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[Federal Register Volume 77, Number 237 (Monday, December 10, 2012)]
[Rules and Regulations]
[Pages 73294-73302]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-29203]

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CONSUMER PRODUCT SAFETY COMMISSION

16 CFR Part 1700

[CPSC Docket No. CPSC-2012-0005]

Requirements for Child-Resistant Packaging: Products Containing 
Imidazolines Equivalent to 0.08 Milligrams or More

AGENCY: Consumer Product Safety Commission.

ACTION: Final rule.

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SUMMARY: The Consumer Product Safety Commission (CPSC, Commission, or 
we) is issuing a rule to require child-resistant (CR) packaging for any 
over-the-counter or prescription product containing the equivalent of 
0.08 milligrams or more of an imidazoline, a class of drugs that 
includes tetrahydrozoline, naphazoline, oxymetazoline, and 
xylometazoline, in a

[[Page 73295]]

single package. Imidazolines are a family of drugs that are 
vasoconstrictors indicated for nasal congestion and/or ophthalmic 
irritation. Products containing imidazolines can cause serious adverse 
reactions, such as central nervous system (CNS) depression, decreased 
heart rate, and depressed ventilation in children who accidentally 
ingest them. Based on the scientific data, the Commission has 
determined that availability of 0.08 milligrams or more of an 
imidazoline in a single package, by reason of its packaging, is such 
that special packaging is required to protect children under 5 years 
old from serious personal injury or illness due to handling or 
ingesting such a substance. The Commission takes this action under the 
Poison Prevention Packaging Act of 1970 (PPPA) and voted to publish 
this notice in the Federal Register.

DATES: Effective date: This rule is effective December 10, 2013.
    Applicability: This rule applies to products packaged on or after 
that date.

FOR FURTHER INFORMATION CONTACT: Carol Afflerbach, Compliance Officer, 
Office of Compliance and Field Operations, Consumer Product Safety 
Commission, 4330 East West Highway, Bethesda, MD 20814; telephone (301) 
504-7529; cafflerbach@cpsc.gov.

SUPPLEMENTARY INFORMATION: 

I. Background

A. Relevant Statutory and Regulatory Provisions

    The Poison Prevention Packaging Act of 1970 (PPPA), 15 U.S.C. 1471-
1476, authorizes the Commission to establish standards for the 
``special packaging'' of any household substance if: (1) The degree or 
nature of the hazard to children in the availability of such substance, 
by reason of its packaging, is such that special packaging is required 
to protect children from serious personal injury or serious illness 
resulting from handling, using, or ingesting such substance, and (2) 
the special packaging is technically feasible, practicable, and 
appropriate for such substance.
    Special packaging, also referred to as ``child-resistant (CR) 
packaging,'' is: (1) Designed or constructed to be significantly 
difficult for children under 5 years of age to open or obtain a toxic 
or harmful amount of the substance contained therein within a 
reasonable time, and (2) not difficult for ``normal adults'' to use 
properly. 15 U.S.C. 1471(4). Household substances for which the 
Commission may require CR packaging include (among other categories) 
foods, drugs, or cosmetics, as these terms are defined in the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321). 15 U.S.C. 1471(2)(B). The 
Commission has issued performance requirements for special packaging. 
16 CFR 1700.15, 1700.20.
    Section 4(a) of the PPPA, 15 U.S.C. 1473(a), allows the 
manufacturer or packer to package a nonprescription product subject to 
special packaging standards in one size of non-CR packaging, only if 
the manufacturer (or packer) also supplies the substance in CR packages 
of a popular size, and the non-CR packages bear conspicuous labeling 
stating: ``This package for households without young children.'' 15 
U.S.C. 1473(a), 16 CFR 1700.5.
    To protect children younger than 5 years old from serious personal 
injury following ingestion, the rule requires CR packaging for any 
over-the-counter (OTC) or prescription product containing the 
equivalent of 0.08 milligrams or more of an imidazoline (including 
tetrahydrozoline, naphazoline, oxymetazoline, or xylometazoline) in a 
single package.

B. Imidazolines

    Imidazolines are a family of drugs that are used as decongestants 
in eye drops and nasal products. Imidazolines are used as topical 
decongestants because they produce vasoconstriction when administered 
to the eye or nasal mucosa. In the eye, the imidazolines relieve 
redness due to minor eye irritations by causing vasoconstriction of the 
blood vessels on the surface of the eye and eyelid (Facts and 
Comparisons, Ophthalmic Decongestants, Pharmacology, 2011). The onset 
of vasoconstriction after topical application is within minutes. As 
nasal decongestants, imidazolines temporarily relieve nasal congestion 
or stuffy nose due to the common cold, hay fever, or other upper 
respiratory allergies (Facts and Comparisons, Nasal Decongestants, 
Pharmacology 2011). The imidazolines cause vasoconstriction in mucous 
membranes, which decreases blood flow and leads to shrinking of swollen 
nasal mucosa and increased drainage of the sinuses.
    Topical and nasal administration of imidazolines results in little 
absorption into the general circulation. Orally ingested imidazolines, 
however, are absorbed into the general circulation leading to systemic 
effects. Even though death from ingesting imidazolines is rare, 
ingestion can result in severe life-threatening consequences, such as 
central nervous system (CNS) depression and cardiovascular effects. 
Specific symptoms of CNS depression upon ingestion of imidazolines 
range from drowsiness to coma, with a concurrent depression of the 
respiratory system. Other reported CNS side effects include: Headache, 
lightheadedness, dizziness, tremor, insomnia, nervousness, 
restlessness, giddiness, psychological disturbances, prolonged 
psychosis, and weakness. Imidazolines have led to CNS depression and 
insomnia in different children. Prominent cardiovascular effects in 
response to overdose include low blood pressure and slowed heart rate. 
The medical literature and evidence from collected samples demonstrate 
that despite the danger of ingesting imidazolines, imidazoline-
containing products are not manufactured in CR packaging.
    Eye drops containing imidazolines are widely available at drug, 
grocery, and mass market retailers. Imidazoline eye drops generally 
come in small squeeze bottles. The most common size is the 1/2-ounce 
(15 milliliters) bottle, and the second most common size appears to be 
a 1-ounce bottle (30 milliliters). One-quarter ounce (8 milliliters) 
bottles are also available.
    Nasal sprays containing imidazolines are widely available at drug, 
grocery, and mass market retailers. Some packages are used by rapidly 
squeezing the bottle to spray the product into a nostril. Other 
packages have a pump mechanism that activates the spray. As with eye 
drops, 1/2-ounce containers are the most common container size, and 1-
ounce bottles are the second most common size.
    We are aware of approximately 45 manufacturers who sell topical 
decongestant products under about 64 different labels. Because some 
manufacturers produce both nasal and ophthalmic products, the number of 
manufacturers within the market for topical decongestants is not the 
sum of the manufacturers of ophthalmic products, plus the manufacturers 
of nasal products.
    We estimate that approximately 45 million units of ophthalmic 
decongestants containing imidazolines are sold annually, with estimated 
annual sales receipts of approximately $180 million. We estimate that 
approximately 39 million units of nasal products containing 
imidazolines are sold annually, generating annual sales receipts of 
approximately $233 million.
    Commission staff examined 12 packages--10 eye drops, 1 nasal spray, 
and 1 nasal drops--of over-the-counter products that contain 
imidazolines. The 10 eye drop samples were packaged in squeeze-to-
dispense plastic dropper bottles. The nasal spray was packaged in a 
plastic bottle with an attached metered

