3646 Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules 

1The Commission voted 4–0 to publish this 

notice in the Federal Register. Commissioner 

Robert S. Adler issued a statement, which can be 

found at http://www.cpsc.gov/pr/statements.html. 

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 

Agreement States the flexibility to 

enhance accountability; retain use of 

tools to track the location and 

movement of devices, manufacturers 

and service providers within the State 

limit; address issues specific to their 

jurisdictions; continue programs that 

have proven beneficial; and to adopt 

requirements based on their specific 

circumstances and needs. As directed 

by the Commission, the NRC staff will 

assess the degree to which the 

Agreement States modify their programs 

as a result of the change in compatibility 

category and analyze any transboundary 

impacts to regulated entities, 

particularly those operating on a 

multistate basis. If transbounday 

problems are identified, the staff will 

suggest any corrective actions that might 

be necessary (ADAMS Accession No. 

ML103360262). The Commission also 

plans to consider proposed updates to 

the Policy Statement on Adequacy and 

Compatibility of Agreement State 

Programs and associated guidance 

documents to include both safety and 

source security considerations in the 

determination process. 

Closure of the Petition for Rulemaking 

In its SRM, the Commission 

addressed all of the issues raised in the 

PRM: The Commission disapproved 

publication of the final rule and 

approved the change in compatibility 

for 10 CFR 31.5 and 10 CFR 31.6. The 

NRC is closing this PRM because all of 

the petitioners’ requests have been 

resolved. 

Dated at Rockville, Maryland, this 22nd 

day of December 2011. 

For the Nuclear Regulatory Commission. 

R.W. Borchardt, 

Executive Director for Operations. 

[FR Doc. 2012–1523 Filed 1–24–12; 8:45 am] 

BILLING CODE 7590–01–P 

DEPARTMENT OF COMMERCE 

National Oceanic and Atmospheric 

Administration 

15 CFR Part 922 

[Docket No. 100908440–1615–01] 

RIN 0648–BA24 

Proposed Expansion of Fagatele Bay 

National Marine Sanctuary, Regulatory 

Changes, and Sanctuary Name Change 

AGENCY: Office of National Marine 

Sanctuaries (ONMS), National Ocean 

Service (NOS), National Oceanic and 

Atmospheric Administration (NOAA), 

Department of Commerce (DOC). 

ACTION: Re-opening of public comment 

period. 

SUMMARY: On October 21, 2011, NOAA 

published a proposed rule in the 

Federal Register to revise the 

regulations for the Fagatele Bay National 

Marine Sanctuary (76 FR 65566). This 

notice re-opens the public comment 

period stated in that proposed rule until 

March 9, 2012. 

DATES: NOAA will accept public 

comments on the proposed rule 

published at 76 FR 65566 (October 21, 

2011) through March 9, 2012. 

ADDRESSES: The instructions for 

submitting comments are detailed in the 

proposed rule published on October 21, 

2011 (76 FR 65566). 

FOR FURTHER INFORMATION CONTACT: 

Gene Brighouse at (684) 633–7792. 

Dated: January 17, 2012. 

Daniel J. Basta, 

Director, Office of National Marine 

Sanctuaries. 

[FR Doc. 2012–1499 Filed 1–24–12; 8:45 am] 

BILLING CODE 3510–NK–P 

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

DATES: Written comments must be 

received by April 9, 2012. 

ADDRESSES: You may submit comments, 

identified by Docket No. CPSC–2012– 

0005, by any of the following methods: 

Electronic Submissions 

Submit electronic comments in the 

following way: 

Federal eRulemaking Portal: http:// 

www.regulations.gov. Follow the 

instructions for submitting comments. 

To ensure timely processing of 

comments, the Commission is no longer 

accepting comments submitted by 

electronic mail (email) except through 

http://www.regulations.gov. 

