of an emergency. The agency 
is unaware of data to support the length of time that any particular 
preservative concentrate is safe and effective. Manufacturers of these 
products are advised to follow CGMPs.

I. Labeling

    One comment proposed several labeling revisions under Sec.  349.78. 
Under Sec.  349.78(a), the comment added to the statement of identity 
the terms ``neutralizer'' and ``neutralizing solution.''
    As stated in section II.A of this document, the agency does not 
believe that the term ``neutralize'' properly describes the action of 
these products and, therefore, is not proposing this term or any 
variation of this term in the monograph.
    Under Sec.  349.78(b)(1) and (b)(2), the comment added the terms 
``acid'' and ``alkali.'' Under Sec.  349.78(b)(5), the comment provided 
for indications for eyes that have been subjected to industrial glare 
such as welder's arc and ``other workplace irritants.'' The comment 
argued that demulcents have a long history of use for soothing the 
burning sensation associated with welder's arc and other workplace 
irritants that dry the eye. The comment explained that this indication 
is an extension of Sec.  349.60(b)(2), which provides for temporary 
relief due to exposure to the sun.
    The agency agrees that if an emergency first aid eyewash will 
assist in the prevention of permanent damage to the eye(s) due to 
industrial glare, this indication should be included in the uses 
section of the labeling. However, as stated in section II.G of this 
document, the agency needs supporting documentation for this use.
    The agency believes the term ``particulate contamination'' is a 
general term that could include the comment's request for an indication 
for ``other workplace irritants.'' The agency agrees that there are 
potential instances in the industrial setting where particulate matter 
could cause eye damage and that an eyewash solution could alleviate the 
seriousness of the condition. Accordingly, the agency is proposing the 
terms ``acid,'' ``alkali,'' and ``particulate contamination'' in new 
Sec.  349.82(b) as examples of causes of injury.
    Under Sec.  349.78(d)(3), the comment suggested the following 
directions for emergency first aid eyewash products:
    For eyewash products packaged in a container that also serves as 
an eyecup. Remove safety seal and cap. Avoid contamination of rim of 
bottle. Place rim over affected eye, pressing tightly to prevent the 
escape of the liquid, and tilt the head backward. Open eyelid wide 
and rotate eyeball to ensure thorough bathing with the solution. Use 
only unopened bottle on the eyes.
The comment explained that many large volume (up to 32 oz) first aid 
eyewash solutions are packaged in containers with wide flanged rims 
that fit over the eye.
    The agency agrees that containers that also serve as eyecups should 
be addressed in the monograph and is including this information, with a 
few modifications, in Sec.  349.82(d)(1). The agency notes that eyecups 
generally promote retention of material that may be injurious to the 
eye instead of allowing the injurious material to be washed away and 
down the face. The use of eyecups in the setting of workplace irritants 
should be discouraged. The agency also obtained and reviewed 
representative current labeling for a number of these products (Ref. 
17) to develop the labeling in this proposal.

III. The Agency's Proposal

    The agency tentatively concludes that the references support the 
safety and effectiveness of emergency first aid eyewash drug products 
to remove acid or alkali chemicals and that, in particular, immediate 
flushing of the eye with fluid is urgently needed to lessen the impact 
of the alkalis. The agency also acknowledges that burns from alkalis 
penetrate the ocular tissues rapidly and produce damages that are 
widespread, uncontrolled, and progressive. However, the agency does not 
believe that a chemical irritant should be counteracted with another 
chemical. The agency believes that immediate and copious irrigation 
with fluid is the most important step and that the amount of time prior 
to irrigation is a critical factor in determining the amount of 
residual damage.
    The effectiveness of an emergency eyewash appears dependent upon 
the steady flow of copious amounts of fluid to the injured eye(s). 
Emergency first aid eyewashes serve as an interim step in first aid 
care by providing immediate flushing of the eye and allowing the 
accident victim to be transported to the facility's first aid station 
or a hospital while the flushing treatment is in progress. Accordingly, 
the agency is proposing to amend the final monograph for OTC ophthalmic 
drug products to include a section on emergency first aid eyewashes.

