UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 Office of Prevention, Pesticides and Toxic Substances March 11, 2003 SUBJECT: Carbaryl: Agency Response To Comments On Phase 5 Risk Assessment; DP Barcodes: D286511, D286777, D286506, D286775, D286771, D286478, D286920& D286510, and D286456; PC Code: 056801 FROM: Jeffrey L. Dawson, Chemist/ Risk Assessor Reregistration Branch 1 Health Effects Division ( 7509C)

Felicia Fort, Chemist Reregistration Branch 1 Health Effects Division ( 7509C)

Kit Farwell, DVM/ Toxicologist Reregistration Branch 1 Health Effects Division ( 7509C)

THRU: Whang Phang, PhD, Branch Senior Scientist Reregistration Branch 1 Health Effects Division ( 7509C)

TO: Anthony Britten, Chemical Review Manager Reregistration Branch 3 Special Review & Reregistration Division ( 7508C)

Attached is the Agency's response to Phase 5 error correction comments provided by several organizations on the previous version of the human health effects risk assessment ( D284580/ July 30, 2002). The intent of this document is to illustrate how the comments were considered in the revisions to the risk assessment. Each comment is summarized below along with the Agency response and any associated changes in the risk assessment. Appropriate identifying information is also included ( e. g., submitter, DP Barcode, document cited, etc.). Many of the comments included issues related to both the human health risk assessment and the eco risk assessment. Only those comments that pertain to the human health risk assessment are addressed herein. All comments related to the development of EECs used for drinking water assessments have been addressed separately by the Environmental Fate and Effects Division. 2 # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT D286511: ORGANIZATION = BEYOND PESTICIDES, AUTHOR = JESSICA LUNSFORD, DATE = 10/ 23/ 02 1 Docketing error. Comments have been included in the process despite any error. None 2 Assessment fails to implement the 10x safety factor based on several issues including: dietary data;

market share changes; 3x and lack of a true NOAEL for the chronic assessment; and maximum versus typical application rates. The Agency has considered these issues including: the CMBS data have been characterized; potential market share changes are being evaluated; the 3x safety factor for the chronic assessment is based on current Agency policy; and the rates are based on the best use information available ( see Appendix A). None, unless there are additional changes with the interpretation and characterization of the CMBS and the market share analysis will be considered in the development of the risk management package for carbaryl.

3 Selective use of the CMBS ( carbamate market basket survey)

and other residue data for analysis. The Agency has presented the dietary risks in a way that considers the results of the CMBS with the appropriate characterization. None, unless there are additional changes with the interpretation and characterization of the CMBS.

4 Residential product market share changes should be considered. The Agency is evaluating the potential impacts of such market share changes. None, the market share analysis will be considered in the development of the risk management package for carbaryl.

5 Intermediate term risks should be considered in the residential assessment. Intermediate term risks, where appropriate ( i. e., in post application situations), were considered by the Agency. None. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 3 6 Actual rates exceed maximum labeled rates by up to a factor of 2. The Agency does not consider misuse scenarios in its assessments.

Additionally, the claims made were unsubstantiated. None, the referenced scenarios were unsubstantiated.

7 Several risk management recommendations were made. The Agency will consider these during the risk management phase. None.

D286511: ORGANIZATION = WA TOXICS COALITION & NW COALITION FOR ALTERNATIVES TO PESTICIDES, AUTHORS = E. SCHREDER & P. LIND, DATE = 10/ 28/ 02 1 Several comments were made on ecological effects. WA state water and sediment data were cited. The Agency used water data from several sources in WA state in its oyster bed use assessment. EFED will address the remaining comments. None related to the oyster bed assessment.

EFED will address the remaining comments.

2 A concern for market share changes was expressed. The Agency is evaluating the potential impacts of such market share changes. None, the market share analysis will be considered in the development of the risk management package for carbaryl.

D286511: ORGANIZATION = NRDC, AUTHOR = JENNIFER SASS, DATE = 10/ 28/ 02 1 Several recommendations were made including: cancellation of all granular formulations, cancellation of all pet uses, and use a 10x FQPA safety factor. The Agency will consider these during the risk management phase.

The Agency has also evaluated the application of the FQPA factor under the most current policy. [ See Appendix A for further explanation regarding the FQPA factor.] None. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 4 2 Carbaryl is an n methyl carbamate and should be included with the OPs for cumulative assessment since " they clearly share a mode of action." There are differences in pharmacokinetics and pharmacodynamics between OPs and carbamates, cholinesterase inhibition is by different biochemical mechanisms, resulting in different time course of events: time to peak effect, t1/ 2, duration of action, and recovery time after exposure. EPA is investigating the pharmacokinetics and pharmacodynamics of N methyl carbamates for the cumulative assessment of these pesticides. None.

3 The Agency has " disregarded adverse effects on developing brain structure and function." Several Agency documents were cited to support this claim. Please refer to Appendix A. See the response to D286511/ comment 1 above. [ Also, please refer to Appendix A.]

4 " Farm children are especially vulnerable to pesticide exposure and are not adequately considered."

Work from several researchers has been cited to support this claim ( e. g., Fenske and Hill). The Agency is currently evaluating its position on the exposures of farmchildren. Preliminary analysis of available information does not indicate significant differences in exposures for farmchildren compared to the general population. None at this time outside of appropriate characterization will be added to the assessment to address this issue that reflects the most currently available information. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 5 5 Water issues were addressed including: non agricultural run off ( e. g., landscape and golf course use) and DWLOCs. NRDC indicates they anticipate EECs would be worse if non agricultural run off was considered. EFED will address this comment. EFED will address this comment.

6 Dietary ( food) issues were addressed including: composite PDP samples were used to estimate single servings consumed,

farmstand/ UPIK sources of commodities were not considered,

and percent crop treated values were " wrongly" used to adjust acute dietary risk estimates. The dietary risk assessment was conducted in accordance with Agency policy. The Agency is currently evaluating its position on UPIK sources of commodities. None at this time outside of appropriate characterization will be added to the assessment to address this issue that reflects the most currently available information.

7 Recommendations were made based on the residential risk estimates including: MOEs for residential handlers, MOEs for children on lawns, and MOEs for children after contact with treated pets. NRDC also cited the lack of a transferable residue study on pets. The Agency will consider these during the risk management phase. None. It should also be noted a recently submitted transferable residue study for dog collars was integrated into the current assessment.

8 Comments were made regarding the magnitude of occupational MOEs. The Agency will consider these during risk management. None. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 6 9 Comments were made regarding a lack of exposure data for some occupational scenarios. NRDC indicated that a 10x FQPA factor should be applied in these cases. The Agency does not, under the FQPA statute, apply the FQPA factor to occupational exposure scenarios. None, the scenarios in question will be further investigated during the risk management phase to develop a better understanding of their use to allow for a more informed risk management decision.

D286777: ORGANIZATION = CHERRY MARKETING INST., AUTHOR = PHIL KORSON, DATE = 10/ 22/ 02 1 Efficacy, use, and information on alternatives were presented. In tart cherries, carbaryl is used on ~ 9% of the acres with an average of 1.3 applications annually. In sweet cherries, ~ 31% of acres with an average of 1.6 applications annually are completed. Mechanical harvest was indicated as the predominant method. The FDA mandated zero tolerance for cherry fruit fly larva was also described. The Agency will consider this information in the development of the updated risk assessment and during risk management. None, outside of additional characterization of occupational risks will be included as appropriate.

D286506: ORGANIZATION = CA STRAWBERRY COMMISSION, AUTHOR = JAN SHARP, DATE = 10/ 23/ 02 1 Efficacy of bait products was discussed and the need for a 3 day PHI versus the current 7 day PHI.

Harvest intervals of 3 days were presented as normal practice in strawberry cultivation. No additional data were presented,

but additional work by IR 4 was discussed that would not be available for this process. The Agency will consider this information in the risk management process. None, outside of additional characterization of occupational risks will be included as appropriate. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 7 D286506: ORGANIZATION = MI STATE UNIV/ OCEANA CTY, AUTHOR = KIMBERLY SMITH, DATE = 10/ 29/ 02 1 The lack of alternatives, the impact of a 5 day REI ( based on previous assessment), and zero tolerance criteria for asparagus beetle were discussed. The Agency will consider this information in the risk management process. None, outside of additional characterization of occupational risks will be included as appropriate.

D286506: ORGANIZATION = US ASPARAGUS INDUSTRY, AUTHOR = SCHREIBER & BAKKER, DATE =

10/ 28/ 02 1 The lack of alternatives, the impact of a 5 day REI ( based on previous assessment), zero tolerance criteria for beetle damage, and the unique need for carbaryl at harvest time because it controls adult asparagus beetles were discussed. Use information was also presented including: NASS information about MI that indicates growers apply carbaryl to ~ 90% of acres  4x/ year and at about ½ that frequency in the east. The Agency will consider this information in the risk management process. None, outside of additional characterization of occupational risks will be included as appropriate. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 8 D286506: ORGANIZATION = US APPLE ASSOC., AUTHOR = JIM CRANNEY, DATE = 10/ 28/ 02 1 The critical biological and economic needs for carbaryl when used for thinning apples was discussed along with issues associated with alternatives ( they are not as favorable because they are dose and climate dependent). The Agency will consider this information in the risk management process. None, outside of additional characterization of occupational risks will be included as appropriate. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 9 D286775: ORGANIZATION = NAT. AG. APPL. ASSOC., AUTHOR = ANDREW MOORE, DATE = 10/ 25/ 02 1 The use of " antiquated" PHED data, numerous educational efforts,

the use of GPS instead of flaggers,

and the need for additional exposure data were discussed. The Agency concurs with NAAA that the PHED data used in this assessment may not accurately reflect exposures associated with the most cutting edge technologies.

