[Federal Register: February 22, 2007 (Volume 72, Number 35)]
[Proposed Rules]               
[Page 7941-7945]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr22fe07-13]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 352

[Docket No. 2006N-0479]
RIN 0910-AF43

 
Insect Repellent-Sunscreen Drug Products for Over-the-Counter 
Human Use; Request for Information and Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Request for data and information.

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SUMMARY: The Food and Drug Administration (FDA) is seeking information 
to formulate a regulatory position on insect repellent products that 
contain over-the-counter (OTC) sunscreen ingredients. FDA is 
considering amending its monograph for OTC sunscreen drug products (the 
regulation that establishes conditions under which these drug products 
are generally recognized as safe and effective and not misbranded) to 
add conditions for marketing insect repellent-sunscreen drug products. 
The insect repellent ingredients in these products are regulated by the 
Environmental Protection Agency (EPA). Elsewhere in this issue of the 
Federal Register is a companion document in which EPA is also 
requesting information and comments on these products. The decision on 
what regulations, if any, to propose will be based, in part, on 
information and comments submitted in response to this request for data 
and information.

DATES: Submit written or electronic comments by May 23, 2007.

ADDRESSES: You may submit comments, identified by Docket No. 2006N-0479 
or RIN 0910-AF43, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov. 

Follow the instructions for submitting comments.
     Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments. 

Follow the instructions for submitting comments on the agency Web site.

Written Submissions

    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No. and Regulatory Information Number (RIN) for this 
rulemaking. All comments received will be posted without change to 
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm, including any personal 

information provided. For additional information on submitting 
comments, see the ``Comments'' heading of the SUPPLEMENTARY INFORMATION 
section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm 

and insert the docket number, found in brackets in the heading of this 
document, into the ``Search'' box and follow the prompts and/or go to 
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Matthew R. Holman, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, MS 5411, Silver Spring, MD 20993, 301-796-
2090.

SUPPLEMENTARY INFORMATION:

I. Background

A. Description of Insect Repellent-Sunscreen Drug Products

    FDA and EPA are seeking information to formulate a regulatory 
position for combination insect repellent-sunscreen drug products for 
use on human skin. Because sunscreen drug products are regulated by FDA 
and the insect repellent components of these products are separately 
regulated by EPA, both agencies are seeking comments to

[[Page 7942]]

determine how these combination products should be regulated.
    Currently, approximately 20 combination insect repellent-sunscreen 
drug products are available for consumers. These products consist of 
one of three insect repellents (N,N-diethyl-meta-toluamide (DEET), oil 
of citronella, or IR3535) and a sunscreen component (one or more 
sunscreen ingredients). Combination insect repellent-sunscreen drug 
products are available in lotion, cream, and spray-on formulations and 
are currently marketed for use by the entire family. Due to concerns 
about the potential conflict in the directions for use and other 
labeling requirements for the insect repellent and the sunscreen 
components of the product, EPA postponed a regulatory decision on 
combination DEET/sunscreen products in its Reregistration Eligibility 
Decision (RED) for DEET (December 1998) until additional information 
could be obtained. This document solicits opinion and comment from the 
public to assist both agencies in regulating these products.

