[Federal Register Volume 77, Number 16 (Wednesday, January 25, 2012)]
[Proposed Rules]
[Pages 3646-3653]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-1446]
=======================================================================
-----------------------------------------------------------------------
CONSUMER PRODUCT SAFETY COMMISSION
16 CFR Part 1700
[CPSC Docket No. CPSC-2012-0005]
Products Containing Imidazolines Equivalent to 0.08 Milligrams or
More
AGENCY: Consumer Product Safety Commission.
ACTION: Notice of proposed rulemaking.
-----------------------------------------------------------------------
SUMMARY: The Consumer Product Safety Commission (``CPSC,''
``Commission,'' or ``we'') is proposing 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 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 treated with these drugs or who
accidentally ingest them. Based on the scientific data, the Commission
preliminarily finds 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, using, or
ingesting such a substance. We are taking this action under the Poison
Prevention Packaging Act of 1970 (``PPPA'').\1\
---------------------------------------------------------------------------
\1\ The Commission voted 4-0 to publish this notice in the
Federal Register. Commissioner Robert S. Adler issued a statement,
which can be found at http://www.cpsc.gov/pr/statements.html.
---------------------------------------------------------------------------
DATES: Written comments must be received by April 9, 2012.
ADDRESSES: You may submit comments, identified by Docket No. CPSC-2012-
0005, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov. Follow the
instructions for submitting comments. To ensure timely processing of
comments, the Commission is no longer accepting comments submitted by
electronic mail (email) except through http://www.regulations.gov.
Written Submissions
Submit written submissions in the following way:
Mail/Hand delivery/Courier (for paper, disk, or CD-ROM
submissions), preferably in five copies, to: Office of the Secretary,
Consumer Product Safety Commission, Room 802, 4330 East West Highway,
Bethesda, MD 20814; telephone (301) 504-7923.
Instructions: All submissions received must include the agency name
and docket number for this notice of proposed rulemaking. All comments
received may be posted without change, including any personal
identifiers, contact information, or other personal information
provided, to http://www.regulations.gov. Do not submit confidential
business information, trade
[[Page 3647]]
secret information, or other sensitive or protected information
electronically. Such information should be submitted in writing.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov.
FOR FURTHER INFORMATION CONTACT: Cheryl A. Osterhout Ph.D.,
Pharmacologist, Project Manager, Directorate for Health Sciences,
Consumer Product Safety Commission, 4330 East West Highway, Bethesda,
MD 20814; telephone (301) 504-7290; costerhout@cpsc.gov.
SUPPLEMENTARY INFORMATION:
I. Background
A. What is the purpose of the proposed rule?
To protect children younger than 5 years old from serious personal
injury following ingestion, the proposed rule would require 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. Why is CR packaging necessary for certain OTC or prescription
products containing imidazolines?
Imidazolines are a family of drugs that are used as decongestants
in eye drops and nasal products. Topical and nasal administration of
imidazolines result in little absorption into the general circulation.
Orally ingested, however, imidazolines 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
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. 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 products are not
manufactured in CR packaging.
C. What statutory authority does CPSC have to regulate child resistant
packaging?
The Poison Prevention Packaging Act of 1970 (``PPPA''), 15 U.S.C.
1471-1476, authorizes us 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 we 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). We have 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.
II. Toxicity of Imidazolines
Tab A of the CPSC staff's briefing package, available at http://www.cpsc.gov/library/foia/foia12/brief/imidazolines.pdf contains the
Directorate for Health Sciences' toxicity review for imidazolines,
referred to hereinafter as ``Tab A: Staff Briefing Package.''
A. What medical conditions are imidazolines used to treat?
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.
B. What health risks are there for people who overdose on or orally
ingest imidazolines?
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 normal 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 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 one 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
[[Page 3648]]
severe life-threatening consequences, including decreased breathing,
decreased heart rate, and loss of consciousness, which require
hospitalization to ensure recovery. Table 3, in section III.B of this
preamble, summarizes relevant cases of imidazoline ingestion.
