[Federal Register Volume 77, Number 237 (Monday, December 10, 2012)]
[Rules and Regulations]
[Pages 73294-73302]
From the Federal Register Online via the Government Publishing 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; [email protected].
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
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Eye drops..................................... 5,437 0.18 161 3,564-7,309
Nose Sprays \2\............................... 1,213 0.29 37 534-1891
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Total..................................... 6,650 0.16 198 4,550-8,749
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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