B. Regulatory Status of the Insect Repellent Ingredients

    EPA regulates insect repellents under the Federal Insecticide, 
Fungicide, and Rodenticide Act (FIFRA). Three insect repellent active 
ingredients are currently used in combination with sunscreens: DEET, 
oil of citronella, and IR3535. EPA recently registered two other insect 
repellents, p-menthane-3,8-diol and picaridin. However, neither is 
currently available in combination with a sunscreen. Both DEET and oil 
of citronella have undergone reregistration, which entailed an 
evaluation and analysis of the complete database for each ingredient by 
EPA. IR3535, p-menthane-3,8-diol, and picaridin are registered 
chemicals evaluated by the registration process, which involves a 
similar analysis by EPA. They have not yet undergone the reregistration 
analysis.
1. DEET
    In December 1998, EPA completed its RED for DEET (Ref. 1), which 
includes the active ingredient N,N-diethyl-meta-toluamide and its 
isomers. DEET products, which are applied directly to skin and/or 
clothing, are available in numerous formulations (e.g., aerosol and 
non-aerosol sprays, creams, lotions, sticks, foams, and towelettes) and 
concentrations (products range from about 4 percent to 100 percent 
active ingredient). DEET is an insect and mite repellent labeled for 
use in households/domestic dwellings, on the human body and clothing, 
on cats, dogs, and horses, and in pet living/sleeping quarters.
    Based on pesticide usage information mainly for 1990 (Ref. 1), an 
average annual estimate of the domestic usage of DEET is 4 million 
pounds (active ingredient). About 30 percent of the U.S. population 
uses DEET annually as an insect repellent (this figure includes about 
27 percent of adult males, 31 percent of adult females, and 34 percent 
of children). Approximately 21 percent of U.S. households use DEET 
annually. About 19 percent of households use DEET on household members, 
and about 4 percent of households that have cats and/or dogs use DEET 
on those pets.
    EPA indicated in its DEET RED (Ref. 1):
    The Agency is concerned about consumer use of products that 
combine sunscreen and DEET, since directions to reapply sunscreens 
generously and frequently may promote greater use of DEET than 
needed for pesticidal efficacy and thus pose unnecessary exposure to 
DEET. DEET labels currently recommend that products be used 
sparingly and not be reapplied too often. Sunscreen products, 
however, recommend frequent reapplication. No benefits attach to use 
of DEET more frequently than necessary to achieve its purpose.
    EPA did not make a regulatory decision regarding these DEET-
sunscreen products at that time because it believed that it had not yet 
obtained adequate information.
2. Oil of Citronella
    In February 1997, EPA completed its RED for Oil of Citronella (Ref. 
2). This decision includes a comprehensive reassessment of the required 
target data and the use patterns of currently registered oil of 
citronella products. Oil of citronella is a biochemical pesticide. It 
is registered as an animal repellent and as an insect repellent/feeding 
depressant. Oil of citronella is the volatile oil obtained from the 
steam distillation of freshly cut or partially dried grasses 
(Cymbopogon nardus (Rendal) and Cymbopogon winterianus (Jowitt)). Two 
varieties of citronella oil exist commercially: ``Ceylon type'' 
(derived from C. nardus) and ``Java type'' (derived from C. 
winterianus).
    Based on pesticide survey usage information for 1991 and 1992 (Ref. 
2), annual oil of citronella domestic usage ranged approximately from 
33,000 to 48,000 pounds active ingredient for four sites: Domestic 
dwellings; ornamentals; human face, skin, and clothing; and 
manufacturing. The largest markets, in terms of total pounds active 
ingredient, for oil of citronella as an insect repellent are: Human 
face, skin, and clothing (56 to 74 percent); domestic dwelling 
[outdoor] (22 to 41 percent); and ornamentals (1.5 to 2.0 percent). The 
balance is used for manufacturing.
    In the RED (Ref. 2), EPA required all oil of citronella products 
with label claims for repelling mosquitoes, fleas, and ticks to have a 
minimum protection time of 1 hour. The directions for use must also 
contain the following statement pertaining to maintenance of repellent 
activity: ``For maximum repellent effectiveness of this product, repeat 
applications at 1 hour intervals.'' The RED allows the labeling to 
claim a protection time longer than 1 hour so long as it can be 
supported by product performance data showing an acceptable level of 
repellent activity. Because the principal uses of oil of citronella are 
dermal, special precautionary labeling related to dermal sensitization 
and irritation is required for all products with use directions for 
dermal application. EPA (Ref. 2) requires oil of citronella-sunscreen 
products for dermal application to bear the following precautionary 
statements regarding dermal sensitivity: ``For external use only. Avoid 
contact with eyes. Discontinue if irritation or rash appears. Use on 
children under 6 months of age only with the advice of a physician.'' 
These precautionary statements are consistent with the warnings and 
directions (regarding use on children under 6 months of age) that 
appear in FDA's stayed monograph for OTC sunscreen drug products (part 
352 (21 CFR part 352)).
3. IR3535
    The third currently registered insect repellent used in combination 
with a sunscreen is IR3535 (CAS number 52304-36-6). In 1997, EPA 
classified IR3535 as a biochemical for the following reasons (Ref. 3): 
(1) It is functionally identical to naturally occurring beta-alanine, 
(2) both ingredients repel insects, (3) their basic molecular structure 
is identical, (4) the end groups are not likely to contribute to 
toxicity, and (5) IR3535 acts to control the target pest via a nontoxic 
mode of action. IR3535 is a technical grade synthetic biochemical 
pesticide that is produced by an integrated process. It is a liquid 
containing 98 percent 3-[N-Butyl-N-acetyl]-aminopropionic acid, ethyl 
ester as the active ingredient and 2 percent inert ingredients.
4. p-menthane-3,8-diol and KBR 3023
    There are two insect repellent active ingredients that are not 
currently used in a combination insect repellent-sunscreen drug 
product. However, for the purposes of completeness, all

