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

Home , Naphazoline, Oxymetazoline, Xylometazoline

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

certain generally-licensed devices, and DEPARTMENT OF COMMERCE class of drugs that includes specific licensing of all generally- tetrahydrozoline, naphazoline, licensed devices currently registered by National Oceanic and Atmospheric oxymetazoline, and xylometazoline, in a the NRC. Administration single package. Imidazolines are a The NRC believes that the change to family of drugs that are vasoconstrictors 15 CFR Part 922 indicated for nasal congestion and/or compatibility category C will allow ophthalmic irritation. Products Agreement States the flexibility to [Docket No. 100908440–1615–01] containing imidazolines can cause enhance accountability; retain use of RIN 0648–BA24 serious adverse reactions, such as tools to track the location and central nervous system (‘‘CNS’’) movement of devices, manufacturers Proposed Expansion of Fagatele Bay depression, decreased heart rate, and and service providers within the State National Marine Sanctuary, Regulatory depressed ventilation in children limit; address issues specific to their Changes, and Sanctuary Name Change treated with these drugs or who jurisdictions; continue programs that AGENCY: Office of National Marine accidentally ingest them. Based on the have proven beneficial; and to adopt Sanctuaries (ONMS), National Ocean scientific data, the Commission requirements based on their specific Service (NOS), National Oceanic and preliminarily finds that availability of circumstances and needs. As directed Atmospheric Administration (NOAA), 0.08 milligrams or more of an by the Commission, the NRC staff will Department of Commerce (DOC). imidazoline in a single package, by assess the degree to which the reason of its packaging, is such that ACTION: Re-opening of public comment Agreement States modify their programs special packaging is required to protect period. as a result of the change in compatibility children under 5 years old from serious category and analyze any transboundary SUMMARY: On October 21, 2011, NOAA personal injury or illness due to impacts to regulated entities, published a proposed rule in the handling, using, or ingesting such a particularly those operating on a Federal Register to revise the substance. We are taking this action multistate basis. If transbounday regulations for the Fagatele Bay National under the Poison Prevention Packaging problems are identified, the staff will Marine Sanctuary (76 FR 65566). This Act of 1970 (‘‘PPPA’’).1 suggest any corrective actions that might notice re-opens the public comment DATES: Written comments must be be necessary (ADAMS Accession No. period stated in that proposed rule until received by April 9, 2012. ML103360262). The Commission also March 9, 2012. ADDRESSES: You may submit comments, plans to consider proposed updates to DATES: NOAA will accept public identified by Docket No. CPSC–2012– the Policy Statement on Adequacy and comments on the proposed rule 0005, by any of the following methods: Compatibility of Agreement State published at 76 FR 65566 (October 21, Electronic Submissions Programs and associated guidance 2011) through March 9, 2012. Submit electronic comments in the documents to include both safety and ADDRESSES: The instructions for following way: source security considerations in the submitting comments are detailed in the Federal eRulemaking Portal: http:// determination process. proposed rule published on October 21, www.regulations.gov. Follow the 2011 (76 FR 65566). Closure of the Petition for Rulemaking instructions for submitting comments. FOR FURTHER INFORMATION CONTACT: To ensure timely processing of In its SRM, the Commission Gene Brighouse at (684) 633–7792. comments, the Commission is no longer addressed all of the issues raised in the Dated: January 17, 2012. accepting comments submitted by PRM: The Commission disapproved Daniel J. Basta, electronic mail (email) except through publication of the final rule and Director, Office of National Marine http://www.regulations.gov. approved the change in compatibility Sanctuaries. Written Submissions for 10 CFR 31.5 and 10 CFR 31.6. The [FR Doc. 2012–1499 Filed 1–24–12; 8:45 am] Submit written submissions in the NRC is closing this PRM because all of BILLING CODE 3510–NK–P the petitioners’ requests have been following way: resolved. Mail/Hand delivery/Courier (for paper, disk, or CD–ROM submissions), Dated at Rockville, Maryland, this 22nd CONSUMER PRODUCT SAFETY preferably in five copies, to: Office of the day of December 2011. COMMISSION Secretary, Consumer Product Safety For the Nuclear Regulatory Commission. 16 CFR Part 1700 Commission, Room 802, 4330 East West R.W. Borchardt, Highway, Bethesda, MD 20814; Executive Director for Operations. [CPSC Docket No. CPSC–2012–0005] telephone (301) 504–7923. Instructions: All submissions received [FR Doc. 2012–1523 Filed 1–24–12; 8:45 am] Products Containing Imidazolines must include the agency name and BILLING CODE 7590–01–P Equivalent to 0.08 Milligrams or More docket number for this notice of proposed rulemaking. All comments AGENCY: Consumer Product Safety Commission. received may be posted without change, including any personal identifiers, ACTION: Notice of proposed rulemaking. contact information, or other personal SUMMARY: The Consumer Product Safety information provided, to http:// Commission (‘‘CPSC,’’ ‘‘Commission,’’ www.regulations.gov. Do not submit or ‘‘we’’) is proposing a rule to require confidential business information, trade child-resistant (‘‘CR’’) packaging for any 1 The Commission voted 4–0 to publish this over-the-counter or prescription product notice in the Federal Register. Commissioner containing the equivalent of 0.08 Robert S. Adler issued a statement, which can be milligrams or more of an imidazoline, a found at http://www.cpsc.gov/pr/statements.html.