U.S. Food and Drug Administration (``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. Other reported
cardiovascular adverse events include: palpitation (rapid heart rate),
cardiac arrhythmia (variation from the normal rhythm of the heart),
coronary occlusion (partial or complete obstruction of blood flow in a
coronary artery), pulmonary embolism (lodging of mass in a lung),
subarachnoid hemorrhage (bleeding between brain and surrounding
tissues), myocardial infarction (interruption of blood supply to part
of the heart, causing heart cells to die), stroke, and death associated
with cardiac reactions in adults. Other systemic side effects can
include: blanching (temporary whitening of the skin), sweating, nausea,
gastric irritation, weakness, and high blood sugar (POISINDEX[supreg],
2011).
C. What treatment options are available for imidazoline overexposure?
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 imidazolines
is supportive based on symptoms. For example, mechanical respiration
would be administered to those with severe respiratory depression.
III. Ingestion and Injury Data
A. What data on imidazoline poisonings is contained in the National
Electronic Injury Surveillance System (``NEISS'')?
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 (Boja, 2001). NEISS is a statistically valid injury
surveillance and follow-back database that we maintain 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 us 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. Our review of data obtained
from CAP is summarized in Tab B of the Staff's Briefing Package,
hereinafter Tab B: Staff Briefing Package.
We searched the CAP database for incidents between January 1997 and
December 2009, involving household products that typically contain
imidazolines. During that time, there were an estimated 5,675 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 (81 percent) involved
eye drops.
Table 1--Estimated Imidazoline Product-Related Injuries to Children Under 5 Years Old, 1997-2009, by Product
Group
----------------------------------------------------------------------------------------------------------------
Estimated Coefficient 95% confidence
Product injuries of variation Sample size interval
----------------------------------------------------------------------------------------------------------------
Eye drops...................................... 4,571 0.19 138 2,831-6,311
Nose Sprays \2\................................ 1,104 0.31 34 426-1,782
----------------------------------------------------------------
Total...................................... 5,675 0.18 172 3,666-7,684
----------------------------------------------------------------------------------------------------------------
Source: U.S. Consumer Product Safety Commission National Electronic Injury Surveillance System and Children and
Poisoning System, 2011.
The following table of NEISS In-Depth Investigations qualitatively
illustrates that children were able to obtain access to imidazoline
packages.
---------------------------------------------------------------------------
\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.
[[Page 3649]]
Table 2--Selected In-Depth Investigation NEISS Reports Showing Child Access to Imidazoline Products
----------------------------------------------------------------------------------------------------------------
How accessed (from case
NEISS Case Age Imidazoline product narrative)
----------------------------------------------------------------------------------------------------------------
991018HEP9007...................... 13-month-old.......... Eye drops............. Eye drops were on counter.
Bottle may have been
partially open. Child
found with open bottle of
eye drops with cap in her
mouth.
050525HEP9006...................... 15-month-old.......... Eye drops............. Parents saw child playing
with bottle of eye drops.
She had gotten cap off.
Parents noted cap was
broken on examination.
080714HEP9016...................... 15-month-old.......... Eye drops............. Child found playing with
empty bottle of eye drops.
980430HEP9006...................... 18-month-old.......... Eye drops............. Older sibling opened bottle
and gave to victim.
050907HEP9001...................... 20-month-old.......... Eye drops............. Eye drops on low dresser,
child was able to reach
with her hands. Parents
say child can open
``anything.''
011023HEP9001...................... 23-month-old.......... Eye drops............. Child pulled eye drops off
counter and removed lid.
000531HEP9005...................... 2-year-old............ Nasal Spray........... Child came out of bathroom
with empty bottle. Bottle
had not been put away
properly and was within
victim's reach.
000601HEP9015...................... 2-year-old............ Eye drops............. Mother left bottle on sink
in bathroom after using
it. Victim came out of
bathroom sucking on
bottle. Not clear if child
or mother took cap off.