[[Page 73296]]

pump sprayer, and the nasal drop was packaged in a squeeze-to-dispense 
plastic dropper bottle. All of the eye drop product bottles were 
finished with continuous threads, and the bottle openings were fitted 
with plastic dropper plugs. The nasal spray bottle was finished with 
continuous threads onto which a metered pump dispenser was attached. 
The pump mechanism was not child resistant. The nasal drops were 
packaged in a squeeze-dropper bottle, finished with continuous threads, 
and the bottle opening was fitted with a dropper plug. None of the 
samples of eye drops, nasal spray, or nasal drops was packaged using 
special packaging.

C. The Proposed Rule

    On January 25, 2012, the Commission issued a notice of proposed 
rulemaking (NPR) that proposed requiring CR packaging for imidazoline 
preparations containing 0.08 milligrams or more of imidazolines in a 
single package. 77 FR 3646.
    The Commission received five comments in response to the proposed 
rule. Two comments address the amount of time necessary to develop, 
test, and produce CR packaging for imidazolines, and they request 
additional time beyond the 1-year effective date proposed in the NPR. 
Two comments pertain to imidazoline nasal and ophthalmic packaging, and 
one comment concerns the derivation of the proposed regulation level of 
0.08 milligrams or more of imidazolines in a single package. We respond 
to each of these comments below.
Effective Date
    Comment: Two commenters indicate that the proposed effective date 
of 1 year is too short. One commenter concludes: ``it is not feasible 
for manufacturers to comply with the proposed one (1) year effective 
date'' and opines that 2 years would be required at a minimum. 
Regarding nasal products, the commenter contends that this amount of 
time is required because it will probably be necessary to replace the 
commonly used single-piece cap with two-component CR protection caps. 
The commenter also notes that most ophthalmic finishes \1\ are 13mm-
15mm; that there are no CR closures available smaller than 18mm; and 
therefore, new CR packages will also be required for ophthalmic 
products. The commenter provides a timeline identifying the various 
steps of the CR packaging development, testing, and approval process, 
and the time range for the expected completion of each stage. The 
commenter requests that the Commission consider a 1-year stay of 
enforcement in addition to the 1-year effective date recommended in the 
NPR to allow manufacturers 2 years after publication of the rule to 
comply. This commenter also states that additional time beyond the one 
year effective date and one year stay of enforcement may be required by 
some manufacturers, especially if the products in question are subject 
to U.S. Food and Drug Administration (FDA) requirements for new drug 
applications (NDAs) or abbreviated new drug applications (ANDAs). This 
additional approval process, the commenter reports, could require an 
additional 6 to 12 months. This commenter also requests that 
manufacturers be granted extended stays of enforcement on a case-by-
case basis, if required.
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    \1\ The word ``finish,'' in this sense, refers to the protruding 
threads on the bottle's opening, which hold the cap or closure. A 
container and its corresponding closure must have matching finishes.
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    A second commenter states that it manufactures sterile eye drops 
that require ``specialized aseptic processing,'' notes that the process 
for developing CR packages suitable for sterile ophthalmic products is 
complex and ``based upon historical experience with the regulated 
design and qualification activities required for aseptically filled 
sterile products,'' and requests that the effective date of the rule be 
extended to 24 months.
    Response: We agree with the first commenter's analysis of the steps 
necessary to comply with a CR packaging requirement and the time frames 
associated with each step. We also agree with the second commenter's 
statement that producing sterile products will take 24 months, such 
that a conditional 12-month stay of enforcement is warranted. We 
address our assessment of the anticipated duration of each step in the 
process of developing, testing, and producing CR packaging, and we 
highlight each step identified in the commenter's submission. The first 
commenter states that design development will take 2 to 4 months, and 
we believe that this range is typical for modern computer-assisted 
design processes. We note that there are several nonpatented designs, 
and one patented design for CR packaging for imidazoline products that, 
if purchased or licensed by a manufacturer, could reduce the duration 
of the design development stage to 1 month or less. The commenter 
states that prototype tooling will take from 4 to 6 months, and we have 
been advised by independent sources that mold tool production typically 
takes 4 to 5 months, with an additional month for production testing to 
ensure that the mold tool can be used at the intended production rate. 
The commenter estimates that CR protocol testing will take 
approximately 3 months, and we have been advised by CR protocol test 
providers that such testing for child-resistant and senior-friendly 
packaging typically takes 2 to 4 months, depending on the complexity of 
the CR system. The commenter states that industrial scale-up for 
packaging and validation will take from 7 to 11 months because of the 
possibility that existing filling and capping equipment will need to be 
replaced, or at least significantly modified, depending on the design 
of the CR closure. Independent sources have advised us that this work 
should take less than 6 months if a similar sterile process is already 
in place and between 6 and 12 months if new equipment must be 
installed. According to the commenter, adoption and validation of the 
new filling line will take between 3 and 6 months, which is the time 
range provided by manufacturers of similar products in connection with 
previous regulatory activity. The commenter states that stability 
testing will take between 3 and 12 months, a timeframe that is 
consistent with FDA Stability Test Guidelines of 1 year for regular 
stability testing and 6 months for accelerated stability testing, which 
is intended to increase the rate at which the degradation reactions 
take place. The commenter states that the FDA review process for an NDA 
or an ANDA can take from 6 months to a year. The FDA advises that 10 
months is the median review time for NDAs, while the ANDA review 
process typically does not take as long; however, permission must be 
obtained before filing an ANDA, which can take up to 6 months alone.
    Based on the foregoing review and analysis of the steps necessary 
to develop, test, and produce CR packaging for products that contain 
imidazolines, as well as the time frames for each of those steps, the 
Commission agrees that more than 1 year may well be necessary. Thus, 
the Commission will grant a conditional 1-year stay of enforcement to 
provide additional time to produce CR packaging for these products. 
This issue is discussed further in Section VI of the preamble.
Packaging Issues
    Comment--One commenter notes that the NPR failed to consider one 
type of nasal spray package. The package in question ``is a glass 
bottle which houses the imidazoline drug product, with a crimped seal 
holding the pump in place and with [a] detachable nozzle.'' The