[[Page 7943]]

currently registered insect repellents are discussed within this 
document.
    The first ingredient is p-menthane-3,8-diol, a biochemical 
pesticide that is chemically synthesized, although the natural oil can 
be extracted from lemon eucalyptus leaves and twigs (Ref. 4). It can be 
used in spray and lotion products to repel insects such as mosquitoes.
    The other insect repellent is KBR 3023, which contains the active 
ingredient picaridin. This chemical is currently formulated only for 
application to human skin. In December 2000, EPA registered a 15 
percent pump-spray, 10 percent aerosol spray, 7 percent cream, 7 
percent pump-spray, 5 percent cream, and 5 percent pump-spray (Ref. 5).

C. Regulatory Status of the Sunscreen Ingredients

    In the Federal Register of May 21, 1999 (64 FR 27666), FDA issued a 
final monograph for OTC sunscreen drug products in part 352, 
establishing conditions under which these products are generally 
recognized as safe and effective and not misbranded. The monograph 
includes 16 sunscreen active ingredients in Sec.  352.10; provides for 
combinations of sunscreen active ingredients in Sec.  352.20; specifies 
required labeling in Sec. Sec.  352.50, 352.52, and 352.60; and sets 
forth required testing procedures in Sec. Sec.  352.70 through 352.77. 
Once the monograph becomes effective, any drug product (including any 
combination insect repellent-sunscreen drug product) that contains 
unsuitable inactive ingredients or active drug ingredients that do not 
comply with the monograph will be considered a new drug and require an 
approved new drug application (NDA) before it may be legally marketed 
in the United States.
    Initially, the final monograph was to become effective on May 21, 
2001, but FDA subsequently extended that date to December 31, 2002 (65 
FR 36319, June 8, 2000). FDA then stayed the effective date of the 
monograph until further notice (66 FR 67485, December 31, 2001). FDA 
has delayed this effective date as it prepares an amendment to part 352 
to address formulation, labeling, and testing requirements for 
ultraviolet A (UVA) radiation protection and to revise some of the 
requirements for ultraviolet B (UVB) radiation protection in a more 
comprehensive final monograph.
    Historically, FDA has used its enforcement discretion to allow the 
marketing of insect repellent-sunscreen drug products pending the 
issuance of the final sunscreen monograph so long as the products 
contained sunscreen ingredients included in the FDA rulemaking and were 
registered with EPA. These types of products were first marketed before 
the OTC drug review began in 1972, and FDA has not explicitly addressed 
them at any time in the rulemaking for OTC sunscreen drug products. 
Because they have always contained a pesticide, the combination insect 
repellent-sunscreen products have also historically been registered 
with and regulated by EPA.
    FDA is now interested in determining whether it should further 
amend that monograph to address these combination products. Once the 
final monograph for sunscreen drug products becomes effective, any 
combination product containing an unsuitable inactive ingredient or an 
active drug ingredient that is not included in the final monograph will 
be considered a new drug and need an NDA to be legally marketed, even 
if the product is also registered with EPA. Thus, one purpose of this 
document is to gather information to help FDA formulate its regulatory 
position toward these combination products.

D. Regulatory Jurisdiction Over Insect Repellent-Sunscreen Drug 
Products

    In the Federal Register of December 22, 1971 (36 FR 24234), the 
Department of Health, Education, and Welfare (DHEW) and EPA published a 
Memorandum of Agreement (the Agreement) regarding matters of mutual 
responsibility under the Federal Food, Drug, and Cosmetic Act (FFDCA) 
and the FIFRA. The Agreement was amended in the Federal Register of 
September 6, 1973 (38 FR 24233). This Agreement does not explicitly 
address products that combine sunscreen and insect repellent active 
ingredients. As noted, one purpose of this document is to solicit 
comments regarding the complexities of joint jurisdiction of these 
combination products.

