EPA Registration Division contact: Barbara Madden, ( 703) 305 6463 Petition Numbers 5E6965, 5E6966, and 5E6967 Summary of Petitions EPA has received pesticide petitions ( PP# 5E6965, 5E6966, and 5E6967) from Interregional Research Project # 4 ( IR 4), 681 US Highway # 1 South, North Brunswick, NJ 08902 3390, proposing, pursuant to section 408( d) of the Federal Food, Drug, and Cosmetic Act ( FFDCA), 21 U. S. C. 346a( d), to amend 40 CFR part 180.377 by establishing tolerances for residues of diflubenzuron, ( N [[( 4 chlorophenyl) amino] carbonyl] 2,6 difluorobenzamide and metabolites convertible to pchloroaniline expressed as diflubenzuron] in or on the raw agricultural commodities [ brassica, leafy greens subgroup 5B and turnip greens at 8.0 ppm, eggplant and okra at 1.0 ppm, peanut at 0.2 ppm, barley grain, oat grain, wheat grain at 0.06 ppm, forage of barley, oat and wheat at 5.0 ppm, hay of barley, oat and wheat at 2.0 ppm, straw of barley, oat and wheat at 2.0 ppm, and aspirated grain fractions of barley, oat and wheat at 3.0 ppm and pummelo at 0.5 ppm.] EPA has determined that the petition contains data or information regarding the elements set forth in section 408( d)( 2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry 1. Plant metabolism. The nature of the residue in plants and livestock is adequately understood. In plants, the metabolism of diflubenzuron was investigated in soybeans, oranges and rice. The main component of residues in rice was CPU; levels of PCA were negligible to nondetectable The main component of the residues in soybeans and oranges was the parent diflubenzuron ( DFB). A considerable portion of the residues were bound. DFB showed very limited absorption and translocation in plants with most of the residues remaining on the surface.

2. Analytical method. A practical analytical method for detecting and quantifying levels of diflubenzuron in or on food with a limit of detection that allows monitoring of the residue at or above the level set in the tolerance was used to determine residues in wheat and barley commodities.

Residues of the individual analytes are detectable and quantifiable using three separate analytical methods. Residues of diflubenzuron are extracted from wheat and barley with dichloromethane and are purified with deactivated florisil. An aliquot of the extract is hydrolyzed with phosphoric acid and the diflubenzuron is partitioned into hexane. The resulting extract is derivatized in heptafluorobutyric anhydride ( HFBA). Quantification of diflubenzuron is accompanied by gas chromatography using electron capture detection.

The analytical method for quantitation of the 4 chlorophenylurea requires ethyl acetate extraction of the residue from the crop matrix. Column chromatography is utilized for clean up of the extract immediately prior to derivitiation with HFBA. Derivatized extracts are analyzed by gas chromatography equipped with an electron capture detector.

Analysis for the determination of PCA residues in wheat and barley matrices utilizes an internal standard method. Samples of matrix to be analyzed are fortified with an internal standard. Residues of 14C PCA and the internal standard are subjected to acid and base hydrolysis. The final extract is passed through a florisil column for clean up and derivatized with HFBA in hexane. An aliquot of the derivatized extract is analyzed by gas chromatography equipped with Mass Spectrometry detection. Recovery of PCA is determined from the combined peak areas for the two mass spectral ions obtained from the derivatized PCA relative to the response factor derived from the combined areas of the corresponding two mass spectral ions of the internal standard.

3. Magnitude of residues. Raw agricultural commodities, treated according to the proposed label, were sampled. The analytical data demonstrated that residues in crops are not expected to exceed the proposed tolerance levels.

Analysis of treated crops shows that the proposed tolerances are adequate to cover residues likely to be present from the use of diflubenzuron on the proposed crops.

B. Toxicological Profile 1. Acute toxicity. Studies for diflubenzuron technical indicate the acute oral toxicity in rats and mice is > 4,640 mg/ kg, and the acute dermal toxicity in rats is > 10,000 mg/ kg. The acute inhalation LC50 in rats is > 35 mg/ l ( 6 hours). Diflubenzuron technical is not an eye or skin irritant to rabbits, and is not a dermal sensitizer in guinea pigs.

2. Genotoxicity. Diflubenzuron did not show any mutagenic activity in point mutation assays employing S. typhimurium, S. cerevisiae, or L5178Y Mouse Lymphoma cells. Diflubenzuron did not induce chromosomal aberrations in Chinese Hamster Ovary cells and did not induce unscheduled DNA synthesis in human WI 38 cells. Diflubenzuron was also negative in Mouse Micronucleus and Mouse Dominant Lethal assays and it did not induce cell transformation in Balb/ 3T3 cells.

3. Reproductive and developmental toxicity. In a rat developmental toxicity study, diflubenzuron was administered by oral gavage to pregnant female rats at dosage levels of 0, 1, 2 and 4 mg/ kg/ day. No treatment related effects were seen. A subsequent study was conducted in pregnant Sprague Dawley rats at a dose of 0 and 1,000 mg/ kg/ day. No maternal toxicity was observed. The incidence of fetuses with skeletal abnormalities was slightly increased in the treated group, but was within historical background range. The NOEL for maternal and developmental toxicity in rats was greater than 1,000 mg/ kg/ day. Diflubenzuron was also administered by oral gavage to pregnant New Zealand White rabbits at dosage levels of 0, 1, 2 and 4 mg/ kg/ day. No treatment related effects were seen. A subsequent study was conducted in pregnant rabbits at a dose of 0 and 1,000 mg/ kg/ day. No maternal or developmental toxicity was seen. The NOEL for maternal and developmental toxicity in rabbits was greater than 1,000 mg/ kg/ day.