[[Page 73297]]

metered pump is housed in a metal case, the rim of which is crimped to 
the glass bottle. A plastic nozzle is placed over the pump, and the 
overcap is attached to the nozzle. Consumers access the product by 
squeezing the package between the thumb and first two fingers, causing 
an aerosolized form of the product to be released from the nozzle's 
tip.
    The commenter believes that this package is inherently child 
resistant because it is a unit-dose package. The commenter requests 
that CPSC staff provide clarification ``as to what could constitute a 
pass or failure of such a package.''
    Response: We disagree with the commenter's fundamental premise that 
unit-dose packages are inherently child resistant. In fact, we believe 
that unit-dose packages are not inherently CR. It is likely that a 
child can easily access the contents because neither the pumping 
action, nor the overcap or nozzle attachments are CR, and it is 
reasonably foreseeable that a child could access more than the 
regulated quantity of the contents. Either the pump action or the 
overcap must be child resistant.
    Comment--One commenter asks: ``for nasal sprays that contain 
Imidazoline equivalent to 0.08 milligrams or more, is Child-Resistant 
packaging required for crimp-on pumps?'' The commenter acknowledges 
that continuous thread (CT) closures and squeezable packages permit a 
child to have access to the entire contents, but states that metered-
dose pumps crimped onto a rigid bottle would permit a child access to 
``only one dose at a time.'' In addition, the commenter states: ``it is 
not likely to be ingested due to its aerosol form.''
    Response--As stated in the response to the previous comment, unit-
dose packaging is not inherently CR. Child-resistant packaging is 
required for the pump action and/or the overcap. We also disagree that 
an aerosolized form of the product would not be ingested by a child.
Regulated Level of Imidazoline
    Comment-- One commenter asks whether the lowest observed adverse 
effect level (LOAEL) (i.e., 0.75 mg) should first be normalized to mg/
kg and then extrapolated to a 25-pound child before applying a tenfold 
safety factor, resulting in a no observable adverse effect level 
(NOAEL) of 0.18 mg.
    Response--The proposed regulated level (0.08 mg imidazoline) was 
based upon an actual imidazoline case with a safety factor applied to 
the dose ingested. Notably, ingestions expressed as normalized doses 
show that adverse effects occurred at levels within about the same 
range of imidazoline (0.1-0.3 mg/kg). Moreover, another case in the 
medical literature documents an adolescent who developed persistent 
cardiovascular and neurological effects after ingestion of 
approximately 0.07 to 0.1 mg/kg of tetrahydrozoline, which is also 
consistent with the proposed imidazoline level e.g., 0.07 mg/kg (lower 
end of range) x 11.4 kg child = ~ 0.8 mg / 10 fold-safety factor = 0.08 
mg.