However, more recent data have not been produced to date than those used in the assessment. It is also not clear what portion of the industry uses older technology versus the more updated nozzle technology described in NAAA's submission.

The Agency still includes flaggers in its assessments because NAAA's own use survey indicates they are still used in a small percentage of applications (~ 15%). The Agency characterizes this as such in its assessments for risk managers. None, outside of additional characterization of occupational risks will be included as appropriate. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 10 D286771: ORGANIZATION = NW HORT. COUNCIL, AUTHOR = MICHAEL WILLETT, DATE = 10/ 29/ 02 1 The inability to use closed cabs for applying carbaryl in tree fruit because of the tree canopy shape ( apple and cherry examples were provided) was discussed. Potential economic impacts were also discussed. No additional information was provided to substantiate this comment ( e. g., a comparison of the size of tree canopies versus tractor size, etc.). However, the Agency will consider this comment during risk management. None outside of providing additional characterization as appropriate. The Agency also considered open cab airblast applicator scenarios with individuals wearing protective headgear which is related to this issue.

2 The methodology used to calculate surface water concentrations for dietary risk and eco risk assessment was criticized. EFED will address this comment. EFED will address this comment.

3 Use of the CMBS ( carbamate market basket survey) was encouraged for calculating dietary risk. The Agency has considered the CMBS in its calculations. In the previous assessment dietary risks were evaluated both with and without the CMBS which is also the case in the current assessment. The only changes would be related to additional language related to the interpretation and characterization of the CMBS. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 11 D286478: ORGANIZATION = USDA APHIS, AUTHOR = CARL BAUSCH, DATE = 10/ 28/ 02 1 Comments described the Grasshopper and Mormon Cricket Suppression program mandated by the Plant Protection Act ( 7USC7717). ULV and bait applications ( aerial & ground) are used up to a maximum application rate of 0.50 lb ai/ acre. A NEPA EIS has been completed. It was also indicated that site specific environmental assessments " will be developed as specific areas are targeted for treatment; these EA's will address sensitive areas,

Statelisted endangered and threatened species as well as Federal candidate species."

[ NEPA] = National Environmental Protection Act [ EIS]= Environmental Impact Statement [ EA] = Environmental Assessment The Agency will consider this program as appropriate in the risk assessment. As such, the Agency obtained information directly from USDA/ APHIS on the details of how this program is conducted and used this information to update the risk assessment. The Agency added occupational scenarios that reflect USDA/ APHIS use patterns.

Residential scenarios were not added to address this use since it is analogous to any drift situation where current Agency policy applies. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 12 D286920 & D286510: ORGANIZATION = WELLMARK, AUTHORS = CRAWFORD & SANDBERG, DATE =

10/ 25/ 02 1 A study conducted by Mississippi State University ( Boone et al) was referenced. The biological monitoring component of the study was discussed and the argument made that a lack of TCP ( a urinary metabolite from exposure to chlorpyrifos collars) increase in urine over time for children living with treated pets is an indication of little or no exposure from collar use. The Agency has considered the referenced biological monitoring data but has rejected it for use in risk assessment. This decision was made predominantly because the data are inconclusive. In this study,

children's activities were not correlated with the time or their contact with treated animals. None outside of providing additional characterization language as appropriate.

2 The Agency used an emission term developed based on data from MSU ( Boone et al) for collars of 0.00029mg/ cm2/ gram ai/ day. This was said to be too conservative because it is the value measured closest to the collar area and " a toddler will also have contact with other regions of the animal."

Boone measured residues on different sections of the animals and the Agency used the results from near the head/ neck for assessments. The value cited from Boone et al actually represents the average concentration over all areas of the treated dogs. None, outside of additional characterization language as appropriate. Also see response to comment 3 below as the Agency also used data from a recently submitted collar residue study to evaluate exposures in context with the Boone et al data. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 13 3 A study ( MRID 45792201) that determined the amount of residues that transferred from 10 dogs wearing carbaryl collars ( 16% ai)

was conducted. Measurements of transferability by people petting dogs for 20 minutes over all regions of the animals were taken at 24 hours, 96 hours and 1 week after placement of the collars. A separate study ( report not provided)

was also conducted that measured residue release from collars. The Agency used these data to calculate a residue transferability rate of 2.6% to evaluate non collar products. The Agency also evaluated collar use with the data from this study both distibuting residues locally around the collar and over the entire dog for comparative purposes. The Agency revised its assessment to use these data to provide companion risk assessments for non collar pet products ( basically for comparative purposes). The data were also used directly to assess pet collar use.

4 The percent of transferable residue that was used by the Agency in its calculations ( 20%) is an overestimate. Additionally, the 50% saliva extraction factor was said to overestimate exposure since the solubility of carbaryl is very low in water. With regard to the transferability issue, the Agency calculated risks in several different ways as indicated above in the response to comment 3 and there were no changes in the trend of the results. The comment on saliva extraction fails to account for the mechanical agitation that would be expected in a toddler's mouth.

This factor has also been taken for review to the FIFRA SAP. Additional characterization language will be provided and the results based on the study will be incorporated into the assessment as appropriate. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 14 5 It was indicated that the suburban resident biomonitoring study supported the continued use of carbaryl pet products. Also, it was reported " the results of this study,

which contains biological monitoring of all age groups,

indicate that the Agency has overestimated the exposure of users of carbaryl products." The Agency does not concur with this statement because ( 1) no reliable biological monitoring data are available for defining absorbed dose estimates from pet uses and ( 2) the interpretation of the results of the biological monitoring estimate is inappropriate because the use patterns are so dissimilar. The results of the biological monitoring study actually agree quite closely with the calculations from the risk assessment on residential turf. The Agency has never indicated that similarities between lawn and pet care uses. None outside of additional characterization language to address this comment. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 15 D286456: ORGANIZATION = BAYER CROP SCIENCE, AUTHORS = NOT LISTED, DATE = 10/ 28/ 02 D286456: GENERAL COMMENTS, PART 1 ( starts pg 4)

1 The application of a 3x factor for the lack of a NOAEL in the chronic dog study was discussed. A 5 week study in dogs supports a NOAEL of 3.1 mg/ kg/ day rather than it being a LOAEL. The 3x factor should be removed. Brain ChE inhibition of 20% in the chronic dog study is considered toxicologically significant. None.

2 Label changes need to be made to reflect the results of the confined rotational crop ( CRC) study. The CRC study demonstrates " that no plant back restriction is needed and no tolerances for rotational crops are required." The Agency concluded that the rotational crop study was adequate and that the current label restriction against rotating crops for which carbaryl is not registered is adequate.

No changes should be made to the label. None 3 Inconsistencies in the EFED review and revised HED risk assessment should be corrected. Monitoring data should be considered. The Agency will correct any inconsistencies. Monitoring data will be considered and used as appropriate. Inconsistencies will be corrected and monitoring data will be incorporated as determined to be appropriate.

D286456: LINE BY LINE COMMENTS ON TOXICOLOGY DATABASE, PART 2 ( starts pg 6)

1 ( Pg6/ ¶ 2/ L1 16) Bayer concurs with the Agency's interpretation of the data supporting the FQPA factor of 1. None. None. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 16 2 ( Pg6/ ¶ 3/ L1 10) Carbaryl presents no imminent carcinogenic risk because:

( 1) high doses produce tumors via a non genotoxic mechanism, possibly related to altered metabolism, ( 2) at doses < MTD there was increased tumor incidence in only 1 site of 1 sex of 1 species, ( 3) the p53 knockout model was negative ( its been demonstrated to be sensitive to vascular tumor induction by reference chemicals), ( 4) weight of evidence shows no potential for genotoxicity, and ( 5)

epidemiological data in production workers shows no increase in tumors. ( 1) Non genotoxic mechanism has not been demonstrated; ( 2) in addition to vascular tumors,

preneoplastic lesions were seen at inadequate dose in mice, if mice had been tested at an adequate dose,

tumors may have developed; ( 3) p53 mouse has not been validated by EPA; ( 4) DNA reactivity is manifested as chromosomal aberrations in cultured mammalian cells, are effects on karyokinesis and cytokinesis, as well as stress genes associated with oxidative damage.

Also, see further discussion of epidemiological study of workers below. None.

3 ( Pg6 7/ ¶ 4 1/ L5 15) Same as comment 1 in General Comments Section ( Pt 1). Same as comment 1 in General Comments Section ( Pt 1). Same as comment 1 in General Comments Section ( Pt 1). # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 17 4 ( Pg11/ ¶ 3/ L1 10) Risks from carbaryl contained in cigarette smoke are " insignificant and is not calculable." The Agency did calculate noncancer risks for carbaryl contained in cigarette smoke with the acknowledgment that both sidestream and main stream smoke were included which is a likely overestimate of exposure. The Agency did not attempt to calculate cancer risks attributable from carbaryl contained in cigarette smoke because it would be indistinguishable from other chronic health effects associated with smoking ( including cancer). None.