In a rat reproduction study, diflubenzuron was fed to two generations of male and female rats at dietary concentrations of 0, 10, 20, 40, and 160 ppm. No effects were seen on parental body weight gain and there were no reproductive effects. In a subsequent study, diflubenzuron was fed to two generations of male and female rats at dietary concentrations of 500, 5,000 and 50,000 ppm. Systemic adult toxicity was seen at all dosage levels. No effects were seen on reproductive parameters, however, litter and mean pup weights of F1 offspring were reduced at 50,000. The NOEL for reproductive toxicity in rats was 50,000 ppm ( 2.5 g/ kg/ day), and for pre weaning development it was 5,000 ppm ( 250 mg/ kg/ day).

4. Subchronic toxicity.[ To assess subchronic toxicity, a four week inhalation study and a three week dermal study were conducted. In the inhalation study rats were exposed nose only to 10, 30 or 100 mg/ m3 for 6 hours per day, 5 days per week for 4 weeks. Treatment related findings were a slight reduction in erythrocytes, hemoglobin and hematocrit in male and female rats at a concentration of 100 mg/ m3 and an increase in total bilirubin in high dose female rats. There was no effect on methemoglobin concentration at any dose level. The NOEL for subchronic inhalation toxicity was 30 mg/ m3.

In the dermal toxicity study, diflubenzuron was applied to the backs of male and female CD rats for three weeks at dose levels of 20, 500 and 1,000 mg/ kg/ day. Hematology evaluation showed reductions in red blood cell ( RBC), hemoglobin ( Hgb) and hematocrit values at 500 and 1,000 mg/ kg/ day. An increased incidence of polychromasia, hypochromasia and anisocytosis was seen at 500 and 1,000 mg/ kg/ day. An increase in methemoglobin and sulfhemoglobin values was seen at 1,000 mg/ kg/ day. The NOEL for systemic toxicity was 20 mg/ kg/ day. Also, a dermal absorption factor of 0.5% for systemic absorption, was derived from a study where rats were dosed with either 0.005 or 0.05 mg/ cm2 of [ 14C] diflubenzuron technical. This value can be used for converting dermal exposure to oral equivalents.

5. Chronic toxicity. Diflubenzuron was given by capsule to male and female Beagle dogs for one year at dose levels of 0, 2, 10, 50 and 250 mg/ kg/ day. Body weight gain was slightly reduced in females at 250 mg/ kg/ day. Absolute liver and spleen weights were increased in males given 50 and 250 mg/ kg/ day. A reduction in hemoglobin and mean corpuscular hemoglobin concentration, with an elevation in reticulocyte count, was seen at 50 and 250 mg/ kg/ day. Methemoglobin and sulfhemoglobin values were increased at doses of 10 mg/ kg/ day and greater. Histopathological findings were limited to pigmented macrophages and Kupffer cells in the liver at doses of 50 and 250 mg/ kg/ day. The NOEL for chronic toxicity in dogs was 2 mg/ kg/ day.

Diflubenzuron was fed to male and female Sprague Dawley rats for two years at dose levels of 0, 156, 625, 2,500 and 10,000 ppm. Methemoglobin values were elevated in female rats at all dose levels and in male rats at the two highest dose levels. Sulfhemoglobin was elevated in females, only, at dose levels of 2,500 and 10,000 ppm. Mean corpuscular volume ( MCV) and reticulocyte counts were increased in high dose females. Spleen and liver weights were elevated at the two highest doses. Histopathological examination demonstrated an increase in hemosiderosis of the liver and spleen, bone marrow and erythroid hyperplasia and areas of cellular alteration in the liver. In another study diflubenzuron was administered to male and female CD rats for two years at dose levels of 0, 10, 20, 40 and 160 ppm. Elevated methemoglobin levels were seen in high dose males and females. No additional effects, including carcinogenic findings, were observed. The NOEL for chronic toxicity in rats was 40 ppm ( 2 mg/ kg/ day).

A ninety one week oncogenicity study in CFLP mice was conducted at doses of 0, 16, 80, 400, 2,000 and 10,000 ppm. There was no increase in tumor incidence as a result of diflubenzuron administration. Target organ effects included: increased methemoglobin and sulfhemoglobin values, Heinz bodies, increased liver and spleen weight, hepatocyte enlargement and vacuolation, extramedullary hemopoiesis in the liver and spleen, siderocytosis in the spleen and pigmented Kupffer cells. A NOEL for these effects was 16 ppm ( 2 mg/ kg/ day).

Diflubenzuron was fed to male and female Sprague Dawley rats for two years at dose levels of 0, 156, 625, 2,500 and 10,000 ppm. Methemoglobin values were elevated in female rats at all dose levels and in male rats at the two highest dose levels. Blood sulfhemoglobin was elevated in females, only, at dose levels of 2,500 and 10,000 ppm. MCV and reticulocyte counts were increased in high dose females. Spleen and liver weights were elevated at the two highest doses. Histopathological examination demonstrated an increase in hemosiderosis of the liver and spleen, bone marrow and erythroid hyperplasia and areas of cellular alteration in the liver. There was no increase in tumor formation. In another study diflubenzuron was administered to male and female CD rats for two years at dose levels of 0, 10, 20, 40 and 160 ppm. Elevated methemoglobin levels were seen in high dose males and females. No additional effects, including carcinogenic findings, were observed.