011023HEP9003...................... 2-year-old............ Eye drops............. Used chair to get to
medicine cabinet in
kitchen. Took out eye
drops and opened them.
Mother found child on
kitchen counter with open
eye drops in hand.
020130HEP9003...................... 2-year-old............ Eye drops............. Took eye drops out of
mother's purse and opened
tightly closed cap.
970306HEP9001...................... 2-year-old............ Eye drops............. Child found in bedroom with
open bottle of eye drops.
She opened bottle with her
teeth.
990301HEP9015...................... 2-year-old............ Eye drops............. Child took bottle of eye
drops off of dresser and
unscrewed top.
990416HEP9008...................... 2-year-old............ Nasal Spray........... Child was in bedroom
watching TV on bed. Took
nasal spray off of
nightstand next to bed.
Open, empty bottle found
on bed.
990419HEP9022...................... 2-year-old............ Eye drops............. Bottle left on counter in
bathroom was found empty
in child's hand.
991018HEP9012...................... 2-year-old............ Eye drops............. Child found holding bottle
of eye drops; cap had been
removed and was in his
mouth.
020321HEP9004...................... 3-year-old............ Eye drops............. Child found in bedroom with
opened bottle of eye
drops.
091009HEP9010...................... 4-year-old............ Eye drops............. Bottle left on counter.
Child was found with open
bottle.
----------------------------------------------------------------------------------------------------------------
B. What data on imidazoline poisonings are contained in the FDA's
Adverse Event Reporting System (``AERS'')?
The AERS is a database of voluntary reports from health care
professionals and consumers, and 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
involving both children and adults occurring between October 1968 and
August 2010, for us to review. 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 across all ages associated with the use of imidazolines. 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 Tab B: Staff Briefing Package.
C. What other information is available on the frequency, volume, and
severity of ingestion of imidazolines?
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. Very serious adverse effects
occurred in response to small oral doses of imidazolines; these are
highlighted in Table 3 below, from highest to lowest dose in
milligrams.
In MedWatch reports of adverse events occurring in response to
ingestion of imidazolines, 43 cases occurred in children under 5 years
old. Tetrahydrozoline ingestions constituted the majority of the cases
(88 percent). There were no reported deaths related to imidazoline
ingestion. See Tab A: Staff Briefing Package, Appendix A, 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
[[Page 3650]]
and liver function of the newborn caused the drugs to clear the
newborn's system slower 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 two 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 Tab A: Staff
Briefing Package.
Table 3--Relevant Cases of Imidazoline Ingestion
--------------------------------------------------------------------------------------------------------------------------------------------------------
Estimated dose Onset/symptoms Age Result Reference
--------------------------------------------------------------------------------------------------------------------------------------------------------
2.8-5.6 mg oxymetazoline............ Within 5 minutes. Child 18 mos................ Given fluids and admitted FDA MedWatch 439578450001 6/
passed out and stopped to ICU. Aroused from coma 2004.
breathing. Given CPR and 8-10 hours later. Released
taken to ER. later that day. Having
headaches 3-4 times daily.
3-4 mg naphazoline.................. ``Soon'' became ``quite 3 yrs................. Several hours.............. Waring 1945.
drowsy'' for several hours.
3-4 mg naphazoline.................. One hour after ingestion. 22 mos................ Child warmed and treated Hainsworth 1948.
Became hypothermic, with caffeine and oxygen.
lethargic, irritable, Symptoms resolved after 15
pale, irregular gasping hrs.
respirations,
hypertension, bradycardia.
Followed by
unconsciousness and
imperceptible respirations.
2-2.5 mg tetrahydrozoline........... 90 minutes Lethargic, 17 mos................ Pediatric intensive care Jensen et al. 1989.
decreased heart rate, unit Recovered 24 hrs.
decreased blood pressure.
Up to 2 mg tetrahydrozoline......... Sharp increase and then 22 mos................ Pediatric intensive care FDA540321.
decrease of heart rate. unit.
1.25-2.5 mg tetrahydrozoline........ Decreased heart rate 16 mos................ Admitted to hospital FDA671307.