II. Toxicity of Imidazolines

    The Commission's Directorate for Health Sciences reviewed the 
toxicity of imidazolines. Imidazolines are used as topical 
decongestants because they produce vasoconstriction when administered 
to the eye or nasal mucosa. In the eye, the imidazolines relieve 
redness due to minor eye irritations by causing vasoconstriction of the 
blood vessels on the surface of the eye and eyelid (Facts and 
Comparisons, Ophthalmic Decongestants, Pharmacology, 2011). The onset 
of vasoconstriction after topical application is within minutes. As 
nasal decongestants, imidazolines temporarily relieve nasal congestion 
or stuffy nose due to the common cold, hay fever, or other upper 
respiratory allergies (Facts and Comparisons, Nasal Decongestants, 
Pharmacology 2011). The imidazolines cause vasoconstriction in mucous 
membranes, which decreases blood flow and leads to shrinking of swollen 
nasal mucosa and increased drainage of the sinuses.
    The therapeutically effective dose of imidazolines occurs within a 
narrow dose range, with toxic effects occurring at doses close to, or 
at, therapeutic levels. CNS depression (ranging from drowsiness to deep 
sedation) may occur after recommended doses in infants. Overdoses 
(doses not specified) of these medications have caused initial spikes 
of high blood pressure, leading to slowed heart rate, drowsiness, and 
rebound low blood pressure in adults. A shock-like syndrome with 
abnormally low blood pressure and slowed heart rate may also occur. 
Warnings on tetrahydrozoline- and naphazoline-containing OTC drugs 
state that their use may cause CNS depression, leading to coma in 
pediatric patients. Xylometazoline and oxymetazoline symptoms of 
overdose include: extreme tiredness, sweating, dizziness, a slowed 
heartbeat, and coma.
    When the drug is absorbed, it can act systemically within the body. 
Topical administration of imidazolines to the eye produces local 
effects to the blood vessels of the eye, but little is absorbed into 
the general circulation. (For purposes of this document, we interpret 
``absorption'' as the passage of a drug from its site of administration 
into the blood plasma.)
    Nasal administration of imidazolines causes an intense degree of 
vasoconstriction, and therefore, negligible absorption of the drug into 
the general circulation (POISINDEX,[supreg] 2011). However, with oral 
ingestion, imidazolines are absorbed into the general circulation, 
leading to systemic effects. These drugs are absorbed quickly, and 
symptoms can occur in as little as 1 hour, peaking at 8 hours, and 
resolving after 12-36 hours. Even though the symptoms resolve in a 
relatively short amount of time, ingestion of imidazolines can result 
in severe life-threatening consequences, including decreased breathing, 
decreased heart rate, and loss of consciousness, which require 
hospitalization to ensure recovery.
    FDA regulations pertaining to ``Cold, Cough, Allergy, 
Bronchodilator, and Antiasthmatic Drug Products for Over-the-Counter 
Human Use,'' at 21 CFR 341.80(c)(2)(iv), require the product label for 
products containing naphazoline hydrochloride at a concentration of 
0.05 percent to state: ``Do not use this product in children under 12 
years of age because it may cause sedation if swallowed.'' Specific 
symptoms of CNS depression upon ingestion of imidazolines range from 
drowsiness to coma, with a concurrent depression of the respiratory 
system. Other observed CNS side effects include: Headache, 
lightheadedness, dizziness, tremor, insomnia, nervousness, 
restlessness, giddiness, psychological disturbances, prolonged 
psychosis, and weakness. Imidazolines have led to CNS depression and 
insomnia in different individuals. The insomnia, seen in a few cases, 
may be an unpredictable, idiosyncratic reaction (i.e., a drug effect 
that occurs in a small number of people due to age, genetics, or 
disease state). Prominent cardiovascular effects in response to 
overdose include rebound low blood pressure and slowed heart rate.
    No specific treatment for imidazoline overexposure exists. Naloxone 
(an opioid blocker) has been used without consistent success. Gastric 
lavage is not recommended more than 1 hour after ingestion because the 
imidazolines are absorbed quickly after ingestion, leading to CNS 
depression and a greater risk of aspiration into the lungs. Activated 
charcoal may be used up to 1 hour after ingestion; but again, due to 
the CNS depression, there is a greater risk of aspiration into the 
lungs. Therefore, treatment of the clinical effects from

[[Page 73298]]

imidazolines is supportive, based on symptoms. For example, mechanical 
respiration would be administered to those with severe respiratory 
depression.

III. Ingestion and Injury Data

    As discussed more extensively in the NPR, staff reviewed several 
sources for information on adverse health effects from ingestion of 
imidazolines. These sources are the National Electronic Injury 
Surveillance System (NEISS), and the FDA's Adverse Event Reporting 
System (AERS).
    The CPSC's Directorate for Health Sciences maintains the Children 
and Poisoning (CAP) system, a subset of NEISS records containing 
additional information obtained through NEISS involving children under 
5 years old. NEISS is a statistically valid injury surveillance and 
follow-back database that the Commission maintains of consumer product-
related injuries occurring in the United States. Injury data are 
gathered from the emergency departments (ED) of approximately 100 
hospitals selected as a probability sample of all 5,000+ U.S. hospitals 
with emergency departments. The system's foundation rests on emergency 
department surveillance data, but the system also has the flexibility 
to gather additional data at either the surveillance or the 
investigation level. Surveillance data enable the Commission to make 
timely national estimates of the number of injuries associated with 
(but not necessarily caused by) specific consumer products. This data 
also provides evidence of the need for further study of particular 
products. Subsequent follow-back studies yield important clues to the 
cause and likely prevention of injuries and deaths. For additional 
information on NEISS, see the CPSC's Web site at: http://www.cpsc.gov/cpscpub/pubs/3002.html.
    CAP includes data on each pediatric poisoning, chemical burn, or 
ingestion case reported from a NEISS hospital, as well as data on some 
ingestions that could lead to poisoning. We searched the CAP database 
for incidents between January 1997 and December 2011, involving 
household products that typically contain imidazolines. During that 
time, there were an estimated 6,650 emergency room-treated injuries 
associated with household products containing imidazolines involving 
children under 5 years old. Table 1 below shows the injury estimates 
for each of the product groups involved in these incidents. Four-fifths 
of the estimated injuries (82 percent) involved eye drops.
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    \2\ The estimate for this category is highly variable due to 
small sample size and high coefficient of variation. These numbers 
should be interpreted with caution.

