	UNITED STATES ENVIRONMENTAL PROTECTION	AGENCY

	WASHINGTON, D.C.  20460

OFFICE OF PREVENTION,  PESTICIDES AND

TOXIC SUBSTANCES

January 10, 2007

SUBJECT: 	ETHOFUMESATE: HED Revised Human Health Risk Assessment For
Phase 5; Response to Bayer CropScience Phase 4 Comments and Review of
the Dermal Penetration Study with Ethofumesate, MRID 46866901

PC Code 110601.  DP Barcode DP296939/DP296953

Regulatory Action: Phase 5 Reregistration Action

Risk Assessment Type: Single Chemical Aggregate

FROM:		Nancy McCarroll, Geneticist

Toxicology Branch

Health Effects Division (7509C)

THRU:		Alberto Protzel, PhD, Branch Senior Scientist

Toxicology Branch

Health Effects Division (7509C)

TO:		Laura Parsons, Chemical Review Manager

Special Review and Reregistration Division (SRRD)

(7508W)

and

		Nathan Mottl, Chemical Review Manager

SRRD (7508W)

cc:  Shanna Recore and Bill Hazel,  RRB2

On June 12, 2006, Bayer CropScience submitted a Rodent In Vivo Dermal
Penetration  Study (MRID 46866901) to address the issue of unacceptable
MOEs resulting from the use of the default 100% dermal absorption for
occupational and residential dermal exposures to ethofumesate.   The
dermal absorption study has been reviewed and found to be
acceptable/guideline.   Accordingly, the dermal absorption factor of 27%
from the combined radioactivity absorbed and that remaining in/on the
skin at the 10-hour exposure duration for the low dose was used to
refine exposure and risk estimates for the unacceptable MOEs.   In
addition, the sponsor submitted a document entitled “Refined
Occupational and Residential Assessment for Ethofumesate” (MRID
46867601) based on the new dermal absorption factor.  The Agency’s
Executive Summary for the Dermal Absorption Study as well as responses
from HED regarding earlier comments associated with the use of the 100%
default dermal absorption factor and an issue related to residues of the
metabolite NC 20645 in livestock commodities are presented below.

HAZARD CHARACTERIZATION/ASSESSMENT CONSIDERATIONS

No comments were submitted by the sponsor dealing with the Hazard
Characterization/Assessment.  However, the Executive Summary for the
dermal absorption study is presented below:

CITATION:	Muriel Odin-Feurtet [14C]-Ethofumesate: In vivo Dermal
Absorption Study in the Male Rat;  Report of Study SA 05289  MRID
46866901, June 19, 2006. Unpublished.

SPONSOR:	Bayer AG, Bayer CropScience, Alfred Nobel Str. 50, 40789
Monheim, Germany

EXECUTIVE SUMMARY

In a dermal absorption rat study (MRID No. 46866901), ethofumesate
(phenyl-UL-14C, >99%) was applied to Sprague-Dawley Crl:CD (SD) rats at
dose levels of 3, 9 and 20 μg/cm2.  A single dermal application of the
test material in aqueous methyl cellulose was made to the shaved dorsal
skin (12 cm2 area) of a total of 48 animals (4 per time group/16 per
dose) and the animals were monitored for absorption at 1, 10, 24 and 168
hours after dosing.  The 168 hour group underwent skin wash at 10 hours
and was carried to 168 hours before termination.  The following table
summarizes mean percent absorption at each time period for the three
dose groups.

Table 1.  Dermal Absorption Rate Summary

Dose Level

(µg/cm2)		Mean Percentage of Dose Absorbed & In/On Skin

	1 hour	10 hours	24 hours	168 hours**

	Absorbed	skin*	absorbed	skin	absorbed	Skin	absorbed	skin

3

9

20	5.63

1.68

2.64	4.33

3.07

4.50	23.14

15.90

9.95	3.42

1.99

2.30	32.51

26.83

18.99	6.87

2.09

1.38	20.95

24.69

12.51	0.72

0.49

0.27

* amount of radioactivity in/on skin after skin wash

** washed at 10 hours and carried to 168 hours prior to termination

Mean recoveries of applied radioactivity from all dose groups ranged
from 86 to 102%.  Mean absorption based on urinary/fecal excretion,
blood, carcass, and cage wash ranged from 1.68 to 32.51%.  Total
radioactivity absorbed clearly increased with increasing exposure time
for all doses and the highest absorption rate consistently occurred at
the 24 hour exposure duration.  Absorbed radioactivity decreased with
increasing dose for the 10 and 24 hour exposure durations indicating
that the skin was approaching saturation of penetration for these
exposure durations. The majority of the absorbed radioactivity was
consistently found in the urine for all doses and durations.  Absorbed
dose found in the urine and feces increased with increasing exposure
duration indicating that absorbed test material is increasingly absorbed
and eliminated over time. Negligible amounts were present in blood
samples analyzed for all dose/duration groups.  Amount of radioactivity
present in the carcass at 1, 10 and 24 hour exposure durations ranged
from 1.5-6.2%.  The amount of radioactively found in the carcass was
significantly reduced at 168 hr post-wash exposure duration.