5 ( Pg16/ ¶ 2/ L1 3) There is no clear scientific basis for requesting a 90

day inhalation study in rats. A submission from Crop Life America on this topic was included that discussed ( 1) spray droplet size based on ASAE criteria, ( 2) particle deposition in the respiratory tract,

and ( 3) the guidelines for 28 or 90

day inhalation toxicity studies. Spray droplets are large and inhalation MOEs for liquid formulations are generally greater than ~ 50,000. However, use of dust,

granular, and bait applications have MOEs ranging from 28  714. An inhalation study is still required to address these concerns. None. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 18 D286456: SUPPORTING DISCUSSION COMMENTS ON TOXICOLOGY DATABASE, PART 2 ( starts pg 16)

1 Several topics pertaining to the combined oncogenicity/ chronic toxicity studies were discussed including: ( 1) the data are considered equivocal since tumors occurred in 1 site of 1 sex of 1 species, ( 2) adequate historical control data were not available from the laboratory that conducted the studies, ( 3) the lack of significant histopathological findings at the 1 year sacrifice which didn't correlate well with the detection of tumors in certain tissues, and another slide review was completed by " independent pathologists." ( 1) Pre neoplastic lesions seen at inadequate dose in mice, if tested at adequate dose, tumors may have developed; ( 2) tumor incidence was compared to concurrent controls and historical data submitted by registrant; ( 3) analysis in the CARC report is based on a reevaluation of slides from the mouse carcinogenicity study by an acceptable Pathology Working Group which was performed in accordance with PR Notice 94 5 ( D233467; HED document 012394). None. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 19 2 Several topics pertaining to the combined oncogenicity/ chronic toxicity studies were discussed including: those addressed above in comment 1 and altered metabolism from " unrealistically high" doses may impact formation of tumors,

and the significance of vascular tumors. It could not be determined if there was a change in metabolism in mice at 1000 ppm, a dose that caused tumors. The DNA binding study had limited sensitivity. The P 450 study showed that carbaryl is a weak enzyme inducer in mice but there were no studies to examine the effect of increasing doses. Alteration in metabolism, by itself, is not sufficient evidence of a nonlinear mode of action, and there was no correlation between the metabolic shift and increased toxicity or tumor formation. None.

3 The epidemiological/ worker exposure information was discussed. " The population of exposed persons with the highest and most consistent carbaryl exposure, show no indication of effects on tumor incidence." The sample of workers was too small and the period of follow up to too short to permit definitive conclusions. None. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 20 D286456: COMMENTS ON DIETARY EXPOSURE ANALYSIS, PART 3 ( starts pg 24)

1 Bayer concurs with the Agency's last revisions to the dietary analysis including: use of processing factors,

use of cooking and washing factors,

removal of non supported commodities, use of updated PAD and Q1* values, and use of 1994

1998 CFSII data. None. None.

2 The utility of the carbamate market basket survey was discussed.

Additionally, the protocols for sample preparation in various commodities were presented from the CMBS and PDP for comparative purposes. It was indicated that it was " the professional judgement of the study designers" to add " gentle rubbing to the protocol but not the drying process." These comments have been addressed in the revised dietary assessment. These comments have been addressed in the revised dietary assessment. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 21 3 The use and surrogation of monitoring residue data was discussed. This included a ranking of types of residue data ( i. e., closer to the dinner plate is preferable for risk assessment). The Agency's decompositing approach was discussed and a line by line examination for each food and food form was performed with an accompanying proposal for which source of residue data to use for each. These comments have been addressed in the revised dietary assessment. These comments have been addressed in the revised dietary assessment.

4 The need to update the percent crop treated data used in the assessment was discussed. The revised dietary assessment will include revised percent crop treated data. The revised dietary assessment will include revised percent crop treated data.

5 A strategy was proposed for refining the dietary risk assessment that included: replacement of residue data for leafy crops, use of 1999 2000 PDP data for newly sampled crops, and refine the data used for squash and peaches. These comments have been addressed in the revised dietary assessment. These comments have been addressed in the revised dietary assessment. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 22 D286456: LINE BY LINE COMMENTS ON ESTIMATED ENVIRON. CONC., PART 4 ( starts pg 33)

1 ( Pg9/ ¶ 3/ L1 16) The use of " the drinking water program conducted by the registrant provides a real world assessment of the potential for human exposure to carbaryl in drinking water derived from surface water." These data were advocated over the use of PRZM/ EXAMS. EFED will address this comment. EFED will address this comment.

2 ( Section 4.3) Comments were made concerning inconsistencies between EFED and the HED risk assessment chapter. The Agency will correct any inconsistencies. Monitoring data will be considered and used as appropriate. Inconsistencies will be corrected and monitoring data will be incorporated as determined to be appropriate.

3 ( Pg40/ ¶ 3/ L1 16) Comments were related to item 1 above. EFED will address this comment. EFED will address this comment.

4 ( Pg40/ ¶ 6) Information was provided about NAWQA and the recovery of carbaryl residues in the multi residue methods. This was done in response to general comments included in the risk assessment pertaining to the referenced analytical method. EFED will address this comment. EFED will address this comment.

5 ( Pg41/ ¶ 3) HED risk assessment is inconsistent with EFED RED chapter. The Agency will correct any inconsistencies. Inconsistencies will be corrected as determined to be appropriate. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 23 6 ( Pg41/ ¶ 3/ L12) Information was provided concerning sampling methods that describes why NAWQA and the Bayer drinking water study results are different.

Essentially, differences were attributed to the different types of sample locations used in both studies. Results of the drinking water study were also compared to the EPA/ USGS reservoir study and the USDA PDP drinking water study. EFED will address this comment. EFED will address this comment. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 24 7 ( Pg41/ ¶ 3/ Last line) Information was provided concerning the determination of peak water concentrations. The distributions can be used to obtain up to the 99th % tile. The peak concentration was in a small river while most community water systems are likely to be on larger bodies of water.

Therefore, " peak values are not likely to be an order of magnitude greater than the amounts present in the collected samples."

Additionally, because the maximum observed concentration is more than an order of magnitude less than the DWLOC for carbaryl the drinking water study should be sufficient to demonstrate that concentrations of carbaryl " do not result in an unacceptable contribution to dietary exposure." EFED will address this comment. EFED will address this comment. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 25 8 ( Pg41/ ¶ 4/ L1 2) Comments were provided concerning the use of peak water concentrations for risk assessments rather than specific percentiles ( e. g., 95th or 99th). A more thorough discussion of the concentration distributions should be provided. EFED will address this comment. EFED will address this comment.

9 ( Pg41 42/ ¶ 5) Additional comments were made concerning the use of the drinking water monitoring study instead of PRZM EXAMS. EFED will address this comment. EFED will address this comment.

D286456: LINE BY LINE COMMENTS ON 5/ 30/ 02 RESIDUE CHEMISTRY CHAPTER, PART 5 ( starts pg 38)

1 ( Pg6/ ¶ 1& 2) Comments were made concerning an inconsistency with ¶ 4 pertaining to the lack of storage stability data on dried fruit.

Information in ¶ 4 indicates there is an adequate study on raisins. The Agency will correct any inconsistencies. Inconsistencies will be corrected as determined to be appropriate.

2 ( Pg9/ ¶ 16) Comments were made concerning the requirements for 20 field trials on wheat hay. A comparison was made to grasses that are another major component in cattle diets that required only 12 field trials. The number of trials required for a crop takes into account not only its production acreage, but also its dietary significance which is why the Agency requires 20 field trials on wheat hay and only 12 for grasses. None # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 26 3 ( Pg7/ ¶ 4) The Agency indicated tolerances were needed for citrus fruit oil, raisins, wet apple pomace,

and rice hulls. It was indicated that tolerances in raisins and wet apple pomace were not needed because the HAFT for apples or grapes times their respective concentration factors are below 1.5x the reassessed tolerances for apples and grapes, respectively. The Agency will correct any inconsistencies. Inconsistencies will be corrected as determined to be appropriate.

4 ( Pg12/ ¶ 2) The label restriction concerning rotational crops requires updating. The Agency concluded that the rotational crop study was adequate and that the current label restriction against rotating crops for which carbaryl is not registered is adequate.

No changes should be made to the label. None # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 27 D286456: SUPPORTING DISCUSSION COMMENTS ON RESIDUE CHEMISTRY DATABASE, PART 5 ( starts pg 40)

1 A confined rotational crop study ( MRID 43651701) was discussed.

Additionally, it was presented that " the results of the CRC study demonstrate that no plant back restriction is needed and no tolerances for rotational crops are required." The Agency concluded that the rotational crop study was adequate and that the current label restriction against rotating crops for which carbaryl is not registered is adequate.

No changes should be made to the label. None D286456: LINE BY LINE COMMENTS ON OCC./ RES. EXPOSURE ASSESSMENT, PART 6 ( starts pg 42)

1 ( Sec 2.1.3) For calculations involving treatment to over 350 acres, it was indicated that there is poor correlation between exposure and the acres treated. This was attributed to an " efficiency of application" associated with the treatment of larger acreages ( e. g.,

rather than use a number of small volume jugs a mechanical transfer device would be used). This analysis was based on an ethoprop biomonitoring study ( MRID 45621501). The AHETF was identified as a body that would investigate this phenomena further. The Agency has had similar concerns and welcomes the additional data that could be generated under the AHETF that could be used to refine its approach. This will not, however,

occur in a manner that will be timely for the carbaryl risk management decision. Analysis of the ethoprop study is inconclusive with regard to this issue. Additional characterization language will be provided and the results based on the study will be incorporated into the assessment as appropriate. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 28 2 The inability to use closed cabs for applying carbaryl in tree fruit was described because of the tree canopy shape. It was also indicated that the Agency should differentiate between its available tree and grape data instead of combining them as is now done and that a protection factor be applied for the use of headgear. No information was provided to substantiate the comment about cab entry into orchards ( e. g., a comparison of the size of tree canopies versus tractor size, etc.).

However, the Agency will consider this comment during risk management. Additionally, headgear for open cab airblast applicators with high levels of personal protective equipment was used in the assessment. Characterization language will be provided as appropriate to address this issue.