  Table 1--Estimated Imidazoline Product-Related Injuries to Children Under 5 Years Old, 1997-2011, by Product
                                                      Group
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                                                   Estimated    Coefficient of                   95% Confidence
                    Product                        injuries        variation      Sample size       interval
----------------------------------------------------------------------------------------------------------------
Eye drops.....................................           5,437            0.18             161       3,564-7,309
Nose Sprays \2\...............................           1,213            0.29              37          534-1891
                                               -----------------------------------------------------------------
    Total.....................................           6,650            0.16             198       4,550-8,749
----------------------------------------------------------------------------------------------------------------
Source: U.S. Consumer Product Safety Commission National Electronic Injury Surveillance System and Children and
  Poisoning System, 2011.

    As set forth in tabular form in the NPR, In-Depth Investigations 
(IDIs) were assigned in connection with certain NEISS-reported 
imidazoline ingestion incidents. A selection of these IDIs reveals 
various scenarios in which children between the ages of 13 months and 4 
years gained access to imidazoline products including young children 
who removed caps from eye drop bottles left within their reach; 
obtained an eye drop bottle from an older sibling; used a chair to 
access an eye drop bottle in a medicine cabinet; and took a bottle of 
eye drops out of his mother's purse. See NPR, Table 2, section III.A 
(77 FR 3649), for a summary of IDIs of selected incidents.
    The AERS is a database of voluntary reports from health care 
professionals and consumers, along with mandatory reports from 
manufacturers. AERS is maintained by the FDA and contains reports of 
adverse events and medication errors for all FDA-approved drugs and 
therapeutic biologic products. We asked the FDA for all AERS reports 
mentioning the imidazolines tetrahydrozoline, oxymetazoline, 
xylometazoline, or naphazoline. FDA provided 1,041 reports for 772 
distinct cases for us to review involving both children and adults 
occurring between October 1968 and August 2010. We checked for cases 
related to imidazolines, excluded the cases with concomitant drugs, and 
determined that 67 cases (with 115 total reports) were in scope for 
consideration in this rulemaking.
    Reports through the AERS system show a wide variety of adverse 
events associated with the use of imidazolines across all ages. The top 
three system/organ classes with reported adverse events were 
psychiatric disorders (52 reports); nervous system disorders (47 
reports); and respiratory, thoracic, and mediastinal disorders (38 
reports). Sixty-two out of 67 in-scope cases (93 percent) reported an 
adverse event in one of the top three system/organ classes. (Reports 
can include more than one adverse event, so individual reports may be 
recorded in more than one system/organ class.) Our review of these 
cases is contained in the January 11, 2012, Staff Briefing Package: 
http://www.cpsc.gov/LIBRARY/FOIA/FOIA12/brief/imidazolines.pdf.
    The volumes of imidazoline ingestions in children (under the age of 
5) that were reported from two sources, the FDA's AERS database 
(MedWatch reports) and the medical literature, ranged from several 
drops to a high of 30 mL (2 tablespoons). The volume ingested was 
unknown in several imidazoline cases. As set forth in Table 3 in the 
NPR, very serious adverse effects occurred in response to small oral 
doses of imidazolines. For example, a 2-year-old child who ingested 
between 1 and 1.5 mg of tetrahydrozoline, experienced decreased blood 
pressure and respiration, and he was placed on mechanical respiration 
in the pediatric intensive care unit for 18 hours. Also, a 16-month-old 
child who ingested between 1.25 and 2.5 mg of tetrahydrozoline 
experienced decreased heart rate, depressed respiration, and was 
admitted to the hospital overnight.
    In MedWatch reports of adverse events occurring in response to 
ingestion of imidazolines, 43 cases occurred in children under 5 years 
old.

[[Page 73299]]

Tetrahydrozoline ingestions constituted the majority of the cases (88 
percent). There were no reported deaths related to imidazoline 
ingestion. See: http://www.cpsc.gov/LIBRARY/FOIA/FOIA12/brief/imidazolines.pdf: January 11, 2012, Staff Briefing Package, for a 
complete list of cases.
    The most recent imidazoline ingestion case cites the lowest dose of 
ingestion of which we are aware that caused severe adverse symptoms in 
a child. The case involved a 25-day-old infant who suffered apnea after 
being treated with tetrahydrozoline nasal drops (0.05 percent). The 
mother inadvertently administered the nasal drops by the oral route 
three times per day with 0.5 ml/day (0.25 mg). The immature kidney and 
liver function of the newborn caused the drugs to clear the newborn's 
system more slowly than in an adult. CPSC staff reviewing this case 
report considered the three doses of nasal drops to be additive and 
calculated the total dose for this case to be 0.75 mg. After the second 
dose, the child was not feeding well and had low muscle tone. Two hours 
after the second dose, he developed apnea. After the third dose was 
administered, the child was brought to the hospital and admitted with a 
respiratory rate of four breaths per minute and a slowed heart rate. 
The infant was treated with naloxone, resolving the apnea and 
bradycardia. After 2 days, the child was in good condition and was 
discharged. After follow-up 10 days later, the child was in normal 
condition (Katar et al. 2010).
    Our review of the ingestion data is contained in: http://www.cpsc.gov/LIBRARY/FOIA/FOIA12/brief/imidazolines.pdf: January 11, 
2012, Staff Briefing Package.

