73294 Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 

1EPA. 1998. Health Effects Test Guidelines, 

OPPTS 870.2400 Acute Eye Irritation. EPA 712–C– 

98–195. Washington, DC: U.S. Environmental 

Protection Agency. (Available: http:// 

iccvam.niehs.nih.gov/SuppDocs/FedDocs/EPA/ 

EPA_870_2400.pdf) 

2OECD. 2002. OECD Guideline for the Testing of 

Chemicals 405: Acute Eye Irritation/Corrosion. 

Paris: Organisation for Economic Co-operation and 

Development. (Available: http:// 

iccvam.niehs.nih.gov/SuppDocs/FedDocs/OECD/ 

OECDtg405.pdf) 

other than skin tissue is being 

considered. A substance could also be 

labeled corrosive based on the outcome 

of any of the approved test methods 

described in the CPSC’s animal testing 

policy set forth in 16 CFR 1500.232, 

including data from in vitro or in silico 

test methods that the Commission has 

approved; or a validated weight-ofevidence analysis comprising all of the 

following that are available: Existing 

human and animal data, structure 

activity relationships, physicochemical 

properties, and chemical reactivity data. 

(4) The definition of irritant in section 

2(j) of the act (restated in paragraph 

(b)(8) of this section) is supplemented 

by the following: Irritant includes 

primary irritant to the skin, as well as 

substances irritant to the eye or to 

mucous membranes. Primary irritant 

means a substance that is not corrosive 

and that human experience data 

indicate is a primary irritant; and/or 

means a substance that results in an 

empirical score of five or more when 

tested by the method described in 

1500.41; and/or a substance that can be 

considered a primary irritant based on 

the outcome of any of the approved test 

methods described in the CPSC’s animal 

testing policy set forth in 16 CFR 

1500.232, including data from in vitro or 

in silico test methods that the 

Commission has approved; or a 

validated weight-of-evidence analysis 

comprising all of the following that are 

available: existing human and animal 

data, structure activity relationships, 

physicochemical properties, and 

chemical reactivity data. Eye irritant 

means a substance that human 

experience data indicate is an irritant to 

the eye; and/or means a substance for 

which a positive test is obtained when 

tested by the method described in 

1500.42; and/or means a substance that 

can be considered an eye irritant based 

on the outcome of any of the approved 

test methods described in the CPSC’s 

animal testing policy set forth in 16 CFR 

1500.232, including data from in vitro or 

in silico test methods that the 

Commission has approved; or a 

validated weight-of-evidence analysis 

comprising all of the following that are 

available: existing human and animal 

data, structure activity relationships, 

physicochemical properties, and 

chemical reactivity data. 

* * * * * 

■ 3. Amend § 1500.40 by revising the 

introductory text to read as follows: 

§ 1500.40 Method of testing toxic 

substances. 

Guidelines for testing the toxicity of 

substances, including testing that does 

not require animals, are presented in the 

CPSC’s animal testing policy set forth in 

16 CFR 1500.232. A weight-of-evidence 

analysis, including any of the following: 

existing human and animal data, 

structure activity relationships, 

physicochemical properties; and 

chemical reactivity, or validated in vitro 

or in silico testing are recommended to 

evaluate existing information before in 

vivo tests are considered. If in vivo 

testing is conducted, a sequential testing 

strategy is recommended to reduce the 

number of test animals. The method of 

testing the toxic substances referred to 

in § 1500.3(c)(1)(ii)(C) and (c)(2)(iii) is as 

follows: 

* * * * * 

■ 4. In § 1500.41, add five sentences at 

the start of the introductory text to read 

as follows: 

§ 1500.41 Method of testing primary 

irritant substances. 

Guidelines for testing the dermal 

irritation and corrosivity properties of 

substances, including testing that does 

not require animals, are presented in the 

CPSC’s animal testing policy set forth in 

16 CFR 1500.232. A weight-of-evidence 

analysis or a validated in vitro test 

method is recommended to evaluate 

existing information before in vivo tests 

are considered. This analysis should 

include all of the following that are 

available: human and animal data, 

structure activity relationships, 

physicochemical properties, and dermal 

toxicity. If in vivo testing is conducted, 

a sequential testing strategy is 

recommended to reduce the number of 

test animals. The method of testing the 

dermal corrosivity and primary 

irritation of substances referred to in 

§ 1500.3(c)(3) and (4), respectively, is a 

patch-test technique on the abraded and 

intact skin of the albino rabbit, clipped 

free of hair. * * * 

* * * * * 

■ 5. Amend § 1500.42 by adding 

introductory text, revising the first 

sentence of paragraph (a)(1), and 

revising paragraph (c) to read as follows: 

§ 1500.42 Test for eye irritants. 

Guidelines for in vivo and in vitro 

testing of ocular irritation of substances, 

including testing that does not require 

animals, are presented in the CPSC’s 

animal testing policy set forth in 16 CFR 

1500.232. A weight-of-evidence analysis 

or a validated in vitro test method is 

recommended to evaluate existing 

information before in vivo tests are 

considered. This analysis should 

include any of the following: Existing 

human and animal data on ocular or 

dermal irritation, structure activity 

relationships, physicochemical 

properties, and chemical reactivity. If in 

vivo testing is conducted, a sequential 

testing strategy is recommended to 

reduce the number of test animals. 

Additionally, the routine use of topical 

anesthetics, systemic analgesics, and 

humane endpoints to avoid or minimize 

pain and distress in ocular safety testing 

is recommended. 

(a)(1) In the method of testing the 

ocular irritation of a substance referred 

to in § 1500.3(c)(4), six albino rabbits are 

used for each test substance * * * 

* * * * * 

(c) To assist testing laboratories and 

others interested in interpreting ocular 

irritation test results, the CPSC animal 

testing policy Web page at http:// 

www.cpsc.gov/library/ 

animaltesting.html will contain the 

scoring system defined in the U.S. 

EPA’s Test Guideline, OPPTS 870.2400: 

Acute Eye Irritation 1 or the OECD Test 

Guideline 405: Acute Eye Irritation/ 

Corrosion.2

Dated: November 29, 2012. 

Todd A. Stevenson, 

Secretary, U.S. Consumer Product Safety 

Commission. 

[FR Doc. 2012–29258 Filed 12–7–12; 8:45 am] 

BILLING CODE 6355–01–P 

CONSUMER PRODUCT SAFETY 

COMMISSION 

16 CFR Part 1700 

[CPSC Docket No. CPSC–2012–0005] 

Requirements for Child-Resistant 

Packaging: Products Containing 

Imidazolines Equivalent to 0.08 

Milligrams or More 

AGENCY: Consumer Product Safety 

Commission. 

ACTION: Final rule. 

SUMMARY: The Consumer Product Safety 

Commission (CPSC, Commission, or we) 

is issuing a rule to require childresistant (CR) packaging for any overthe-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 


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Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 73295 

single package. Imidazolines are a 

family of drugs that are vasoconstrictors 

indicated for nasal congestion and/or 

ophthalmic irritation. Products 

containing imidazolines can cause 

serious adverse reactions, such as 

central nervous system (CNS) 

depression, decreased heart rate, and 

depressed ventilation in children who 

accidentally ingest them. Based on the 

scientific data, the Commission has 

determined that availability of 0.08 

milligrams or more of an imidazoline in 

a single package, by reason of its 

packaging, is such that special 

packaging is required to protect children 

under 5 years old from serious personal 

injury or illness due to handling or 

ingesting such a substance. The 

Commission takes this action under the 

Poison Prevention Packaging Act of 

1970 (PPPA) and voted to publish this 

notice in the Federal Register. 