VerDate Mar<15>2010 18:18 Jan 24, 2012 Jkt 226001 PO 00000 Frm 00007 Fmt 4702 Sfmt 4702 E:\FR\FM\25JAP1.SGM 25JAP1 sroberts on DSK5SPTVN1PROD with PROPOSALS Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules 3647

secret information, or other sensitive or imidazolines, imidazoline products are minor eye irritations by causing protected information electronically. not manufactured in CR packaging. vasoconstriction of the blood vessels on Such information should be submitted the surface of the eye and eyelid (Facts C. What statutory authority does CPSC in writing. and Comparisons, Ophthalmic have to regulate child resistant Docket: For access to the docket to Decongestants, Pharmacology, 2011). packaging? read background documents or The onset of vasoconstriction after comments received, go to http:// The Poison Prevention Packaging Act topical application is within minutes. www.regulations.gov. of 1970 (‘‘PPPA’’), 15 U.S.C. 1471–1476, As nasal decongestants, imidazolines FOR FURTHER INFORMATION CONTACT: authorizes us to establish standards for temporarily relieve nasal congestion or Cheryl A. Osterhout Ph.D., the ‘‘special packaging’’ of any stuffy nose due to the common cold, hay Pharmacologist, Project Manager, household substance if: (1) The degree fever, or other upper respiratory Directorate for Health Sciences, or nature of the hazard to children in allergies (Facts and Comparisons, Nasal Consumer Product Safety Commission, the availability of such substance, by Decongestants, Pharmacology 2011). 4330 East West Highway, Bethesda, MD reason of its packaging, is such that The imidazolines cause vasoconstriction 20814; telephone (301) 504–7290; special packaging is required to protect in mucous membranes, which decreases [email protected]. children from serious personal injury or blood flow and leads to shrinking of serious illness resulting from handling, swollen nasal mucosa and increased SUPPLEMENTARY INFORMATION: using, or ingesting such substance, and drainage of the sinuses. (2) the special packaging is technically I. Background B. What health risks are there for people feasible, practicable, and appropriate for who overdose on or orally ingest A. What is the purpose of the proposed such substance. rule? Special packaging, also referred to as imidazolines? To protect children younger than 5 ‘‘child-resistant (CR) packaging,’’ is: (1) The therapeutically effective dose of years old from serious personal injury designed or constructed to be imidazolines occurs within a narrow following ingestion, the proposed rule significantly difficult for children under dose range with toxic effects occurring would require CR packaging for any 5 years of age to open or obtain a toxic at doses close to, or at, therapeutic over-the-counter (‘‘OTC’’) or or harmful amount of the substance levels. CNS depression (ranging from prescription product containing the contained therein within a reasonable drowsiness to deep sedation) may occur equivalent of 0.08 milligrams or more of time, and (2) not difficult for ‘‘normal after normal doses in infants. Overdoses an imidazoline (including adults’’ to use properly. 15 U.S.C. (doses not specified) of these tetrahydrozoline, naphazoline, 1471(4). Household substances for medications have caused initial spikes oxymetazoline, or xylometazoline) in a which we may require CR packaging of high blood pressure leading to slowed single package. include (among other categories) foods, heart rate, drowsiness, and rebound low blood pressure in adults. A shock-like B. Why is CR packaging necessary for drugs, or cosmetics, as these terms are defined in the Federal Food, Drug, and syndrome with abnormally low blood certain OTC or prescription products pressure and slowed heart rate may also containing imidazolines? Cosmetic Act (21 U.S.C. 321). 15 U.S.C. 1471(2)(B). We have performance occur. Warnings on tetrahydrozoline- Imidazolines are a family of drugs that requirements for special packaging. 16 and naphazoline-containing OTC drugs are used as decongestants in eye drops CFR 1700.15, 1700.20. state that use may cause CNS depression and nasal products. Topical and nasal Section 4(a) of the PPPA, 15 U.S.C. leading to coma in pediatric patients. administration of imidazolines result in 1473(a), allows the manufacturer or Xylometazoline and oxymetazoline little absorption into the general packer to package a nonprescription symptoms of overdose include: extreme circulation. Orally ingested, however, product subject to special packaging tiredness, sweating, dizziness, a slowed imidazolines are absorbed into the standards in one size of non-CR heartbeat and coma. general circulation leading to systemic packaging only if the manufacturer (or When the drug is absorbed, it can act effects. Even though death from packer) also supplies the substance in systemically within the body. Topical ingesting imidazolines is rare, ingestion CR packages of a popular size, and the administration of imidazolines to the can result in severe life-threatening non-CR packages bear conspicuous eye produces local effects to the blood consequences, such as central nervous labeling stating: ‘‘This package for vessels of the eye, but little is absorbed system (‘‘CNS’’) depression and households without young children.’’ 15 into the general circulation. (For cardiovascular effects. Specific U.S.C. 1473(a), 16 CFR 1700.5. purposes of this document, we interpret symptoms of CNS depression upon ‘‘absorption’’ as the passage of a drug ingestion of imidazolines range from II. Toxicity of Imidazolines from its site of administration into the drowsiness to coma, with a concurrent Tab A of the CPSC staff’s briefing blood plasma.) depression of the respiratory system. package, available at http:// Nasal administration of imidazolines Other observed CNS side effects www.cpsc.gov/library/foia/foia12/brief/ causes an intense degree of include: headache, lightheadedness, imidazolines.pdf contains the vasoconstriction, and therefore, dizziness, tremor, insomnia, Directorate for Health Sciences’ toxicity negligible absorption of the drug into ® nervousness, restlessness, giddiness, review for imidazolines, referred to the general circulation (POISINDEX , psychological disturbances, prolonged hereinafter as ‘‘Tab A: Staff Briefing 2011). However, with oral ingestion, psychosis, and weakness. Imidazolines Package.’’ imidazolines are absorbed into the have led to CNS depression and general circulation, leading to systemic insomnia in different individuals. A. What medical conditions are effects. These drugs are absorbed Prominent cardiovascular effects in imidazolines used to treat? quickly, and symptoms can occur in as response to overdose include low blood Imidazolines are used as topical little as one hour, peaking at 8 hours, pressure and slowed heart rate. The decongestants because they produce and resolving after 12–36 hours. Even medical literature and evidence from vasoconstriction when administered to though the symptoms resolve in a collected samples demonstrate that the eye or nasal mucosa. In the eye, the relatively short amount of time, despite the danger of ingesting imidazolines relieve redness due to ingestion of imidazolines can result in