Additionally, the Agency incorporated headgear into its assessment for open cab airblast applicators as it is apparent based on the comment that Bayer would be willing to address this issue through labeling. The Agency applied a 50 percent protection factor for headgear use only to applicators who were also wearing maximum levels of personal protective equipment ( e. g., coveralls, gloves,

respirator).

3 The use of ARTF proposed transfer coefficients was discussed. An illustration was provided for tree crop activities. The transfer coefficients that were proposed include 84 cm2/ hr for low exposure activities such as propping, 493 cm2/ hr for low exposure activities such as scouting, pruning and pinching and 1440 cm2/ hr for high exposure activities such as hand harvest and thinning. The Agency is currently evaluating the results of the entire ARTF project. Much of the decisions needed to modify the Agency's currently used policy 3.1 rest on this review which is still pending. The Agency did, however, modify TC values for tree crop harvesters ( based on ARTF data) and thinners ( correcting a study error). It should also be mentioned that Bayer Crop Science conducted a biological monitoring study in tree harvesters and thinners. Preliminary results support the Agency's current value for thinning. This study has not yet been formally submitted. The Agency has used the updated tree crop thinner and harvester TCs in its most recent assessment. # ISSUE AGENCY RESPONSE ACTIONS NEEDED FOR RISK ASSESSMENT 29 4 A suburban resident biological monitoring study has been conducted. Bayer urges the Agency to consider these data in its evaluation of residential exposures. The Agency has reviewed this study and will incorporate it as appropriate in the assessment. The results of this study were incorporated into the assessment as appropriate.

D286456: COMMENTS ON AGGREGATE RISK ASSESSMENT & CHARACTERIZATION, PART 7 ( starts pg 46)

1 Comments were made concerning the use of deterministic risk assessment approaches, the use of updated use information from surveys and biological monitoring,

and the Bayer Crop Science plans to submit probabilistic model analyses to support carbaryl registrations. The Agency will consider the results of the recently submitted probabilistic assessment as appropriate. It will be considered in conjunction with the results of the HED risk assessment. None to the risk assessment document itself.

The Agency will develop a separate review and analysis of the submission as appropriate.

Both the probabilistic assessment and the HED risk assessment will be considered concurrently during risk management.

D286456: APPENDICES  VARIOUS APPENDICES WERE ATTACHED THAT CONTAINED SPECIFIC INPUTS SUGGESTED BY BAYER, THESE WERE CONSIDERED AS APPROPRIATE ( starts pg 47) 30 Appendix A: Agency Response To NRDC Comments 31 D286511: ORGANIZATION = NRDC, AUTHOR = JENNIFER SASS, DATE = 10/ 28/ 02 The National Resource Defense Council ( NRDC) contends that the Agency should retain the full default 10x Food Quality Protection Act Safety Factor ( FQPA SF) for carbaryl for the protection of infants and children.

On August 27, 1998, the FQPA SF Committee recommended the retention of the 10X FQPA safety factor for carbaryl owing to the incompleteness of the toxicology data base, specifically, the lack of acceptable studies of pre natal developmental toxicity in rats and rabbits and two generation reproduction toxicity in rats ( Txr. No. 012834).

The following year, EPA received and reviewed pre natal developmental toxicity studies in rats and rabbits. On December 13, 1999 and on April 30, 2001, the FQPA SF Committee recommended the retention of the of the 10X FQPA safety factor due to the lack of the twogeneration reproduction study in rats, as well as the concerns for the results of the developmental neurotoxicity study ( Txr. No. 013891).

The registrant subsequently submitted a two generation reproduction study in rats and conducted morphometric measurements of brains of rats in the developmental neurotoxicity study ( HIARC report, March 5, 2002). On April 3, 2002, the FQPA SF Committee, based on the weight of evidence of all available studies ( both submitted to the Health Effects Division [ HED], as well as those published in the literature) determined that reliable data demonstrated that the safety of infants and children will be protected by the use of a 3x FQPA SF for chronic dietary and long term dermal and inhalation exposures. The 3x FQPA SF was applied to extrapolate a NOAEL ( no observed adverse effect level) from a LOAEL ( lowestobserved adverse effect level). For acute dietary and short and intermediate term exposures, the Committee recommended that the FQPA SF be reduced to 1x ( Txr. No. 0050634).

This determination was based on an analysis of the toxicology data which followed the approach described in the 2002 guidance document, Determination of the Appropriate FQPA Safety Factor( s) in Tolerance Assessment ( February 28, 2002). This analysis entails 1) determination of the level of concern for the effects observed when considered in the context of all available toxicity data; 2) identification of any residual concerns after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment of this chemical; and 3) if residual concerns are identified, a determination as to whether these residual concerns can be addressed by a special FQPA safety factor.

Following are individual NRDC comments on the FQPA factor and the HED responses. 32 NRDC Comment: The FQPA memos of December 13, 1999 and April 30, 2001 both say that the 10x FQPA safety factor was retained because the developmental neurotoxicity study showed significant changes in morphometric measurements. Decreased cerebellar length in the 10 mg/ kg/ day group is " still regarded as a treatment related effect".

HED Response: The reasons for retaining the 10x FQPA safety factor in 1999 and 2001 were not only due to concerns about the need for additional brain morphometric measurements, but also due to the datagap for a reproduction study.

Since the FQPA documents of December 13, 1999 and April 30, 2001 were written, a twogeneration reproduction study and new brain morphometric measurements in control and high dose groups from the developmental neurotoxicity study in rats were received and reviewed. Based on these new data, the FQPA SF Committee reconsidered the safety factor in 2002.

In addition to these new data, the Committee used a weight of the evidence approach to determining the magnitude of the FQPA safety factor that differed slightly from the approach it used in 1999 and 2001. This weight of evidence approach included an analysis of data from different studies considered together and included 1) determination of the level of concern for the effects observed when considered in the context of all available toxicity data; and 2) identification of any residual concerns after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment of this chemical. This approach is described in the guidance document, Determination of the Appropriate FQPA Safety Factor( s) in Tolerance Assessment ( February 28, 2002).

The FQPA SF Committee analyzed the degree of concern and uncertainties present in the developmental neurotoxicity study. The Committee reported that there was no concern for the lack of brain morphometric measurements in the offspring at the mid dose because even at the high dose, the morphometric changes were minimal and it is unlikely that adverse effects would be seen at the mid dose level. There was no concern for the lack of comparative data in adults and offspring for cholinesterase inhibition because no alterations in the functional observational battery ( FOB) were seen in pups. Other studies have shown that when cholinesterase inhibition was seen, it usually was accompanied by FOB alterations. Additionally, the results of the National Institute for Environmental Health Sciences study indicate that there is no difference in the levels at which cholinesterase inhibition occurs in pups and adults. This study showed that the dose related decrease in cholinesterase activity in the brain and blood of dams at gestation day 19 was very similar to the fetal brain cholinesterase levels taken at the same time. Because limiting carbaryl to levels which will not cause cholinesterase inhibition in adults will be equally protective of infants and children, an acute RfD for Carbaryl, using the NOAEL of 1 mg/ kg/ day in the developmental neurotoxicity study in rats, is protective of single dose exposures to infants and children. 33 NRDC Comment: In referring to the April 3, 2002 FQPA SF Committee report, the NRDC says that " the FQPA committee seems to suddenly alter their position on the developmental neurotoxicity study results, without any new data, and in spite of statistically significant alterations in cerebellar structure and size in female pups. The FQPA committee indicates that the morphometric changes observed at the high dose were minimal, and therefore, ' it is unlikely that adverse effects would be seen at the mid dose level ( 1 mg/ kg/ day)'. This is stated without any supportive data, and contrary to the study results."

" Moreover, in the April 3, 2002 document, discussed above, the Agency erroneously determines that the high dose in the rat developmental neurotoxicity study can be accepted as a lowest affect level ( LOAEL). Therefore the Agency erroneously determines that the middose of 1 mg/ kg/ day in the developmental neurotoxicity study is acceptable for the NOAEL, despite the complete lack of morphometric data from the mid dose group."

HED Response: The developmental neurotoxicity study results were re evaluated because new data became available for analysis by the Hazard Identification Assessment Review Committee ( HIARC): the registrant conducted new brain morphometric measurements in control and high dose groups in the developmental neurotoxicity study ( Txr No. 0050307).

Toxicity studies are designed to determine the type of toxicity which occurs and the doses at which this occurs. The risk assessment methodology used by EPA relies on two key measures of toxicity, the lowest dose at which toxicity occurs, the LOAEL or lowestobserved adverse effect level, and the next lower dose, the NOAEL, or no observed adverseeffect level, at which toxicity is not observed. An ideal study would provide both a clear LOAEL and NOAEL. In the carbaryl developmental neurotoxicity study, morphometric analysis was conducted in control and high dose groups ( 10 mg/ kg/ day), but not in low dose ( 0.1 mg/ kg/ day) or mid dose ( 1.0 mg/ kg/ day) groups. Upon review of the data, HED requested that morphometric analysis of the low dose and mid dose groups be conducted, but this was not possible due to technical difficulties because the brain tissues had dried during the preservation process.

Since effects on brain morphometric measurements occurred in the high dose group, but measurements were not possible in the low dose and mid dose groups, a NOAEL was extrapolated. HED considers extrapolation reasonable in this case because there is high confidence in the adequacy of the doses tested and any concern for the lack of morphometric analysis at the mid dose was negated since even at the high dose, the changes, although statistically significant, were minimal in nature and were judged not likely to be present at the mid dose.