IV. Level for Regulation

    The Commission is issuing a rule requiring special packaging for 
any over-the-counter or prescription product containing the equivalent 
of 0.08 milligrams or more of an imidazoline in a single package. The 
absorption of imidazolines after oral ingestion can lead to 
unpredictable and profound CNS depression, including depressed 
respiration and cardiovascular events. Data indicate that children 
under 5 years old are accidentally ingesting imidazoline-containing 
products. Even though death from imidazoline exposure is rare, many of 
these events result in serious life-threatening consequences requiring 
hospitalization and intensive care monitoring for recovery. See NPR, 
Section Table 3, section III.C (77 FR 3650), for a summary of relevant 
cases of imidazoline ingestion.
    Mindlin (1966) reported a case in which a 1-year-old girl ingested 
\1/2\ to 1 teaspoon (2.5-5 mL) of tetrahydrozoline eye drops and 
suffered CNS depression with slowed respiration and decreased heart 
rate. Based on this ingestion, recent publications define 2.5 mL 
tetrahydrozoline (0.05 percent, 1.25 mg) as the dose at which serious 
toxicity from imidazoline exposure can occur after ingestion (Holmes 
and Berman, 1999; Eddy and Howell 2000). The preamble to the proposed 
FDA rule for OTC nasal decongestants reported that the minimum oral 
dose of oxymetazoline in an adult causing measurable cardiovascular 
effects (on blood pressure and heart rate) was 1.8 mg of oxymetazoline 
(41 FR 38312, 38398 (September 9, 1976)). This minimum dose may be 
lower for children because they appear to be more sensitive to 
imidazoline effects than adults (Brainerd and Olmstead, 1956). Cases 
indicate that ingestion of as little as 0.75 mg of imidazolines can 
result in serious illness in children, requiring supportive therapy 
(Katar et al., 2010; Summary see Table 3). The most recent case of 
imidazoline ingestion is reviewed in section III of this preamble. It 
involved a 25-day-old infant who suffered apnea after being treated 
with tetrahydrozoline nasal drops (0.05 percent). CPSC staff reviewing 
this case report calculated the total dose for this case to be 0.75 mg, 
which is the lowest dose the ingestion of which we are aware, caused 
severe adverse symptoms in a child.
    Because serious effects on the heart and breathing rates occur with 
the ingestion of as little as 0.75 mg of tetrahydrozoline, we consider 
this the lowest observed adverse effect level (LOAEL). All of the 
imidazolines cause potent central and peripheral sympathetic effects, 
but tetrahydrozoline has the highest potency for CNS sedative/
depressive effects and the lowest potency for cardiac effects. 
Oxymetazoline and naphazoline are the most potent imidazolines for 
peripheral cardiac effects and have an 8-10 times lower maximum daily 
dose than tetrahydrozoline (0.4 mg, 0.3 mg and 3.2 mg, respectively). 
Xylometazoline and oxymetazoline have a longer duration of action than 
tetrahydrozoline (12 hrs., 10 hrs., and 4-6 hrs., respectively).
    Applying a safety factor of 10 to the LOAEL to derive a recommended 
regulated level of 0.08 mg for all imidazolines is appropriate in order 
to protect children from serious health effects following ingestion of 
this family of drugs. The level of 0.08 mg would require all known 
imidazolines currently on the market to be placed in CR packaging. The 
assumptions underlying the use of safety factors are that by using 
these factors, both the public health and sensitive populations are 
protected. Further assumptions hold that humans are somewhere between 
10 and 1,000 times more sensitive to some toxic agents than animals, 
and adults are less sensitive than children. Hence, a safety assessment 
can be conducted using the proper toxicological evaluation with 
different populations to establish the NOAEL (no observable adverse 
effect level) or its equivalent. We used a tenfold safety factor to 
divide the LOAEL to reach a NOAEL level.
    The regulated dose level is expected reasonably to protect children 
under 5 years of age from serious personal injury or illness. The 
Commission proposed this level and received one comment on it, which we 
addressed in Section I of the preamble.

V. Statutory Considerations

A. Hazard to Children

    As noted above, the toxicity data concerning children's oral 
ingestion of imidazolines demonstrate that they can cause serious 
illness and injury to children. Moreover, imidazolines are available to 
children in common household products, such as eye drops and nasal 
sprays. Products containing imidazolines currently do not use CR 
packaging. The Commission concludes that a regulation is needed to 
ensure that products subject to the regulation will be placed in CR 
packaging by any current, as well as new manufacturers.
    Pursuant to Section 3(a) of the PPPA, 15 U.S.C. 1472(a), the 
Commission finds that the degree and nature of the hazard to children 
from handling, using, or ingesting imidazolines is such that special 
packaging is required to protect children from serious illness. The 
Commission bases this finding on the toxic nature of imidazolines and 
the accessibility of products containing imidazolines in the home.

B. Technically Feasibility, Practicability, and Appropriateness

    In issuing a standard for special packaging under the PPPA, the 
Commission also is required to find the special packaging is 
``technically feasible, practicable and appropriate.'' 15 U.S.C. 1472 
(a)(2). For special packaging to be technically feasible, the 
technology must be available, or can be readily developed and 
implemented to produce packaging that conforms to established 
standards. A package is practicable if the special packaging is 
adaptable to modern mass production

[[Page 73300]]