DATES: Effective date: This rule is 

effective December 10, 2013. 

Applicability: This rule applies to 

products packaged on or after that date. 

FOR FURTHER INFORMATION CONTACT: 

Carol Afflerbach, Compliance Officer, 

Office of Compliance and Field 

Operations, Consumer Product Safety 

Commission, 4330 East West Highway, 

Bethesda, MD 20814; telephone (301) 

504–7529; cafflerbach@cpsc.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

A. Relevant Statutory and Regulatory 

Provisions 

The Poison Prevention Packaging Act 

of 1970 (PPPA), 15 U.S.C. 1471–1476, 

authorizes the Commission to establish 

standards for the ‘‘special packaging’’ of 

any household substance if: (1) The 

degree or nature of the hazard to 

children in the availability of such 

substance, by reason of its packaging, is 

such that special packaging is required 

to protect children from serious 

personal injury or serious illness 

resulting from handling, using, or 

ingesting such substance, and (2) the 

special packaging is technically feasible, 

practicable, and appropriate for such 

substance. 

Special packaging, also referred to as 

‘‘child-resistant (CR) packaging,’’ is: (1) 

Designed or constructed to be 

significantly difficult for children under 

5 years of age to open or obtain a toxic 

or harmful amount of the substance 

contained therein within a reasonable 

time, and (2) not difficult for ‘‘normal 

adults’’ to use properly. 15 U.S.C. 

1471(4). Household substances for 

which the Commission may require CR 

packaging include (among other 

categories) foods, drugs, or cosmetics, as 

these terms are defined in the Federal 

Food, Drug, and Cosmetic Act (21 U.S.C. 

321). 15 U.S.C. 1471(2)(B). The 

Commission has issued performance 

requirements for special packaging. 16 

CFR 1700.15, 1700.20. 

Section 4(a) of the PPPA, 15 U.S.C. 

1473(a), allows the manufacturer or 

packer to package a nonprescription 

product subject to special packaging 

standards in one size of non-CR 

packaging, only if the manufacturer (or 

packer) also supplies the substance in 

CR packages of a popular size, and the 

non-CR packages bear conspicuous 

labeling stating: ‘‘This package for 

households without young children.’’ 15 

U.S.C. 1473(a), 16 CFR 1700.5. 

To protect children younger than 5 

years old from serious personal injury 

following ingestion, the rule requires CR 

packaging for any over-the-counter 

(OTC) or prescription product 

containing the equivalent of 0.08 

milligrams or more of an imidazoline 

(including tetrahydrozoline, 

naphazoline, oxymetazoline, or 

xylometazoline) in a single package. 

B. Imidazolines 

Imidazolines are a family of drugs that 

are used as decongestants in eye drops 

and nasal products. Imidazolines are 

used as topical decongestants because 

they produce vasoconstriction when 

administered to the eye or nasal 

mucosa. In the eye, the imidazolines 

relieve redness due to minor eye 

irritations by causing vasoconstriction 

of the blood vessels on the surface of the 

eye and eyelid (Facts and Comparisons, 

Ophthalmic Decongestants, 

Pharmacology, 2011). The onset of 

vasoconstriction after topical 

application is within minutes. As nasal 

decongestants, imidazolines temporarily 

relieve nasal congestion or stuffy nose 

due to the common cold, hay fever, or 

other upper respiratory allergies (Facts 

and Comparisons, Nasal Decongestants, 

Pharmacology 2011). The imidazolines 

cause vasoconstriction in mucous 

membranes, which decreases blood flow 

and leads to shrinking of swollen nasal 

mucosa and increased drainage of the 

sinuses. 

Topical and nasal administration of 

imidazolines results in little absorption 

into the general circulation. Orally 

ingested imidazolines, however, are 

absorbed into the general circulation 

leading to systemic effects. Even though 

death from ingesting imidazolines is 

rare, ingestion can result in severe lifethreatening consequences, such as 

central nervous system (CNS) 

depression and cardiovascular effects. 

Specific symptoms of CNS depression 

upon ingestion of imidazolines range 

from drowsiness to coma, with a 

concurrent depression of the respiratory 

system. Other reported CNS side effects 

include: Headache, lightheadedness, 

dizziness, tremor, insomnia, 

nervousness, restlessness, giddiness, 

psychological disturbances, prolonged 

psychosis, and weakness. Imidazolines 

have led to CNS depression and 

insomnia in different children. 

Prominent cardiovascular effects in 

response to overdose include low blood 

pressure and slowed heart rate. The 

medical literature and evidence from 

collected samples demonstrate that 

despite the danger of ingesting 

imidazolines, imidazoline-containing 

products are not manufactured in CR 

packaging. 

Eye drops containing imidazolines are 

widely available at drug, grocery, and 

mass market retailers. Imidazoline eye 

drops generally come in small squeeze 

bottles. The most common size is the 

1/2-ounce (15 milliliters) bottle, and the 

second most common size appears to be 

a 1-ounce bottle (30 milliliters). Onequarter ounce (8 milliliters) bottles are 

also available. 

Nasal sprays containing imidazolines 

are widely available at drug, grocery, 

and mass market retailers. Some 

packages are used by rapidly squeezing 

the bottle to spray the product into a 

nostril. Other packages have a pump 

mechanism that activates the spray. As 

with eye drops, 1/2-ounce containers 

are the most common container size, 

and 1-ounce bottles are the second most 

common size. 

We are aware of approximately 45 

manufacturers who sell topical 

decongestant products under about 64 

different labels. Because some 

manufacturers produce both nasal and 

ophthalmic products, the number of 

manufacturers within the market for 

topical decongestants is not the sum of 

the manufacturers of ophthalmic 

products, plus the manufacturers of 

nasal products. 

We estimate that approximately 45 

million units of ophthalmic 

decongestants containing imidazolines 

are sold annually, with estimated 

annual sales receipts of approximately 

$180 million. We estimate that 

approximately 39 million units of nasal 

products containing imidazolines are 

sold annually, generating annual sales 

receipts of approximately $233 million. 

Commission staff examined 12 

packages—10 eye drops, 1 nasal spray, 

and 1 nasal drops—of over-the-counter 

products that contain imidazolines. The 

10 eye drop samples were packaged in 

squeeze-to-dispense plastic dropper 

bottles. The nasal spray was packaged in 

a plastic bottle with an attached metered 


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73296 Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 

1The word ‘‘finish,’’ in this sense, refers to the 

protruding threads on the bottle’s opening, which 

hold the cap or closure. A container and its 

corresponding closure must have matching finishes. 

pump sprayer, and the nasal drop was 

packaged in a squeeze-to-dispense 

plastic dropper bottle. All of the eye 

drop product bottles were finished with 

continuous threads, and the bottle 

openings were fitted with plastic 

dropper plugs. The nasal spray bottle 

was finished with continuous threads 

onto which a metered pump dispenser 

was attached. The pump mechanism 

was not child resistant. The nasal drops 

were packaged in a squeeze-dropper 

bottle, finished with continuous 

threads, and the bottle opening was 

fitted with a dropper plug. None of the 

samples of eye drops, nasal spray, or 

nasal drops was packaged using special 

packaging. 

C. The Proposed Rule 

On January 25, 2012, the Commission 

issued a notice of proposed rulemaking 

(NPR) that proposed requiring CR 

packaging for imidazoline preparations 

containing 0.08 milligrams or more of 

imidazolines in a single package. 77 FR 

3646. 