Written Submissions 

Submit written submissions in the 

following way: 

Mail/Hand delivery/Courier (for 

paper, disk, or CD–ROM submissions), 

preferably in five copies, to: Office of the 

Secretary, Consumer Product Safety 

Commission, Room 802, 4330 East West 

Highway, Bethesda, MD 20814; 

telephone (301) 504–7923. 

Instructions: All submissions received 

must include the agency name and 

docket number for this notice of 

proposed rulemaking. All comments 

received may be posted without change, 

including any personal identifiers, 

contact information, or other personal 

information provided, to http:// 

www.regulations.gov. Do not submit 

confidential business information, trade 


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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 http:// 

www.regulations.gov. 

FOR FURTHER INFORMATION CONTACT: 

Cheryl A. Osterhout Ph.D., 

Pharmacologist, Project Manager, 

Directorate for Health Sciences, 

Consumer Product Safety Commission, 

4330 East West Highway, Bethesda, MD 

20814; telephone (301) 504–7290; 

costerhout@cpsc.gov. 

SUPPLEMENTARY INFORMATION: 

I. Background 

A. What is the purpose of the proposed 

rule? 

To protect children younger than 5 

years old from serious personal injury 

following ingestion, the proposed rule 

would require CR packaging for any 

over-the-counter (‘‘OTC’’) or 

prescription product containing the 

equivalent of 0.08 milligrams or more of 

an imidazoline (including 

tetrahydrozoline, naphazoline, 

oxymetazoline, or xylometazoline) in a 

single package. 

B. Why is CR packaging necessary for 

certain OTC or prescription products 

containing imidazolines? 

Imidazolines are a family of drugs that 

are used as decongestants in eye drops 

and nasal products. Topical and nasal 

administration of imidazolines result in 

little absorption into the general 

circulation. Orally ingested, however, 

imidazolines are absorbed into the 

general circulation leading to systemic 

effects. Even though death from 

ingesting imidazolines is rare, ingestion 

can result in severe life-threatening 

consequences, such as central nervous 

system (‘‘CNS’’) depression and 

cardiovascular effects. Specific 

symptoms of CNS depression upon 

ingestion of imidazolines range from 

drowsiness to coma, with a concurrent 

depression of the respiratory system. 

Other observed CNS side effects 

include: headache, lightheadedness, 

dizziness, tremor, insomnia, 

nervousness, restlessness, giddiness, 

psychological disturbances, prolonged 

psychosis, and weakness. Imidazolines 

have led to CNS depression and 

insomnia in different individuals. 

Prominent cardiovascular effects in 

response to overdose include low blood 

pressure and slowed heart rate. The 

medical literature and evidence from 

collected samples demonstrate that 

despite the danger of ingesting 

imidazolines, imidazoline products are 

not manufactured in CR packaging. 

C. What statutory authority does CPSC 

have to regulate child resistant 

packaging? 

The Poison Prevention Packaging Act 

of 1970 (‘‘PPPA’’), 15 U.S.C. 1471–1476, 

authorizes us to establish standards for 

the ‘‘special packaging’’ of any 

household substance if: (1) The degree 

or nature of the hazard to children in 

the availability of such substance, by 

reason of its packaging, is such that 

special packaging is required to protect 

children from serious personal injury or 

serious illness resulting from handling, 

using, or ingesting such substance, and 

(2) the special packaging is technically 

feasible, practicable, and appropriate for 

such substance. 

Special packaging, also referred to as 

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

designed or constructed to be 

significantly difficult for children under 

5 years of age to open or obtain a toxic 

or harmful amount of the substance 

contained therein within a reasonable 

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

adults’’ to use properly. 15 U.S.C. 

1471(4). Household substances for 

which we may require CR packaging 

include (among other categories) foods, 

drugs, or cosmetics, as these terms are 

defined in the Federal Food, Drug, and 

Cosmetic Act (21 U.S.C. 321). 15 U.S.C. 

1471(2)(B). We have performance 

requirements for special packaging. 16 

CFR 1700.15, 1700.20. 