Most of the unabsorbed radioactivity was found in the skin washes from
each dose/duration (48-88%).  Amount of radioactive dose on the treated
skin after wash and termination ranged from 0.3 to 7%.  Although there
was no clearly discernable pattern of radioactivity remaining in/on
treated skin indicating the extent to which skin residues continue to be
absorbed post-wash, it is reasonable to assume that that test material
remaining in/on skin is absorbed.  Therefore, a dermal absorption factor
of 27%, from the combined radioactivity absorbed and that remaining
in/on the skin at the 10 hour exposure duration for the low dose, would
be considered appropriate for use in risk assessment.

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.7600; OECD none) for a dermal
penetration study in rats.

The full DER is listed under TXR No. 0054284.

RESIDUE CHEMISTRY CONSIDERATIONS

HED response to Bayer comment A7 re: analysis of metabolite NC 20645 in
livestock commodities

Bayer comment A7. In the RED (Document A, Page 17, Table 5) it is stated
that “… residues of a major animal metabolite (NC 20645) were not
determined.” This is further discussed on Page 56 of Document D. BCS
believe it can be shown that this

metabolite is minor. The current analytical method (MRID 43412901,
Appendix 3; Bayer Report B002201, Method No. B-93R-04/05) that was used
for the cattle feeding study does recover NC 20645 as NC 9607 in milk.
The residues of ethofumesate, NC 8493, NC 9607 and NC 20645 were each
<0.01 ppm in all milk samples at up to 10X the maximum theoretical
dietary burden (MTDB). Extensive metabolism work (MRID 42364504, Bayer
Report A82968) has shown that NC 20645 exceeds 10% of the total
radioactive residue only in kidney, the tissue with the highest residue.
 Based on the conservative estimates of dietary exposure, it can be
shown that it will account for <0.01% RfD. Using appropriate ruminant
diets and transfer factors from the ruminant metabolism study (MRID
42364504, Bayer Report A82968), it can also be calculated that NC 20645
will not exceed the current tolerance level (0.05 ppm) in kidney at the
1X dosing level.  NC 20645 is, therefore, an insignificant contributor
of exposure to the human population resulting from use of ethofumesate.
Efforts to quantify NC 20645 in kidney will not lead to a significantly
improved dietary risk assessment.

Document A.  Reregistration Eligibility Decision (RED) for Ethofumesate,
September, 2005

Document D.  Ethofumesate: HED Revised Human Health Risk Assessment For
Phase 4; Response to Bayer CropScience Phase 3 Comments. August 4, 2005.
PC Code 110601

HED response

HED continues to feel that additional data concerning residues of the
metabolite NC 20645 in livestock commodities would permit dietary risk
refinement and confirmation of assumptions in the 9/05 RED.  However, we
have taken a more risk-based and “value-added” approach as we,
again, consider Bayer’s request.  The following overriding
considerations permit taking such an approach:

Only ruminant kidney, a minor human food, could potentially bear finite
ethofumesate residues based on an exaggerated rate metabolism study
(from S. Funk, 12/3/92, D180705).

Residues in milk from an exaggerated rate (30x) cow feeding study did
not contain detectable residues of ethofumesate, NC 8493, or NC 9607
(all <0.01 ppm).  Metabolite NC 20645 would have been included (as NC
9607) since milk samples were acidified.  Milk often serves as an
indicator of mammalian tissues.  We can only assume that NC 20645 would
not have been determined in tissues as those samples were apparently not
acidified.  Only one fat sample contained residues >LOD of 0.01 ppm
(0.02 ppm of parent compound) (L. Cheng, 8/9/95, D209084 and D 210002).

The only treated feed items for cattle, goats, horses, and sheep are
sugar beet tops and the hay, forage, and regrowth of grasses grown for
seed.  [There are no treated hog or poultry feed items.]   These are
very minor, localized, and seasonal feed items.  They are esoteric feed
items that HED believes will never be fed to the same animals.

In the case of grass grown for seed, most is grown in the Pacific
Northwest which produces only 5% of the U.S. beef supply.

In the case of sugar beets, only 0.8% of the nation’s sugar beet tops
are available to be used as livestock feed (HED’s Chemistry Science
Advisory Council, Minutes of 6/30/04 meeting).

The most recent human health risk assessment (J. Morales, 7/6/05,
D296927) presented the dietary acute risk as being 4% of the aPAD
(females 13-49 were the only relevant population).  Chronic risks were
<1% of the cPAD in all population subgroups.  These were very
conservative risk estimates given that all foods were assumed to bear
tolerance-level residues and for 100% to have been treated.

Therefore, from a risk perspective, there is no basis upon which to
require a new ruminant feeding study provided that ethofumesate is not
used on major livestock feed items and/or finite residues of
ethofumesate, NC 8493, NC 9607, and NC 20645 do not result in livestock
commodities from treated feed items.  If a new ruminant feeding study
becomes necessary, analysis of all four residues of concern in tissues
and milk is to be conducted.