The Commission received five 

comments in response to the proposed 

rule. Two comments address the 

amount of time necessary to develop, 

test, and produce CR packaging for 

imidazolines, and they request 

additional time beyond the 1-year 

effective date proposed in the NPR. Two 

comments pertain to imidazoline nasal 

and ophthalmic packaging, and one 

comment concerns the derivation of the 

proposed regulation level of 0.08 

milligrams or more of imidazolines in a 

single package. We respond to each of 

these comments below. 

Effective Date 

Comment: Two commenters indicate 

that the proposed effective date of 1 year 

is too short. One commenter concludes: 

‘‘it is not feasible for manufacturers to 

comply with the proposed one (1) year 

effective date’’ and opines that 2 years 

would be required at a minimum. 

Regarding nasal products, the 

commenter contends that this amount of 

time is required because it will probably 

be necessary to replace the commonly 

used single-piece cap with twocomponent CR protection caps. The 

commenter also notes that most 

ophthalmic finishes 1 are 13mm–15mm; 

that there are no CR closures available 

smaller than 18mm; and therefore, new 

CR packages will also be required for 

ophthalmic products. The commenter 

provides a timeline identifying the 

various steps of the CR packaging 

development, testing, and approval 

process, and the time range for the 

expected completion of each stage. The 

commenter requests that the 

Commission consider a 1-year stay of 

enforcement in addition to the 1-year 

effective date recommended in the NPR 

to allow manufacturers 2 years after 

publication of the rule to comply. This 

commenter also states that additional 

time beyond the one year effective date 

and one year stay of enforcement may 

be required by some manufacturers, 

especially if the products in question 

are subject to U.S. Food and Drug 

Administration (FDA) requirements for 

new drug applications (NDAs) or 

abbreviated new drug applications 

(ANDAs). This additional approval 

process, the commenter reports, could 

require an additional 6 to 12 months. 

This commenter also requests that 

manufacturers be granted extended 

stays of enforcement on a case-by-case 

basis, if required. 

A second commenter states that it 

manufactures sterile eye drops that 

require ‘‘specialized aseptic 

processing,’’ notes that the process for 

developing CR packages suitable for 

sterile ophthalmic products is complex 

and ‘‘based upon historical experience 

with the regulated design and 

qualification activities required for 

aseptically filled sterile products,’’ and 

requests that the effective date of the 

rule be extended to 24 months. 

Response: We agree with the first 

commenter’s analysis of the steps 

necessary to comply with a CR 

packaging requirement and the time 

frames associated with each step. We 

also agree with the second commenter’s 

statement that producing sterile 

products will take 24 months, such that 

a conditional 12-month stay of 

enforcement is warranted. We address 

our assessment of the anticipated 

duration of each step in the process of 

developing, testing, and producing CR 

packaging, and we highlight each step 

identified in the commenter’s 

submission. The first commenter states 

that design development will take 2 to 

4 months, and we believe that this range 

is typical for modern computer-assisted 

design processes. We note that there are 

several nonpatented designs, and one 

patented design for CR packaging for 

imidazoline products that, if purchased 

or licensed by a manufacturer, could 

reduce the duration of the design 

development stage to 1 month or less. 

The commenter states that prototype 

tooling will take from 4 to 6 months, 

and we have been advised by 

independent sources that mold tool 

production typically takes 4 to 5 

months, with an additional month for 

production testing to ensure that the 

mold tool can be used at the intended 

production rate. The commenter 

estimates that CR protocol testing will 

take approximately 3 months, and we 

have been advised by CR protocol test 

providers that such testing for childresistant and senior-friendly packaging 

typically takes 2 to 4 months, depending 

on the complexity of the CR system. The 

commenter states that industrial scaleup for packaging and validation will 

take from 7 to 11 months because of the 

possibility that existing filling and 

capping equipment will need to be 

replaced, or at least significantly 

modified, depending on the design of 

the CR closure. Independent sources 

have advised us that this work should 

take less than 6 months if a similar 

sterile process is already in place and 

between 6 and 12 months if new 

equipment must be installed. According 

to the commenter, adoption and 

validation of the new filling line will 

take between 3 and 6 months, which is 

the time range provided by 

manufacturers of similar products in 

connection with previous regulatory 

activity. The commenter states that 

stability testing will take between 3 and 

12 months, a timeframe that is 

consistent with FDA Stability Test 

Guidelines of 1 year for regular stability 

testing and 6 months for accelerated 

stability testing, which is intended to 

increase the rate at which the 

degradation reactions take place. The 

commenter states that the FDA review 

process for an NDA or an ANDA can 

take from 6 months to a year. The FDA 

advises that 10 months is the median 

review time for NDAs, while the ANDA 

review process typically does not take 

as long; however, permission must be 

obtained before filing an ANDA, which 

can take up to 6 months alone. 

Based on the foregoing review and 

analysis of the steps necessary to 

develop, test, and produce CR packaging 

for products that contain imidazolines, 

as well as the time frames for each of 

those steps, the Commission agrees that 

more than 1 year may well be necessary. 

Thus, the Commission will grant a 

conditional 1-year stay of enforcement 

to provide additional time to produce 

CR packaging for these products. This 

issue is discussed further in Section VI 

of the preamble. 

Packaging Issues 

Comment—One commenter notes that 

the NPR failed to consider one type of 

nasal spray package. The package in 

question ‘‘is a glass bottle which houses 

the imidazoline drug product, with a 

crimped seal holding the pump in place 

and with [a] detachable nozzle.’’ The 


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Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 73297 

metered pump is housed in a metal 

case, the rim of which is crimped to the 

glass bottle. A plastic nozzle is placed 

over the pump, and the overcap is 

attached to the nozzle. Consumers 

access the product by squeezing the 

package between the thumb and first 

two fingers, causing an aerosolized form 

of the product to be released from the 

nozzle’s tip. 

The commenter believes that this 

package is inherently child resistant 

because it is a unit-dose package. The 

commenter requests that CPSC staff 

provide clarification ‘‘as to what could 

constitute a pass or failure of such a 

package.’’ 

Response: We disagree with the 

commenter’s fundamental premise that 

unit-dose packages are inherently child 

resistant. In fact, we believe that unitdose packages are not inherently CR. It 

is likely that a child can easily access 

the contents because neither the 

pumping action, nor the overcap or 

nozzle attachments are CR, and it is 

reasonably foreseeable that a child 

could access more than the regulated 

quantity of the contents. Either the 

pump action or the overcap must be 

child resistant. 

Comment—One commenter asks: ‘‘for 

nasal sprays that contain Imidazoline 

equivalent to 0.08 milligrams or more, is 

Child-Resistant packaging required for 

crimp-on pumps?’’ The commenter 

acknowledges that continuous thread 

(CT) closures and squeezable packages 

permit a child to have access to the 

entire contents, but states that metereddose pumps crimped onto a rigid bottle 

would permit a child access to ‘‘only 

one dose at a time.’’ In addition, the 

commenter states: ‘‘it is not likely to be 

ingested due to its aerosol form.’’ 

Response—As stated in the response 

to the previous comment, unit-dose 

packaging is not inherently CR. Childresistant packaging is required for the 

pump action and/or the overcap. We 

also disagree that an aerosolized form of 

the product would not be ingested by a 

child. 

Regulated Level of Imidazoline 

Comment— One commenter asks 

whether the lowest observed adverse 

effect level (LOAEL) (i.e., 0.75 mg) 

should first be normalized to mg/kg and 

then extrapolated to a 25-pound child 

before applying a tenfold safety factor, 

resulting in a no observable adverse 

effect level (NOAEL) of 0.18 mg. 