As discussed in the HIARC reports ( March 5, 2002 and May 9, 2002) and the FQPA SF Committee report ( April 3, 2002), both committees determined that it was unlikely that there would be any adverse effects on brain morphometry at the next lower dose of 1 mg/ kg/ day, which was 1/ 10 the dose at which the effects of minimal severity were noted. HED considers 34 this conclusion reasonable because effects were of minimal severity and dose spacing between the mid dose and high dose groups was large. Had the effects been more severe, or had the dose for the high dose group been closer to that for the mid dose group, then HED would be more likely to require an additional safety factor to compensate for the weakness in the data.

NRDC Comment: " In the April 3, 2002 document discussed above, the Agency determined that the 2 generation reproduction study demonstrated quantitative evidence of increased susceptibility of the young animals following exposure to carbaryl. Results demonstrated that the NOAEL for parents was 27 mg/ kg/ day for males and 30 mg/ kg/ day for females, based on decreases in body weight, weight gain, and food consumption. In the offspring the NOAEL was 5 mg/ kg/ day in males and 6 mg/ kg/ day in females ( 5 6X lower than in adults) based on pup death. It is obvious that pups are more susceptible to carbaryl toxicity and that the endpoint measured in pups is far more extreme than for adults, death versus weight loss. Therefore, it is likely that pups are even more susceptible that the study data indicates."

HED Response: Offspring toxicity did occur at doses below those causing parental toxicity. However, the dose response relationship for the offspring effects was well characterized with a clear NOAEL. The dose used for establishing the Chronic Reference Dose ( cRfD) for chronic dietary risk assessment is lower than that NOAEL, and well below the dose at which offspring toxicity occurred. The HIARC performed the analysis for any residual uncertainties for pre and postnatal toxicity and concluded that there were no residual uncertainties for preand postnatal toxicity and the potential risk to infants and children is fully characterized.

HED agrees with NRDC that the offspring NOAEL is 5 6 fold lower than the parental NOAEL. However, HED believes that the chronic RfD is sufficiently protective of infants and children for potential adverse effects from exposure to carbaryl based on the following factors. 1) The extrapolated NOAEL of 1 mg/ kg/ day used for deriving the cRfD ( LOAEL of 3 mg/ kg/ day ÷ 3x UF) is 5 fold lower than the NOAEL of 5 mg/ kg/ day in the two generation reproduction study. 2) Use of the 1 mg/ kg/ day results in a lower cRfD ( 0.01 mg/ kg/ day) rather than the use of 5 mg/ kg/ day which would have resulted in a higher ( less protective) cRfD ( 0.05 mg/ kg/ day). 3) The cRfD is based on the most sensitive species ( dogs) exhibiting the most sensitive endpoint ( cholinesterase inhibition) at the lowest administered dose ( 1 mg/ kg/ day) and therefore provides additional protection for the effects seen in rats ( including the reproduction and developmental neurotoxicity studies). 4) The critical study selected for the cRfD is of longer duration ( 1 year) and thus appropriate for the chronic dietary assessments, rather than the reproduction study which is of shorter duration ( 13 weeks). 5) The data indicate no differences between rat pups and adults with regard to cholinesterase inhibition, which is the endpoint of concern for the cRfD. Therefore, the Agency believes that the 3x FQPA safety factor is adequate for the protection of infants and children from long term exposure to carbaryl. 35 NRDC Comment: The NRDC letter characterizes the decision to reduce the FQPA SF from 10x to 1x as, " an about face, without supportive data, and in contradiction to the reported results of the study".

HED Response: The decision to reduce the FQPA SF to 3x for chronic dietary and longterm dermal and inhalation exposures and to 1x for acute dietary and short and intermediateterm exposures, was made following receipt and evaluation of new data. The new data which became available included a new reproduction study and new brain morphometric measurements in control and high dose animals in the developmental neurotoxicity study.

These data were examined very carefully by two separate committees ( HIARC and FQPA SF Committee) using the approach described in Determination of the Appropriate FQPA Safety Factor( s) in Tolerance Assessment ( February 28, 2002). The committees used a weight ofevidence approach in which data from different studies are considered together and entails 1) determination of the level of concern for the effects observed when considered in the context of all available toxicity data; and 2) identification of any residual concerns after establishing toxicity endpoints and traditional uncertainty factors to be used in the risk assessment of this chemical.

The purpose of the FQPA infant's and children's health safety factor is " to take into account potential pre and post natal toxicity and completeness of data with respect to exposure and toxicity to infants and children" ( FFDCA section 408( b)( 2)( C)). Because these developmental effects are well characterized, and appropriate safety factors are applied to the NOAEL derived from the developmental neurotoxicity study, and there are no concerns or residual uncertainties for pre and/ or postnatal toxicity, the committees concluded that there is no need for an additional FQPA safety factor to address potential pre or postnatal toxicity. 36 NRDC Comment: " The endpoint of all toxicological studies used in the carbaryl assessment ignores regional variability in responses within different brain regions, and masks local perturbations that may be very severe. NRDC believes that histopathological examination may reveal regionally affected brain areas. Also, behavioral and cognitive testing, including learning and memory tests, reflex tests, and others, are key to assessing the true toxic effects of any neurotoxic and fetotoxic chemicals. Most importantly, with any developmental neurotoxic chemical such as carbaryl, effects are the result of more than the magnitude of the dose. Rather, the effect is dependant on the dose, the duration of the effect ( ChEI), and the stage of developmental at which the exposure takes place. Exposures during key windows of susceptibility during neural developmental, even at very low doses, are most likely to have permanent, devastating effects on neural function, including behavior and cognition. The effects of carbaryl exposure on fetuses, infants, and children have not been adequately described in this assessment."

" In addition to paying attention to sensitive biological endpoints, it is also essential to recognize the value of these physiological systems to the complete integrity of a person. For example, neurotoxic damage resulting in the permanent loss of several IQ points in a lab animal may not even be detectable, but may severely limit the potential of a person or exposed population. For instance, inability to pay attention, mood changes, inability to predict consequences of actions, and explosive temper are all result of fetal exposure to alcohol. While these effects might seem subtle or almost negligible in an animal study measuring crude endpoints such as BW changes or fetal death, they can cripple the social and emotional potential of an affected human."

HED Response: A number of toxicity studies were evaluated for the carbaryl risk assessment. These included guideline studies required by law ( 40 CFR Part 158), nonguideline studies, and studies from the open literature. These toxicity studies for carbaryl examined many sensitive toxicity endpoints in acute, subchronic, and chronic toxicity studies in a variety of species, as well as in vivo and in vitro mutagenicity studies.

Specifically, these studies evaluated histopathology of different regions of the brain, cholinesterase activity in different brain regions, cholinesterase activity in blood, neurobehavior in adults and offspring, and made observations for clinical signs of toxicity. Cognitive functions of learning and memory were evaluated in the developmental neurotoxicity study.

The developmental and reproduction studies evaluated effects to fetuses after exposure during the critical period during which development of the fetus occurs. The reproduction study evaluated toxicity in offspring after exposure to fetuses throughout gestation, and to offspring by exposure through nursing and subsequent diet during development to adulthood.

In addition, postmortem examinations were conducted, organ weights were determined, histopathological examinations were conducted for all tissues and organs, and urinalyses and numerous clinical chemistry and hematological analyses were conducted. 37 This robust toxicology database indicates that the endpoint which is most likely to show adverse effects at the lowest dose is cholinesterase inhibition. Therefore, if infants and children are protected for cholinesterase inhibition, HED believes they are protected for any other type of adverse effects resulting from exposure to carbaryl. HED believes that the risk assessment addresses all potential effects that may result during the windows of development for fetuses, infants, and children.


[Federal Register Volume 79, Number 127 (Wednesday, July 2, 2014)]
[Notices]
[Pages 37750-37754]
[FR Doc No: 2014-15373]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2013-N-1524]

Bulk Drug Substances That May Be Used To Compound Drug Products
in Accordance With Section 503B of the Federal Food, Drug, and Cosmetic
Act, Concerning Outsourcing Facilities; Revised Request for Nominations

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice; revised request for nominations.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is preparing
to develop a list of bulk drug substances (active ingredients) that may
be used to compound drug products in accordance with section 503B of
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) concerning
outsourcing facilities. In response to a notice published in the
Federal Register of December 4, 2013, interested groups and individuals
previously nominated a wide variety of substances for this list.
However, many of those nominations were not for bulk drug substances
used in compounding as active ingredients, and none included sufficient
information to justify inclusion of the nominated substances on the
list. To improve the efficiency of the process for developing the list
of bulk drug substances that may be used to compound drug products
under section 503B of the FD&C Act, FDA is providing more detailed
information on what it needs to evaluate a nomination. Because the
deadline for nominations has passed, FDA is reopening the nomination
process so that interested persons can submit nominations of bulk drug
substances and provide adequate support to justify placing the
substances on the list. Bulk drug substances that were previously
nominated will not be further considered unless they are renominated
and adequately supported. Substances that are not adequately supported
will not be placed on the list.

DATES: Submit written or electronic nominations for the bulk drug
substances list by September 30, 2014.

ADDRESSES: You may submit nominations, identified by Docket No. FDA-
2013-N-1524, by any of the following methods.

Electronic Submissions

    Submit electronic nominations in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

    Submit written nominations in the following ways:
     Mail/Hand delivery/Courier (for paper submissions):
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name
and Docket No. FDA-2013-N-1524 for this request for nominations. All
nominations received may be posted without change to http://www.regulations.gov, including any personal information provided. For
additional information on submitting nominations, see the ``Request for
Nominations'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
    Docket: For access to the docket to read background documents or
nominations received, go to http://www.regulations.gov and insert the
docket number, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Emily Helms Williams, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6280, Silver Spring, MD 20993-0002, 301-
796-3381.