From a regulatory perspective, however, there remains a tolerance
enforcement consideration, i.e., uncertainty whether the livestock
tolerance enforcement method is capable of detecting NC 20645.  The
livestock tolerance enforcement method is to be validated for
ethofumesate, NC 8493, NC 9607, and NC 20645 in tissues and milk.

OCCUPATIONAL AND RESIDENTIAL EXPOSURE (ORE) CONSIDERATIONS

HED response to Bayer comments on ORE issues:

μg/lb ai handled, respectively, an application rate of 22.5 lb ai/ton,
and assuming 30 tons treated per day and a handler weight of 60 kg, the
dermal exposure estimate is 0.259 mg/kg/day and the inhalation exposure
estimate is 0.0135 mg/kg/day. Assuming 100% dermal and inhalation
absorption, the total dose is 0.273 mg/kg/day. With a NOAEL of 30
mg/kg/day, the total MOE is 110. This estimate indicates acceptable
worker risk for commercial treatment of dry bulk fertilizer with
ethofumesate for workers wearing the required PPE on the Nortron® SC
Herbicide label (single layer of clothes with water proof gloves) with
open pour mixing and loading. No engineering controls are required for
commercial mixing/loading of ethofumesate on dry bulk fertilizer. We
note two typographical errors on page 2 of the Document B in the text
above and below the Table 1 - “Handler Risks for Dry Fertilizer
Applications on Sugar Beets”: (a) the text for the maximal labeled
rate of 4.5 pts/acre (0.56 lb ai/acre) should be corrected to read as
“4.5 pts/acre (2.25 lb a.i./acre)”; (b) “the footnote 3: each ton
(2000 lb)of fertilizer would require 30 lb of ethofumesate active
ingredient”. The 30 lb value should be changed to 22.5 lb a.i. as used
in the Table above (it reflects the labeled 5.63 gallons of Nortron SC
that contains 4 lb a.i/per gallon).

HED response:  EPA researched the process of commercial impregnation of
liquid pesticides into dry bulk fertilizer during the reregistration of
alachlor, which also has this labeled use-pattern.  The Agency’s
Biological and Economic Analysis Division provided (April 28, 1998, memo
George Keitt) provided the following information obtained through the
University of Illinois Extension Service:

In commercial settings, the liquid pesticide is metered from a mini-bulk
tank (several hundred gallons) to a mixing drum via a closed system.
The liquid pesticide is sprayed onto the fertilizer, which is stirred by
an auger that lifts it to the top of the drum.  After impregnation, the
treated fertilizer is gravity-fed through a hopper onto a conveyor belt
leading to an auger truck, which carries it to the field.  Because all
processes are mechanized, there is minimal exposure to either the
mixer/loader at the treatment site or the loader at the transfer sites.

  SEQ CHAPTER \h \r 1  Information supplied by Monsanto confirmed that
impregnation of fertilizer in a mixing tower is typically a closed
system operation.   Therefore, EPA   SEQ CHAPTER \h \r 1 estimates risk
for mixers/loaders impregnating the dry bulk fertilizer in commercial
operations by assuming use of engineering controls (metered delivery
from a mini-bulk tank).  HED notes that   SEQ CHAPTER \h \r 1 the amount
of active ingredient necessary to impregnate the tons of fertilizer that
can be processed in a day is too large to be handled by opening
individual bottles or containers.

If Bayer CropScience is aware of commercial operations that impregnate
bulk fertilizers with liquid pesticides using open mix/loading systems,
they may submit information about such commercial systems.  HED would
welcome data about the commercial impregnation of dry bulk fertilizers
with liquid pesticides.

EPA will revise the typographical errors on page 2 of Document B.

Bayer CropScience Comment A2: On page 27 in the labels change summary
table of the RED, the Agency requires chemical resistant gloves on
ethofumesate labels. The PPE indicated on the existing labels (e.g.
Nortron SC and Prograss) for the three ethofumesate products are
appropriate for the chemical compositions of the respective products.

HED response:   SEQ CHAPTER \h \r 1 When the WPS was promulgated and PR
Notice 93-7 was developed, EPA took the opportunity to require
registrants to specify the type of glove material that was highly
protective for each specific end-use product (active ingredient and
solvent) and to select the appropriate chemical-resistance category for
that end-use product.  Registrants with end-use products that had no
solvents (dry formulations) or where the solvent was only water did not
select a chemical-resistance category and listed "waterproof" gloves on
their labeling,   since all waterproof materials are highly resistant to
such products.   In addition, in early -entry situations (a minimum of 4
hours after application is complete), solvents are presumed to have
volatilized leaving early-entry workers exposed to the dry residue
consisting mainly of active ingredient and inert carriers.  There again,
the appropriate glove type was deemed to be “waterproof” gloves.

	Once the labels with these revised personal protective equipment
statements appeared on the market, questions from users and Extension
personnel arose about why the gloves were listed as "waterproof", but
aprons, footwear, and headgear were listed as "chemical-resistant."
Questions also arose as to why no chemical-resistant category was listed
on labels for the dry and water-based formulations and about what types
of materials were "chemical-resistant" to that formulation, so the
correct type of material for aprons, footwear, and headgear could be
selected.   In addition, as OPP made active-ingredient-specific PPE
decisions during reregistration, registration, and special review
processes, it became increasingly complicated to list gloves as
"chemical-resistant or waterproof, as appropriate" each time gloves were
discussed.