Response—The proposed regulated 

level (0.08 mg imidazoline) was based 

upon an actual imidazoline case with a 

safety factor applied to the dose 

ingested. Notably, ingestions expressed 

as normalized doses show that adverse 

effects occurred at levels within about 

the same range of imidazoline (0.1–0.3 

mg/kg). Moreover, another case in the 

medical literature documents an 

adolescent who developed persistent 

cardiovascular and neurological effects 

after ingestion of approximately 0.07 to 

0.1 mg/kg of tetrahydrozoline, which is 

also consistent with the proposed 

imidazoline level e.g., 0.07 mg/kg (lower 

end of range) × 11.4 kg child = ∼ 0.8 mg 

÷ 10 fold-safety factor = 0.08 mg. 

II. Toxicity of Imidazolines 

The Commission’s Directorate for 

Health Sciences reviewed the toxicity of 

imidazolines. Imidazolines are used as 

topical decongestants because they 

produce vasoconstriction when 

administered to the eye or nasal 

mucosa. In the eye, the imidazolines 

relieve redness due to minor eye 

irritations by causing vasoconstriction 

of the blood vessels on the surface of the 

eye and eyelid (Facts and Comparisons, 

Ophthalmic Decongestants, 

Pharmacology, 2011). The onset of 

vasoconstriction after topical 

application is within minutes. As nasal 

decongestants, imidazolines temporarily 

relieve nasal congestion or stuffy nose 

due to the common cold, hay fever, or 

other upper respiratory allergies (Facts 

and Comparisons, Nasal Decongestants, 

Pharmacology 2011). The imidazolines 

cause vasoconstriction in mucous 

membranes, which decreases blood flow 

and leads to shrinking of swollen nasal 

mucosa and increased drainage of the 

sinuses. 

The therapeutically effective dose of 

imidazolines occurs within a narrow 

dose range, with toxic effects occurring 

at doses close to, or at, therapeutic 

levels. CNS depression (ranging from 

drowsiness to deep sedation) may occur 

after recommended doses in infants. 

Overdoses (doses not specified) of these 

medications have caused initial spikes 

of high blood pressure, leading to 

slowed heart rate, drowsiness, and 

rebound low blood pressure in adults. A 

shock-like syndrome with abnormally 

low blood pressure and slowed heart 

rate may also occur. Warnings on 

tetrahydrozoline- and naphazolinecontaining OTC drugs state that their 

use may cause CNS depression, leading 

to coma in pediatric patients. 

Xylometazoline and oxymetazoline 

symptoms of overdose include: extreme 

tiredness, sweating, dizziness, a slowed 

heartbeat, and coma. 

When the drug is absorbed, it can act 

systemically within the body. Topical 

administration of imidazolines to the 

eye produces local effects to the blood 

vessels of the eye, but little is absorbed 

into the general circulation. (For 

purposes of this document, we interpret 

‘‘absorption’’ as the passage of a drug 

from its site of administration into the 

blood plasma.) 

Nasal administration of imidazolines 

causes an intense degree of 

vasoconstriction, and therefore, 

negligible absorption of the drug into 

the general circulation (POISINDEX,®

2011). However, with oral ingestion, 

imidazolines are absorbed into the 

general circulation, leading to systemic 

effects. These drugs are absorbed 

quickly, and symptoms can occur in as 

little as 1 hour, peaking at 8 hours, and 

resolving after 12–36 hours. Even 

though the symptoms resolve in a 

relatively short amount of time, 

ingestion of imidazolines can result in 

severe life-threatening consequences, 

including decreased breathing, 

decreased heart rate, and loss of 

consciousness, which require 

hospitalization to ensure recovery. 

FDA regulations pertaining to ‘‘Cold, 

Cough, Allergy, Bronchodilator, and 

Antiasthmatic Drug Products for Overthe-Counter Human Use,’’ at 21 CFR 

341.80(c)(2)(iv), require the product 

label for products containing 

naphazoline hydrochloride at a 

concentration of 0.05 percent to state: 

‘‘Do not use this product in children 

under 12 years of age because it may 

cause sedation if swallowed.’’ Specific 

symptoms of CNS depression upon 

ingestion of imidazolines range from 

drowsiness to coma, with a concurrent 

depression of the respiratory system. 

Other observed CNS side effects 

include: Headache, lightheadedness, 

dizziness, tremor, insomnia, 

nervousness, restlessness, giddiness, 

psychological disturbances, prolonged 

psychosis, and weakness. Imidazolines 

have led to CNS depression and 

insomnia in different individuals. The 

insomnia, seen in a few cases, may be 

an unpredictable, idiosyncratic reaction 

(i.e., a drug effect that occurs in a small 

number of people due to age, genetics, 

or disease state). Prominent 

cardiovascular effects in response to 

overdose include rebound low blood 

pressure and slowed heart rate. 

No specific treatment for imidazoline 

overexposure exists. Naloxone (an 

opioid blocker) has been used without 

consistent success. Gastric lavage is not 

recommended more than 1 hour after 

ingestion because the imidazolines are 

absorbed quickly after ingestion, leading 

to CNS depression and a greater risk of 

aspiration into the lungs. Activated 

charcoal may be used up to 1 hour after 

ingestion; but again, due to the CNS 

depression, there is a greater risk of 

aspiration into the lungs. Therefore, 

treatment of the clinical effects from 


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73298 Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 

2The estimate for this category is highly variable 

due to small sample size and high coefficient of 

variation. These numbers should be interpreted 

with caution. 

imidazolines is supportive, based on 

symptoms. For example, mechanical 

respiration would be administered to 

those with severe respiratory 

depression. 

III. Ingestion and Injury Data 

As discussed more extensively in the 

NPR, staff reviewed several sources for 

information on adverse health effects 

from ingestion of imidazolines. These 

sources are the National Electronic 

Injury Surveillance System (NEISS), and 

the FDA’s Adverse Event Reporting 

System (AERS). 

The CPSC’s Directorate for Health 

Sciences maintains the Children and 

Poisoning (CAP) system, a subset of 

NEISS records containing additional 

information obtained through NEISS 

involving children under 5 years old. 

NEISS is a statistically valid injury 

surveillance and follow-back database 

that the Commission maintains of 

consumer product-related injuries 

occurring in the United States. Injury 

data are gathered from the emergency 

departments (ED) of approximately 100 

hospitals selected as a probability 

sample of all 5,000+ U.S. hospitals with 

emergency departments. The system’s 

foundation rests on emergency 

department surveillance data, but the 

system also has the flexibility to gather 

additional data at either the surveillance 

or the investigation level. Surveillance 

data enable the Commission to make 

timely national estimates of the number 

of injuries associated with (but not 

necessarily caused by) specific 

consumer products. This data also 

provides evidence of the need for 

further study of particular products. 

Subsequent follow-back studies yield 

important clues to the cause and likely 

prevention of injuries and deaths. For 

additional information on NEISS, see 

the CPSC’s Web site at: http:// 

www.cpsc.gov/cpscpub/pubs/3002.html. 

CAP includes data on each pediatric 

poisoning, chemical burn, or ingestion 

case reported from a NEISS hospital, as 

well as data on some ingestions that 

could lead to poisoning. We searched 

the CAP database for incidents between 

January 1997 and December 2011, 

involving household products that 

typically contain imidazolines. During 

that time, there were an estimated 6,650 

emergency room-treated injuries 

associated with household products 

containing imidazolines involving 

children under 5 years old. Table 1 

below shows the injury estimates for 

each of the product groups involved in 

these incidents. Four-fifths of the 

estimated injuries (82 percent) involved 

eye drops. 