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

1473(a), allows the manufacturer or 

packer to package a nonprescription 

product subject to special packaging 

standards in one size of non-CR 

packaging only if the manufacturer (or 

packer) also supplies the substance in 

CR packages of a popular size, and the 

non-CR packages bear conspicuous 

labeling stating: ‘‘This package for 

households without young children.’’ 15 

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

II. Toxicity of Imidazolines 

Tab A of the CPSC staff’s briefing 

package, available at http:// 

www.cpsc.gov/library/foia/foia12/brief/ 

imidazolines.pdf contains the 

Directorate for Health Sciences’ toxicity 

review for imidazolines, referred to 

hereinafter as ‘‘Tab A: Staff Briefing 

Package.’’ 

A. What medical conditions are 

imidazolines used to treat? 

Imidazolines are used as topical 

decongestants because they produce 

vasoconstriction when administered to 

the eye or nasal mucosa. In the eye, the 

imidazolines relieve redness due to 

minor eye irritations by causing 

vasoconstriction of the blood vessels on 

the surface of the eye and eyelid (Facts 

and Comparisons, Ophthalmic 

Decongestants, Pharmacology, 2011). 

The onset of vasoconstriction after 

topical application is within minutes. 

As nasal decongestants, imidazolines 

temporarily relieve nasal congestion or 

stuffy nose due to the common cold, hay 

fever, or other upper respiratory 

allergies (Facts and Comparisons, Nasal 

Decongestants, Pharmacology 2011). 

The imidazolines cause vasoconstriction 

in mucous membranes, which decreases 

blood flow and leads to shrinking of 

swollen nasal mucosa and increased 

drainage of the sinuses. 

B. What health risks are there for people 

who overdose on or orally ingest 

imidazolines? 

The therapeutically effective dose of 

imidazolines occurs within a narrow 

dose range with toxic effects occurring 

at doses close to, or at, therapeutic 

levels. CNS depression (ranging from 

drowsiness to deep sedation) may occur 

after normal doses in infants. Overdoses 

(doses not specified) of these 

medications have caused initial spikes 

of high blood pressure leading to slowed 

heart rate, drowsiness, and rebound low 

blood pressure in adults. A shock-like 

syndrome with abnormally low blood 

pressure and slowed heart rate may also 

occur. Warnings on 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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3648 Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules 

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. 

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 

http://www.cpsc.gov/cpscpub/pubs/ 

3002.html. 

CAP includes data on each pediatric 

poisoning, chemical burn, or ingestion 

case reported from a NEISS hospital, as 

well as data on some ingestions that 

could lead to poisoning. Our review of 

data obtained from CAP is summarized 

in Tab B of the Staff’s Briefing Package, 

hereinafter Tab B: Staff Briefing 

Package. 

We searched the CAP database for 

incidents between January 1997 and 

December 2009, involving household 

products that typically contain 

imidazolines. During that time, there 

were an estimated 5,675 emergency 

room-treated injuries associated with 

household products containing 

imidazolines involving children under 5 

years old. Table 1 below shows the 

injury estimates for each of the product 

groups involved in these incidents. 

Four-fifths of the estimated injuries (81 

percent) involved eye drops. 

TABLE 1—ESTIMATED IMIDAZOLINE PRODUCT-RELATED INJURIES TO CHILDREN UNDER 5 YEARS OLD, 1997–2009, BY

PRODUCT GROUP

Product Estimated 

injuries 

Coefficient 

of variation 

Sample 

size 

95% 

confidence 

interval 

Eye drops ....................................................................................................... 4,571 0.19 138 2,831–6,311 

Nose Sprays 2 ................................................................................................ 1,104 0.31 34 426–1,782 

Total ........................................................................................................ 5,675 0.18 172 3,666–7,684 

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

The following table of NEISS In-Depth 

Investigations qualitatively illustrates 

that children were able to obtain access 

to imidazoline packages. 


