Products Containing Imidazolines Equivalent to 0.08 Milligrams or More, 3646-3653 [2012-1446]
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Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules
certain generally-licensed devices, and
specific licensing of all generallylicensed devices currently registered by
the NRC.
The NRC believes that the change to
compatibility category C will allow
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particularly those operating on a
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[FR Doc. 2012–1499 Filed 1–24–12; 8:45 am]
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CONSUMER PRODUCT SAFETY
COMMISSION
[FR Doc. 2012–1523 Filed 1–24–12; 8:45 am]
Products Containing Imidazolines
Equivalent to 0.08 Milligrams or More
BILLING CODE 7590–01–P
16 CFR Part 1700
[CPSC Docket No. CPSC–2012–0005]
Consumer Product Safety
Commission.
ACTION: Notice of proposed rulemaking.
sroberts on DSK5SPTVN1PROD with PROPOSALS
AGENCY:
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
SUMMARY:
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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
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: https://
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
https://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 https://
www.regulations.gov. Do not submit
confidential business information, trade
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 https://www.cpsc.gov/pr/statements.html.
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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 https://
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
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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
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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 https://
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
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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 tetrahydrozolineand 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®,
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
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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®, 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 followback 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
https://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
injuries
Product
Coefficient
of variation
95%
confidence
interval
Sample
size
4,571
1,104
0.19
0.31
138
34
2,831–6,311
426–1,782
Total ........................................................................................................
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Eye drops .......................................................................................................
Nose Sprays 2 ................................................................................................
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.
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TABLE 2—SELECTED IN-DEPTH INVESTIGATION NEISS REPORTS SHOWING CHILD ACCESS TO IMIDAZOLINE PRODUCTS
Age
Imidazoline
product
How accessed
(from case narrative)
991018HEP9007 .................
13-month-old .....................
Eye drops ..........................
050525HEP9006 .................
15-month-old .....................
Eye drops ..........................
080714HEP9016 .................
980430HEP9006 .................
050907HEP9001 .................
15-month-old .....................
18-month-old .....................
20-month-old .....................
Eye drops ..........................
Eye drops ..........................
Eye drops ..........................
011023HEP9001 .................
000531HEP9005 .................
23-month-old .....................
2-year-old ..........................
Eye drops ..........................
Nasal Spray .......................
000601HEP9015 .................
2-year-old ..........................
Eye drops ..........................
011023HEP9003 .................
2-year-old ..........................
Eye drops ..........................
020130HEP9003 .................
2-year-old ..........................
Eye drops ..........................
970306HEP9001 .................
2-year-old ..........................
Eye drops ..........................
990301HEP9015 .................
2-year-old ..........................
Eye drops ..........................
990416HEP9008 .................
2-year-old ..........................
Nasal Spray .......................
990419HEP9022 .................
2-year-old ..........................
Eye drops ..........................
991018HEP9012 .................
2-year-old ..........................
Eye drops ..........................
020321HEP9004 .................
3-year-old ..........................
Eye drops ..........................
091009HEP9010 .................
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NEISS Case #
4-year-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.
Parents saw child playing with bottle of eye drops.
She had gotten cap off. Parents noted cap was broken on examination.
Child found playing with empty bottle of eye drops.
Older sibling opened bottle and gave to victim.
Eye drops on low dresser, child was able to reach
with her hands. Parents say child can open ‘‘anything.’’
Child pulled eye drops off counter and removed lid.
Child came out of bathroom with empty bottle. Bottle
had not been put away properly and was within victim’s reach.
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.
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.
Took eye drops out of mother’s purse and opened
tightly closed cap.
Child found in bedroom with open bottle of eye drops.
She opened bottle with her teeth.
Child took bottle of eye drops off of dresser and unscrewed top.
Child was in bedroom watching TV on bed. Took
nasal spray off of nightstand next to bed. Open,
empty bottle found on bed.
Bottle left on counter in bathroom was found empty in
child’s hand.
Child found holding bottle of eye drops; cap had been
removed and was in his mouth.