6. Animal metabolism. DFB in rats at a single dose of 100 mg/ kg and 5 mg/ kg single and multiple oral doses depicted limited absorption from the gastrointestinal tract. No major difference was observed between the single and multiple doses. In single dose treatments, after 7 days, 20% and 3% of the applied dose 5 and 100 mg/ kg, respectively were excreted in urine, while 79% and 98% of the applied dose 5 and 100 mg/ kg, respectively, were eliminated in the feces. Very little bioaccumulation in the tissues was observed. In the feces, only unchanged parent compound was detected. Several metabolites were observed in the urine which are, among others, 2 6 difluorobenzoic acid ( DFBA), 2,6 diflurophippuric acid, 2 6 difluorobenzamide ( DFBAM), and 2 hydroxydiflubenzuron ( 2 HDFB). An unresolved peak that was characterized as p chloroaniline ( PCA) and/ or p chlorophenylurea ( CPU) was found. This latter peak accounted for about 2% of the administered dose ( 5 mg/ kg). To resolve if PCA and CPU are indeed metabolites of DFB, rats were administered a single oral dose, 100 mg/ kg of 14C DFB. The major metabolites identified in rat urine were 4 chloroaniline 2 sulfate, accounting for almost 50% of the total radioactive residue ( TRR) in the urine and N ( 4 chlorophenyl) oxamic acid which accounted for about 15% of the ( TRR). Neither CPU, PCA nor their N hydroxylderivatives were found in rat urine at a limit of detection of 23 parts per billion ( ppb). As in the previous study, DFB was the only residue found in the feces.

7. Metabolite toxicology. NCI/ NTP conducted chronic feeding and gavage studies with pchloroaniline ( PCA), a minor potential metabolite of diflubenzuron, in Fischer 344 rats and B6C3F1 mice.

PCA was administered in the diet to Fischer 344/ N rats at dietary concentrations of 250 and 500 ppm for 78 weeks, followed by a 24 week observation period. A slight body weight depression was seen in high dose females rats, compared to controls. Survival was reduced in high dose males compared to controls. In male rats there was a slight increase in uncommon fibromas or fibrosarcomas of the spleen, which was not statistically significant. Non neoplastic proliferative and chronic inflammatory lesions were found in spleens of treated rats. It was concluded that, under the conditions of the assay, sufficient evidence was not found to establish the carcinogenicity of PCA for Fischer 344/ N rats.

PCA was administered 5 days/ week by oral gavage, as a hydrochloride salt in water, to male and female F344/ N rats at doses of 0, 2, 6 or 18 mg/ kg/ day. Mean body weights of dosed rats were generally within 5% of those of controls throughout the study. High dose animals generally showed mild hemolytic anemia and dose related methemoglobinemia. Non neoplastic lesions seen were bone marrow hyperplasia, hepatic hemosiderosis and splenic fibrosis, suggesting treatment related effects on the hematopoietic system. Adrenal medullary hyperplasia was observed in high dose female rats. The incidence of uncommon sarcomas of the spleen was significantly increased in high dose male rats. A marginal increase in pheochromocytomas of the adrenal gland was seen in high dose male and female rats. It was concluded that, under the conditions of this 2 year gavage study, there was clear evidence of carcinogenic activity of PCA hydrochloride for male Fischer 344/ N rats and equivocal evidence of carcinogenic activity of PCA hydrochloride for female Fischer 344/ N rats.

PCA was administered in the diet to B6C3F6 mice at dietary concentrations of 2500 and 5000 ppm for 78 weeks followed by a 13 week observation period. A body weight depression was seen in treated mice of both sexes, compared to controls. An increased incidence of hemangiomas and hemangiosarcomas in spleen, kidney, liver and other sites was seen in treated mice of both sexes; however this increase was not statistically significant compared to controls. Non neoplastic proliferative and chronic inflammatory lesions were found in spleens of treated mice. The evidence was considered insufficient to conclusively relate the hemangiomatous tumors in mice to compound administration. It was concluded that, under the conditions of the assay, sufficient evidence was not found to establish the carcinogenicity of PCA for B6C3F1 mice. PCA hydrochloride was administered 5 days/ week by oral gavage to male and female B6C3F1 mice at doses of 0, 3, 10, or 30 mg/ kg/ day. Mean body weights of high dose male and female mice were generally within 5% of those of controls throughout the study. The incidence of hepatocellular adenomas or carcinomas ( combined) was increased in a non dose dependent manner in treated male mice. Metastasis of carcinoma to the lung was seen in the high dose group. An increased incidence of hemangiosarcomas of the liver or spleen was seen in high dose male mice. It was concluded that, under the conditions of this 2 year gavage study, there was some evidence of carcinogenic activity of PCA hydrochloride for male B6C3F1 mice and no evidence of carcinogenic activity of PCA hydrochloride for female B6C3F1 mice.

In addition to PCA, 4 chlorophenylurea ( CPU) is also a potential minor metabolite of diflubenzuron. By association with Monuron, the EPA had assumed that CPU has oncogenic potential with the same carcinogenic potency ( q1*) as Monuron. 9. Endocrine disruption . The standard battery of required studies has been completed and evaluated to determine potential estrogenic or endocrine effects of diflubenzuron. These studies include an evaluation of the potential effects on reproduction and development, and an evaluation of the pathology of the endocrine organs following repeated or long term exposure. These studies are generally considered to be sufficient to detect any endocrine effects. No such effects were noted in any of the studies with diflubenzuron.