VerDate Mar<15>2010 18:18 Jan 24, 2012 Jkt 226001 PO 00000 Frm 00008 Fmt 4702 Sfmt 4702 E:\FR\FM\25JAP1.SGM 25JAP1 sroberts on DSK5SPTVN1PROD with PROPOSALS 3648 Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules

severe life-threatening consequences, subarachnoid hemorrhage (bleeding occurring in the United States. Injury including decreased breathing, between brain and surrounding tissues), data are gathered from the emergency decreased heart rate, and loss of myocardial infarction (interruption of departments (ED) of approximately 100 consciousness, which require blood supply to part of the heart, hospitals selected as a probability hospitalization to ensure recovery. causing heart cells to die), stroke, and sample of all 5,000+ U.S. hospitals with Table 3, in section III.B of this preamble, death associated with cardiac reactions emergency departments. The system’s summarizes relevant cases of in adults. Other systemic side effects foundation rests on emergency imidazoline ingestion. can include: blanching (temporary department surveillance data, but the U.S. Food and Drug Administration whitening of the skin), sweating, system also has the flexibility to gather (‘‘FDA’’) regulations pertaining to nausea, gastric irritation, weakness, and additional data at either the surveillance ® ‘‘Cold, Cough, Allergy, Bronchodilator, high blood sugar (POISINDEX , 2011). or the investigation level. Surveillance and Antiasthmatic Drug Products for C. What treatment options are available data enable us to make timely national Over-the-Counter Human Use,’’ at 21 for imidazoline overexposure? estimates of the number of injuries CFR 341.80(c)(2)(iv), require the product associated with (but not necessarily label for products containing No specific treatment for imidazoline caused by) specific consumer products. naphazoline hydrochloride at a overexposure exists. Naloxone (an This data also provides evidence of the concentration of 0.05 percent to state: opioid blocker) has been used without need for further study of particular consistent success. Gastric lavage is not ‘‘Do not use this product in children products. Subsequent follow-back recommended more than 1 hour after under 12 years of age because it may studies yield important clues to the ingestion because the imidazolines are cause sedation if swallowed.’’ Specific cause and likely prevention of injuries absorbed quickly after ingestion, leading symptoms of CNS depression upon and deaths. For additional information to CNS depression and a greater risk of ingestion of imidazolines range from on NEISS, see the CPSC’s Web site at aspiration into the lungs. Activated drowsiness to coma, with a concurrent http://www.cpsc.gov/cpscpub/pubs/ charcoal may be used up to 1 hour after depression of the respiratory system. 3002.html. Other observed CNS side effects ingestion; but again, due to the CNS include: headache, lightheadedness, depression, there is a greater risk of CAP includes data on each pediatric dizziness, tremor, insomnia, aspiration into the lungs. Therefore, poisoning, chemical burn, or ingestion nervousness, restlessness, giddiness, treatment of the clinical effects from case reported from a NEISS hospital, as psychological disturbances, prolonged imidazolines is supportive based on well as data on some ingestions that psychosis, and weakness. Imidazolines symptoms. For example, mechanical could lead to poisoning. Our review of have led to CNS depression and respiration would be administered to data obtained from CAP is summarized insomnia in different individuals. The those with severe respiratory in Tab B of the Staff’s Briefing Package, insomnia, seen in a few cases, may be depression. hereinafter Tab B: Staff Briefing Package. an unpredictable, idiosyncratic reaction III. Ingestion and Injury Data (i.e., a drug effect that occurs in a small We searched the CAP database for number of people due to age, genetics, A. What data on imidazoline poisonings incidents between January 1997 and or disease state). is contained in the National Electronic December 2009, involving household Prominent cardiovascular effects in Injury Surveillance System (‘‘NEISS’’)? products that typically contain response to overdose include rebound The CPSC’s Directorate for Health imidazolines. During that time, there low blood pressure and slowed heart Sciences maintains the Children and were an estimated 5,675 emergency rate. Other reported cardiovascular Poisoning (‘‘CAP’’) system, a subset of room-treated injuries associated with adverse events include: palpitation NEISS records containing additional household products containing (rapid heart rate), cardiac arrhythmia information obtained through NEISS imidazolines involving children under 5 (variation from the normal rhythm of involving children under 5 years old years old. Table 1 below shows the the heart), coronary occlusion (partial or (Boja, 2001). NEISS is a statistically injury estimates for each of the product complete obstruction of blood flow in a valid injury surveillance and follow- groups involved in these incidents. coronary artery), pulmonary embolism back database that we maintain of Four-fifths of the estimated injuries (81 (lodging of mass in a lung), consumer product-related injuries percent) involved eye drops.