Child found in bedroom with opened bottle of 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
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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
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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
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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 passed out
and stopped breathing. Given CPR
and taken to ER.
18 mos .................
FDA MedWatch
439578450001 6/
2004.
3–4 mg naphazoline.
3–4 mg naphazoline.
3 yrs .....................
1.3 mg
tetrahydrozoline.
‘‘Soon’’ became ‘‘quite drowsy’’ for
several hours.
One hour after ingestion. Became
hypothermic, lethargic, irritable,
pale, irregular gasping respirations,
hypertension, bradycardia. Followed by unconsciousness and imperceptible respirations.
90 minutes Lethargic, decreased
heart rate, decreased blood pressure.
Sharp increase and then decrease of
heart rate.
Decreased heart rate Lethargic, difficult to arouse, depressed respiration.
2 hrs. Ataxic, pale, drowsy, decreased heart rate, decreased respiration.
30 min. Lethargic, difficulty breathing,
vomiting, loss of consciousness.
Given fluids and admitted to ICU.
Aroused from coma 8–10 hours
later. Released later that day. Having headaches 3–4 times daily.
Several hours .....................................
1–1.5 mg
tetrahydrozoline.
2–3 hrs Lethargy, decreased blood
pressure, decreased respiration.
2 yrs .....................
0.25 mg x 3 or
0.75 *
tetrahydrozoline.
2 hrs. Apnea, decreased respirations,
slowed heart rate.
25 days ................
2–2.5 mg
tetrahydrozoline.
Up to 2 mg
tetrahydrozoline.
1.25–2.5 mg
tetrahydrozoline.
1.25–2.5 mg
tetrahydrozoline.
Waring 1945.
22 mos .................
Child warmed and treated with caffeine and oxygen. Symptoms resolved after 15 hrs.
Hainsworth 1948.
17 mos .................
Pediatric intensive care unit Recovered 24 hrs.
Jensen et al. 1989.
22 mos .................
Pediatric intensive care unit ...............
FDA540321.
16 mos .................
Admitted to hospital overnight ............
FDA671307.
1 yr .......................
Admitted to hospital Recovered 24
hrs.
Mindlin 1966.
2 yrs .....................
Admitted to hospital, treated with
charcoal. Released from hospital
same day, symptoms resolved.
Pediatric intensive care unit Mechanical respiration for 18 hrs Recovered 48 hrs.
Admitted to hospital Naloxone, Continuous positive airway pressure,
oxygen Recovered 2 days.
FDA 43222810001.
Tobias 1996.
Katar et al. 2010.
* Due to diminished clearance of drugs by the liver and kidney of the newborn, the three doses are considered additive.
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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 imidazolinecontaining 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-
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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
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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.
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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
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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
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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-todispense 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
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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
§ 1700.14(a), all substances listed in
§ 1700.14 must meet the requirements
for special packaging contained in
§ 1700.20(a) (on testing procedures for
special packaging). Proposed
§ 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
§ 1700.15(a), (b), and (c). Section
1700.15(a) contains general
requirements for special packaging,
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such as the special packaging must
continue to function with the
effectiveness specifications set forth in
§ 1700.15(b). Section 1700.15(b), on
effectiveness specifications, provides
criteria that special packaging tested
pursuant to § 1700.20 must meet.
Finally, § 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.
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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
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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 nonidentical 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
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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
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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.
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
XIII. References
Import Tolerances for Residues of
Unapproved New Animal Drugs in
Food
Please see all citing references in the
staff’s briefing package, available at
https://www.cpsc.gov/library/foia/foia12/
brief/imidazolines.pdf.
List of Subjects in 16 CFR Part 1700
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:
§ 1700.14 Substances requiring special
packaging.
(a) * * *
(33) Imidazolines. Any over-thecounter 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
§ 1700.15(a), (b), and (c).
[FR Doc. 2012–1446 Filed 1–24–12; 8:45 am]
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BILLING CODE 6355–01–P
21 CFR Parts 10, 20, 25, and 510
[Docket No. FDA–2001–N–0075 (formerly
Docket No. 2001N–0284)]
RIN 0910–AF78
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Proposed rule.