C. Aggregate Exposure 1. Dietary Exposure. An evaluation of chronic dietary exposure, including drinking water, has been performed for the U. S. population and various population subgroups including infants and children. One day single dose oral studies in rats and mice indicated there were no significant acute effects observed. As only marginal effects were noted, an acute exposure assessment is not needed for diflubenzuron.

i. Food. The dietary exposure from diflubenzuron was estimated based on the average residue values from the various currently labeled raw agricultural commodities ( RAC's), the proposed brassica leafy greens and turnip greens, eggplant and okra, peanut, barley, oat and wheat uses. Percent of crop treated was also factored into the estimate. Residues in meat, milk and egg products were obtained from extrapolation of metabolism study data to anticipated livestock dietary burdens. The dietary exposure analysis was estimated based on 1989 92 USDA food consumption data. For the U. S. population ( total), the dietary exposure of diflubenzuron was estimated as 0.000172 mg/ kg/ day. For nursing and non nursing infants, the exposure was estimated as 0.000105 and 0.000225 mg/ kg/ day, respectively. For children, the exposure was 0.000303 and 0.000166 mg/ kg/ day for 1 6 year olds and 7 12 year olds, respectively.

The dietary exposure from p chloroaniline and 4 chlorophenylurea ( CPU) which have been detected in some food products was also determined. Average residues or ½ the LOQ from field trials for registered and proposed crops were used. Residues in meat, milk, and eggs were obtained from extrapolation of metabolism data to anticipated livestock dietary burdens. The percent treated of each crop was also factored into the exposure estimate. For the U. S. population ( total), the dietary exposure of PCA was estimated at 0.000003 mg/ kg/ day. For the U. S. population ( total), the dietary exposure of CPU was estimated at 0.000006 mg/ kg/ day.

ii. Drinking water. [ Diflubenzuron degrades in soil relatively quickly with an aerobic half life ranging from 3 7 days. Major degradates include difluorobenzoic acid ( DFBA) and CPU. DFBA is further metabolized through decarboxylation and ring cleavage by soil microbes whereas CPU is slowly degraded to soil bound entities. Under anaerobic aquatic conditions, diflubenzuron has a half life of 34 days with the main degradates being DFBA and CPU. In surface water, diflubenzuron is degraded by microbes with a half life of 5 10 days.

The soil mobility of diflubenzuron is considered quite limited based on a number of experimental studies as well as by computer modeling. CPU has also been shown to be relatively immobile in soil. Although DFBA shows mobility in soil, it is rapidly degraded. Therefore, based on results of laboratory and field studies, it is not likely that diflubenzuron or its degradates will impact ground water quality to any significant extent.

Based on EPA's SCI GRO and Tier II PRZM EXAM ( IR and PC area) modeling, the average annual mean concentration of diflubenzuron in ground and surface water sources is not expected to exceed 0.067 ppb and 0.32 ppb, respectively. CPU in ground and surface water is not expected to exceed 0.065 ppb and 0.23 ppb, respectively. Because PCA is only a minor metabolite in the environment, it will not be considered in the drinking water assessment. The Drinking Water Level of Concern ( DWLOC) for chronic ( non cancer) exposure to diflubenzuron in drinking water from registered and proposed uses was determined as 694 ppb for the U. S. population ( total) and approximately 196 ppb for children 1 2, the most highly exposed population sub group. The DWLOC for chronic ( cancer) exposure to CPU in drinking water was determined as 2.1 ppb for the U. S. population ( total). The estimated maximum concentrations of diflubenzuron and CPU in ground and surface water are less than the DWLOC's as a contribution to chronic aggregate exposure. 2. Non dietary exposure. Diflubenzuron is a restricted use pesticide based on its toxicity to aquatic invertebrates. This restricted use classification makes it unavailable for use by homeowners. Occupational uses of diflubenzuron may expose people in residential locations, parks, or forests treated with diflubenzuron. Based on very low residues detected in forestry dissipation studies, a low dermal absorption rate ( 0.5%), and extremely low dermal and inhalation toxicity, these uses are expected to result in insignificant risk, and are therefore not included in the aggregate risk assessment.

D. Cumulative Effects The registrant has considered the potential for cumulative effects of diflubenzuron and other substances with a common mechanism of toxicity. The mammalian toxicity of diflubenzuron is well defined. We are not aware of any other pesticide product registered in the United States that could be metabolized to p chloroaniline. For this reason, consideration of potential cumulative effects of residues from pesticidal substances with a common mechanism of action as diflubenzuron is not appropriate. Thus, only the potential exposures to diflubenzuron were considered in the total exposure assessment.

E. Safety Determination 1. U. S. population. Based on the available toxicology and exposure database for diflubenzuron, the registrant has determined that the total non occupational aggregate exposure from diflubenzuron would occur from food and drinking water routes. Based on the 0.02 mg/ kg/ day RfD ( reference dose) derived from the dog chronic NOEL of 2 mg/ kg/ day and a 100 fold safety factor, chronic dietary exposure to the U. S. population ( total) is 0.9% of the RfD. Aggregate exposure does not exceed 100% of the RfD when the potential theoretical residues in drinking water are included.

For PCA, the total non occupational aggregate exposure would occur from the dietary route. The risk from diflubenzuron derived PCA can be estimated using a linear extrapolation of the dose response from the rat chronic study conducted by the National Toxicology Program in which rats were dosed via gavage with p chloroaniline [ hydrochloride] for 24 months. EPA has determined the q1* as 0.112 based on the combined incidence of liver adenomas and carcinomas in male mice. Using this q1*, the theoretical risk to the U. S. population ( total) from dietary exposure to diflubenzuron derived PCA was estimated at 3.81 x 10 7.