	Due to the confusion by users and complications during
active-ingredient-based PPE determinations, HED, SRRD, and RD personnel
decided to discontinue the "waterproof" glove language and gradually
convert to "chemical-resistant gloves" for all end-use products,
including dry and water-based formulations.  The labels for dry and
water-based formulations would list chemical resistance category "A" and
the label language would be:  "chemical-resistant gloves such as (or
“made of”) any waterproof material."  This language exactly
parallels the label language for other formulation types, i.e.,
"chemical-resistant gloves such as barrier laminate or viton."

Bayer CropScience Comment A3:  On page 28 in the labels change summary
table of the RED, the Agency requires closed mixing/loading for on-site
mixing and loading of liquid formulations. Based on EPA’s estimates,
this statement should be limited to commercial treatment of dry bulk
fertilizers. However, BCS’ assessment in Note A1 above indicates that
this statement is not necessary for that scenario either. Therefore
statements requiring the use of closed mixing and loading systems are
not appropriate for any use of ethofumesate products.

HED response:  HED agrees that closed system mixing loading requirements
should be limited to commercial impregnation of dry bulk fertilizers.

Bayer CropScience Comment A4: On page 29 in the labels change summary
table of the RED, the Agency requires the following statement: ”Do not
enter or allow worker entry into treated areas during the restricted
entry interval (REI) of 12 hours for all crops, except turf grown for
sod. The REI for turf is 9 days. The REI for each crop is listed in the
directions for use associated with each crop.” The 9 day REI for turf
is currently appropriate for the Prograss® Herbicide label, which
allows a 3 lb ai/acre maximum application rate. However, this statement
is not appropriate for turf use of Nortron® SC Herbicide because the
maximum turf application rate for Nortron® SC Herbicide is 1.5 lb
ai/acre. The current REI for Nortron® SC Herbicide following
application to turf should be 3 days. These REIs are currently based on
the conservative assumption of 100% dermal absorption for ethofumesate.
An ethofumesate dermal absorption study is now in progress. Results of
this study are expected to allow a refinement of the dermal dose,
resulting in a decrease in the absorbed dose of ethofumesate, with a
subsequent lowering of all REIs.

HED response: It is EPA policy to regulate on the highest labeled rate.
The 3 lb ai/acre rate is the maximum labeled turf application rate for
all ornamental turf uses.  HED has received the ethofumesate dermal
absorption study and has reassessed dermal dose and postapplication
risks using the results of that study (see Table 3 below).  Using the
new dermal absorption study restricted-entry interval will now be 3 days
at the 3 lb ai/acre rate.

No additional harvest prohibition is necessary.

Bayer CropScience Comment A5:  On page 31 in the labels change summary
table of the RED, the Agency requires the following statement: “Do not
harvest treated sod for 16 days following application.” The 16 day
preharvest interval (PHI) for turf is currently appropriate for the
Prograss® Herbicide label, which allows a 3 lb ai/acre maximum
application rate. However, this statement is not appropriate for turf
use of Nortron® SC Herbicide because the maximum turf application rate
for Nortron® SC Herbicide is 1.5 lb ai/acre. The current PHI for
Nortron® SC Herbicide following application to turf should be 8 days.
These PHIs are currently based on the conservative assumption of 100%
dermal absorption for ethofumesate. An ethofumesate dermal absorption
study is now in progress. Results of this study are expected to allow a
refinement of the dermal dose, resulting in a decrease in the absorbed
dose of ethofumesate, with a subsequent lowering of these PHIs.

HED response: It is EPA policy to regulate on the highest labeled rate.
The 3 lb ai/acre rate is the maximum labeled turf application rate for
all ornamental turf uses.  HED has received the ethofumesate dermal
absorption study and has reassessed dermal dose and postapplication
risks using the results of that study (see Table 3 below).  Using the
new dermal absorption study, the restricted-entry interval will now be 3
days at the 3 lb ai/acre rate.  No additional harvest prohibition is
necessary.

Bayer CropScience Comment A6: A Summary Note: Every occupational and
residential risk estimate in the ethofumesate RED assumes 100% dermal
absorption. An ethofumesate dermal absorption study is now in progress
and BCS will submit the report in May, 2006. Results of this study are
expected to allow a refinement of the dermal dose, resulting in a
decrease in the total absorbed dose of ethofumesate. The lower total
absorbed doses of ethofumesate will result in more accurate, lower, risk
estimates for all occupational and residential uses of ethofumesate.

HED response:  HED has received the ethofumesate dermal absorption study
and has reassessed dermal dose and handler and postapplication risks
using the results of that study.  See table 1, 2, 3, and 4 below.