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

95% Product Estimated Coefficient Sample confidence injuries of variation size interval

Eye drops ...... 4,571 0.19 138 2,831–6,311 Nose Sprays 2 ...... 1,104 0.31 34 426–1,782

Total ...... 5,675 0.18 172 3,666–7,684 Source: U.S. Consumer Product Safety Commission National Electronic Injury Surveillance System and Children and Poisoning System, 2011.

The following table of NEISS In-Depth that children were able to obtain access Investigations qualitatively illustrates to imidazoline packages.

2 The estimate for this category is highly variable variation. These numbers should be interpreted due to small sample size and high coefficient of with caution.

VerDate Mar<15>2010 18:18 Jan 24, 2012 Jkt 226001 PO 00000 Frm 00009 Fmt 4702 Sfmt 4702 E:\FR\FM\25JAP1.SGM 25JAP1 sroberts on DSK5SPTVN1PROD with PROPOSALS Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules 3649

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

Imidazoline How accessed NEISS Case # Age product (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 bro- ken 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 ‘‘any- thing.’’ 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 un- screwed 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 across all ages associated with the use ingested was unknown in several are contained in the FDA’s Adverse of imidazolines. The top three system/ imidazoline cases. Very serious adverse Event Reporting System (‘‘AERS’’)? organ classes with reported adverse effects occurred in response to small The AERS is a database of voluntary events were psychiatric disorders (52 oral doses of imidazolines; these are reports from health care professionals reports); nervous system disorders (47 highlighted in Table 3 below, from and consumers, and mandatory reports reports); and respiratory, thoracic, and highest to lowest dose in milligrams. from manufacturers. AERS is mediastinal disorders (38 reports). In MedWatch reports of adverse maintained by the FDA and contains Sixty-two out of 67 in-scope cases (93 events occurring in response to reports of adverse events and percent) reported an adverse event in ingestion of imidazolines, 43 cases medication errors for all FDA-approved one of the top three system/organ occurred in children under 5 years old. drugs and therapeutic biologic products. classes. (Reports can include more than Tetrahydrozoline ingestions constituted We asked the FDA for all AERS reports one adverse event, so individual reports the majority of the cases (88 percent). mentioning the imidazolines may be recorded in more than one There were no reported deaths related to tetrahydrozoline, oxymetazoline, system/organ class.) Our review of these imidazoline ingestion. See Tab A: Staff xylometazoline, or naphazoline. FDA cases is contained in Tab B: Staff Briefing Package, Appendix A, for a provided 1,041 reports for 772 distinct Briefing Package. complete list of cases. cases involving both children and adults C. What other information is available The most recent imidazoline ingestion occurring between October 1968 and on the frequency, volume, and severity case cites the lowest dose of ingestion August 2010, for us to review. We of ingestion of imidazolines? of which we are aware that caused checked for cases related to severe adverse symptoms in a child. The imidazolines, excluded the cases with The volumes of imidazoline case involved a 25-day-old infant who concomitant drugs, and determined that ingestions in children (under the age of suffered apnea after being treated with 67 cases (with 115 total reports) were in 5) that were reported from two sources, tetrahydrozoline nasal drops (0.05 scope for consideration in this the FDA’s AERS database (‘‘MedWatch percent). The mother inadvertently rulemaking. reports’’) and the medical literature, administered the nasal drops by the oral Reports through the AERS system ranged from several drops to a high of route three times per day with 0.5 ml/ show a wide variety of adverse events 30 mL (2 tablespoons). The volume day (0.25 mg). The immature kidney

VerDate Mar<15>2010 18:18 Jan 24, 2012 Jkt 226001 PO 00000 Frm 00010 Fmt 4702 Sfmt 4702 E:\FR\FM\25JAP1.SGM 25JAP1 sroberts on DSK5SPTVN1PROD with PROPOSALS 3650 Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules

and liver function of the newborn feeding well and had low muscle tone. resolving the apnea and bradycardia. caused the drugs to clear the newborn’s Two hours after the second dose, he After two days, the child was in good system slower than in an adult. CPSC developed apnea. After the third dose condition and was discharged. After staff reviewing this case report was administered, the child was brought follow-up 10 days later, the child was in considered the three doses of nasal to the hospital and admitted with a normal condition (Katar et al. 2010). drops to be additive and calculated the respiratory rate of four breaths per Our review of the ingestion data is total dose for this case to be 0.75 mg. minute and a slowed heart rate. The contained in Tab A: Staff Briefing After the second dose, the child was not infant was treated with naloxone, Package.