For CPU, total aggregate exposure could occur from food and drinking water. The EPA has determined that since CPU is structurally related to Monuron the most potent Q1* of 1.52 x 10 2 ( based on male rat liver neoplastic nodule and/ or carcinoma combined tumor rates) from the NTP carcinogenesis data for Monuron should be used for assessing cancer risk from CPU. Using this Q1* the theoretical risk to the U. S. population ( total) from dietary exposure to CPU was estimated at 8.53 x 10 8. The aggregate cancer risk including drinking water does not exceed the level of concern.

2. Infants and children. The dietary exposure of diflubenzuron was calculated as 0.000105 and 0.000225 mg/ kg/ day respectively for nursing and non nursing infants. These values are 0.5% and 1.1% respectively of the RfD for diflubenzuron. The dietary exposure from diflubenzuron in children 3 5 and 6 12 years old was determined as 0.000299 mg/ kg/ day and 0.000176 mg/ kg/ day, respectively, These values are 1.5% and 0.9% of the RfD, respectively. Aggregate exposure from food and drinking water does not exceed the level of concern. As previously discussed, the NOEL's for maternal and developmental toxicity in rats and rabbits were greater than 1,000 mg/ kg/ day, and the NOEL for reproductive toxicity was greater than 5,000 mg/ kg/ day. Therefore, based on the completeness and reliability of the toxicity data and the conservative exposure assessment, the registrant concludes that there is reasonable certainty that no harm will result in infants and children from aggregate exposure to residues of diflubenzuron and its conversion products containing the p chloroaniline moiety.

F. International Tolerances There are no Codex, Canadian, or Mexican limits for residues of diflubenzuron on brassica leafy greens, turnip greens, eggplant, okra, peanut, barley, oat, wheat or pummelo.


[Federal Register Volume 76, Number 69 (Monday, April 11, 2011)]
[Notices]
[Pages 19997-19998]
[FR Doc No: 2011-8524]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2010-P-0593]

Determination That FENTORA (Fentanyl Citrate) Buccal Tablet, 300
Micrograms, Was Not Withdrawn From Sale for Reasons of Safety or
Effectiveness

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) has determined that
FENTORA (fentanyl citrate) buccal tablet, 300 micrograms (mcg), was not
withdrawn from sale for reasons of safety or effectiveness. This
determination will allow FDA to approve abbreviated new drug
applications (ANDAs) for fentanyl citrate buccal tablet, 300 mcg, if
all other legal and regulatory requirements are met.

FOR FURTHER INFORMATION CONTACT: Reena Raman, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, rm. 6238, Silver Spring, MD 20993-0002, 301-
796-7577.

SUPPLEMENTARY INFORMATION: In 1984, Congress enacted the Drug Price
Competition and Patent Term Restoration Act of 1984 (Pub. L. 98-417)
(the 1984 amendments), which authorized the approval of duplicate
versions of drug products approved under an ANDA procedure. ANDA
applicants must, with certain exceptions, show that the drug for which
they are seeking approval contains the same active ingredient in the
same strength and dosage form as the ``listed drug,'' which is a
version of the drug that was previously approved. ANDA applicants do
not have to repeat the extensive clinical testing otherwise necessary
to gain approval of a new drug application (NDA). The only clinical
data required in an ANDA are data to show that the drug that is the
subject of the ANDA is bioequivalent to the listed drug.
    The 1984 amendments include what is now section 505(j)(7) of the
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)), which
requires FDA to publish a list of all approved drugs. FDA publishes
this list as part of the ``Approved Drug Products With Therapeutic
Equivalence Evaluations,'' which is known generally as the ``Orange
Book.'' Under FDA regulations, drugs are removed from the list if the
Agency withdraws or suspends approval of the drug's NDA or ANDA for
reasons of safety or effectiveness or if FDA determines that the listed
drug was withdrawn from sale for reasons of safety or effectiveness (21
CFR 314.162). Under Sec.  314.161(a)(1) (21 CFR 314.161(a)(1)), the
Agency must determine whether a listed drug was withdrawn from sale for
reasons of safety or effectiveness before an ANDA that refers to that
listed drug may be approved. FDA may not approve an ANDA that does not
refer to a listed drug.
    FENTORA (fentanyl citrate) buccal tablet, 300 mcg, is the subject
of NDA 21-947, held by Cephalon, Inc., and initially approved on
September 25, 2006. FENTORA is indicated for the management of
breakthrough pain in

patients with cancer who are already receiving and who are tolerant to
around-the-clock opioid therapy for their underlying persistent cancer
pain.
    FENTORA (fentanyl citrate) buccal tablet, 300 mcg, is currently
listed in the ``Discontinued Drug Product List'' section of the Orange
Book.
    Watson Laboratories, Inc., submitted a citizen petition dated
November 16, 2010 (Docket No. FDA-2010-P-0593), under 21 CFR 10.30,
requesting that the Agency determine whether FENTORA (fentanyl citrate)
buccal tablet, 300 mcg, was withdrawn from sale for reasons of safety
or effectiveness.
    After considering the citizen petition and reviewing Agency
records, FDA has determined under Sec.  314.161 that FENTORA (fentanyl
citrate) buccal tablet, 300 mcg, was not withdrawn for reasons of
safety or effectiveness. The petitioner has identified no data or other
information suggesting that FENTORA (fentanyl citrate) buccal tablet,
300 mcg, was withdrawn for reasons of safety or effectiveness. We have
carefully reviewed our files for records concerning the withdrawal of
FENTORA (fentanyl citrate) buccal tablet, 300 mcg, from sale. We have
also independently evaluated relevant literature and data for possible
postmarketing adverse events and have found no information that would
indicate that this product was withdrawn from sale for reasons of
safety or effectiveness.
    Accordingly, the Agency will continue to list FENTORA (fentanyl
citrate) buccal tablet, 300 mcg, in the ``Discontinued Drug Product
List'' section of the Orange Book. The ``Discontinued Drug Product
List'' delineates, among other items, drug products that have been
discontinued from marketing for reasons other than safety or
effectiveness. ANDAs that refer to FENTORA (fentanyl citrate) buccal
tablet, 300 mcg, may be approved by the Agency as long as they meet all
other legal and regulatory requirements for the approval of ANDAs. If
FDA determines that labeling for this drug product should be revised to
meet current standards, the Agency will advise ANDA applicants to
submit such labeling.