Table 1.   Summary Table for Ethofumesate Short & Intermediate – Term
Exposures

Exposure Scenarios	Crop4	Application Rate5 (lbs ai/acre or lbs ai/
gallon)	Daily Amount Treated6

(acres or gallons)	Baseline Dermal1 +Baseline Inhalation2 MOE8	PPE-G
Dermal3 + Baseline Inhalation2

MOE8	Combined Engineering Control Dermal + Baseline Inhalation

Mixer/Loader

Mixing/Loading Liquids for Aerial application	Turf: grown for seed	1.88
350	3.5	370	-

Mixing/Loading Liquids for Aerial application	Turf: grown for sod 	3	350
2.2	230	-

Mixing/Loading Liquids for Aerial application	Turf: grown for sod	1.5
350	4.4	460	-

Mixing/Loading Liquids for Aerial application	Sugar Beets	3.75	1200	0.51
54	110

Mixing/Loading Liquids for Groundboom application	Sugar Beets	3.75	200
3.1	320	-

Mixing/Loading Liquids for Groundboom application	Swiss Chard	3	80	9.6
1000	-

Mixing/Loading Liquids for Groundboom application	Table Beets grown for
seed	3	80	9.6	1000	-

Mixing/Loading Liquids for Groundboom application	Table Beets	1.9	80	15
1600	-

Mixing/Loading Liquids for Groundboom application	Carrots	2	80	14	1500	-

Mixing/Loading Liquids for Groundboom application	Spinach	1	80	29	3000	-

Mixing/Loading Liquids for Groundboom application	Turf: grown for seed
1.88	80	15	1600	-

Mixing/Loading Liquids for Groundboom application	Turf: grown for sod	3
80	9.6	1000	-

Mixing/Loading Liquids for Groundboom application	Turf: grown for sod
1.5	80	19	2000	-

Mixing/Loading Liquids for Groundboom application	Golf Course Fairways
and Tees	3	40	19	2000	-

Loading Granulars for Tractor-Drawn Spreaders application	Sod Farms	1.5
80	3800	-	-

Applicator

Applying Sprays via Aerial Equipment	Turf: grown for seed	1.88	350	N/A
N/A	1900 (closed cockpit engineering controls)

Applying Sprays via Aerial Equipment	Turf: grown for sod	3	350	N/A	N/A
1200 (closed cockpit engineering controls)

Applying Sprays via Aerial Equipment	Turf: grown for sod	1.5	350	N/A	N/A
2400 (closed cockpit engineering controls)

Applying Sprays via Aerial Equipment	Sugar Beets	3.75	1200	N/A	N/A	280
(closed cockpit engineering controls)

Applying Sprays via Groundboom Equipment	Sugar Beets	3.75	200	530	-	-

Applying Sprays via Groundboom Equipment	Swiss Chard	3	80	1700	-	-

Applying Sprays via Groundboom Equipment	Table Beets grown for seed	3	80
1700	-	-

Applying Sprays via Groundboom Equipment	Table Beets	1.9	80	2600	-	-

Applying Sprays via Groundboom Equipment	Carrots	2	80	2500	-	-

Applying Sprays via Groundboom Equipment	Spinach	1	80	5000	-	-

Applying Sprays via Groundboom Equipment	Turf: grown for seed	1.88	80
2600	-	-

Applying Sprays via Groundboom Equipment	Turf: grown for sod	3

1700	-	-

Applying Sprays via Groundboom Equipment	Turf: grown for sod	1.5	80	3300
-	-

Applying Sprays via Groundboom Equipment	Golf Course	3	40	3300	-	-

Applying Sprays via Groundboom Equipment	Golf Course Fairways and Tees
1.5	40	6600	-	-

Applying Granulars via Tractor Drawn Spreader	Turf: grown for sod	1.5	80
3900	-	-

Flagger

Flagging for Aerial Sprays Applications	Turf grown for seed	1.88	350	820
N/A	-

Flagging for Aerial Sprays Applications	Turf: grown for sod	3	350	520
N/A	-

Flagging for Aerial Sprays Applications	Turf: grown for sod	1.5	350	1000
N/A	-

Flagging for Aerial Sprays Applications	Sugar Beets	3.75	350	410	N/A	-

Mixer/Loader/Applicator

Mixing/Loading/Applying Liquid Concentrates with Low Pressure Handwand
(PHED)	Residential Lawns	3	5	4.4	820	-

Mixing/Loading/Applying Liquid Concentrates with Low Pressure Handwand
(ORETF)	Residential Lawns	3	5	30	1300	-

Mixing/Loading/Applying Liquid Concentrates with handgun sprayer (ORETF)
Residential Lawns	3	5	No data	970	-

Footnotes:

- scenario passed at previous PPE level.

1Baseline dermal represent long pants, long sleeved shirts, shoes, and
socks.  Values are reported in the PHED Surrogate Exposure Guide dated
August 1998.

2Baseline inhalation represent no respirator.  Values are reported in
the PHED Surrogate Exposure Guide dated August 1998.

3PPE-G dermal represent long pants, long sleeved shirts, shoes, socks
and gloves.  Values are reported in the PHED Surrogate Exposure Guide
dated August 1998.

4Crops and use patterns are from product labeling.

5Application rates are based on maximum values found in various sources
including LUIS and various labels.  In most scenarios, a range of
maximum application rates is used to represent the range of rates for
different crops/sites/uses.  Application rates upon which the analysis
is based are presented as lb ai/A.