TABLE 1—ESTIMATED IMIDAZOLINE PRODUCT-RELATED INJURIES TO CHILDREN UNDER 5 YEARS OLD, 1997–2011, BY

PRODUCT GROUP

Product Estimated 

injuries 

Coefficient 

of variation Sample size 95% Confidence interval 

Eye drops ..................................................................................................... 5,437 0.18 161 3,564¥7,309 

Nose Sprays 2 .............................................................................................. 1,213 0.29 37 534¥1891 

Total ...................................................................................................... 6,650 0.16 198 4,550¥8,749 

Source: U.S. Consumer Product Safety Commission National Electronic Injury Surveillance System and Children and Poisoning System, 2011. 

As set forth in tabular form in the 

NPR, In-Depth Investigations (IDIs) were 

assigned in connection with certain 

NEISS-reported imidazoline ingestion 

incidents. A selection of these IDIs 

reveals various scenarios in which 

children between the ages of 13 months 

and 4 years gained access to imidazoline 

products including young children who 

removed caps from eye drop bottles left 

within their reach; obtained an eye drop 

bottle from an older sibling; used a chair 

to access an eye drop bottle in a 

medicine cabinet; and took a bottle of 

eye drops out of his mother’s purse. See 

NPR, Table 2, section III.A (77 FR 3649), 

for a summary of IDIs of selected 

incidents. 

The AERS is a database of voluntary 

reports from health care professionals 

and consumers, along with mandatory 

reports from manufacturers. AERS is 

maintained by the FDA and contains 

reports of adverse events and 

medication errors for all FDA-approved 

drugs and therapeutic biologic products. 

We asked the FDA for all AERS reports 

mentioning the imidazolines 

tetrahydrozoline, oxymetazoline, 

xylometazoline, or naphazoline. FDA 

provided 1,041 reports for 772 distinct 

cases for us to review involving both 

children and adults occurring between 

October 1968 and August 2010. We 

checked for cases related to 

imidazolines, excluded the cases with 

concomitant drugs, and determined that 

67 cases (with 115 total reports) were in 

scope for consideration in this 

rulemaking. 

Reports through the AERS system 

show a wide variety of adverse events 

associated with the use of imidazolines 

across all ages. The top three system/ 

organ classes with reported adverse 

events were psychiatric disorders (52 

reports); nervous system disorders (47 

reports); and respiratory, thoracic, and 

mediastinal disorders (38 reports). 

Sixty-two out of 67 in-scope cases (93 

percent) reported an adverse event in 

one of the top three system/organ 

classes. (Reports can include more than 

one adverse event, so individual reports 

may be recorded in more than one 

system/organ class.) Our review of these 

cases is contained in the January 11, 

2012, Staff Briefing Package: http:// 

www.cpsc.gov/LIBRARY/FOIA/FOIA12/ 

brief/imidazolines.pdf. 

The volumes of imidazoline 

ingestions in children (under the age of 

5) that were reported from two sources, 

the FDA’s AERS database (MedWatch 

reports) and the medical literature, 

ranged from several drops to a high of 

30 mL (2 tablespoons). The volume 

ingested was unknown in several 

imidazoline cases. As set forth in Table 

3 in the NPR, very serious adverse 

effects occurred in response to small 

oral doses of imidazolines. For example, 

a 2-year-old child who ingested between 

1 and 1.5 mg of tetrahydrozoline, 

experienced decreased blood pressure 

and respiration, and he was placed on 

mechanical respiration in the pediatric 

intensive care unit for 18 hours. Also, a 

16-month-old child who ingested 

between 1.25 and 2.5 mg of 

tetrahydrozoline experienced decreased 

heart rate, depressed respiration, and 

was admitted to the hospital overnight. 

In MedWatch reports of adverse 

events occurring in response to 

ingestion of imidazolines, 43 cases 

occurred in children under 5 years old. 


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Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 73299 

Tetrahydrozoline ingestions constituted 

the majority of the cases (88 percent). 

There were no reported deaths related to 

imidazoline ingestion. See: http:// 

www.cpsc.gov/LIBRARY/FOIA/FOIA12/ 

brief/imidazolines.pdf: January 11, 

2012, Staff Briefing Package, for a 

complete list of cases. 

The most recent imidazoline ingestion 

case cites the lowest dose of ingestion 

of which we are aware that caused 

severe adverse symptoms in a child. The 

case involved a 25-day-old infant who 

suffered apnea after being treated with 

tetrahydrozoline nasal drops (0.05 

percent). The mother inadvertently 

administered the nasal drops by the oral 

route three times per day with 0.5 ml/ 

day (0.25 mg). The immature kidney 

and liver function of the newborn 

caused the drugs to clear the newborn’s 

system more slowly than in an adult. 

CPSC staff reviewing this case report 

considered the three doses of nasal 

drops to be additive and calculated the 

total dose for this case to be 0.75 mg. 

After the second dose, the child was not 

feeding well and had low muscle tone. 

Two hours after the second dose, he 

developed apnea. After the third dose 

was administered, the child was brought 

to the hospital and admitted with a 

respiratory rate of four breaths per 

minute and a slowed heart rate. The 

infant was treated with naloxone, 

resolving the apnea and bradycardia. 

After 2 days, the child was in good 

condition and was discharged. After 

follow-up 10 days later, the child was in 

normal condition (Katar et al. 2010). 

Our review of the ingestion data is 

contained in: http://www.cpsc.gov/ 

LIBRARY/FOIA/FOIA12/brief/ 

imidazolines.pdf: January 11, 2012, Staff 

Briefing Package. 

IV. Level for Regulation 

The Commission is issuing a rule 

requiring special packaging for any 

over-the-counter or prescription product 

containing the equivalent of 0.08 

milligrams or more of an imidazoline in 

a single package. The absorption of 

imidazolines after oral ingestion can 

lead to unpredictable and profound CNS 

depression, including depressed 

respiration and cardiovascular events. 

Data indicate that children under 5 

years old are accidentally ingesting 

imidazoline-containing products. Even 

though death from imidazoline 

exposure is rare, many of these events 

result in serious life-threatening 

consequences requiring hospitalization 

and intensive care monitoring for 

recovery. See NPR, Section Table 3, 

section III.C (77 FR 3650), for a 

summary of relevant cases of 

imidazoline ingestion. 

Mindlin (1966) reported a case in 

which a 1-year-old girl ingested 1⁄2 to 1 

teaspoon (2.5–5 mL) of tetrahydrozoline 

eye drops and suffered CNS depression 

with slowed respiration and decreased 

heart rate. Based on this ingestion, 

recent publications define 2.5 mL 

tetrahydrozoline (0.05 percent, 1.25 mg) 

as the dose at which serious toxicity 

from imidazoline exposure can occur 

after ingestion (Holmes and Berman, 

1999; Eddy and Howell 2000). The 

preamble to the proposed FDA rule for 

OTC nasal decongestants reported that 

the minimum oral dose of 

oxymetazoline in an adult causing 

measurable cardiovascular effects (on 

blood pressure and heart rate) was 1.8 

mg of oxymetazoline (41 FR 38312, 

38398 (September 9, 1976)). This 

minimum dose may be lower for 

children because they appear to be more 

sensitive to imidazoline effects than 

adults (Brainerd and Olmstead, 1956). 

Cases indicate that ingestion of as little 

as 0.75 mg of imidazolines can result in 

serious illness in children, requiring 

supportive therapy (Katar et al., 2010; 

Summary see Table 3). The most recent 

case of imidazoline ingestion is 

reviewed in section III of this preamble. 

