```

[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]

=======================================================================
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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.

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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\
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    \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.

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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
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                                                    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.
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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.

[[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
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