SUPPLEMENTARY INFORMATION:

I. Background

    Under the Drug Quality and Security Act (Pub. L. 113-54), which
added section 503B to the Federal Food, Drug, and Cosmetic Act (FD&C
Act) (21 U.S.C. 353b), outsourcing facilities \1\ may qualify for
certain exemptions from the FD&C Act if the conditions set forth in the
statute are satisfied. Those conditions include that an outsourcing
facility does not compound drug products using a bulk drug substance
unless the bulk drug substance appears on a list established by the
Secretary identifying bulk drug substances for which there is a
clinical need (the 503B list), or the drug product compounded from such
bulk drug substance appears on the drug shortage list in effect under
section 506E of the FD&C Act (21 U.S.C. 356e) (FDA drug shortage list)
at the time of compounding, distribution, and dispensing, and each of
the following conditions are met: (1) If an applicable monograph exists
under the United States Pharmacopeia, the National Formulary, or
another compendium or pharmacopeia recognized by the Secretary for
purposes of this paragraph, the bulk drug substance complies with the
monograph; (2) the bulk drug substance is manufactured by an
establishment that is registered under section 510 of the FD&C Act (21
U.S.C. 360); and (3) the bulk drug substance is accompanied by a valid
certificate of analysis (see section 503B(a)(2) of the FD&C Act).
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    \1\ ``Outsourcing facilities'' are facilities that meet certain
conditions described in section 503B of the FD&C Act, including
registering with FDA as an outsourcing facility.
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    Section 503B refers to the definition of ``bulk drug substance'' in
FDA regulations at Sec.  207.3(a)(4) (21 CFR 207.3(a)(4)). See section
503B(a)(2) of the FD&C Act. As defined in Sec.  207.3(a)(4), a ``bulk
drug substance'' is any substance that is represented for use in a drug
and that, when used in the manufacturing, processing, or packaging of a
drug, becomes an active ingredient or a finished dosage form of the
drug, but the term does not include intermediates used in the synthesis
of such substances.
    An ``active ingredient'' is any component that is intended to
furnish pharmacological activity or other direct effect in the
diagnosis, cure, mitigation, treatment, or prevention of disease, or to
affect the structure or any function of the body of man or other
animals. The term includes those components that may undergo chemical
change in the manufacture of the drug product and be present in the
drug product in a modified form intended to furnish the specified
activity or effect. See 21 CFR 210.3(b)(7).
    Any component other than an active ingredient is an ``inactive
ingredient.'' See 21 CFR 210.3(b)(8). Inactive ingredients used in
compounded drug products, which commonly include flavorings, dyes,
diluents, or other excipients, need not appear on the Secretary's list
of bulk drug substances to be eligible for use in compounding drug
products and will not be included on the list.
    In a notice dated November 27, 2013, published in the Federal
Register of December 4, 2013 (78 FR 72838), FDA requested nominations
for specific bulk drug substances for the Agency to consider for
placement on the 503B list. In response to that request, 753 comments
were submitted to the docket, most of which nominated substances for
inclusion on the bulk drug substances list. Some comments nominated
several hundred substances, and approximately 10 comments nominated
thousands of substances, including en bloc nominations of substances
listed in the United States Pharmacopeia (USP) or National Formulary,
the British Pharmacopeia, the European Pharmacopeia, the Japanese
Pharmacopeia, the Food Chemicals Codex, the Homeopathic Pharmacopeia of
the United States, and the USP Dietary Supplements Compendium. Several
submissions referenced a spreadsheet entitled ``OTC Active
Ingredients,'' available on FDA's Web site at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM135688.pdf. Those submissions
nominated all of the ingredients on the spreadsheet, which numbered
over 1,700 entries.\2\
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    \2\ The total number of unique ingredients on the spreadsheet
available on FDA's Web site and the nominations that mirrored that
document is lower than this total because the same substances were
listed separately for different indications, according to how they
are listed in the over-the-counter (OTC) monographs and regulations.
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    However, many of the nominated substances are typically inactive
ingredients or foods. Some commonly used inactive ingredients are
occasionally used as the active ingredient in a drug product. See 55 FR
46914 at 46916, November 7, 1990 (noting that 21 CFR 310.545 only
affects the use of the listed ingredients as active ingredients for the
specific indications and that some of the ingredients listed in the
rule, such as sorbitol, sugars, and eucalyptol, have valid uses as
inactive ingredients). Ingredients commonly used as inactive
ingredients in compounded drug products, such as flavorings, dyes,
diluents, or other excipients, need not appear on the Secretary's list
of bulk drug substances to be eligible for use as an inactive
ingredient in compounded drug products, should not be nominated, and
will not be included on the list. All nominations must demonstrate how
the ingredient is used as an active ingredient in a particular
compounded drug product.
    Further, the nominations did not include sufficient information for
the Agency to evaluate the clinical need for drug products compounded
using the bulk drug substance. As stated previously, section 503B
requires FDA to create a list ``identifying bulk drug substances for
which there is a clinical need . . . .'' Section 503B(a)(2)(A)(i) of
the FD&C Act. Although this language is ambiguous, the Agency has
interpreted it to mean that a clinical need to compound with a bulk
drug substance exists where there is a clinical need for a specific
drug product to be compounded with the nominated bulk drug substance.
The Agency believes that this interpretation is consistent with both
the language and purpose of

the statute. Therefore, to qualify for placement on the 503B list, it
is necessary to identify the compounded drug product for which there is
a clinical need and to demonstrate that the nominated bulk drug
substance is required to compound that drug product.
    The nominators of the en bloc submissions provided no justification
for listing any of the specific substances on the list. To the extent
information about the clinical need for the use of a bulk drug
substance in compounded drug products was provided at all in individual
nominations, many of the comments to the docket included a statement
about the need for the use of bulk drug substances in compounding
generally rather than information about the specific clinical need for
drug products compounded using a particular bulk drug substance. For
example, many nominations included the following standardized language
as the explanation of clinical need for compounding with the bulk drug
substance: ``Prescribed dosage forms and strengths not available
commercially. Manufacturer backorders. Possible patient sensitivities
to manufactured product dyes, fillers, preservatives and other
excipients.'' Such statements do not provide sufficient information for
FDA to determine that there is a clinical need to compound a particular
drug product from the nominated bulk drug substance. Because the
information submitted with previous nominations was insufficient, FDA
is unable to determine whether those substances should be included on
the list.
    To improve the efficiency of the process for the development of the
list of bulk drug substances that may be used to compound drug products
under section 503B of the FD&C Act, and because the deadline for
submitting nominations has passed, FDA is reopening the nomination
process so that interested persons have the opportunity to submit
nominations of bulk drug substances and provide adequate support for
placing them on the list. FDA will be able to evaluate only those bulk
drug substances submitted in response to this notice that are supported
with adequate data and information, as described in section II.
    Bulk drug substances that were previously nominated will not be
further considered unless they are renominated and adequately
supported. Substances that are not adequately supported will not be
placed on the list. FDA expects the submissions for each bulk drug
substance to provide the information described in section II. For
example, nominations must include sufficient information to demonstrate
that a particular ingredient meets the definition of ``bulk drug
substance,'' as defined in Sec.  207.3(a)(4). See section 503B(a)(2) of
the FD&C Act. The identification of an ingredient as an ``active
ingredient'' in a regulation, or on a spreadsheet such as the one
listing ``OTC Active Ingredients,'' is not sufficient to demonstrate
that a substance is a bulk drug substance for purposes of the 503B
List. En bloc nominations of substances listed in compendia,
pharmacopeia, or similar reference materials cannot be placed on the
list unless the Agency receives adequate information for each bulk drug
substance to justify its placement on the list. FDA will only be able
to consider bulk drug substances that are supported with the
information requested in section II.
    In section II, FDA identifies the type of information needed to
support a nomination to the 503B list.

II. Request for Nominations

A. Active Ingredients

    Interested groups and individuals may nominate specific bulk
substances for inclusion on the list. Nominations will only be
evaluated if they are for specific active ingredients that meet the
definition of a bulk drug substance in Sec.  207.3(a)(4). Nominated
substances that do not meet this definition will not be included on the
list.
    To fully evaluate a bulk drug substance, FDA needs the following
information about both the bulk drug substance being nominated and the
drug product(s) that will be compounded using such substance:
1. Confirmation That the Nominated Substance Is a Bulk Drug Substance
    A statement that the nominated substance is an active ingredient
that meets the definition of ``bulk drug substance'' in Sec.
207.3(a)(4), and an explanation of why the substance is considered an
active ingredient when it is used in compounded drug products, citing
to specific sources that describe the active properties of the
substance.
2. General Background on the Bulk Drug Substance
     Ingredient name;
     chemical name;
     common name(s); and
     identifying codes, as available, from FDA's Unique
Ingredient Identifiers (UNII) used in the FDA/USP Substance
Registration System, available at http://fdasis.nlm.nih.gov/srs/.
Because substance names can vary, this code, where available, will be
used by the Agency to confirm the exact substance nominated and to
identify multiple nominations of the same substance so the information
can be reviewed together.
     Chemical grade of the ingredient;
     description of the strength, quality, stability, and
purity of the ingredient;
     information about how the ingredient is supplied (e.g.,
powder, liquid); and
     information about recognition of the substance in foreign
pharmacopeias and the status of its registration(s) in other countries,
including whether information has been submitted to USP for
consideration of monograph development.