Lethargic, difficult to overnight.
arouse, depressed
respiration.
1.25-2.5 mg tetrahydrozoline........ 2 hrs. Ataxic, pale, 1 yr.................. Admitted to hospital Mindlin 1966.
drowsy, decreased heart Recovered 24 hrs.
rate, decreased
respiration.
1.3 mg tetrahydrozoline............. 30 min. Lethargic, 2 yrs................. Admitted to hospital, FDA 43222810001.
difficulty breathing, treated with charcoal.
vomiting, loss of Released from hospital
consciousness. same day, symptoms
resolved.
1-1.5 mg tetrahydrozoline........... 2-3 hrs Lethargy, decreased 2 yrs................. Pediatric intensive care Tobias 1996.
blood pressure, decreased unit Mechanical
respiration. respiration for 18 hrs
Recovered 48 hrs.
0.25 mg x 3 or 0.75 * 2 hrs. Apnea, decreased 25 days............... Admitted to hospital Katar et al. 2010.
tetrahydrozoline. respirations, slowed heart Naloxone, Continuous
rate. positive airway pressure,
oxygen Recovered 2 days.
--------------------------------------------------------------------------------------------------------------------------------------------------------
* Due to diminished clearance of drugs by the liver and kidney of the newborn, the three doses are considered additive.
IV. Level for Regulation
Absorption of imidazolines after oral ingestion can lead to
unpredictable and profound CNS depression, including depressed
respiration and cardiovascular events. It has been shown that children
under 5 years old are accidentally ingesting imidazoline-containing
products. The first cases of imidazoline toxicity in children after
accidental ingestion occurred in the mid-1940s, shortly after the
release of naphazoline into the market; and the incidents have
continued to occur for more than 50 years (Waring 1945, Greenblat 1947,
Hainsworth 1948, Meeker 1948, Bucaretchi et al., 2003). Symptoms of
imidazoline toxicity include CNS depression, ranging from drowsiness to
coma, bradycardia, and hypoventilation. 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 Table 3, section III.C of this
preamble, for a summary of relevant cases of imidazoline ingestion.
Mindlin (1966) reported a case in which a 1-year-old girl ingested
between \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). In the preamble to the
proposed FDA rule for OTC nasal decongestants, it was 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 above in section III.C 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 of ingestion of which we
are aware that caused severe adverse symptoms in a child.
[[Page 3651]]
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 (see Tables 1 and 2) 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
NOEL (no observable effect level) or its equivalent. We used a tenfold
safety factor to divide the LOEL to reach a NOEL level.
V. Preliminary Findings Related to Child Resistant Packaging for
Imidazolines
A. Do imidazolines in non-CR packaging pose a hazard to children?
As noted above in sections II.B and III of this document, 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 preliminarily 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.
B. Is it technically feasible, practicable, and appropriate for the
Commission to require special packaging for certain imidazoline-
containing products?
Special packaging under the PPPA is designed to protect children
from serious personal injury or illness. In addition to finding that
special packaging is necessary to protect children, we must find that
special packaging is technically feasible, practicable, and appropriate
for these products (15 U.S.C. 1472(a)(2)). For special packaging to be
technically feasible, the technology must be available to produce
packaging that conforms to established standards. A package is
practicable if the special packaging is adaptable to modern mass
production and assembly line techniques. Finally, packaging is
appropriate if the packaging will protect the integrity of the
substance adequately 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.
Section 2(4) of the PPPA. 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 Tab C: Staff Briefing Package,
for a more detailed discussion of the products.
With package size and/or type changes, 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 1
year from initiating tool design to final production of a new package,
depending upon the complexity of the package.
Based on the foregoing, we preliminarily conclude that available
data support the findings that CR packaging for household products
containing imidazolines is technically feasible, practicable, and
appropriate.
C. Has the Commission made any other findings related to special
packaging?
In establishing a special packaging standard under the PPPA, we
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). We have considered these factors with respect to the
various determinations made in this notice, and preliminarily find no
reason to conclude that the rule is unreasonable or otherwise
inappropriate.