The Food and Drug
Administration (FDA) is proposing to
establish procedures by which a person
may request that the Agency establish or
amend tolerances for unapproved new
animal drugs where edible portions of
animals imported into the United States
may contain residues of such drugs
(import tolerances), as well as
procedures to revoke an existing import
tolerance. Such import tolerances
provide a basis for legally marketing
food of animal origin that is imported
into the United States and contains
residues of unapproved new animal
drugs.
SUMMARY:
Consumer protection, Drugs, Infants
and children, Packaging and containers,
Poison prevention, Toxic substances.
Dated: January 20, 2012.
Todd A. Stevenson,
Secretary, Consumer Product Safety
Commission.
Food and Drug Administration
Submit either electronic or
written comments on the proposed rule
by April 24, 2012. Submit comments on
information collection issues under the
Paperwork Reduction Act of 1995 by
February 24, 2012, (see the ‘‘Paperwork
Reduction Act of 1995’’ section of this
document).
ADDRESSES: You may submit comments,
identified by Docket No. FDA–2001–N–
0075 and RIN 0910–AF78, by any of the
following methods, except that
comments on information collection
issues under the Paperwork Reduction
Act of 1995 must be submitted to the
Office of Regulatory Affairs, Office of
Management and Budget (OMB) (see the
‘‘Paperwork Reduction Act of 1995’’
section of this document).
DATES:
Electronic Submissions
Submit electronic comments in the
following way:
• Federal eRulemaking Portal: https://
www.regulations.gov. Follow the
instructions for submitting comments.
Written Submissions
Submit written submissions in the
following ways:
• Fax: (301) 827–6870.
• Mail/Hand delivery/Courier (for
paperor CD–ROM submissions):
Division of Dockets Management (HFA–
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3653
305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville,
MD 20852.
Instructions: All submissions received
must include the Agency name, Docket
No. FDA–2001–N–0075, and RIN 0910–
AF78 for this rulemaking. All comments
received may be posted without change
to https://www.regulations.gov, including
any personal information provided. For
additional information on submitting
comments, see the ‘‘Comments’’ heading
of the SUPPLEMENTARY INFORMATION
section of this document.
Docket: For access to the docket to
read background documents or
comments received, go to https://
www.regulations.gov and insert the
docket number, found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Division of Dockets
Management, 5630 Fishers Lane, rm.
1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT:
Scott Melton, Center for Veterinary
Medicine (HFV–232), Food and Drug
Administration, 7519 Standish Pl.,
Rockville, MD 20855, (240) 276–8666,
email: scott.melton@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
A. Legislative and Rulemaking
Background
The President signed into law the
Animal Drug Availability Act of 1996
(ADAA) on October 9, 1996. Section 4
of the ADAA amended section 512(a) of
the Federal Food, Drug, and Cosmetic
Act (the FD&C Act) (21 U.S.C. 360b(a))
by adding the following: ‘‘(6) For
purposes of section 402(a)(2)(D) (now
section 402(a)(2)(C)(ii) as a result of the
Food Quality Protection Act), a use or
intended use of a new animal drug shall
not be deemed unsafe under this section
if the Secretary establishes a tolerance
for such drug (import tolerance) and any
edible portion of any animal imported
into the United States does not contain
residues exceeding such tolerance. In
establishing such tolerance, the
Secretary shall rely on data sufficient to
demonstrate that a proposed tolerance is
safe based on similar food safety criteria
used by the Secretary to establish
tolerances for applications for new
animal drugs filed under subsection
(b)(1). The Secretary may consider and
rely on data submitted by the drug
manufacturer, including data submitted
to appropriate regulatory authorities in
any country where the new animal drug
is lawfully used or data available from
a relevant international organization, to
the extent such data are not inconsistent
with the criteria used by the Secretary
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]]>Agencies
[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 https://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: https://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 https://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 https://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 https://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 https://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 https://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
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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 https://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