B. Clinical Need To Compound

    For FDA to be able to meaningfully evaluate a substance, the
information provided regarding the clinical need for compounding with a
bulk drug substance must be specific to the particular substance
nominated and drug product to be compounded. A ``boilerplate'' or
general explanation of clinical need for compounding with bulk drug
substances will not enable FDA to conduct an adequate review.
Prescribers of the compounded drug products who may be in the best
position to explain why there is a clinical need for a compounded drug
product may provide data in support of a nomination. The following
information about clinical need is necessary to provide adequate
support for nominations to the 503B list:
     A statement describing the medical condition(s) that the
drug product to be compounded with the nominated bulk drug substances
is intended to treat (i.e., what patient need is met by the drug
product compounded with the bulk drug substance);
     a list of FDA-approved drug products, if any, that address
the same medical condition;
     if there are FDA-approved drug products that address the
same medical condition, an explanation of why a compounded drug product
is necessary (i.e., why the approved drug product is not suitable for a
particular patient population);
     if the approved drug product is not suitable for a
particular patient population, an estimate of the size of the
population that would need a compounded drug product (e.g., for a drug
product compounded from bulk because of patient allergies or other
intolerances to excipients in FDA-approved drug products, FDA expects
the supporting information to include a good faith estimate of the
patient

population with the specific medical condition that suffers from the
allergy or intolerance, with citations to the literature regarding the
incidence of the condition or a statement that a search was conducted
and no references were found); \3\
---------------------------------------------------------------------------

    \3\ For example, if there is a need to compound a drug product
from bulk drug substances due to patient sensitivity to a
preservative or other excipient in the approved drug product, the
supporting data is expected to set forth the number of patients for
whom the drug product is prescribed that are allergic or sensitive
to that particular excipient.
---------------------------------------------------------------------------

     a bibliography of safety and efficacy data for the drug
compounded using the nominated substance,\4\ if available, including
any relevant peer-reviewed medical literature; and
---------------------------------------------------------------------------

    \4\ FDA recognizes that the available safety and efficacy data
supporting consideration of a bulk drug substance for inclusion on
the list may not be of the same type, amount, or quality as is
required to support a new drug application. Note that data regarding
safety and efficacy, while relevant, is not indicative of a clinical
need for a particular bulk drug substance, and additional
information regarding the clinical need must be provided.
---------------------------------------------------------------------------

     if there is an FDA-approved drug product that includes the
bulk drug substance nominated, an explanation of why the drug product
proposed to be compounded must be compounded from bulk rather than with
the FDA-approved drug product.
    General or boilerplate statements regarding the need to compound
from the bulk drug substance or the benefits of compounding generally
will not be considered sufficient. Note that the Agency does not
consider supply issues, such as backorders, that do not rise to the
level of a drug shortage listed on FDA's drug shortage Web site as
evidence of a clinical need for compounding with a bulk drug substance,
and section 503B of the FD&C Act already allows compounding from bulk
drug substances if the compounded drug product is on the FDA drug
shortage list. Similarly, considerations of cost and convenience will
not be considered indicators of clinical need.

C. Information on the Drug Product That Will Be Compounded With the
Bulk Drug Substance

     Information about the dosage form(s) into which the bulk
drug substance will be compounded;
     information about the strength(s) of the compounded drug
product(s);
     information about the anticipated route(s) of
administration of the compounded drug product(s); and
     information about the previous use(s) of the compounded
drug product(s).

D. Nomination Process

    Because the deadline for submitting nominations has passed, FDA is
reopening the nomination process so that interested persons can submit
nominations of bulk drug substances and have the opportunity to provide
adequate support for placing them on the list. Bulk drug substances
that were previously nominated need to be renominated. Nominators are
encouraged to submit as much of the information identified in this
document as possible. Unless adequate supporting data is received for a
bulk drug substance, FDA will be unable to consider it further for
inclusion on the list.
    Individuals and organizations will be able to comment on nominated
substances after the nomination period has closed or petition FDA to
make additional list amendments after the list is published, in
accordance with 21 CFR 10.30.
    For efficient consolidation and review of nominations, nominators
are encouraged to submit their nominations in an editable Excel file.
Specifically, nominators are encouraged to format their nominations as
follows:

------------------------------------------------------------------------
     Column A--What information is        Column B--put data specific to
               requested?                    the nominated substance
------------------------------------------------------------------------
What is the name of the nominated        Provide the ingredient name.
 ingredient?.
Is the ingredient an active ingredient   Provide an explanation for why
 that meets the definition of ``bulk      it is considered an active
 drug substance'' in Sec.                 ingredient when it is used in
 207.3(a)(4)?                             specific compounded drug
                                          products, and provide
                                          citations to specific sources
                                          that describe its active
                                          properties.
What is the chemical name of the         Chemical name.
 substance?.
What is the common name of the           Common name.
 substance?.
Does the substance have a UNII Code?...  UNII code.
What is the chemical grade of the        Provide the chemical grade.
 substance?.
What is the strength, quality,           Provide the strength, quality,
 stability, and purity of the             stability, and purity
 ingredient?.                             information.
How is the ingredient supplied?........  Describe how the ingredient is
                                          supplied (e.g., powder,
                                          liquid).
Is the substance recognized in foreign   List the foreign pharmacopeias
 pharmacopeias or registered in other     or other countries in which it
 countries?                               is registered.
Has information been submitted about     Put yes, no, or unknown. If
 the substance to the USP for             yes, state the status of the
 consideration of monograph               monograph, if known.
 development?
What medical condition(s) is the drug    Describe the medical
 product compounded with the bulk drug    condition(s) that the drug
 substances intended to treat?            product compounded with the
                                          bulk drug substances is
                                          intended to treat.
Are there other drug products approved   List the other approved
 by FDA to treat the same medical         treatments.
 condition?
If there are FDA-approved drug products  Provide a justification for
 that address the same medical            clinical need, including an
 condition, why is there a clinical       estimate of the size of the
 need for a compounded drug product?      population that would need the
                                          compounded drug.
Are there safety and efficacy data on    Provide a bibliography of
 compounded drugs using the nominated     safety and efficacy data for
 substance?                               the drug compounded using the
                                          nominated substance, if
                                          available, including any
                                          relevant peer-reviewed medical
                                          literature.
If there is an FDA-approved drug         Provide an explanation of why
 product that includes the bulk drug      it is necessary to compound
 substance nominated, is it necessary     from the bulk drug substance.
 to compound a drug product from the
 bulk drug substance rather than from
 the FDA-approved drug product?
What dosage form(s) will be compounded   State the dosage form(s).
 using the bulk drug substance?
What strength(s) will be compounded      List the strength(s) of the
 from the nominated substance?            drug product(s) that will be
                                          compounded from the nominated
                                          substance, or a range of
                                          strengths, if known.
What are the anticipated route(s) of     List the route(s) of
 administration of the compounded drug    administration of the
 product(s)?                              compounded drug product(s).

Has the bulk drug substance been used    Describe previous uses of the
 previously to compound drug              bulk drug substance in
 product(s)?                              compounding.
Is there any other relevant              Provide any other information
 information?.                            you would like FDA to consider
                                          in evaluating the nomination.
------------------------------------------------------------------------

    Interested persons may submit either electronic nominations to
http://www.regulations.gov or written nominations to the Division of
Dockets Management (see ADDRESSES). It is only necessary to send one
set of nominations. Identify nominations with the docket number found
in the brackets in the heading of this document. Received nominations
may be seen in the Division of Dockets Management between 9 a.m. and 4
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

    Dated: June 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-15373 Filed 7-1-14; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register Volume 84, Number 71 (Friday, April 12, 2019)]
[Rules and Regulations]
[Pages 14870-14872]
[FR Doc No: 2019-07263]

=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HOMELAND SECURITY

Coast Guard

33 CFR Part 165

[Docket Number USCG-2019-0024]
RIN 1625-AA00

Safety Zone; Xterra Swim, Intracoastal Waterway; Myrtle Beach, SC

AGENCY: Coast Guard, DHS.

ACTION: Temporary final rule.

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

SUMMARY: The Coast Guard is establishing a temporary safety zone for
certain waters of the Atlantic Intracoastal Waterway in Myrtle Beach,
South Carolina. This action is necessary to provide for the safety of
the swimmers, participant vessels, spectators, and the general public
during the swim portion of the Xterra Triathlon. This regulation
prohibits non-participant vessels and persons from entering, transiting
through, anchoring in, or remaining within the safety zone unless
authorized by the Captain of the Port Charleston or a designated
representative.

DATES: This rule is effective from 7 a.m. through 9 a.m. on April 14,
2019.

ADDRESSES: To view documents mentioned in this preamble as being
available in the docket, go to https://www.regulations.gov, type USCG-
2019-0024 in the ``SEARCH'' box and click ``SEARCH.'' Click on Open
Docket Folder on the line associated with this rule.

FOR FURTHER INFORMATION CONTACT: If you have questions on this rule,
call or email Lieutenant Justin Heck, Sector Charleston Waterways
Management division, Coast Guard; telephone<PHONE_NUMBER>, email
[email protected].

SUPPLEMENTARY INFORMATION:

I. Table of Abbreviations

CFR Code of Federal Regulations
DHS Department of Homeland Security
FR Federal Register
NPRM Notice of proposed rulemaking
Sec.  Section
U.S.C. United States Code

II. Background Information and Regulatory History

    On January 9, 2019, Go Race Productions notified the Coast Guard
that it would be sponsoring the Xterra Swim from 7:30 a.m. to 8:30 a.m.
on April 14, 2019. Approximately 200 swimmers are anticipated to
participate in the swim portion of the event, which is a 1500-yard
course, located on certain waters of the Atlantic Intracoastal Waterway
in Myrtle Beach, South Carolina. In response, on March 1, 2019, the
Coast Guard published an NPRM titled ``Safety Zone, Xterra Swim,
Intracoastal Waterway, Myrtle Beach, SC'' (84 FR 6994). There we stated
why we issued the NPRM, and invited comments on our proposed regulatory
action related to this event. During the comment period that ended
March 30, 2019, we received no comments.