and assembly line techniques. Finally, packaging is appropriate if the 
packaging will adequately protect the integrity of the substance and 
will not interfere with its intended storage or use. All three of these 
conditions must be met before we can require special packaging for a 
product.
    The definition of ``packaging'' is ``the immediate package or 
wrapping in which any household substance is contained for consumption, 
use, or storage by individuals in or about the household.'' The PPPA 
defines ``special packaging'' as packaging that is designed or 
constructed to be significantly difficult for children under 5 years of 
age to open or obtain a toxic or harmful amount of substance within a 
reasonable time and not difficult for normal adults to use properly. 15 
U.S.C. 1471(4). The child-resistance and adult-use-effectiveness of 
special packaging are measured by performance, testing packaging with 
children and senior adults, respectively.
    We evaluated packaging representative of OTC products that contain 
imidazolines. The specimens represent products from all four 
imidazoline families: naphazoline hydrochloride (HCL), oxymetazoline 
HCL, tetrahydrozoline HCL, xylometazoline, and a naphazoline HCL 
combination product. None of the samples used special packaging. The 
eye drops were packaged in squeeze-to-dispense plastic dropper bottles. 
The nasal spray was packaged in a plastic bottle with an attached 
metered-pump sprayer, and the nasal drops were packaged in a squeeze-
to-dispense plastic dropper bottle. See January 11, 2012, Staff 
Briefing Package, for a more detailed discussion of the products: 
http://www.cpsc.gov/library/foia/foia12/brief/imidazolines.pdf.
    With changes to package size and/or type, certain types of 
packaging, such as ASTM Type IA, ASTM Type ID, and a CR metered-pump 
sprayer design, are available to the market to replace the non-CR 
continuously threaded (NCRCT) and the non-CR (NCR) metered-spray pump 
packages. Product packaging assembly line techniques used for the NCR 
packages can be adapted for some of the CR packages already in the 
marketplace. Other product manufacturers may use packages that could 
require changes in assembly- and filling-line techniques. New package 
sizes also may need to be designed. These new packages would require 
new tools to be produced. It could take up to 2 years from initiating 
tool design to final production of a new package, depending upon the 
complexity of the package. The Commission did not receive any comments 
asserting that CR packaging for products containing imidazolines was 
not technically feasible, practicable, or appropriate; although two 
comments addressed the amount of time required to develop, test, and 
produce CR packaging for products containing imidazolines. As will be 
discussed in further detail in Section VI, we have determined that a 
12-month effective date, with an additional 12-month conditional stay 
of enforcement will provide sufficient time for manufacturers to 
produce CR packaging in compliance with this rule.
    Based on the foregoing, the Commission concludes that available 
data support the findings that CR packaging for household products 
containing imidazolines is technically feasible, practicable, and 
appropriate.

C. Other Considerations

    In establishing a special packaging standard under the PPPA, the 
Commission must consider the following:

    1. Reasonableness of the standard;
    2. Available scientific, medical, and engineering data 
concerning special packaging and childhood accidental ingestions, 
illness, and injury caused by household substances;
    3. Manufacturing practices of industries affected by the PPPA; 
and
    4. Nature and use of the household substance.

15 U.S.C. 1472(b). The Commission has considered these factors with 
respect to the various determinations made in this notice, and finds 
that the rule is reasonable and otherwise appropriate.

VI. Effective Date

    The PPPA provides that no regulation shall take effect sooner than 
180 days or later than 1 year from the date such final regulation is 
issued, except that, for good cause, the Commission may establish an 
earlier effective date if it determines an earlier date to be in the 
public interest. 15 U.S.C. 1471n.
    The Commission stated in the preamble to the NPR that because it 
could take up to 1 year to produce a new package for some companies, 
any final rule would become effective 1 year after publication of the 
final rule in the Federal Register.
    As discussed in section I.C. of this preamble, the Commission 
received comments indicating that more than 12 months would be 
necessary to design, develop, test, and manufacture CR packaging for 
many of the products containing imidazolines currently on the market. 
Two commenters indicated that a design could be modified, tested, and 
in commercial use in approximately 24 months. The Commission agrees 
that this time seems reasonable because companies will need to develop 
custom packaging, and the FDA must approve the packaging for acceptable 
sterilization and stability qualities.
    Because there are more than 60 products manufactured by 
approximately 45 companies that will be affected by this rule, and 
because the vast majority of these companies will likely require more 
than 1 year to comply with this rule, the Commission has determined to 
grant a 12-month conditional stay of enforcement of the rule for 
products containing the equivalent of 0.08 milligrams of imidazolines 
in one package, rather than require each manufacturer to request a stay 
of enforcement for each affected product. The Commission believes that 
it is important to establish accountability in meeting the CR 
requirements for products containing imidazolines within 24 months of 
the publication of this rule.
    Therefore, the Commission sets the following conditions for the 1-
year stay of enforcement. First, the manufacturer of an imidazoline 
product containing the equivalent of 0.08 milligrams of imidazolines or 
more must notify the Commission prior to the effective date of the 
final rule of its intent to avail itself of the stay, which notice 
shall include a detailed time line setting forth the steps necessary to 
produce CR packaging for its product(s) and the range of time 
anticipated for completion of each step. Manufacturers should be aware 
that submitting the required notice on or near the effective date of 
the rule may not allow Commission staff sufficient time to review their 
notice for completeness prior to the effective date of the rule. 
Second, each manufacturer providing notice of its intent to avail 
itself of the stay must submit quarterly reports to the Commission for 
each affected product, beginning on the effective date of the rule, and 
on or before the first day of each subsequent quarter during the one 
year stay period. The quarterly report must provide the following 
information: (a) Proposed packaging specifications; (b) estimated 
initial production date; (c) progress made and/or steps completed 
during the quarterly reporting period; and (d) reports of any incidents 
or exposures involving the firm's imidazoline-containing products that 
are subject to the rule. If a manufacturer fails to provide the above-
referenced notice in a timely fashion or timely submit any quarterly 
report, its imidazoline-containing products will be subject to 
enforcement of the CR packaging

[[Page 73301]]

requirement set forth in this rule as of the effective date of the 
rule.
    The rule would add a new paragraph 33 to 16 CFR 1700.14(a), which 
contains a list of substances requiring special packaging. Pursuant to 
Sec.  1700.14(a), all substances listed in Sec.  1700.14 must meet the 
requirements for special packaging contained in Sec.  1700.20(a) (on 
testing procedures for special packaging). Section 1700.14(a)(33) 
provides that any over-the-counter or prescription product containing 
the equivalent of 0.08 milligrams or more of an imidazoline 
(tetrahydrozoline, naphazoline, oxymetazoline, or xylometazoline) in a 
single package, must be packaged in accordance with the provisions of 
Sec.  1700.15(a), (b), and (c). Section 1700.15(a) contains general 
requirements for special packaging, such as the special packaging must 
continue to function with the effectiveness specifications set forth in 
Sec.  1700.15(b). Section 1700.15(b), pertaining to effectiveness 
specifications, provides criteria that special packaging tested 
pursuant to Sec.  1700.20 must meet. Finally, Sec.  1700.15(c) provides 
that special packaging subject to this paragraph (c) may not be reused.