II. Information Requested and Specific Topics for Comment

    Interested persons are asked to review and comment upon all aspects 
of both FDA's and EPA's documents. Interested persons should submit all 
comments to both agencies. Both agencies have potential safety and 
effectiveness concerns for some of these products because of the 
different intervals of time required or recommended between 
applications of sunscreens versus insect repellents. FDA is 
particularly interested in receiving comments on the following topics:

A. Possible Manufacturing Conflicts

    Because they contain ingredients regulated by EPA and FDA, all 
insect repellent-sunscreen drug products currently need to comply with 
both EPA's testing and laboratory requirements in 40 CFR part 158 and 
FDA's current good manufacturing practice for finished pharmaceuticals 
requirements in part 211 (21 CFR part 211). The products will also have 
to meet the testing procedures for OTC sunscreen drug products in part 
352, subpart D, when that monograph becomes effective. The agencies are 
not aware of any specific manufacturing requirements that conflict and 
invite specific comment and information on this subject.
    1. Are manufacturers of insect repellent-sunscreen drug products or 
others aware of any conflicts between the EPA and FDA manufacturing 
requirements for these products? If yes, is there any way to resolve 
the conflict(s)?
    2. Approximately 20 insect repellent-sunscreen drug products are 
currently registered with EPA. If there is a future FDA rulemaking for 
all combination insect repellent-sunscreen drug products, how should 
these currently registered products be addressed in the sunscreen 
monograph? What requirements should be retained, revised, or eliminated 
from the sunscreen monograph?
    3. Have manufacturers of currently marketed insect repellent-
sunscreen drug products conducted any of the testing described in part 
352, subpart D, for their combination product(s), notwithstanding that 
the effective date of part 352 has been stayed? If yes, what problems, 
if any, have they encountered?

B. Possible Formulation Conflicts

    During completion of its DEET RED, EPA solicited information from 
registrants of insect repellent-sunscreen drug products on the 
possibility of formulation conflicts. At that time, EPA received 
information that suggests a potential formulation conflict is 
encountered when sunscreen and insect repellent are used separately (or 
sequentially applied) (Ref. 6). It is unclear whether this formulation 
issue poses a similar or related problem when these ingredients are 
combined into a single product. The agencies invite specific comment 
and information on this subject.

C. Possible Labeling Conflicts

    Insect repellent and sunscreen products each have different 
labeling

[[Page 7944]]

requirements that may conflict when both are combined and packaged in 
one product. The insect repellent component is subject to the labeling 
requirements in 40 CFR 156.10 entitled ``labeling requirements and the 
active ingredient specific requirements.'' For each registered insect 
repellent, these requirements are listed in the registration or 
reregistration documents. The sunscreen component of the product is 
subject to the labeling requirements in Sec.  201.66 (21 CFR 201.66) 
and part 352. However, FDA has stayed these regulations for OTC 
sunscreen drug products until we issue a sunscreen final rule (69 FR 
53801 (September 3, 2004) and 66 FR 67485).
    The agencies are concerned that the labeling format and some of the 
content requirements vary between the EPA and FDA requirements. For 
example, FDA uses the word ``warning'' on labels, while EPA uses the 
word ``caution'' and only uses the word ``warning'' as an indicator of 
toxicity level on pesticide labels. Many of the required warning 
section headings are also different. In addition, the application 
directions for the sunscreen and the insect repellent components may be 
significantly different. For example, the application directions for 
sunscreens state to ``apply liberally (or generously) * * * as needed'' 
and provide for application to more areas of the body than do the 
application instructions for insect repellents, which tend to restrict 
the frequency of application and where and how the product can be 
applied.
    EPA requirements for DEET include labeling that states: ``Apply 
sparingly around ears.'' and ``Do not apply to children's hands.'' The 
directions for some DEET products require a 6-hour interval between 
applications and state: ``Use just enough repellent to cover exposed 
skin and/or clothing'' and ``avoid over-application of this product.'' 
Also, a currently marketed insect repellent (DEET)-sunscreen drug 
product states in its labeling ``frequent reapplication and saturation 
is unnecessary for effectiveness.'' While frequent reapplication may 
not be necessary for the effectiveness of the DEET in this product, 
frequent reapplication may be necessary for the effectiveness of the 
sunscreen.
    Hence, there are many differences between the labeling required by 
FDA for OTC drugs and EPA for pesticides. The labeling formats, 
labeling content, and the order in which information is presented are 
quite different. FDA and EPA are exploring whether they can reconcile 
these differences, safeguard the public health, and still adequately 
meet the requirements of FFDCA and FIFRA.
    1. Concerning an integrated label, can the different instructions 
for the two components (regarding frequency of application and where 
the product can be applied) be reconciled into a single direction that 
does not lead to improper application (i.e., incorrect location), over-
application of the insect repellent, or under-application of the 
sunscreen? Is there labeling that would reflect the differences in 
reapplication intervals for DEET when combined with sunscreen 
ingredients? Oil of citronella when combined with sunscreen 
ingredients? IR3535 when combined with sunscreen ingredients?
    2. The FFDCA requires that all OTC drug products list the 
established name of each inactive ingredient on the outside container 
of the retail package (see section 502(e)(1)(A)(iii) of FFDCA (21 
U.S.C. 352(e)(1)(A)(iii)); also see Sec.  201.66(c)(8)). EPA does not 
require a complete declaration of ``inactive or inert'' ingredients and 
normally does not require insect repellent manufacturers to list the 
identities of inert ingredients on product labels. However, under 
FIFRA, if one inert ingredient is disclosed in product labeling, then 
all inert ingredients must be disclosed. EPA is currently discussing, 
with a wide spectrum of stakeholders, how to make information 
concerning inert ingredients more widely available. The results of 
those discussions will affect combination insect repellent-sunscreen 
drug products as well as other pesticide products. Failure to list all 
of the inactive ingredients in the product's labeling, including all 
such ingredients in the insect repellent, would cause a combination 
insect repellent-sunscreen drug product to be misbranded under the 
FFDCA (see section 502(e)(1)(A)(iii) of FFDCA). Is there a way to label 
combination sunscreen-insect repellent drug products that satisfies 
FFDCA's requirements under section 502(e)(1)(A) of FFDCA but does not 
violate FIFRA? Are those ingredients that are ``inert'' under FIFRA 
also necessarily ``inactive'' under FFDCA?