It involved a 25-day-old infant who 

suffered apnea after being treated with 

tetrahydrozoline nasal drops (0.05 

percent). CPSC staff reviewing this case 

report calculated the total dose for this 

case to be 0.75 mg, which is the lowest 

dose the ingestion of which we are 

aware, caused severe adverse symptoms 

in a child. 

Because serious effects on the heart 

and breathing rates occur with the 

ingestion of as little as 0.75 mg of 

tetrahydrozoline, we consider this the 

lowest observed adverse effect level 

(LOAEL). All of the imidazolines cause 

potent central and peripheral 

sympathetic effects, but 

tetrahydrozoline has the highest 

potency for CNS sedative/depressive 

effects and the lowest potency for 

cardiac effects. Oxymetazoline and 

naphazoline are the most potent 

imidazolines for peripheral cardiac 

effects and have an 8–10 times lower 

maximum daily dose than 

tetrahydrozoline (0.4 mg, 0.3 mg and 3.2 

mg, respectively). Xylometazoline and 

oxymetazoline have a longer duration of 

action than tetrahydrozoline (12 hrs., 10 

hrs., and 4–6 hrs., respectively). 

Applying a safety factor of 10 to the 

LOAEL to derive a recommended 

regulated level of 0.08 mg for all 

imidazolines is appropriate in order to 

protect children from serious health 

effects following ingestion of this family 

of drugs. The level of 0.08 mg would 

require all known imidazolines 

currently on the market to be placed in 

CR packaging. The assumptions 

underlying the use of safety factors are 

that by using these factors, both the 

public health and sensitive populations 

are protected. Further assumptions hold 

that humans are somewhere between 10 

and 1,000 times more sensitive to some 

toxic agents than animals, and adults 

are less sensitive than children. Hence, 

a safety assessment can be conducted 

using the proper toxicological 

evaluation with different populations to 

establish the NOAEL (no observable 

adverse effect level) or its equivalent. 

We used a tenfold safety factor to divide 

the LOAEL to reach a NOAEL level. 

The regulated dose level is expected 

reasonably to protect children under 5 

years of age from serious personal injury 

or illness. The Commission proposed 

this level and received one comment on 

it, which we addressed in Section I of 

the preamble. 

V. Statutory Considerations 

A. Hazard to Children 

As noted above, the toxicity data 

concerning children’s oral ingestion of 

imidazolines demonstrate that they can 

cause serious illness and injury to 

children. Moreover, imidazolines are 

available to children in common 

household products, such as eye drops 

and nasal sprays. Products containing 

imidazolines currently do not use CR 

packaging. The Commission concludes 

that a regulation is needed to ensure 

that products subject to the regulation 

will be placed in CR packaging by any 

current, as well as new manufacturers. 

Pursuant to Section 3(a) of the PPPA, 

15 U.S.C. 1472(a), the Commission finds 

that the degree and nature of the hazard 

to children from handling, using, or 

ingesting imidazolines is such that 

special packaging is required to protect 

children from serious illness. The 

Commission bases this finding on the 

toxic nature of imidazolines and the 

accessibility of products containing 

imidazolines in the home. 

B. Technically Feasibility, Practicability, 

and Appropriateness 

In issuing a standard for special 

packaging under the PPPA, the 

Commission also is required to find the 

special packaging is ‘‘technically 

feasible, practicable and appropriate.’’ 

15 U.S.C. 1472 (a)(2). For special 

packaging to be technically feasible, the 

technology must be available, or can be 

readily developed and implemented to 

produce packaging that conforms to 

established standards. A package is 

practicable if the special packaging is 

adaptable to modern mass production 


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73300 Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 

and assembly line techniques. Finally, 

packaging is appropriate if the 

packaging will adequately protect the 

integrity of the substance and will not 

interfere with its intended storage or 

use. All three of these conditions must 

be met before we can require special 

packaging for a product. 

The definition of ‘‘packaging’’ is ‘‘the 

immediate package or wrapping in 

which any household substance is 

contained for consumption, use, or 

storage by individuals in or about the 

household.’’ The PPPA defines ‘‘special 

packaging’’ as packaging that is 

designed or constructed to be 

significantly difficult for children under 

5 years of age to open or obtain a toxic 

or harmful amount of substance within 

a reasonable time and not difficult for 

normal adults to use properly. 15 U.S.C. 

1471(4). The child-resistance and adultuse-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 January 11, 

2012, Staff Briefing Package, for a more 

detailed discussion of the products: 

http://www.cpsc.gov/library/foia/foia12/ 

brief/imidazolines.pdf. 

With changes to package size and/or 

type, certain types of packaging, such as 

ASTM Type IA, ASTM Type ID, and a 

CR metered-pump sprayer design, are 

available to the market to replace the 

non-CR continuously threaded (NCRCT) 

and the non-CR (NCR) metered-spray 

pump packages. Product packaging 

assembly line techniques used for the 

NCR packages can be adapted for some 

of the CR packages already in the 

marketplace. Other product 

manufacturers may use packages that 

could require changes in assembly- and 

filling-line techniques. New package 

sizes also may need to be designed. 

These new packages would require new 

tools to be produced. It could take up 

to 2 years from initiating tool design to 

final production of a new package, 

depending upon the complexity of the 

package. The Commission did not 

receive any comments asserting that CR 

packaging for products containing 

imidazolines was not technically 

feasible, practicable, or appropriate; 

although two comments addressed the 

amount of time required to develop, 

test, and produce CR packaging for 

products containing imidazolines. As 

will be discussed in further detail in 

Section VI, we have determined that a 

12-month effective date, with an 

additional 12-month conditional stay of 

enforcement will provide sufficient time 

for manufacturers to produce CR 

packaging in compliance with this rule. 

Based on the foregoing, the 

Commission concludes that available 

data support the findings that CR 

packaging for household products 

containing imidazolines is technically 

feasible, practicable, and appropriate. 

C. Other Considerations 

In establishing a special packaging 

standard under the PPPA, the 

Commission must consider the 

following: 

1. Reasonableness of the standard; 

2. Available scientific, medical, and 

engineering data concerning special 

packaging and childhood accidental 

ingestions, illness, and injury caused by 

household substances; 

3. Manufacturing practices of industries 

affected by the PPPA; and 

4. Nature and use of the household 

substance. 

15 U.S.C. 1472(b). The Commission has 

considered these factors with respect to 

the various determinations made in this 

notice, and finds that the rule is 

reasonable and otherwise appropriate. 

VI. Effective Date 

The PPPA provides that no regulation 

shall take effect sooner than 180 days or 

later than 1 year from the date such final 

regulation is issued, except that, for 

good cause, the Commission may 

establish an earlier effective date if it 

determines an earlier date to be in the 

public interest. 15 U.S.C. 1471n. 

The Commission stated in the 

preamble to the NPR that because it 

could take up to 1 year to produce a 

new package for some companies, any 

final rule would become effective 1 year 

after publication of the final rule in the 

Federal Register. 

As discussed in section I.C. of this 

preamble, the Commission received 

comments indicating that more than 12 

months would be necessary to design, 

develop, test, and manufacture CR 

packaging for many of the products 

containing imidazolines currently on 

the market. Two commenters indicated 

that a design could be modified, tested, 

and in commercial use in approximately 

24 months. The Commission agrees that 

this time seems reasonable because 

companies will need to develop custom 

packaging, and the FDA must approve 

the packaging for acceptable 

sterilization and stability qualities. 