    Dated: April 6, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-8524 Filed 4-8-11; 8:45 am]
BILLING CODE 4160-01-P


[Federal Register Volume 79, Number 27 (Monday, February 10, 2014)]
[Notices]
[Pages 7677-7678]
[FR Doc No: 2014-02752]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2009-N-0360]

Agency Information Collection Activities; Proposed Collection;
Comment Request; Food and Drug Administration Safety Communication
Readership Survey

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing an
opportunity for public comment on the proposed collection of certain
information by the Agency. Under the Paperwork Reduction Act of 1995
(the PRA), Federal Agencies are required to publish notice in the
Federal Register concerning each proposed collection of information,
including each proposed extension of an existing collection of
information, and to allow 60 days for public comment in response to the
notice. This notice solicits comments on the FDA Safety Communication
Readership Survey.

DATES: Submit either electronic or written comments on the collection
of information by April 11, 2014.

ADDRESSES: Submit electronic comments on the collection of information
to http://www.regulations.gov. Submit written comments on the
collection of information to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852. All comments should be identified with the docket
number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: FDA PRA Staff, Office of Operations,
Food and Drug Administration, 1350 Piccard Dr., PI50-400B, Rockville,
MD 20850<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal
Agencies must obtain approval from the Office of Management and Budget
(OMB) for each collection of information they conduct or sponsor.
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes Agency requests or requirements that members of
the public submit reports, keep records, or provide information to a
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A))
requires Federal Agencies to provide a 60-day notice in the Federal
Register concerning each proposed collection of information, including
each proposed extension of an existing collection of information,
before submitting the collection to OMB for approval. To comply with
this requirement, FDA is publishing notice of the proposed collection
of information set forth in this document.
    With respect to the following collection of information, FDA
invites comments on these topics: (1) Whether the proposed collection
of information is necessary for the proper performance of FDA's
functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.

FDA Safety Communication (Formerly Known as Public Health Notification)
Readership Survey--(OMB Control Number 0910-0341)--Extension

    Section 705(b) of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 375(b)) gives FDA authority to disseminate information
concerning suspected or imminent danger to public health by any
regulated product. Section 1701(a)(4) of the Public Health Service Act
(42 U.S.C. 300u(a)(4)) also

authorizes FDA to conduct research relating to health information.
    FDA's Center for Devices and Radiological Health (CDRH) carries out
FDA's regulatory responsibilities regarding medical devices and
radiological products. CDRH must be able to effectively communicate
risk to health care practitioners, patients, caregivers, and consumers
when there is a real or suspected threat to the public's health. CDRH
uses safety communications to transmit information concerning these
risks to user communities. Safety communications are released and
available to organizations such as hospitals, nursing homes, hospices,
home health care agencies, manufacturers, retail pharmacies, and other
health care providers, as well as patients, caregivers, consumers, and
patient advocacy groups. Through a process for identifying and
addressing postmarket safety issues related to regulated products, CDRH
determines when to release safety communications.
    FDA seeks to evaluate the clarity, timeliness, and impact of safety
communications by surveying a sample of recipients to determine the
impact of safety communications on the knowledge of the recipients.
Understanding how the target audiences view these publications will aid
in determining what, if any, changes should be considered in their
content, format, and method of dissemination. The collection of this
data is an important step in determining how well CDRH is communicating
risk. The results from this survey will emphasize the quality of the
safety communications and customer satisfaction. This will enable us to
better serve the public by improving the effectiveness of safety
communications.
    We updated the title of the survey from ``FDA Public Health
Notification Readership Survey'' to ``FDA Safety Communication
Readership Survey'' to accurately reflect the information that is being
collected.
    FDA estimates the burden of this collection of information as
follows:

                                                     Table 1--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of
                              Activity                                  Number of      responses per     Total annual    Average burden    Total hours
                                                                       respondents       respondent       responses       per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Public Health Notification Readership Survey.......................             300                3              900         0.17 (10              153
                                                                                minutes)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    Based on the history of the FDA Safety Communication program, it is
estimated that an average of three collections will be conducted per
year. The average burden of response time is estimated at 10 minutes
per survey. This was derived by CDRH staff completing the survey.

    Dated: February 3, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-02752 Filed 2-7-14; 8:45 am]
BILLING CODE 4160-01-P


[Federal Register Volume 85, Number 247 (Wednesday, December 23, 2020)]
[Notices]
[Pages 84007-84009]
[FR Doc No: 2020-28330]

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DEPARTMENT OF LABOR

Occupational Safety and Health Administration

[Docket No. OSHA-2011-0056]

Voluntary Protection Programs Information; Extension of the
Office of Management and Budget's (OMB) Approval of Information
Collection (Paperwork) Requirements

AGENCY: Occupational Safety and Health Administration (OSHA), Labor.