D. Safety Issues

    FDA is aware of only two studies examining percutaneous absorption 
when combining an insect repellent with a sunscreen. One study involved 
hairless mice (Ref. 6) and the other study involved piglets (Ref. 7). 
Both studies demonstrate increased absorption of the insect repellent 
DEET and different sunscreens when the components were combined. Thus, 
FDA would like more information concerning the safety of insect 
repellent-sunscreen drug products:
    1. Is there data available to show whether increased absorption of 
the sunscreen ingredients(s) does or does not occur as a result of 
being combined with an insect repellent ingredient? If so, please 
provide. For example, is there any evidence that absorption increases 
as the particle size of titanium dioxide and zinc oxide decreases (down 
to a few nanometers) in insect repellent-sunscreen products? If so, is 
there evidence regarding the health or safety effects associated with 
the increased absorption?
    2. Are there reports or other information relating to skin 
irritation resulting from use of a combination insect repellent-
sunscreen drug product are manufacturers of these products or others 
aware of? Provide a summary of the types of events reported and, if 
possible, estimate an incidence of occurrence.

E. Effectiveness Issues

    For some insect repellent-sunscreen products, FDA has effectiveness 
concerns because of the interval of time required or recommended 
between applications of the product. EPA identifies reapplication times 
on insect repellent labels so consumers can maintain the maximum 
protection against insect bites but avoid over-exposure. This 
reapplication time relates to the effectiveness of the insect repellent 
portion of the product and not to the sunscreen protection. The 
directions for sunscreen products, which encourage frequent 
reapplication of the drug, relate to the effectiveness of the sunscreen 
component of the product and not to the insect repellent component.
    The differences in directions for use for the insect repellent 
component and the sunscreen component need to be resolved to ensure 
safety and effectiveness of both components and the combination product 
as a whole. For example, the directions for some products containing 
DEET require a 6-hour interval between applications and state ``use 
just enough repellent to cover exposed skin and/or clothing'' and 
``avoid over-application of this product.'' In contrast, the directions 
for sunscreen drug products in Sec.  352.52(d)(1) and (d)(2) state to 
``apply liberally, generously, smoothly, or evenly * * * before sun 
exposure and as needed,'' and ``reapply as needed or after towel 
drying, swimming, or (select `sweating' or `perspiring').'' Section 
352.60(d) of the sunscreen monograph also states that ``when the time 
intervals or age limitations for administration of