Because there are more than 60 

products manufactured by 

approximately 45 companies that will 

be affected by this rule, and because the 

vast majority of these companies will 

likely require more than 1 year to 

comply with this rule, the Commission 

has determined to grant a 12-month 

conditional stay of enforcement of the 

rule for products containing the 

equivalent of 0.08 milligrams of 

imidazolines in one package, rather than 

require each manufacturer to request a 

stay of enforcement for each affected 

product. The Commission believes that 

it is important to establish 

accountability in meeting the CR 

requirements for products containing 

imidazolines within 24 months of the 

publication of this rule. 

Therefore, the Commission sets the 

following conditions for the 1-year stay 

of enforcement. First, the manufacturer 

of an imidazoline product containing 

the equivalent of 0.08 milligrams of 

imidazolines or more must notify the 

Commission prior to the effective date 

of the final rule of its intent to avail 

itself of the stay, which notice shall 

include a detailed time line setting forth 

the steps necessary to produce CR 

packaging for its product(s) and the 

range of time anticipated for completion 

of each step. Manufacturers should be 

aware that submitting the required 

notice on or near the effective date of 

the rule may not allow Commission staff 

sufficient time to review their notice for 

completeness prior to the effective date 

of the rule. Second, each manufacturer 

providing notice of its intent to avail 

itself of the stay must submit quarterly 

reports to the Commission for each 

affected product, beginning on the 

effective date of the rule, and on or 

before the first day of each subsequent 

quarter during the one year stay period. 

The quarterly report must provide the 

following information: (a) Proposed 

packaging specifications; (b) estimated 

initial production date; (c) progress 

made and/or steps completed during the 

quarterly reporting period; and (d) 

reports of any incidents or exposures 

involving the firm’s imidazolinecontaining products that are subject to 

the rule. If a manufacturer fails to 

provide the above-referenced notice in a 

timely fashion or timely submit any 

quarterly report, its imidazolinecontaining products will be subject to 

enforcement of the CR packaging 


srobinson on DSK4SPTVN1PROD with 
Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 73301 

requirement set forth in this rule as of 

the effective date of the rule. 

The rule would add a new paragraph 

33 to 16 CFR 1700.14(a), which contains 

a list of substances requiring special 

packaging. Pursuant to § 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). 

Section 1700.14(a)(33) provides that any 

over-the-counter or prescription product 

containing the equivalent of 0.08 

milligrams or more of an imidazoline 

(tetrahydrozoline, naphazoline, 

oxymetazoline, or xylometazoline) in a 

single package, must be packaged in 

accordance with the provisions of 

§ 1700.15(a), (b), and (c). Section 

1700.15(a) contains general 

requirements for special packaging, 

such as the special packaging must 

continue to function with the 

effectiveness specifications set forth in 

§ 1700.15(b). Section 1700.15(b), 

pertaining to 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. Environmental Impact 

Generally, our regulations are 

considered to have little or no potential 

for affecting the human environment, 

and environmental assessments and 

impact statements are not usually 

required. See 16 CFR 1021.5(a). More 

specifically, requiring CR packaging for 

certain imidazoline-containing products 

is not expected to have an adverse 

impact on the environment. 

Accordingly, the rule falls within the 

categorical exclusion in 16 CFR 

1021.5(b)(2) for product certification 

rules and an environmental assessment 

or environmental impact statement is 

not required. 

VIII. Executive Order 12988 

(Preemption) 

According to Executive Order 12988 

(February 5, 1996), agencies must state 

in clear language the preemptive effect, 

if any, of new regulations. Section 7 of 

the PPPA provides that, generally, when 

a special packaging standard issued 

under the PPPA is in effect, ‘‘no State 

or political subdivision thereof shall 

have any authority either to establish or 

continue in effect, with respect to such 

household substance, any standard for 

special packaging (and any exemption 

therefrom and requirement related 

thereto) which is not identical to the 

[PPPA] standard.’’ 15 U.S.C. 1476(a). A 

state or local standard may be excepted 

from this preemptive effect if: (1) The 

state or local standard provides a higher 

degree of protection from the risk of 

injury or illness than the PPPA 

standard; and (2) the state or political 

subdivision applies to the Commission 

for an exemption from the PPPA’s 

preemption clause and the Commission 

grants the exemption through a process 

specified at 16 CFR part 1061. 15 U.S.C. 

1476(c)(1). In addition, the federal 

government, or a state or local 

government, may establish and continue 

in effect a nonidentical special 

packaging requirement that provides a 

higher degree of protection than the 

PPPA requirement for a household 

substance for the federal, state, or local 

government’s own use. 15 U.S.C. 

1476(b). 

Thus, with the exceptions noted 

above, the rule regarding CR packaging 

for household products containing an 

imidazoline above the regulated level 

would preempt nonidentical state or 

local special packaging standards for 

such imidazoline-containing products. 

IX. Regulatory Flexibility Act 

(Economic Analysis) 

When an agency undertakes a 

rulemaking proceeding, the Regulatory 

Flexibility Act (RFA) generally requires 

that agencies review proposed rules for 

their potential economic impact on 

small entities, including small 

businesses. Section 603 of the RFA calls 

for agencies to prepare, and make 

available for public comment, an initial 

regulatory flexibility analysis describing 

the impact of the proposed rule on small 

entities and identifying impact-reducing 

alternatives. 5 U.S.C. 603. Section 

605(b) of the RFA, however, states that 

this requirement does not apply if the 

head of the agency certifies that the rule, 

if promulgated, will not have a 

significant economic impact on a 

substantial number of small entities and 

the agency provides an explanation for 

that conclusion. 

Nasal and ophthalmic products are 

classified within the NAICS 325412 

Pharmaceutical Preparation 

Manufacturing industry. According to 

the U.S. Small Business 

Administration’s Office of Advocacy, a 

firm classified within NAICS 325412 is 

considered a small business if the firm 

has fewer than 750 employees. Based on 

such classification, out of the 

approximately 45 firms that 

manufacture imidazoline-based eye 

drops and nasal sprays, approximately 

20 firms are defined as ‘‘small 

businesses.’’ There may be more 

manufacturers, in particular, firms that 

manufacture under generic labels, 

which were not identified but that may 

be small businesses. 

As noted in the NPR, the 

Commission’s Directorate of Economic 

Analysis prepared a preliminary 

assessment of the impact of a rule to 

require special packaging for products 

containing imidazolines equivalent to 

0.08 milligrams or more in a single 

package. Based on this assessment, the 

Commission concluded that the 

proposed requirement for products 

containing imidazolines, if finalized, 

would not have a significant impact on 

a substantial number of small 

businesses. The Commission requested 

additional information on the possible 

impact on small businesses, but we 

received no such comments. Moreover, 

the preliminary analysis demonstrated 

that the incremental costs of CR 

packaging for manufacturers are low, 

estimated at no more than a few cents 

per unit for imidazoline products, some 

of which costs manufacturers are likely 

to be able to pass on to consumers. The 

Commission concludes that the rule 

regarding CR packaging for certain 

imidazoline products would not have a 

significant economic impact on a 

substantial number of small entities. 

X. References 

Please see all citing references in 

staff’s briefing package for the proposed 

rule, available at: http://www.cpsc.gov/ 

library/foia/foia12/brief/ 

imidazolines.pdf and for the final rule, 

available at http://www.cpsc.gov/ 

LIBRARY/FOIA/FOIA13/brief/ 

imidazfinal.pdf. 

List of Subjects in 16 CFR Part 1700 

Consumer protection, Drugs, Infants 

and children, Packaging and containers, 

Poison prevention, Toxic substances. 