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TABLE 2—SELECTED IN-DEPTH INVESTIGATION NEISS REPORTS SHOWING CHILD ACCESS TO IMIDAZOLINE PRODUCTS

NEISS Case # Age Imidazoline 

product 

How accessed 

(from case 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 


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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 ................. Given fluids and admitted to ICU. 

Aroused from coma 8–10 hours 

later. Released later that day. Having headaches 3–4 times daily.

FDA MedWatch 

439578450001 6/ 

2004. 

3–4 mg naphazoline.‘‘Soon’’ became ‘‘quite drowsy’’ for 

several hours.

3 yrs ..................... Several hours ..................................... Waring 1945. 

3–4 mg naphazoline.One hour after ingestion. Became 

hypothermic, lethargic, irritable, 

pale, irregular gasping respirations, 

hypertension, bradycardia. Followed by unconsciousness and imperceptible respirations.

22 mos ................. Child warmed and treated with caffeine and oxygen. Symptoms resolved after 15 hrs.Hainsworth 1948. 

2–2.5 mg 

tetrahydrozoline.

90 minutes Lethargic, decreased 

heart rate, decreased blood pressure.

17 mos ................. Pediatric intensive care unit Recovered 24 hrs.Jensen et al. 1989. 

Up to 2 mg 

tetrahydrozoline.

Sharp increase and then decrease of 

heart rate.

22 mos ................. Pediatric intensive care unit ............... FDA540321. 

1.25–2.5 mg 

tetrahydrozoline.

Decreased heart rate Lethargic, difficult to arouse, depressed respiration.16 mos ................. Admitted to hospital overnight ............ FDA671307. 

1.25–2.5 mg 

tetrahydrozoline.

2 hrs. Ataxic, pale, drowsy, decreased heart rate, decreased respiration.1 yr ....................... Admitted to hospital Recovered 24 

hrs.

Mindlin 1966. 

1.3 mg 

tetrahydrozoline.

30 min. Lethargic, difficulty breathing, 

vomiting, loss of consciousness.

2 yrs ..................... Admitted to hospital, treated with 

charcoal. Released from hospital 

same day, symptoms resolved.

FDA 43222810001. 

1–1.5 mg 

tetrahydrozoline.

2–3 hrs Lethargy, decreased blood 

pressure, decreased respiration.

2 yrs ..................... Pediatric intensive care unit Mechanical respiration for 18 hrs Recovered 48 hrs.Tobias 1996. 

0.25 mg x 3 or 

0.75 * 

tetrahydrozoline.

2 hrs. Apnea, decreased respirations, 

slowed heart rate.

25 days ................ Admitted to hospital Naloxone, Continuous positive airway pressure, 

oxygen Recovered 2 days.

Katar et al. 2010. 

* 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 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 lifethreatening 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. 


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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 

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-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 

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. 

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 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 

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 

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

brief/imidazolines.pdf. 

List of Subjects in 16 CFR Part 1700 

Consumer protection, Drugs, Infants 

and children, Packaging and containers, 

Poison prevention, Toxic substances. 

For the reasons given above, the 

Commission proposes to amend 16 CFR 

part 1700 as follows: 

PART 1700—[AMENDED] 

1. The authority citation for part 1700 

continues to read as follows: 

Authority: Pub. L. 91–601, secs. 1–9, 84 

Stat. 1670–74, 15 U.S.C. 1471–76. Secs. 

1700.1 and 1700.14 also issued under Pub. L. 

92–573, sec. 30(a), 88 Stat. 1231. 15 U.S.C. 

2079(a). 

2. Section 1700.14 is amended to add 

paragraph (a)(33) to read as follows: 

§ 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). 

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 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 10, 20, 25, and 510 

[Docket No. FDA–2001–N–0075 (formerly 

Docket No. 2001N–0284)] 

RIN 0910–AF78 

Import Tolerances for Residues of 

Unapproved New Animal Drugs in 

Food 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: 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. 

DATES: 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). 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: http:// 

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– 

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 http://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 http:// 

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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