TABLE 3—RELEVANT CASES OF IMIDAZOLINE INGESTION

Estimated dose Onset/symptoms Age Result Reference

2.8–5.6 mg Within 5 minutes. Child passed out 18 mos ...... Given fluids and admitted to ICU. FDA MedWatch oxymetazoline. and stopped breathing. Given CPR Aroused from coma 8–10 hours 439578450001 6/ and taken to ER. later. Released later that day. Hav- 2004. ing headaches 3–4 times daily. 3–4 mg naphazo- ‘‘Soon’’ became ‘‘quite drowsy’’ for 3 yrs ...... Several hours ...... Waring 1945. line. several hours. 3–4 mg naphazo- One hour after ingestion. Became 22 mos ...... Child warmed and treated with caf- Hainsworth 1948. line. hypothermic, lethargic, irritable, feine and oxygen. Symptoms re- pale, irregular gasping respirations, solved after 15 hrs. hypertension, bradycardia. Fol- lowed by unconsciousness and im- perceptible respirations. 2–2.5 mg 90 minutes Lethargic, decreased 17 mos ...... Pediatric intensive care unit Recov- Jensen et al. 1989. tetrahydrozoline. heart rate, decreased blood pres- ered 24 hrs. sure. Up to 2 mg Sharp increase and then decrease of 22 mos ...... Pediatric intensive care unit ...... FDA540321. tetrahydrozoline. heart rate. 1.25–2.5 mg Decreased heart rate Lethargic, dif- 16 mos ...... Admitted to hospital overnight ...... FDA671307. tetrahydrozoline. ficult to arouse, depressed respiration. 1.25–2.5 mg 2 hrs. Ataxic, pale, drowsy, de- 1 yr...... Admitted to hospital Recovered 24 Mindlin 1966. tetrahydrozoline. creased heart rate, decreased res- hrs. piration. 1.3 mg 30 min. Lethargic, difficulty breathing, 2 yrs...... Admitted to hospital, treated with FDA 43222810001. tetrahydrozoline. vomiting, loss of consciousness. charcoal. Released from hospital same day, symptoms resolved. 1–1.5 mg 2–3 hrs Lethargy, decreased blood 2 yrs ...... Pediatric intensive care unit Mechan- Tobias 1996. tetrahydrozoline. pressure, decreased respiration. ical respiration for 18 hrs Recov- ered 48 hrs. 0.25 mg x 3 or 2 hrs. Apnea, decreased respirations, 25 days ...... Admitted to hospital Naloxone, Con- Katar et al. 2010. 0.75 * slowed heart rate. tinuous positive airway pressure, tetrahydrozoline. oxygen Recovered 2 days. * Due to diminished clearance of drugs by the liver and kidney of the newborn, the three doses are considered additive.

IV. Level for Regulation threatening consequences requiring blood pressure and heart rate) was 1.8 hospitalization and intensive care mg of oxymetazoline (41 FR 38312, Absorption of imidazolines after oral monitoring for recovery. See Table 3, 38398 (September 9, 1976)). This ingestion can lead to unpredictable and section III.C of this preamble, for a minimum dose may be lower for profound CNS depression, including summary of relevant cases of children because they appear to be more depressed respiration and imidazoline ingestion. sensitive to imidazoline effects than cardiovascular events. It has been adults (Brainerd and Olmstead, 1956). shown that children under 5 years old Mindlin (1966) reported a case in Cases indicate that ingestion of as little are accidentally ingesting imidazoline- which a 1-year-old girl ingested between 1 as 0.75 mg of imidazolines can result in containing products. The first cases of ⁄2 to 1 teaspoon (2.5–5 mL) of imidazoline toxicity in children after tetrahydrozoline eye drops and suffered serious illness in children, requiring accidental ingestion occurred in the CNS depression with slowed respiration supportive therapy (Katar et al., 2010; mid-1940s, shortly after the release of and decreased heart rate. Based on this Summary see Table 3). The most recent naphazoline into the market; and the ingestion, recent publications define 2.5 case of imidazoline ingestion is incidents have continued to occur for mL tetrahydrozoline (0.05 percent, 1.25 reviewed above in section III.C of this more than 50 years (Waring 1945, mg) as the dose at which serious toxicity preamble. It involved a 25-day-old Greenblat 1947, Hainsworth 1948, from imidazoline exposure can occur infant who suffered apnea after being Meeker 1948, Bucaretchi et al., 2003). after ingestion (Holmes and Berman, treated with tetrahydrozoline nasal Symptoms of imidazoline toxicity 1999; Eddy and Howell 2000). In the drops (0.05 percent). CPSC staff include CNS depression, ranging from preamble to the proposed FDA rule for reviewing this case report calculated the drowsiness to coma, bradycardia, and OTC nasal decongestants, it was total dose for this case to be 0.75 mg, hypoventilation. Even though death reported that the minimum oral dose of which is the lowest dose of ingestion of from imidazoline exposure is rare, many oxymetazoline in an adult causing which we are aware that caused severe of these events result in serious life- measurable cardiovascular effects (on adverse symptoms in a child.

VerDate Mar<15>2010 18:18 Jan 24, 2012 Jkt 226001 PO 00000 Frm 00011 Fmt 4702 Sfmt 4702 E:\FR\FM\25JAP1.SGM 25JAP1 sroberts on DSK5SPTVN1PROD with PROPOSALS Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules 3651