6Amount treated is based on the area or gallons that can be reasonably
applied in a single day for each exposure scenario of concern based on
the application method and formulation/packaging type. (Standard
EPA/OPP/HED values).

7Total MOE = 1/ [1/MOE(dermal)+1/MOE(inhalation)]

8 Target MOE is 100

Calculations used:

Dermal MOE =   Short & Intermediate-term oral NOAEL/Daily Dermal Dose;

Dermal dose (mg/kg/day) = [unit exposure (mg/lb ai) * Dermal absorption
* Application rate (lb ai/acre) * Daily area treated (acres or gallons)]
/ Body weight;

Inhalation MOE = Short & Intermediate-term oral NOAEL/Daily Inhalation
Dose;

Table 2.  Summary of “Days After Treatment” to Reach the Target MOE
for Short & intermediate-Term Exposure

(Target MOE = 100)

Crop 	Application Rate

(lbs ai/acre)	Exposure Activity Level	Transfer Coefficient (cm2/hr)a
Days After Treatment Target MOEc is Achieved

Sugar beets	1.5	Low	100	0 (12 hours)

Medium	1500	0 (12 hours)

Beets (table grown for seed)	1.5	Low	300	0 (12 hours)

Low	300	0 (12 hours)

Beets (table)	0.33	Low	300	0 (12 hours)

Carrots	2	Low	500	0 (12 hours)

Swiss Chardb	1.5	Medium	1500	0 (12 hours)

a Transfer coefficients from Policy #003.1 “Agricultural Transfer
Coefficients”

b Swiss Chard does not occur in the ARTF survey used to develop Policy
003.1.  Typical transfer coefficient values from the leafy vegetable
transfer coefficient group were used.

c MOE = NOAEL (30 mg/kg/day; based on an oral developmental study) /
dermal dose.

Table 3.  Days After Treatment Target MOE Achieved (Target MOE = 100)

Use Pattern	Application Rate	Postapplication Activity	Transfer
Coefficient a	Days After Treatment Target MOE b Achieved

Golf Course Turf	3	Maintenance

3,400	0

Sod Farms	3	Harvesting

6,800	3

a Transfer coefficients from ARTF.

b MOE = NOAEL (30 mg/kg/day; based on an oral developmental study) /
dermal dose.

Table 4. Residential Exposure Estimates & MOEs for Ethofumesate Treated
Turf

resident

activity

DAT

Tc or Equivalent

Body wgt

ADD

NOAEL

MOE

toddler

(at 3 lb ai/acre)

Playing

0

5200

15

1.17

190

220

toddler

hand to mouth

0

PDR*

15

0.022

190	4200

toddler

object to mouth

0

TTR*

15

0.0056

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Science Advisory Council for Exposure Policy No. 12; revised February
22, 2001.

 PAGE  1

Ethofumesate PC110601 	  OPPTS 870.7600 	Dermal Penetration  Study –
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[Federal Register Volume 85, Number 136 (Wednesday, July 15, 2020)]
[Notices]
[Pages 42871-42876]
[FR Doc No: 2020-15255]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2008-N-0567]

Notice of Decision Not To Designate Coccidioidomycosis as an
Addition to the Current List of Tropical Diseases in the Federal Food,
Drug, and Cosmetic Act

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency), in response
to suggestions submitted to the public docket number FDA-2008-N-0567
between October 1, 2018, and June 30, 2019, has analyzed whether
coccidioidomycosis meets the statutory criteria for designation as a
tropical disease for the purposes of obtaining a priority review
voucher (PRV) under the Federal Food, Drug, and Cosmetic Act (FD&C
Act), namely whether it primarily affects poor and marginalized
populations, and whether there is ``no significant market'' for drugs
that prevent or treat coccidioidomycosis infections in developed
countries. The Agency has determined that coccidioidomycosis does not
meet the statutory criteria for designation as a tropical disease
eligible for PRV consideration because of the potential market for
preventive products (such as vaccines), and therefore declines to
designate it as an addition to the list of tropical disease PRV-
eligible diseases at this time.

DATES: July 15, 2020.

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

FOR FURTHER INFORMATION CONTACT: Katherine Schumann, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 6242, Silver Spring, MD 20993-0002, 301-
796-1300<EMAIL_ADDRESS>or Stephen Ripley, Center for
Biologics Evaluation and Research, Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 71, Rm. 7301, Silver Spring, MD 20993-0002,
240-402-7911.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background: Priority Review Voucher Program
II. Decision Not To Designate Coccidioidomycosis
    A. Coccidioidomycosis
    B. FDA Determination
III. Process for Requesting Additional Diseases To Be Added to the
List
IV. Paperwork Reduction Act
V. References