ACTION: Request for public comments.

-----------------------------------------------------------------------

SUMMARY: OSHA solicits public comments concerning the proposal to
extend the Office of Management and Budget's (OMB) approval of the
information collection requirements contained in Voluntary Protection
Programs Information.

DATES: Comments must be submitted (postmarked, sent, or received) by
February 22, 2021.

ADDRESSES:
    Electronically: You may submit comments and attachments
electronically at http://www.regulations.gov, which is the Federal
eRulemaking Portal. Follow the instructions online for submitting
comments.
    Facsimile: If your comments, including attachments, are not longer
than 10 pages, you may fax them to the OSHA Docket Office at (202) 693-
1648.
    Mail, hand delivery, express mail, messenger, or courier service:
When using this method, you must submit a copy of your comments and
attachments to the OSHA Docket Office, OSHA Docket No. OSHA-2011-0056,
Occupational Safety and Health Administration, U.S. Department of

Labor, Room N-3653, 200 Constitution Avenue NW, Washington, DC 20210.
Please note: While OSHA's Docket Office is continuing to accept and
process submissions by regular mail, due to the COVID-19 pandemic, the
Docket Office is closed to the public and not able to received
submissions to the docket by hand, express mail, messenger, and courier
service.
    Instructions: All submissions must include the agency name and the
OSHA docket number (OSHA-2011-0056) for the Information Collection
Request (ICR). All comments, including any personal information you
provide, such as social security numbers and date of birth, are placed
in the public docket without change, and may be made available online
at http://www.regulations.gov. For further information on submitting
comments see the ``Public Participation'' heading in the section of
this notice titled SUPPLEMENTARY INFORMATION.
    Docket: To read or download comments or other material in the
docket, go to http://www.regulations.gov or the OSHA Docket Office at
the above address. All documents in the docket (including this Federal
Register notice) are listed in the http://www.regulations.gov index;
however, some information (e.g., copyrighted material) is not publicly
available to read or download from the website. All submissions,
including copyrighted material, are available for inspection and
copying at the OSHA Docket Office. You may also contact Theda Kenney at
the below phone number to obtain a copy of the ICR.

FOR FURTHER INFORMATION CONTACT: Seleda Perryman or Theda Kenney,
Directorate of Standards and Guidance, OSHA, U.S. Department of Labor;
telephone<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    The Department of Labor, as part of the continuing effort to reduce
paperwork and respondent (i.e., employer) burden, conducts a
preclearance consultation program to provide the public with an
opportunity to comment on proposed and continuing information
collection requirements in accordance with the Paperwork Reduction Act
of 1995 (PRA) [44 U.S.C. 3506(c)(2)(A)]. This program ensures that
information is in the desired format, reporting burden (time and costs)
is minimal, collection instruments are clearly understood, and OSHA's
estimate of information collection burden is accurate. The Occupational
Safety and Health Act of 1970 (OSH Act) (29 U.S.C. 651 et seq.)
authorizes information collection by employers as necessary or
appropriate for enforcement of the OSH Act or for developing
information regarding the causes and prevention of occupational
injuries, illnesses, and accidents (29 U.S.C. 657).
    The Voluntary Protection Programs (VPP) [47 FR 29025], adopted by
OSHA, established the efficacy of cooperative action among government,
industry, and labor to address employee safety and health issues and to
expand employee protection. To qualify, employers must meet OSHA's
safety and health management criteria which focus on comprehensive
management programs and active employee involvement to prevent or
control worksite safety and health hazards. Employers who qualify
generally view OSHA standards as a minimum level of safety and health
performance, and set their own more stringent standards, wherever
necessary, to improve employee protection. Prospective VPP worksites
must submit an application that includes:
     General applicant information (e.g., site, corporate, and
collective bargaining contact information).
     Injury and illness rate performance information (i.e.,
number of employees and/or applicable contractors on-site, type of work
performed and products produced, North American Industry Classification
System (NAICS), and Recordable Injury and Illness Case Incidence Rate
information.
     Safety and health management program information (i.e.,
description of the applicant's safety and health management programs)
including how the programs successfully addresses management leadership
and employee involvement, worksite analysis, hazard prevention and
control, and safety and health training OSHA uses this information to
determine whether an applicant is ready for a VPP on-site evaluation
and as a verification tool during VPP on-site evaluations. Without this
information, OSHA would be unable to determine which sites are ready
for VPP status.
    Each current VPP applicant is also required to submit an annual
evaluation which addresses how that applicant is continuing the
adherence to programmatic requirements. In 2008, OSHA modified
procedures for VPP applicants, OSHA on-site evaluation, and annual
participant self-evaluation for applicants/participants subject to
OSHA's Process Safety Management (PSM) Standard. Applicants that
perform works that use or produce highly hazardous chemical exceeding
specified limits covered under the PSM standard must submit responses
to the PSM application supplement along with their VPP application.
    Once in the VPP, the participant is required to submit an annual
evaluation detailing the continued adherence to programmatic
requirements. Applicants covered under the PSM standard are required to
submit a PSM questionnaire a supplemental document as part of their
annual submission. OSHA needs this information to ensure that the
participant remains qualified to participate in the VPP between the on-
site evaluations. Without this information, OSHA would be unable to
determine whether applicants are maintaining excellent safety and
health management programs during this interim period.
    In 2009, with the publication of the Federal Register Notice (FRN),
VPP revised the traditional focus on individual fixed worksites (site-
based) by adding two new ways to participate: mobile workforce and
corporate. A significant reorganization of the program helps clarify
the multiple participation options now available.
    Employees of VPP participants may apply to participate in the
Special Government Employee (SGE) Program. The SGE Program offers
private and public sector safety and health professionals and other
qualified participants the opportunity to exchange ideas, gain new
perspectives, and grow professionally while serving as full-fledged
team members on OSHA's VPP on-site evaluations. In that capacity, SGEs
may review company documents, assist with worksite walkthroughs,
interview employees, and assist in preparing VPP on-site evaluation
reports. Potential SGEs must submit an application that includes:
     SGE Eligibility Information Sheet (i.e., applicant's name,
professional credentials, site/corporate contact information, etc.);
     Current Resume;
     Optional Application for Federal Employment OF-612; and
     Confidential Financial Disclosure Report (OGE Form 450).
    OSHA uses the SGE Eligibility Information Sheet to ensure that the
potential SGE works at a VPP site and meets the minimum eligibility
qualifications. The resume is required to provide a detailed
description of their current duties and responsibilities as they relate
to safety and health and the implementation of an effective safety and
health management program. The OGE Form 450 is used to ensure that SGEs
do not participate on on-site evaluations at VPP sites where they have
a financial interest.