Because serious effects on the heart packaging by any current, as well as ID, and a CR metered pump sprayer and breathing rates occur with the new manufacturers. design, are available to the market to ingestion of as little as 0.75 mg of replace the non-CR continuously B. Is it technically feasible, practicable, tetrahydrozoline, we consider this the threaded (NCRCT) and the non-CR and appropriate for the Commission to (NCR) metered spray pump packages. lowest observed adverse effect level require special packaging for certain Product packaging assembly line (‘‘LOAEL’’). All of the imidazolines imidazoline-containing products? cause potent central and peripheral techniques used for the NCR packages sympathetic effects, but Special packaging under the PPPA is can be adapted for some of the CR tetrahydrozoline has the highest designed to protect children from packages already in the marketplace. potency for CNS sedative/depressive serious personal injury or illness. In Other product manufacturers may use effects and the lowest potency for addition to finding that special packages that could require changes in cardiac effects. Oxymetazoline and packaging is necessary to protect assembly- and filling-line techniques. naphazoline are the most potent children, we must find that special New package sizes also may need to be imidazolines for peripheral cardiac packaging is technically feasible, designed. These new packages would effects and have an 8–10 times lower practicable, and appropriate for these require new tools to be produced. It maximum daily dose than products (15 U.S.C. 1472(a)(2)). For could take up to 1 year from initiating tetrahydrozoline (0.4 mg, 0.3 mg and 3.2 special packaging to be technically tool design to final production of a new mg, respectively). Xylometazoline and feasible, the technology must be package, depending upon the oxymetazoline have a longer duration of available to produce packaging that complexity of the package. action than tetrahydrozoline (12 hrs, 10 conforms to established standards. A Based on the foregoing, we hrs, and 4–6 hrs, respectively). package is practicable if the special preliminarily conclude that available packaging is adaptable to modern mass data support the findings that CR Applying a safety factor of 10 to the production and assembly line packaging for household products LOAEL to derive a recommended techniques. Finally, packaging is containing imidazolines is technically regulated level of 0.08 mg for all appropriate if the packaging will protect feasible, practicable, and appropriate. imidazolines is appropriate in order to the integrity of the substance adequately protect children from serious health and will not interfere with its intended C. Has the Commission made any other effects following ingestion of this family storage or use. All three of these findings related to special packaging? of drugs. The level of 0.08 mg would conditions must be met before we can In establishing a special packaging require all known imidazolines (see require special packaging for a product. standard under the PPPA, we must Tables 1 and 2) currently on the market The definition of ‘‘packaging’’ is ‘‘the consider the following: to be placed in CR packaging. (The immediate package or wrapping in 1. Reasonableness of the standard; assumptions underlying the use of which any household substance is 2. Available scientific, medical, and safety factors are that by using these contained for consumption, use, or engineering data concerning special factors, both the public health and storage by individuals in or about the packaging and childhood accidental sensitive populations are protected. household.’’ The PPPA defines ‘‘special ingestions, illness, and injury caused by Further assumptions hold that humans packaging’’ as packaging that is household substances; are somewhere between 10 and 1,000 designed or constructed to be 3. Manufacturing practices of times more sensitive to some toxic significantly difficult for children under industries affected by the PPPA; and agents than animals, and adults are less 5 years of age to open or obtain a toxic 4. Nature and use of the household sensitive than children. Hence, a safety or harmful amount of substance within substance. assessment can be conducted using the a reasonable time and not difficult for 15 U.S.C. 1472(b). We have considered proper toxicological evaluation with normal adults to use properly. Section these factors with respect to the various different populations to establish the 2(4) of the PPPA. The child-resistance determinations made in this notice, and NOEL (no observable effect level) or its and adult-use-effectiveness of special preliminarily find no reason to conclude equivalent. We used a tenfold safety packaging are measured by performance that the rule is unreasonable or factor to divide the LOEL to reach a testing packaging with children and otherwise inappropriate. NOEL level. senior adults, respectively. We evaluated packaging VI. Description of the Proposed Rule V. Preliminary Findings Related to representative of OTC products that The proposed rule would add a new Child Resistant Packaging for contain imidazolines. The specimens paragraph 33 to 16 CFR 1700.14(a), Imidazolines represent products from all four which contains a list of substances A. Do imidazolines in non-CR imidazoline families: naphazoline requiring special packaging. Pursuant to packaging pose a hazard to children? hydrochloride (HCL), oxymetazoline § 1700.14(a), all substances listed in HCL, tetrahydrozoline HCL, § 1700.14 must meet the requirements As noted above in sections II.B and III xylometazoline, and a naphazoline HCL for special packaging contained in of this document, the toxicity data combination product. None of the § 1700.20(a) (on testing procedures for concerning children’s oral ingestion of samples used special packaging. The special packaging). Proposed imidazolines demonstrate that they can eye drops were packaged in squeeze-to- § 1700.14(a)(33) would provide that any cause serious illness and injury to dispense plastic dropper bottles. The over-the-counter or prescription product children. Moreover, imidazolines are nasal spray was packaged in a plastic containing the equivalent of 0.08 available to children in common bottle with an attached metered pump milligrams or more of an imidazoline household products, such as eye drops sprayer, and the nasal drops were (tetrahydrozoline, naphazoline, and nasal sprays. Products containing packaged in a squeeze-to-dispense oxymetazoline, or xylometazoline) in a imidazolines currently do not use CR plastic dropper bottle. See Tab C: Staff single package, must be packaged in packaging. The Commission concludes Briefing Package, for a more detailed accordance with the provisions of preliminarily that a regulation is needed discussion of the products. § 1700.15(a), (b), and (c). Section to ensure that products subject to the With package size and/or type 1700.15(a) contains general regulation will be placed in CR changes, ASTM Type IA, ASTM Type requirements for special packaging,

VerDate Mar<15>2010 18:18 Jan 24, 2012 Jkt 226001 PO 00000 Frm 00012 Fmt 4702 Sfmt 4702 E:\FR\FM\25JAP1.SGM 25JAP1 sroberts on DSK5SPTVN1PROD with PROPOSALS 3652 Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules

such as the special packaging must higher degree of protection than the would be affected by this proposed continue to function with the PPPA requirement for a household regulation may represent a small effectiveness specifications set forth in substance for the Federal, state or local proportion of any one manufacturer’s § 1700.15(b). Section 1700.15(b), on government’s own use. 15 U.S.C. production. Finally, the requirements effectiveness specifications, provides 1476(b). would apply only to products packaged criteria that special packaging tested Thus, with the exceptions noted after the effective date of the pursuant to § 1700.20 must meet. above, the proposed rule regarding CR requirements. Therefore, businesses Finally, § 1700.15(c) provides that packaging for household products would have time to use up existing special packaging subject to this containing an imidazoline above the inventories of product and packaging. paragraph (c) may not be reused. regulated level would preempt non- Based on the foregoing, we conclude identical state or local special packaging preliminarily that the proposed rule VII. Request for Comments standards for such imidazoline regarding CR packaging for certain We invite interested persons to containing products. imidazoline products would not have a submit comments on any aspect of the X. Regulatory Flexibility Act (Economic significant economic impact on a proposed rule. Comments should be substantial number of small entities. submitted in accordance with the Analysis) instructions in the ADDRESSES section at The Regulatory Flexibility Act XI. Trade Secret or Proprietary the beginning of this notice. (‘‘RFA’’) generally requires that agencies Information review proposed rules for their potential Any person responding to this notice VIII. Environmental Impact economic impact on small entities, who believes that any information Generally, our regulations are including small businesses. Section 603 submitted is trade secret or proprietary considered to have little or no potential of the RFA calls for agencies to prepare should specifically identify the exact for affecting the human environment, and make available for public comment portions of the document claimed to be and environmental assessments and an initial regulatory flexibility analysis confidential. We will receive and impact statements are not usually describing the impact of the proposed handle such information confidentially required. See 16 CFR 1021.5(a). More rule on small entities and identifying and in accordance with section 6(a) of specifically, requiring CR packaging for impact-reducing alternatives. 5 U.S.C. the Consumer Product Safety Act certain imidazoline-containing products 603. Section 605(b) of the RFA, (‘‘CPSA’’), 15 U.S.C. 2055(a). Such is not expected to have an adverse however, states that this requirement information will not be placed in a impact on the environment. does not apply if the head of the agency public file and will not be made Accordingly, the rule falls within the certifies that the rule, if promulgated, available to the public simply upon categorical exclusion in 16 CFR will not have a significant economic request. If we receive a request for 1021.5(b)(2) for product certification impact on a substantial number of small disclosure of the information or rules and an environmental assessment entities and the agency provides an conclude that its disclosure is necessary or environmental impact statement is explanation for that conclusion. to discharge our responsibilities, we not required. Nasal and ophthalmic products are will inform the person who submitted classified within the NAICS 325412 IX. Executive Order 12988 (Preemption) the information and provide that person Pharmaceutical Preparation an opportunity to present additional According to Executive Order 12988 Manufacturing industry. According to information and views concerning the (February 5, 1996), agencies must state the U.S. Small Business confidential nature of the information. in clear language the preemptive effect, Administration’s Office of Advocacy, a 16 CFR 1015.18(b). if any, of new regulations. Section 7 of firm classified within NAICS 325412 is Thereafter, we will make a the PPPA provides that, generally, when considered a small business if the firm determination of whether the a special packaging standard issued has fewer than 750 employees. Based on information is trade secret or under the PPPA is in effect, ‘‘no State such classification, out of the proprietary information that cannot be or political subdivision thereof shall approximately 45 firms that released. The determination will be have any authority either to establish or manufacture imidazoline-based eye made in accordance with applicable continue in effect, with respect to such drops and nasal sprays, approximately provisions of the CPSA; the Freedom of household substance, any standard for 20 firms are defined as ‘‘small Information Act (‘‘FOIA’’), 5 U.S.C. special packaging (and any exemption businesses.’’ There may be more 552b; 18 U.S.C 1905; our procedural therefrom and requirement related manufacturers, in particular firms that regulations at 16 CFR part 1015 thereto) which is not identical to the manufacture under generic labels, that governing protection and disclosure of [PPPA] standard.’’ 15 U.S.C. 1476(a). A were not identified but that may be information under provisions of FOIA; state or local standard may be excepted small businesses. and relevant judicial interpretations. If from this preemptive effect if: (1) the Preliminary analysis shows the we conclude that any part of state or local standard provides a higher proposed rule would, if finalized, not information that has been submitted degree of protection from the risk of have a significant impact on a with a claim that the information is a injury or illness than the PPPA substantial number of small businesses. trade secret or proprietary is disclosable, standard; and (2) the state or political First, the incremental costs of CR we will notify the person submitting the subdivision applies to the Commission packaging for manufacturers are low, material in writing and provide at least for an exemption from the PPPA’s estimated at 1.5 cents per unit for 10 calendar days from the receipt of the preemption clause and the Commission imidazoline products. Manufacturers letter for that person to seek judicial grants the exemption through a process are likely to be able to pass on at least relief. 15 U.S.C. 2055(a)(5) and (6); 16 specified at 16 CFR part 1061. 15 U.S.C. some of these costs to consumers. CFR 1015.19(b). 1476(c)(1). In addition, the Federal Second, most manufacturers of OTC government, or a state or local drug products have diverse product XII. Effective Date government, may establish and continue lines that include other products that The PPPA provides that no regulation in effect a nonidentical special would not be covered by this possible shall take effect sooner than 180 days or packaging requirement that provides a regulation. Therefore, the products that later than 1 year from the date a final