I. Background: Priority Review Voucher Program

    Section 524 of the FD&C Act (21 U.S.C. 360n), which was added by
section 1102 of the Food and Drug Administration Amendments Act of 2007
(Pub. L. 110-85), uses a PRV incentive to encourage the development of
new drugs, including biological products, for prevention and treatment
of certain diseases that, in the aggregate, affect millions of people
throughout the world. Further information about the tropical disease
PRV program can be found in the guidance for industry ``Tropical
Disease Priority Review Vouchers,'' available at https://www.fda.gov/media/72569/download. Section 524(a)(3) of the FD&C Act includes a list
of infectious diseases, applications for the prevention or treatment of
which may be eligible to qualify for a PRV, and Congress has amended
that list multiple times to add new diseases since section 524 was
first enacted. Additions to the statutory list of PRV-eligible tropical
diseases by an FDA final order published in the Federal Register can be
accessed at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-program.
    On August 20, 2015, FDA published a final order (80 FR 50559)
(August 2015 final order) designating Chagas disease and
neurocysticercosis as additions to the list of tropical diseases under
section 524 of the FD&C Act. The August 2015 final order also set forth

FDA's interpretation of the statutory criteria for designating
additions to the section 524 list of tropical diseases and expands the
list of tropical diseases under section 524(a)(3)(R) of the FD&C Act.
That section, later redesignated as section 524(a)(3)(S) of the FD&C
Act, authorizes FDA to designate by order ``[a]ny other infectious
disease for which there is no significant market in developed nations
and that disproportionately affects poor and marginalized populations''
as a tropical disease for which approved drug applications may be
eligible for a PRV.
    FDA has applied its criteria as set forth in the August 2015 final
order to analyze whether the fungal infection coccidioidomycosis meets
the statutory criteria for addition to this tropical disease list. As
discussed below, the Agency has determined that coccidioidomycosis does
not meet the statutory criteria for designation as a PRV-eligible
``tropical disease'' under section 524 of the FD&C Act because of the
potential market for preventive measures such as vaccines. Thus, FDA
will not add it to the list of tropical diseases whose applications may
be eligible for a priority review voucher at this time.

II. Decision Not To Designate Coccidioidomycosis

    FDA has considered all disease suggestions submitted to the public
docket (FDA-2008-N-0567) between October 1, 2018, and June 30, 2019, as
potential additions to the list of tropical diseases under section 524
of the FD&C Act, under the docket review process explained on the
Agency's web page at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-program. Based on an assessment of currently available information, and
using the criteria from its August 2015 final order, FDA has determined
that coccidioidomycosis does not currently fulfill the criteria for
addition to the list of diseases eligible for the tropical disease PRV
program under section 524 of the FD&C Act and is not designating it as
an addition to the list at this time.

A. Coccidioidomycosis

    Coccidioidomycosis, also known as ``Valley fever,'' is a systemic
fungal infection caused by inhalation of Coccidioides spp. spores.
Major areas of endemicity include substantial parts of the southwestern
United States. The fungus occurs in the environment, especially in
certain soil types in hot, dry climates, and inhalation may occur after
environmental disturbance such as soil disruption and wind. The species
most commonly associated with disease are C. immitis, which is endemic
to parts of California, and C. posadasii, which is found in Arizona,
Utah, Texas, regions of Mexico, and Central and South America (Ref. 1).
Most reported cases occur in individuals who live in or have traveled
to endemic areas. From 1990 to 2011, the incidence of reported
coccidioidomycosis in the United States increased greater than 8-fold
in areas of endemicity (Ref. 2).
    Manifestations of infection with Coccidioides spp. can range from
subclinical (estimated at one-half to two-thirds of infections), that
might not be detected unless the person is included in a skin test
survey or serologic screening, to acute self-limited respiratory
illness that may be difficult to distinguish from other acute
respiratory infections, to severe disease with chronic or life-
threatening complications (Ref. 3). Acute respiratory
coccidioidomycosis has a 1- to 3-week incubation period and most
commonly presents as a self-limited illness with fever, muscle pain,
cough, rash, weight loss, and malaise (Ref. 4). In areas where the
illness is highly endemic, upwards of 30 percent of community-acquired
pneumonia cases may be caused by Coccidioides spp. (Ref. 5). Five to
ten percent of affected patients develop severe or chronic lung disease
such as cavitary pneumonia, nodules, and bronchiectasis, and in
approximately one percent of patients, infection disseminates to the
central nervous system, skin, joints, or bone. Individuals older than
65 years, smokers, and those with diabetes are at increased risk of
pulmonary complications of coccidioidomycosis, while those with
depressed cellular immune function (Refs. 6 and 7), pregnant women
(Ref. 8), or persons of African or Asian descent have an elevated risk
of disseminated disease (Ref. 9). Coccidioidal meningitis cannot be
reliably cured with current antifungal therapy and has a mortality rate
of approximately 30 percent (Ref. 10). Although the public health
burden attributable to coccidioidomycosis in the United States is
primarily due to morbidity, an estimated 200 coccidioidomycosis-
associated deaths occur each year (Ref. 11).
    Treatment recommendations depend upon the severity, location, and
dissemination of the disease as well as the underlying immune status of
the patient (Ref. 12). A 2016 publication of professional society
guidelines recommends against antifungal therapy in patients with newly
diagnosed, uncomplicated coccidioidal pneumonia, with mild or resolved
symptoms, and without immunosuppressive conditions, advising that such
patients receive supportive measures such as physical therapy and close
monitoring. In individuals with severe disease or disseminated disease,
these guidelines advise antifungal therapy for a minimum of 3 to 6
months with an azole (fluconazole or itraconazole), intravenous
amphotericin B, or both. Patients with immunocompromise or other
underlying conditions may require therapy for 12 months or longer. In
individuals with meningitis due to Coccidioides spp., these guidelines
recommend treatment for life (Ref. 13).
    There are two FDA-approved treatments for coccidioidomycosis:
Amphotericin B deoxycholate, available in brand or generic form, and
ketoconazole. In 2013, FDA warned that ketoconazole should not be used
as a first-line therapy for any fungal infection as it can cause severe
liver injury, adrenal insufficiency, and harmful drug interactions, and
should be prescribed only for endemic mycoses, such as
coccidioidomycosis, when alternative antifungal therapies are not
available or tolerated (Ref. 14). With respect to preventative
products, no vaccines have yet been developed that protect persons from
developing infection or progressing from infection to disease due to C.
immitis, but potential for development of such vaccines has been a
topic of interest in some expert discussions as outlined in the next
section.
1. Significant Market in Developed Nations
    In the August 2015 final order, FDA interpreted the statutory
criterion ``no significant market'' to refer to the market for drugs
for the treatment or prevention of infectious diseases. The August 2015
final order states, ``[b]ecause the statute offers vouchers for
applications for drugs for either the treatment or prevention of
infectious diseases, it is reasonable to assume that `no significant
market' can refer to drugs for the treatment or prevention of
infectious diseases. Thus, FDA will analyze the market for drugs for
both the treatment and prevention of infectious diseases for a
particular infectious disease.'' In other words, if there is a
significant market for either the treatment or prevention of the
infectious disease, the criterion that there be ``no significant
market'' in developed nations is not met.
    The relative importance of prevention markets may vary in part
according to whether most cases of a particular disease in developed
countries are attributable to exposure in those same