IV. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 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). Under the

[[Page 7954]]

 Regulatory Flexibility Act, if a rule has a significant economic 
impact on a substantial number of small entities, an agency must 
analyze regulatory options that would minimize any significant impact 
of the rule on small entities. Section 202(a) of the Unfunded Mandates 
Reform Act requires that agencies prepare a written statement of 
anticipated costs and benefits before proposing any rule that may 
result in an expenditure in any one year by State, local, and tribal 
governments, in the aggregate, or by the private sector, of $100 
million (adjusted annually for inflation).
    The agency believes that this proposed rule is consistent with the 
principles set out in Executive Order 12866 and in these two statutes. 
In addition, the proposed rule is not a significant regulatory action 
as defined by the Executive order. The Unfunded Mandates Reform Act 
does not require FDA to prepare a statement of costs and benefits for 
this proposed rule because the proposed rule is not expected to result 
in any 1-year expenditure that would exceed $100 million adjusted 
annually for inflation. The current inflation adjusted statutory 
threshold is approximately $110 million.
    With respect to the Regulatory Flexibility Act, FDA does not 
believe that the proposed rule would have a significant economic impact 
on a substantial number of small entities. However, the agency 
recognizes the uncertainty of its estimates with respect to the number 
of affected small entities as well as the economic impact of the rule 
on those small entities. The agency therefore requests detailed public 
comment regarding any substantial or significant economic impact that 
this rulemaking would have on manufacturers of OTC emergency first aid 
eyewash drug products.
    The purpose of this proposed rule is to amend the final monograph 
for OTC ophthalmic drug products to include OTC emergency first aid 
eyewash drug products. This proposed rule may increase OTC availability 
of these products and may, as a result, lower the costs to industrial 
facilities and individuals that use such products.
    Manufacturers of the affected products should incur only minor 
costs to relabel their products to meet the monograph requirements. 
These manufacturers can make the required changes whenever they are 
ready to order new product labeling within the 12 months after the 
final rule is issued. Manufacturers of products with annual sales of 
less than $25,000 will have 24 months to complete the required 
relabeling. The agency has been informed that this type of relabeling 
generally costs approximately $3,000 to $4,000 per stockkeeping unit 
(SKU) (i.e., individual products, packages, and sizes). The agency 
estimates that there are approximately 25 manufacturers or marketers of 
40 to 45 products and 50 to 60 SKUs that would be affected by this 
proposed rule.
    Based on this information, the total one-time costs of relabeling 
would be between $150,000 ($3,000 per SKU x 50 SKUs) and $240,000 
($4,000 per SKU x 60 SKUs). Assuming an equal distribution of these 
costs across the 25 affected entities results in an average cost burden 
of $6,000 to $9,600 per firm. The agency believes that actual costs 
would be lower for several reasons. First, most of the required changes 
will be made by private label manufacturers that tend to use relatively 
simple and less expensive labeling. Second, the agency is proposing a 
12-month implementation period that would allow manufacturers to 
coordinate the required changes with routinely scheduled label printing 
and/or revisions. Labeling changes for these products would not be 
required until 12 months after the monograph amendment is issued as a 
final rule and becomes effective. Furthermore, products with less than 
$25,000 per year in sales would not need to be relabeled until 24 
months after the rule becomes final. Thus, manufacturers would have 
time to use up existing labeling stocks and plan for new labeling, 
thereby mitigating some of the costs of this proposed rule. Third, 
manufacturers may be able to implement the new labeling required by 
this proposal at the same time that they implement the new standardized 
format and content labeling required by 21 CFR 201.66. Thus, the total 
relabeling costs associated with two different but related final rules 
may be reduced by implementing the required changes at the same time.
    According to standards established by the Small Business 
Administration, a small pharmaceutical preparations manufacturer (NAICS 
code 325412) employs fewer than 750 people. FDA has determined that 
approximately 88 percent (22 out of 25) of OTC ophthalmic drug product 
manufacturers meet these criteria and can therefore be categorized as 
small entities. The average annual revenue of small entities affected 
by this rule was found to be approximately $10.7 million. Thus, the 
cost of the rule per affected small entity would be between 0.056 
percent ($6,000 / $10.7 million) and 0.09 percent ($9,600 / $10.7 
million) of average annual revenues. FDA is aware of one small entity 
that has average annual revenues of approximately $1 million and 
produces 3 SKUs. The total cost of the final rule for this small entity 
would be between 0.9 percent (3 SKUs x $3,000 per SKU / $1 million) and 
1.2 percent (3 SKUs x $4,000 per SKU / $1 million) of annual revenues. 
Thus the economic impact of the proposed rule on the majority of small 
entities is expected to be much less than 1 percent of annual revenues. 
While these estimates are uncertain, it appears that this proposed rule 
would not have a significant economic impact on a substantial number of 
small entities.
    The agency considered but rejected several alternatives: (1) A 
shorter or longer implementation period, and (2) an exemption from the 
requirements for small entities. While the agency believes that 
industries and accident victims who use these products would benefit 
from having the new labeling in place as soon as possible, the agency 
also acknowledges that coordination of the labeling changes with 
implementation of the new OTC ``Drug Facts'' labeling may significantly 
reduce the costs associated with this proposed rule. Thus, an 
alternative specifying a shorter implementation period was rejected due 
to its inflexibility and potentially greater cost. A longer 
implementation period was also rejected because it would unnecessarily 
delay the benefits of new labeling and revised formulations, where 
applicable, to parties who use these OTC drug products. The agency also 
rejected an exemption for small entities because the new labeling and 
revised formulations, where applicable, would also generate benefits 
for parties who purchase products marketed by those entities. 
Furthermore, the vast majority of firms affected by this proposed rule 
can be classified as small entities. However, an additional year is 
being allowed for products with annual sales of less than $25,000 to 
implement the required changes in order to reduce the potential impact 
of the rule on small entities.
    This proposed rule allows for continued marketing of affected 
products without the risk of regulatory action provided the following 
conditions are met: (1) The product or similarly formulated and labeled 
products were marketed as OTC drugs at the inception of the OTC drug 
review on May 11, 1972, a date that was later extended to on or before 
December 4, 1975 (see 21 CFR 330.13); (2) such product does not 
constitute a hazard to health; (3) the product formulation is not 
regarded to be a prescription drug within the meaning of section 503(b) 
of the Federal Food, Drug, and Cosmetic