VII. Environmental Impact

    Generally, our regulations are considered to have little or no 
potential for affecting the human environment, and environmental 
assessments and impact statements are not usually required. See 16 CFR 
1021.5(a). More specifically, requiring CR packaging for certain 
imidazoline-containing products is not expected to have an adverse 
impact on the environment. Accordingly, the rule falls within the 
categorical exclusion in 16 CFR 1021.5(b)(2) for product certification 
rules and an environmental assessment or environmental impact statement 
is not required.

VIII. Executive Order 12988 (Preemption)

    According to Executive Order 12988 (February 5, 1996), agencies 
must state in clear language the preemptive effect, if any, of new 
regulations. Section 7 of the PPPA provides that, generally, when a 
special packaging standard issued under the PPPA is in effect, ``no 
State or political subdivision thereof shall have any authority either 
to establish or continue in effect, with respect to such household 
substance, any standard for special packaging (and any exemption 
therefrom and requirement related thereto) which is not identical to 
the [PPPA] standard.'' 15 U.S.C. 1476(a). A state or local standard may 
be excepted from this preemptive effect if: (1) The state or local 
standard provides a higher degree of protection from the risk of injury 
or illness than the PPPA standard; and (2) the state or political 
subdivision applies to the Commission for an exemption from the PPPA's 
preemption clause and the Commission grants the exemption through a 
process specified at 16 CFR part 1061. 15 U.S.C. 1476(c)(1). In 
addition, the federal government, or a state or local government, may 
establish and continue in effect a nonidentical special packaging 
requirement that provides a higher degree of protection than the PPPA 
requirement for a household substance for the federal, state, or local 
government's own use. 15 U.S.C. 1476(b).
    Thus, with the exceptions noted above, the rule regarding CR 
packaging for household products containing an imidazoline above the 
regulated level would preempt nonidentical state or local special 
packaging standards for such imidazoline-containing products.

IX. Regulatory Flexibility Act (Economic Analysis)

    When an agency undertakes a rulemaking proceeding, the Regulatory 
Flexibility Act (RFA) generally requires that agencies review proposed 
rules for their potential economic impact on small entities, including 
small businesses. Section 603 of the RFA calls for agencies to prepare, 
and make available for public comment, an initial regulatory 
flexibility analysis describing the impact of the proposed rule on 
small entities and identifying impact-reducing alternatives. 5 U.S.C. 
603. Section 605(b) of the RFA, however, states that this requirement 
does not apply if the head of the agency certifies that the rule, if 
promulgated, will not have a significant economic impact on a 
substantial number of small entities and the agency provides an 
explanation for that conclusion.
    Nasal and ophthalmic products are classified within the NAICS 
325412 Pharmaceutical Preparation Manufacturing industry. According to 
the U.S. Small Business Administration's Office of Advocacy, a firm 
classified within NAICS 325412 is considered a small business if the 
firm has fewer than 750 employees. Based on such classification, out of 
the approximately 45 firms that manufacture imidazoline-based eye drops 
and nasal sprays, approximately 20 firms are defined as ``small 
businesses.'' There may be more manufacturers, in particular, firms 
that manufacture under generic labels, which were not identified but 
that may be small businesses.
    As noted in the NPR, the Commission's Directorate of Economic 
Analysis prepared a preliminary assessment of the impact of a rule to 
require special packaging for products containing imidazolines 
equivalent to 0.08 milligrams or more in a single package. Based on 
this assessment, the Commission concluded that the proposed requirement 
for products containing imidazolines, if finalized, would not have a 
significant impact on a substantial number of small businesses. The 
Commission requested additional information on the possible impact on 
small businesses, but we received no such comments. Moreover, the 
preliminary analysis demonstrated that the incremental costs of CR 
packaging for manufacturers are low, estimated at no more than a few 
cents per unit for imidazoline products, some of which costs 
manufacturers are likely to be able to pass on to consumers. The 
Commission concludes that the rule regarding CR packaging for certain 
imidazoline products would not have a significant economic impact on a 
substantial number of small entities.

X. References

    Please see all citing references in staff's briefing package for 
the proposed rule, available at: http://www.cpsc.gov/library/foia/
foia12/brief/imidazolines.pdf and for the final rule, available at 
http://www.cpsc.gov/LIBRARY/FOIA/FOIA13/brief/imidazfinal.pdf.

List of Subjects in 16 CFR Part 1700

    Consumer protection, Drugs, Infants and children, Packaging and 
containers, Poison prevention, Toxic substances.

    For the reasons given above, the Commission amends 16 CFR part 1700 
to read as follows:

PART 1700--[AMENDED]

0
1. The authority citation for part 1700 continues to read as follows:

    Authority: Pub. L. 91-601, secs. 1-9, 84 Stat. 1670-74, 15 
U.S.C. 1471-76. Secs 1700.1 and 1700.14 also issued under Pub. L. 
92-573, sec. 30(a), 88 Stat. 1231. 15 U.S.C. 2079(a).

0
2. Section 1700.14 is amended by adding paragraph (a)(33) to read as 
follows:

Sec.  1700.14  Substances requiring special packaging.

    (a) * * *
    (33) Imidazolines. Any over-the-counter or prescription product 
containing the equivalent of 0.08

[[Page 73302]]

milligrams or more of an imidazoline (tetrahydrozoline, naphazoline, 
oxymetazoline, or xylometazoline) in a single package, must be packaged 
in accordance with the provisions of Sec.  1700.15(a), (b), and (c).
* * * * *

    Dated: November 29, 2012.
Todd A. Stevenson,
Secretary, Consumer Product Safety Commission.
[FR Doc. 2012-29203 Filed 12-7-12; 8:45 am]
BILLING CODE 6355-01-P
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