For the reasons given above, the 

Commission amends 16 CFR part 1700 

to read as follows: 

PART 1700—[AMENDED] 

■ 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 by 

adding 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 


srobinson on DSK4SPTVN1PROD with 
73302 Federal Register / Vol. 77, No. 237 / Monday, December 10, 2012 / Rules and Regulations 

1Section 806(e) of Title VIII of the Dodd-Frank 

Act requires any financial market utility designated 

by the Financial Stability Oversight Council 

(‘‘Council’’) as systemically important to file with 

its supervisory agency 60 days advance notice of 

changes to its rules, procedures, or operations that 

could materially affect the nature or level of risk 

presented by the financial market utility. 12 U.S.C. 

5465(e)(1)(A). 

2See Securities Exchange Act Release No. 67286 

(June 28, 2012), 77 FR 41602 (July 13, 2012) 

(‘‘Adopting Release’’). 

3Six clearing agencies registered with the 

Commission are DCAs: Chicago Mercantile 

Exchange Inc. (‘‘CME’’), The Depository Trust 

Company (‘‘DTC’’), Fixed Income Clearing 

Corporation (‘‘FICC’’), ICE Clear Credit (‘‘ICC’’), 

National Securities Clearing Corporation (‘‘NSCC’’), 

and The Options Clearing Corporation (‘‘OCC’’). 

However, the Commission is the supervisory agency 

for only DTC, FICC, NSCC, and OCC. 

4See 17 CFR 240.19b–4(n)(1)(i). 

5See 17 CFR 240.19b–4(n)(1)(ii). Currently, DCAs 

file Advance Notices with the Commission via the 

dedicated email address 

AdvanceNoticeFilings@sec.gov. 

6See 17 CFR 240.19b–4(o)(2)(i). 

7See 17 CFR 240.19b–4(o)(2)(ii). The Commission 

has established the dedicated email address 

SBSwapsSubmissions@sec.gov for Security-Based 

Swap Submissions. 

8Adopting Release at 41653, 41654. Currently, 

EFFS is used by self-regulatory organizations 

(‘‘SRO’’), which include registered clearing 

agencies, to file proposed rule changes 

electronically with the Commission pursuant to 

Exchange Act Section 19(b) and Rule 19b–4. 

9See Adopting Release at 41606, 41620. 

10See id. 

11See id. The Commission has maintained a 

dedicated email address to receive Advance Notices 

and a dedicated email address to receive SecurityBased Swap Submissions since July 19, 2012. The 

Commission has received five Advance Notices and 

zero Security-Based Swap Submissions through 

November 28, 2012. 

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). 

* * * * * 

Dated: November 29, 2012. 

Todd A. Stevenson, 

Secretary, Consumer Product Safety 

Commission. 

[FR Doc. 2012–29203 Filed 12–7–12; 8:45 am] 

BILLING CODE 6355–01–P 

SECURITIES AND EXCHANGE 

COMMISSION 

17 CFR Part 240 

[Release No. 34–68357; File No. S7–44–10] 

RIN 3235–AK87 

Extension of Dates for Certain 

Requirements and Amendment of 

Form 19b–4 

AGENCY: Securities and Exchange 

Commission. 

ACTION: Final rule; extension of dates for 

certain requirements. 

SUMMARY: The Commission is amending 

its regulations under the Securities 

Exchange Act of 1934 (‘‘Exchange Act’’) 

to extend the dates for certain 

requirements therein and amending the 

General Instructions to Form 19b-4 to 

clarify the process for submitting 

advance notices and security-based 

swap submissions to the Commission. 

The Commission is extending the dates 

with respect to the requirements that 

designated clearing agencies for which 

the Commission is the supervisory 

agency file advance notices and clearing 

agencies file security-based swap 

submissions with the Commission in an 

electronic format to dedicated email 

addresses to December 10, 2013 in order 

to prevent the scenario that such filings 

are required to be filed with the 

Commission through a system that is 

not yet technologically able to accept 

them. 

DATES: The effective date for this release 

is December 10, 2012. 

FOR FURTHER INFORMATION CONTACT: 

Kenneth Riitho, Special Counsel, at 

551–5592; and Wyatt A. Robinson, 

Attorney-Adviser, at 551–5649, Division 

of Trading and Markets, Securities and 

Exchange Commission, 100 F Street NE., 

Washington, DC 20549–7010. 

SUPPLEMENTARY INFORMATION: 

I. Introduction 

On June 28, 2012, the Commission 

adopted amendments to Rule 19b–4 and 

Form 19b–4 to define and describe 

when notices of proposed changes to 

rules, procedures, or operations are 

required to be filed by designated 

financial market utilities in accordance 

with Section 806(e) of Title VIII of the 

Dodd-Frank Act 1 (‘‘Advance Notices’’), 

to set forth the process for filing such 

Advance Notices with the Commission, 

and to specify the process for a clearing 

agency’s submission for review of any 

security-based swap, or any group, 

category, type, or class of security-based 

swaps that the clearing agency plans to 

accept for clearing (‘‘Security-Based 

Swap Submissions’’).2 The effective 

date for the amendments to Rule 19b– 

4 was August 13, 2012. The effective 

date for all amendments to Form 19b– 

4 and 17 CFR 249.819 is December 10, 

2012. 

Rule 19b–4(n)(1)(i) requires a DCA 3

for which the Commission is the 

supervisory agency to provide an 

Advance Notice to the Commission of 

any proposed change to its rules, 

procedures, or operations that could 

materially affect the nature or level of 

risks presented by such DCA.4 Except as 

provided in Rule 19b–4(n)(1)(ii), a DCA 

for which the Commission is the 

supervisory agency is required to submit 

such Advance Notice to the Commission 

electronically on Form 19b–4. Rule 19b– 

4(n)(1)(ii) requires a DCA that files an 

Advance Notice with the Commission 

prior to December 10, 2012 to file such 

Advance Notice in an electronic format 

to a dedicated email address established 

by the Commission.5

Rule 19b–4(o)(2)(i) requires that 

except as provided in Rule 19b– 

4(o)(2)(ii), a clearing agency shall 

submit each Security-Based Swap 

Submission to the Commission 

electronically on Form 19b–4.6 Rule 

19b–4(o)(2)(ii) requires a clearing 

agency that files a Security-Based Swap 

Submission with the Commission prior 

to December 10, 2012 to file such 

Security-Based Swap Submission in 

electronic format to a dedicated email 

address established by the 

Commission.7

The amendments to Form 19b–4 

contained in the Adopting Release 

provide that, among other things, after 

December 10, 2012, Advance Notices 

and Security-Based Swap Submissions, 

and amendments, extensions, and 

withdrawals thereto, shall be filed in an 

electronic format through the Electronic 

Form 19b-4 Filing System (‘‘EFFS’’).8

II. Discussion 

A. Rules 19b–4(n)(1)(ii) and 19b– 

4(o)(2)(ii) 

The Commission stated in the 

Adopting Release that it was in the 

process of designing and implementing 

EFFS system upgrades that are 

necessary for Advance Notices and 

Security-Based Swap Submissions to be 

filed through EFFS.9 The Commission 

anticipated in the Adopting Release that 

the EFFS system upgrades would be 

completed no later than December 10, 

2012.10 Prior to December 10, 2012, 

DCAs for which the Commission is the 

supervisory agency are required to file 

Advance Notices and clearing agencies 

are required to file Security-Based Swap 

Submissions through dedicated email 

addresses established by the 

Commission.11

Though the Commission has made 

progress on designing and 

implementing the EFFS system 

upgrades since the date of the Adopting 

Release, the Commission has 

determined that additional time is 

required to design, test, and implement 

the EFFS system upgrades. Therefore, 

the Commission is amending Rule 19b– 


srobinson on DSK4SPTVN1PROD with