[[Page 7955]]

Act (21 U.S.C. 353(b)); (4) the product is an OTC drug and does not 
bear claims for serious disease conditions that require the attention 
and supervision of a licensed practitioner.
    Emergency first aid eyewash products and eye irrigating solutions 
that do not meet the previous criteria may not be marketed OTC pending 
evaluation of these products for the treatment of chemical burns and 
for irrigation of the eye(s) unless the product is the subject of an 
approved new drug application (NDA).
    This analysis of impacts shows that the proposed rule is not 
economically significant under Executive Order 12866 and that the 
agency has undertaken important steps to reduce the burden to small 
entities. This analysis of impacts, together with other relevant 
sections of this document, serves as the agency's initial regulatory 
flexibility analysis, as required by the Regulatory Flexibility Act. 
The agency will reassess the economic impact of this rulemaking in the 
preamble to the final rule.

V. Paperwork Reduction Act of 1995

    FDA tentatively concludes that the labeling requirements proposed 
in this document are not subject to review by the Office of Management 
and Budget because they do not constitute a ``collection of 
information'' under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 
et seq.). Rather, the proposed labeling statements are a ``public 
disclosure of information originally supplied by the Federal government 
to the recipient for the purpose of disclosure to the public'' (5 CFR 
1320.3(c)(2)).

VI. Environmental Impact

    The agency has determined under 21 CFR 25.31(a) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
the agency tentatively concludes that the proposed rule does not 
contain policies that have federalism implications as defined in the 
Executive order and, consequently, a federalism summary impact 
statement has not been prepared.

VIII. Request for Comments

    Interested persons may submit to the Dockets Management Branch (see 
ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments to http://www.fda. gov/
dockets/ecomments or three hard copies of any written comments, except 
that individuals may submit one hard copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document and may be accompanied by a supporting memorandum or 
brief. Received comments may be seen in the Dockets Management Branch 
between 9 a.m. and 4 p.m., Monday through Friday.

IX. Proposed Effective Date

    FDA is proposing that any final rule that may issue based on this 
proposal become effective 12 months after its date of publication in 
the Federal Register.

X. References

    The following references are on display in the Dockets Management 
Branch (see ADDRESSES) under Docket No. 80N-145B and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Comment No. AP.
    2. Comment 1.
    3. Comment 2.
    4. Comment 3.
    5. Comment 4.
    6. Comment 5.
    7. Comment 6.
    8. ``External Disease and Cornea,'' 1989-1990, Basic and 
Clinical Science Course, American Academy of Ophthalmology, San 
Francisco, CA, pp. 130-133, 1989.
    9. Potts, A. M., ``Toxic Responses of the Eye,'' Casarett and 
Doull's Toxicology: The Basic Science of Poisons, 3d ed., Macmillan 
Publishing Co., New York, NY, pp. 478-485, 1986.
    10. Raker, R. E., Conn's Current Therapy 1990, W. B. Saunders 
Co., Philadelphia, PA, p. 1035, 1990.
    11. Dreisbach, R. H., and W. O. Robertson, ``Emergency 
Management of Poisoning,'' Handbook of Poisoning: Prevention, 
Diagnosis & Treatment, 12th ed., Appleton & Lange, Norwalk, CT, pp. 
28-29, 1987.
    12. Siverston, K. T., ``Ocular Toxicity,'' Manual of Toxicologic 
Emergencies, Year Book Medical Publishers, Inc., Chicago, IL, pp. 
115-118, 1989.
    13. Tapley, D. F. et al., ``The Eyes,'' The Columbia University 
College of Physicians and Surgeons Complete Home Medical Guide, 
Crown Publishers, Inc., New York, NY, pp. 696-697, 1989.
    14. Behrman, R. E., and V. C. Vaughan, ``Injuries to the Eye,'' 
Nelson Textbook of Pediatrics, 13th ed., W. B. Saunders Co., 
Philadelphia, PA, pp. 1472-1473, 1987.
    15. ``Occupational Health Guidelines for Ethyl Chloride,'' 
National Institute for Occupational Safety and Health, pp. 1-4, 
September 1978.
    16. Dorland's Illustrated Medical Dictionary, 27th ed., W. B. 
Saunders Co., Philadelphia, PA, p.252, 1988, s.v. ``buffer.''
    17. Comment 7.