    OSHA Challenge is designed to reach and guide employers and
companies in all major industry groups who are strongly committed to
improving their safety and health management programs and possibly
pursuing recognition in the VPP. The Challenge Administrators
application is used to: (1) Conduct a preliminary analysis of the
applicant's knowledge of safety and health management programs; and (2)
make a determination regarding the applicant's qualifications to become
a Challenge Administrator. Once a Challenge Administrator is approved,
the Administrator will review each challenge candidate's application/
annual submissions to ensure that all necessary information is
provided, prior to forwarding to OSHA's National Office for acceptance
and analysis.

II. Special Issues for Comment

    OSHA has a particular interest in comments on the following issues:
     Whether the information collection requirements are
necessary for the proper performance of the agency's functions,
including whether the information is useful;
     The accuracy of the agency's estimate of the burden (time
and costs) of the information collection requirements, including the
validity of the methodology and assumptions used;
     The quality, utility, and clarity of the information
collected; and
     Ways to minimize the burden on employers who must comply;
for example, by using automated or other technological information
collection and transmission techniques.

III. Proposed Actions

    OSHA is requesting an adjustment decrease of 363 burden hours from
90,863 to 90,500 hours. The decrease is primarily due to the lack of
Challenge participation, and lack of training of new SGE applicants and
re-approval training of existing SGEs due to the negative impact of the
COVID-19 imposed on all OSHA Cooperative Programs.
    Type of Review: Extension of a currently approved collection.
    Title: Voluntary Protection Programs Information.
    OMB Control Number: 1218-0239.
    Affected Public: Business or other for-profits.
    Number of Respondents: 4,052.
    Total Respondents: 3,601.
    Frequency: Various.
    Estimated Total Total Burden Hours: 90,500.
    Estimated Cost (Operation and Maintenance): $0.

IV. Public Participation--Submission of Comments on This Notice and
internet Access to Comments and Submissions

    You may submit comments in response to this document as follows:
(1) Electronically at http://www.regulations.gov, which is the Federal
eRulemaking Portal; (2) by facsimile (fax); or (3) by hard copy. Please
note: While OSHA's Docket Office is continuing to accept and process
submissions by regular mail, due to the COVID-19 pandemic, the Docket
Office is closed to the public and not able to receive submissions to
the docket by hand, express mail, messenger, and courier service. All
comments, attachments, and other material must identify the agency name
and the OSHA docket number for the ICR (Docket No. OSHA-2011-0056). You
may supplement electronic submissions by uploading document files
electronically. If you wish to mail additional materials in reference
to an electronic or facsimile submission, you must submit them to the
OSHA Docket Office (see the section of this notice titled ADDRESSES).
The additional materials must clearly identify your electronic comments
by your name, date, and the docket number so the agency can attach them
to your comments.
    Because of security procedures, the use of regular mail may cause a
significant delay in the receipt of comments.
    Comments and submissions are posted without change at http://www.regulations.gov. Therefore, OSHA cautions commenters about
submitting personal information such as social security numbers and
date of birth. Although all submissions are listed in the http://www.regulations.gov index, some information (e.g., copyrighted
material) is not publicly available to read or download through this
website.
    All submissions, including copyrighted material, are available for
inspection and copying at the OSHA Docket Office. Information on using
the http://www.regulations.gov website to submit comments and access
the docket is available at the website's ``User Tips'' link. Contact
the OSHA Docket Office at<PHONE_NUMBER>, (TTY<PHONE_NUMBER>) for
information about materials not available through the website, and for
assistance in using the internet to locate docket submissions. Contact
the OSHA Docket Office for information about materials not available
through the website, and for assistance in using the internet to locate
docket submissions.

V. Authority and Signature

    Loren Sweatt, Principal Deputy Assistant Secretary of Labor for
Occupational Safety and Health, directed the preparation of this
notice. The authority for this notice is the Paperwork Reduction Act of
1995 (44 U.S.C. 3506) and Secretary of Labor's Order No. 1-2012 (77 FR
3912).

    Signed at Washington, DC, on December 17, 2020.
Loren Sweatt,
Principal Deputy Assistant Secretary of Labor for Occupational Safety
and Health.
[FR Doc. 2020-28330 Filed 12-22-20; 8:45 am]
BILLING CODE 4510-26-P