VerDate Mar<15>2010 18:18 Jan 24, 2012 Jkt 226001 PO 00000 Frm 00013 Fmt 4702 Sfmt 4702 E:\FR\FM\25JAP1.SGM 25JAP1 sroberts on DSK5SPTVN1PROD with PROPOSALS Federal Register / Vol. 77, No. 16 / Wednesday, January 25, 2012 / Proposed Rules 3653

regulation is issued, except that, for DEPARTMENT OF HEALTH AND 305), Food and Drug Administration, good cause, we may establish an earlier HUMAN SERVICES 5630 Fishers Lane, rm. 1061, Rockville, effective date if we determine an earlier MD 20852. date to be in the public interest. 15 Food and Drug Administration Instructions: All submissions received U.S.C. 1471n. Because it could take up must include the Agency name, Docket to 1 year to produce a new package for 21 CFR Parts 10, 20, 25, and 510 No. FDA–2001–N–0075, and RIN 0910– AF78 for this rulemaking. All comments some companies, we intend that any [Docket No. FDA–2001–N–0075 (formerly final rule become effective 1 year after Docket No. 2001N–0284)] received may be posted without change to http://www.regulations.gov, including the publication of a final rule in the RIN 0910–AF78 any personal information provided. For Federal Register. additional information on submitting Import Tolerances for Residues of XIII. References comments, see the ‘‘Comments’’ heading Unapproved New Animal Drugs in of the SUPPLEMENTARY INFORMATION Please see all citing references in the Food section of this document. staff’s briefing package, available at AGENCY: Food and Drug Administration, Docket: For access to the docket to http://www.cpsc.gov/library/foia/foia12/ HHS. read background documents or brief/imidazolines.pdf. comments received, go to http:// ACTION: Proposed rule. www.regulations.gov and insert the List of Subjects in 16 CFR Part 1700 SUMMARY: The Food and Drug docket number, found in brackets in the Consumer protection, Drugs, Infants Administration (FDA) is proposing to heading of this document, into the and children, Packaging and containers, establish procedures by which a person ‘‘Search’’ box and follow the prompts and/or go to the Division of Dockets Poison prevention, Toxic substances. may request that the Agency establish or amend tolerances for unapproved new Management, 5630 Fishers Lane, rm. For the reasons given above, the animal drugs where edible portions of 1061, Rockville, MD 20852. Commission proposes to amend 16 CFR animals imported into the United States FOR FURTHER INFORMATION CONTACT: part 1700 as follows: may contain residues of such drugs Scott Melton, Center for Veterinary (import tolerances), as well as Medicine (HFV–232), Food and Drug PART 1700—[AMENDED] procedures to revoke an existing import Administration, 7519 Standish Pl., tolerance. Such import tolerances Rockville, MD 20855, (240) 276–8666, 1. The authority citation for part 1700 provide a basis for legally marketing email: [email protected]. continues to read as follows: food of animal origin that is imported SUPPLEMENTARY INFORMATION: into the United States and contains Authority: Pub. L. 91–601, secs. 1–9, 84 I. Background Stat. 1670–74, 15 U.S.C. 1471–76. Secs. residues of unapproved new animal 1700.1 and 1700.14 also issued under Pub. L. drugs. A. Legislative and Rulemaking 92–573, sec. 30(a), 88 Stat. 1231. 15 U.S.C. Background DATES: Submit either electronic or 2079(a). written comments on the proposed rule The President signed into law the 2. Section 1700.14 is amended to add by April 24, 2012. Submit comments on Animal Drug Availability Act of 1996 paragraph (a)(33) to read as follows: information collection issues under the (ADAA) on October 9, 1996. Section 4 Paperwork Reduction Act of 1995 by of the ADAA amended section 512(a) of § 1700.14 Substances requiring special February 24, 2012, (see the ‘‘Paperwork the Federal Food, Drug, and Cosmetic packaging. Reduction Act of 1995’’ section of this Act (the FD&C Act) (21 U.S.C. 360b(a)) (a) * * * document). by adding the following: ‘‘(6) For purposes of section 402(a)(2)(D) (now (33) Imidazolines. Any over-the- ADDRESSES: You may submit comments, section 402(a)(2)(C)(ii) as a result of the counter or prescription product identified by Docket No. FDA–2001–N– 0075 and RIN 0910–AF78, by any of the Food Quality Protection Act), a use or containing the equivalent of 0.08 intended use of a new animal drug shall milligrams or more of an imidazoline following methods, except that comments on information collection not be deemed unsafe under this section (tetrahydrozoline, naphazoline, if the Secretary establishes a tolerance oxymetazoline, or xylometazoline) in a issues under the Paperwork Reduction Act of 1995 must be submitted to the for such drug (import tolerance) and any single package, must be packaged in Office of Regulatory Affairs, Office of edible portion of any animal imported accordance with the provisions of Management and Budget (OMB) (see the into the United States does not contain § 1700.15(a), (b), and (c). ‘‘Paperwork Reduction Act of 1995’’ residues exceeding such tolerance. In Dated: January 20, 2012. section of this document). establishing such tolerance, the Todd A. Stevenson, Secretary shall rely on data sufficient to Electronic Submissions demonstrate that a proposed tolerance is Secretary, Consumer Product Safety safe based on similar food safety criteria Commission. Submit electronic comments in the following way: used by the Secretary to establish [FR Doc. 2012–1446 Filed 1–24–12; 8:45 am] • Federal eRulemaking Portal: http:// tolerances for applications for new BILLING CODE 6355–01–P www.regulations.gov. Follow the animal drugs filed under subsection instructions for submitting comments. (b)(1). The Secretary may consider and rely on data submitted by the drug Written Submissions manufacturer, including data submitted Submit written submissions in the to appropriate regulatory authorities in following ways: any country where the new animal drug • Fax: (301) 827–6870. is lawfully used or data available from • Mail/Hand delivery/Courier (for a relevant international organization, to paperor CD–ROM submissions): the extent such data are not inconsistent Division of Dockets Management (HFA– with the criteria used by the Secretary

VerDate Mar<15>2010 18:18 Jan 24, 2012 Jkt 226001 PO 00000 Frm 00014 Fmt 4702 Sfmt 4702 E:\FR\FM\25JAP1.SGM 25JAP1 sroberts on DSK5SPTVN1PROD with PROPOSALS