List of Subjects in 21 CFR Part 349

    Labeling, Over-the-counter drugs.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 349 be amended as follows:

PART 349--OPHTHALMIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

    1. The authority citation for 21 CFR part 349 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    2. Section 349.22 is added to subpart B to read as follows:


Sec.  349.22  Emergency first aid eyewashes.

    These products contain water, agents to achieve the pH within a 
range of 6.6 and 7.4, and a suitable antimicrobial preservative agent. 
Additionally, they may contain tonicity agents to establish isotonicity 
with tears and agents for buffering the pH.

    3. Section 349.82 is added to subpart C to read as follows:


Sec.  349.82  Labeling of emergency first aid eyewash drug products.

    (a) Statement of identity. The labeling of the product identifies 
the product with one of the following: ``Emergency first aid eyewash,'' 
``First aid eye rinse,'' or ``Emergency eyewash.''
    (b) Indications. The labeling of the product states, under the 
heading ``Uses'', ``for'' [select one of the following: ``flushing,'' 
or ``irrigating''] ``the eye to reduce chances of severe injury caused 
by acid, alkali, or particulate contamination''.
    (c) Warnings. In addition to the warnings in Sec.  349.50 (the 
``Replace cap after using,'' warning in Sec.  349.50(c)(1) should only 
be used if applicable), the labeling of the product contains the 
following warnings under the heading ``Warnings'' for all emergency 
eyewash products:
    (1) ``Do not use [in bold type] [bullet]\1\ for injection [bullet] 
in intraocular surgery [bullet] internally [bullet] if

[[Page 7956]]

solution changes color or becomes cloudy''.
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    \1\ See Sec.  201.66(b)(4) of this chapter for definition of 
bullet symbol.
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    (2) ``Ask a doctor if you have [in bold type] [bullet] eye pain 
[bullet] changes in vision [bullet] redness or irritation of the eye 
after use [bullet] an injury caused by an alkali''.
    (d) Directions. The labeling of the product states, as appropriate, 
under the heading ``Directions'', ``[bullet] do not dilute solution or 
reuse bottle [in bold type] [bullet] hold container a few inches above 
the eye [bullet] control rate of flow by pressure on bottle [bullet] 
flush affected area for a minimum of 20 minutes [bullet] continue 
flushing with water if necessary [bullet] obtain medical treatment''.
    (1) For products packaged in a container that also serves as an 
eyecup. The labeling states ``[bullet] use only unopened bottle 
[bullet] remove safety seal and cap [bullet] avoid contamination of rim 
of bottle [bullet] place rim over affected eye [bullet] tilt head 
backward [bullet] open eyelids wide [bullet] throughly bathe eye with 
solution [bullet] allow solution to flow away from eye''. The 
directions in this paragraph shall be placed in sequence with the 
directions provided in paragraph (d) of this section, as appropriate.
    (2) For products intended for use with a nozzle applicator. The 
labeling states ``[bullet] flush affected eye as needed [bullet] 
control flow of solution by pressure on bottle''.
    (3) For products that use a concentrate with potable water. The 
word ``concentrate'' shall be in bold type. Labeling must provide 
adequate directions for adding the concentrate to potable water to 
obtain a solution that meets the requirements of Sec.  349.22. The 
directions shall also state that the concentrate should be added to 
potable water to have a fully constituted solution available in advance 
of an emergency.

    Dated: January 31, 2003.
Margaret M. Dotzel,
Assistant Commissioner for Policy.
[FR Doc. 03-3927 Filed 2-18-03; 8:45 am]
BILLING CODE 4160-01-S