[[Page 7945]]

the individual ingredients differ, the directions for the combination 
product may not contain any dosage that exceeds those established for 
any individual ingredient in the applicable OTC drug monograph(s), and 
may not provide for use by any age group lower than the highest minimum 
age limit established for any individual ingredient.''
    Concerns about effectiveness also stem from a study (Ref. 8) 
indicating that separate application of sunscreen followed by DEET 
resulted in a decrease in sun protection factor (SPF) after application 
of the insect repellent. Thus, FDA is soliciting comment on the 
following questions:
    1. Is there additional evidence suggesting that application of a 
sunscreen product followed by application of a separate insect 
repellent product results in a decrease in the sunscreen's SPF? Is 
there evidence suggesting that sequential application of the products 
has no adverse effect on the sunscreen?
    2. Is there evidence suggesting that combining a sunscreen and 
insect repellent in a single formulation adversely impacts the 
effectiveness of the sunscreen? Is there evidence suggesting that such 
a combination has no adverse impact on the sunscreen component?
    3. Are there effective concentrations of the insect repellent 
ingredients that could be used to allow for liberal application and 
frequent reapplication of the insect repellent-sunscreen drug products, 
as directed by the sunscreen directions, without jeopardizing the 
safety of the consumer? How does this vary by insect repellent 
ingredient? Would any of the insect repellent ingredients be effective 
at such concentrations?
    4. Is there information available to show whether there are any 
chemical or physical incompatibilities between insect repellent and 
sunscreen active ingredients when used in combination products or when 
used separately? Are there any sunscreen ingredients that should not be 
used with a specific insect repellent ingredient?
    5. If an insect repellent ingredient (e.g., DEET) is labeled for 6-
hour intervals between applications, can the effectiveness of the 
sunscreen be assured if the product cannot be applied more often than 
every 6 hours? Is there a need for a minimal SPF to assure the 
effectiveness of the combination product considering the wide variation 
in minimal erythemal dose (MED) between individuals and the need for 
reapplication due to physical stress such as toweling or rubbing of the 
skin? If the answer is yes, what minimal SPF value should be required, 
and what is the basis for that SPF value?
    6. Is there information available to demonstrate that there are 
product performance benefits [other than the convenience of using one 
product instead of two] derived from the concurrent application of the 
insect repellent and the sunscreen (as opposed to sequential 
application of these products separately)? Please submit any data that 
you reference.
    7. Oil of Citronella products are labeled to repeat applications at 
1 hour intervals for maximum repellent effectiveness. Is it possible 
that insect repellent-sunscreen drug products can be formulated in such 
a way that the insect repellent reapplication intervals coincide more 
closely with the sunscreen reapplication intervals? Can this be done 
without jeopardizing the safety or effectiveness of these products?

III. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments on this document. Three 
copies of all written comments are to be submitted. Individuals 
submitting written comments or anyone submitting electronic comments 
may submit one 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 Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday.

IV. References

    The following references are on display in the Division of Dockets 
Management (see ADDRESSES) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. EPA Reregistration Eligibility Decision for DEET, 1998.
    2. EPA Reregistration Eligibility Decision for Oil of 
Citronella, 1997.
    3. EPA Biopesticide Registration Eligibility Document for 
IR3535, 1999.
    4. EPA Biopesticide Registration Eligibility Document for p-
menthane-3,8-diol, 2000.
    5. EPA Decision Memorandum on KBR 3023, 2000.
    6. Ross, E. A. et al., ``Insect Repellent Interactions: 
Sunscreens Enhance DEET (N,N-Diethyl-M-Toluamide) Absorption,'' Drug 
Metabolism and Disposition, 32:783-785, 2004.
    7. Gu, X. et al., ``In Vitro Evaluation of Concurrent Use of 
Commercially Available Insect Repellent and Sunscreen 
Preparations,'' British Journal of Dermatology, 152: 1263-1267, 
2005.
    8. Montemarano, A. D. et al., ``Insect Repellents and the 
Efficacy of Sunscreens,'' The Lancet, 349:1670-1671, 1997.
    This request for information and comment is issued under sections 
201, 501, 502, 503, 505, 510, and 701 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, and 371) and 
under authority of the Commissioner of Food and Drugs.

    Dated: December 5, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E7-2890 Filed 2-21-07; 8:45 am]

BILLING CODE 4160-01-S