III. Legal Authority and Need for Rule

    The Coast Guard is issuing this rule under authority in 46 U.S.C.
70034 (previously 33 U.S.C. 1231). The Captain of the Port Charleston
(COTP) has determined that potential hazards associated with the large
number of participants during the swim will be a safety concern. The
purpose of the rule is to ensure the safety of the participants,
spectators, the general public, vessels and the navigable waters in the
safety zone before, during, and after the scheduled event.

IV. Discussion of Comments, Changes, and the Rule

    As noted above, we received no comments on our NPRM published March
1, 2019. There are no changes in the regulatory text of this rule from
the proposed rule in the NPRM.
    This rule establishes a safety zone from 7:00 a.m. to 9:00 a.m. on
April 14, 2019. The safety zone will cover a portion of the Atlantic
Intracoastal Waterway in Myrtle Beach, South Carolina. Approximately
200 swimmers are anticipated to participate in the race. The duration
of the zone is intended to ensure the safety of the participants, the
general public, vessels and the navigable waters before, during, and
after the scheduled 7:30 a.m. to 8:30 a.m. swim. No vessel or person
will be permitted to enter, transit through, anchor in or remain within
the safety zone without obtaining permission from COTP Charleston or a
designated representative. If authorization to enter, transit through,
anchor in, or remain within the safety zone is granted by the COTP or a
designated representative, all persons and vessels receiving such
authorization must comply with the instructions of the COTP or a
designated representative. The Coast Guard will provide notice of the
safety zone by local notice to mariners, broadcast notice to mariners,
or by on-scene designated representatives.

V. Regulatory Analyses

    We developed this rule after considering numerous statutes and
Executive orders related to rulemaking. Below we summarize our analyses
based on a number of these statutes and Executive orders, and we
discuss First Amendment rights of protestors.

A. Regulatory Planning and Review

    Executive Orders 12866 and 13563 direct agencies to assess the
costs and benefits of available regulatory alternatives and, if
regulation is necessary, to select regulatory approaches that maximize
net benefits. Executive Order 13771 directs agencies to control
regulatory costs through a budgeting process. This rule has not been
designated a ``significant regulatory action,'' under Executive Order
12866. Accordingly, this rule has not been reviewed by the Office of
Management and Budget (OMB), and pursuant to OMB guidance it is exempt
from the requirements of Executive Order 13771.
    This regulatory action determination is based on: (1) The temporary
safety zone will only be enforced for two hours; (2) although persons
and vessels may not enter, transit through, anchor in, or remain within
the regulated area without authorization from the COTP Charleston or a
designated representative, they may operate in the surrounding area
during the enforcement period; and, (3) the Coast Guard will provide
advance notification of the safety zone to the local maritime community
by Local Notice to Mariners and Broadcast Notice to Mariners, or by on-
scene designated representatives.

B. Impact on Small Entities

    The Regulatory Flexibility Act of 1980, 5 U.S.C. 601-612, as
amended, requires Federal agencies to consider the potential impact of
regulations on small entities during rulemaking. The term ``small
entities'' comprises small businesses, not-for-profit organizations
that are independently owned and operated and are not dominant in their
fields, and governmental jurisdictions with populations of less than
50,000. The Coast Guard received zero comments from the Small Business
Administration on this rulemaking. The Coast Guard certifies under 5
U.S.C. 605(b) that this rule will not have a significant economic
impact on a substantial number of small entities.
    While some owners or operators of vessels intending to transit the
safety zone may be small entities, for the reasons stated in section
V.A. above, this rule will not have a significant economic impact on
any vessel owner or operator.
    Under section 213(a) of the Small Business Regulatory Enforcement
Fairness Act of 1996 (Pub. L. 104-121), we want to assist small
entities in understanding this rule. If the rule would affect your
small business, organization, or governmental jurisdiction and you have
questions concerning its provisions or options for compliance, please
contact the person listed in the FOR FURTHER INFORMATION CONTACT
section.
    Small businesses may send comments on the actions of Federal
employees who enforce, or otherwise determine compliance with, Federal
regulations to the Small Business and Agriculture Regulatory
Enforcement Ombudsman and the Regional Small Business Regulatory
Fairness Boards. The Ombudsman evaluates these actions annually and
rates each agency's responsiveness to small business. If you wish to
comment on actions by employees of the Coast Guard, call 1-888-REG-FAIR
(1-888-734-3247). The Coast Guard will not retaliate against small
entities that question or complain about this rule or any policy or
action of the Coast Guard.

C. Collection of Information

    This rule will not call for a new collection of information under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).

D. Federalism and Indian Tribal Governments

    A rule has implications for federalism under Executive Order 13132,
Federalism, if it has a substantial direct effect on the States, on the
relationship between the national government and the States, or on the
distribution of power and responsibilities among the various levels of
government. We have analyzed this rule under that Order and have
determined that it is consistent with the fundamental federalism
principles and preemption requirements described in Executive Order
13132.
    Also, this rule does not have tribal implications under Executive
Order 13175, Consultation and Coordination with Indian Tribal
Governments, because it does not have a substantial direct effect on
one or more Indian tribes, on the relationship between the Federal
Government and Indian tribes,

or on the distribution of power and responsibilities between the
Federal Government and Indian tribes. If you believe this rule has
implications for federalism or Indian tribes, please contact the person
listed in the FOR FURTHER INFORMATION CONTACT section.

E. Unfunded Mandates Reform Act

    The Unfunded Mandates Reform Act of 1995 (2 U.S.C. 1531-1538)
requires Federal agencies to assess the effects of their discretionary
regulatory actions. In particular, the Act addresses actions that may
result in the expenditure by a State, local, or tribal government, in
the aggregate, or by the private sector of $100,000,000 (adjusted for
inflation) or more in any one year. Though this rule will not result in
such an expenditure, we do discuss the effects of this rule elsewhere
in this preamble.

F. Environment

    We have analyzed this rule under Department of Homeland Security
Directive 023-01 and Commandant Instruction M16475.1D, which guide the
Coast Guard in complying with the National Environmental Policy Act of
1969 (42 U.S.C. 4321-4370f), and have determined that this action is
one of a category of actions that do not individually or cumulatively
have a significant effect on the human environment. This rule involves
a safety zone that will prohibit persons and vessels from entering,
transiting through, anchoring in, or remaining within a limited area
near Myrtle Beach, SC, on the waters of the Intracoastal Waterway in
Myrtle Beach, SC, during a race event lasting two hours. It is
categorically excluded from further review under paragraph L60(a) of
Appendix A, Table 1 of DHS Instruction Manual 023-01-001-01, Rev. 01. A
Record of Environmental Consideration supporting this determination is
available in the docket where indicated under ADDRESSES.

G. Protest Activities

    The Coast Guard respects the First Amendment rights of protesters.
Protesters are asked to contact the person listed in the FOR FURTHER
INFORMATION CONTACT section to coordinate protest activities so that
your message can be received without jeopardizing the safety or
security of people, places or vessels.

List of Subjects in 33 CFR Part 165

    Harbors, Marine safety, Navigation (water), Reporting and
recordkeeping requirements, Security measures, Waterways.

    For the reasons discussed in the preamble, the Coast Guard amends
33 CFR part 165 as follows:

PART 165--REGULATED NAVIGATION AREAS AND LIMITED ACCESS AREAS

0
1. The authority citation for part 165 continues to read as follows:

    Authority: 46 U.S.C. 70034, 70051; 33 CFR 1.05-1, 6.04-1, 6.04-
6, and 160.5; Department of Homeland Security Delegation No. 0170.1.

0
2. Add Sec.  165.T07-0024 to read as follows:

Sec.  165.T07-0024   Safety Zone; Xterra Swim, Myrtle Beach SC.

    (a) Location. The following is a safety zone: Certain waters of the
Atlantic Intracoastal Waterway within the following two points of
position and the North shore: 33[deg]45'03'' N, 78[deg]50'47'' W to
33[deg]45'18'' N, 78[deg]50'14'' W, located in Myrtle Beach, South
Carolina. All coordinates are North American Datum 1983.
    (b) Definition. The term ``designated representative'' means Coast
Guard Patrol Commanders, including Coast Guard coxswains, petty
officers, and other officers operating Coast Guard vessels, and
Federal, state, and local officers designated by or assisting the
Captain of the Port Charleston in the enforcement of the regulated
areas.
    (c) Regulations. (1) All persons and vessels are prohibited from
entering, transiting through, anchoring in, or remaining within the
regulated area unless authorized by the Captain of the Port Charleston
or a designated representative.
    (2) Persons and vessels desiring to enter, transit through, anchor
in, or remain within the regulated area may contact the Captain of the
Port Charleston by telephone at<PHONE_NUMBER>, or a designated
representative via VHF radio on channel 16, to request authorization.
If authorization to enter, transit through, anchor in, or remain within
the regulated area is granted by the Captain of the Port Charleston or
a designated representative, all persons and vessels receiving such
authorization must comply with the instructions of the Captain of the
Port Charleston or a designated representative.
    (3) The Coast Guard will provide notice of the regulated area by
Local Notice to Mariners, Broadcast Notice to Mariners, and on-scene
designated representatives.
    (d) Enforcement period. This rule will be enforced from 7:00 a.m.
until 9:00 a.m. on April 14, 2019.

    Dated: April 5, 2019.
J.W. Reed,
Captain, U.S. Coast Guard, Captain of the Port Charleston.
[FR Doc. 2019-07263 Filed 4-11-19; 8:45 am]
BILLING CODE 9110-04-P