VI. Description of the Proposed Rule
The proposed 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).
Proposed Sec. 1700.14(a)(33) would provide 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,
[[Page 3652]]
such as the special packaging must continue to function with the
effectiveness specifications set forth in Sec. 1700.15(b). Section
1700.15(b), on 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. Request for Comments
We invite interested persons to submit comments on any aspect of
the proposed rule. Comments should be submitted in accordance with the
instructions in the ADDRESSES section at the beginning of this notice.
VIII. 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.
IX. 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 proposed rule regarding
CR packaging for household products containing an imidazoline above the
regulated level would preempt non-identical state or local special
packaging standards for such imidazoline containing products.
X. Regulatory Flexibility Act (Economic Analysis)
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, that were not identified but that may
be small businesses.
Preliminary analysis shows the proposed rule would, if finalized,
not have a significant impact on a substantial number of small
businesses. First, the incremental costs of CR packaging for
manufacturers are low, estimated at 1.5 cents per unit for imidazoline
products. Manufacturers are likely to be able to pass on at least some
of these costs to consumers. Second, most manufacturers of OTC drug
products have diverse product lines that include other products that
would not be covered by this possible regulation. Therefore, the
products that would be affected by this proposed regulation may
represent a small proportion of any one manufacturer's production.
Finally, the requirements would apply only to products packaged after
the effective date of the requirements. Therefore, businesses would
have time to use up existing inventories of product and packaging.
Based on the foregoing, we conclude preliminarily that the proposed
rule regarding CR packaging for certain imidazoline products would not
have a significant economic impact on a substantial number of small
entities.
XI. Trade Secret or Proprietary Information
Any person responding to this notice who believes that any
information submitted is trade secret or proprietary should
specifically identify the exact portions of the document claimed to be
confidential. We will receive and handle such information
confidentially and in accordance with section 6(a) of the Consumer
Product Safety Act (``CPSA''), 15 U.S.C. 2055(a). Such information will
not be placed in a public file and will not be made available to the
public simply upon request. If we receive a request for disclosure of
the information or conclude that its disclosure is necessary to
discharge our responsibilities, we will inform the person who submitted
the information and provide that person an opportunity to present
additional information and views concerning the confidential nature of
the information. 16 CFR 1015.18(b).
Thereafter, we will make a determination of whether the information
is trade secret or proprietary information that cannot be released. The
determination will be made in accordance with applicable provisions of
the CPSA; the Freedom of Information Act (``FOIA''), 5 U.S.C. 552b; 18
U.S.C 1905; our procedural regulations at 16 CFR part 1015 governing
protection and disclosure of information under provisions of FOIA; and
relevant judicial interpretations. If we conclude that any part of
information that has been submitted with a claim that the information
is a trade secret or proprietary is disclosable, we will notify the
person submitting the material in writing and provide at least 10
calendar days from the receipt of the letter for that person to seek
judicial relief. 15 U.S.C. 2055(a)(5) and (6); 16 CFR 1015.19(b).
XII. Effective Date
The PPPA provides that no regulation shall take effect sooner than
180 days or later than 1 year from the date a final
[[Page 3653]]
regulation is issued, except that, for good cause, we may establish an
earlier effective date if we determine an earlier date to be in the
public interest. 15 U.S.C. 1471n. Because it could take up to 1 year to
produce a new package for some companies, we intend that any final rule
become effective 1 year after the publication of a final rule in the
Federal Register.
XIII. References
Please see all citing references in the staff's briefing package,
available at http://www.cpsc.gov/library/foia/foia12/brief/imidazolines.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 proposes to amend 16
CFR part 1700 as follows:
PART 1700--[AMENDED]
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).
2. Section 1700.14 is amended to add 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 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: January 20, 2012.
Todd A. Stevenson,
Secretary, Consumer Product Safety Commission.
[FR Doc. 2012-1446 Filed 1-24-12; 8:45 am]
BILLING CODE 6355-01-P