countries (or would be in the absence of a preventive product such as
vaccine) or to movement between countries of persons exposed elsewhere,
because preventive measures may be more widely important if exposure
could be local and unavoidable than if the potential for exposure is
restricted to a small group of travelers. For example, in the August
24, 2018, final order adding four diseases to the PRV-eligible list (83
FR 42904), chikungunya and Lassa fever were noted as being principally
imported diseases in their limited occurrence in developed countries
(as also noted for Chagas disease and neurocysticercosis in the August
2015 final order), rabies prophylaxis was analyzed and estimated at
below 0.1 percent per year in the United States, and cryptococcal
meningitis was noted as not having prophylaxis recommendations at
present even in highly immunocompromised patients. Conversely, in the
August 24, 2018, document (83 FR 42896), a significant market for
prevention was noted as the reason for not adding pneumocystis
pneumonia to the PRV-eligible list.
    In the current analysis, FDA has found that a sizeable direct
market may exist for products to prevent coccidioidomycosis (e.g.,
vaccines) in developed nations, depending upon the specific attributes
of the product and the recommended population. For this reason, the
statutory criterion that there be ``no significant market for
prevention or treatment'' of coccidioidomycosis is not met. (21 U.S.C.
360n(a)(3)(S)).
    The United States is a high-income economy according to the World
Bank list of high-income countries and therefore is considered a
developed country for purposes of this order (Ref. 15). The true
incidence of coccidioidomycosis in the United States is difficult to
establish because reporting is not required in all States, case
definitions may vary, and many cases are misdiagnosed or lack
confirmatory testing (Refs. 11 and 16). However, up to 150,000 new
infections caused by Coccidioides spp. are estimated to occur annually
in the United States (Ref. 3).
    The incidence of reported coccidioidomycosis in the United States
has increased in Arizona, California, Nevada, New Mexico, and Utah,
from 5.3 per 100,000 population in 1998 to 42.6 per 100,000 in 2011
(Ref. 2). While approximately 96 percent of infections reported in 2017
in the United States occurred in Arizona and California (Ref. 11),
coccidioidomycosis is increasingly being recognized outside these
regions (Refs. 17 and 18). Proposed reasons for the rise in cases and
geographic expansion include changes to the local environment due to
climate variation and soil disruption, greater exposure of higher risk
individuals, including the immunocompromised, and increased numbers of
susceptible individuals living in or traveling to endemic regions
(Refs. 9 and 19).
    A recent Morbidity and Mortality Weekly Report (MMWR) surveillance
summary noted fluctuating total numbers of reported U.S. cases in
recent years (22,634 in 2011, 8,232 in 2014, 14,364 in 2017), all
substantially higher than numbers reported annually in the United
States from 1998 to 2000. The MMWR surveillance summary addressed
potential factors contributing to such fluctuations, including
environmental, population, and reporting changes; noted ``Preliminary
modeling estimates of the actual number of cases suggest that the
number of symptomatic cases nationwide could be 6 to 14 times higher
than the number reported to public health authorities''; and
recommended ``[h]ealth care providers should consider a diagnosis of
coccidioidomycosis in patients who live or work in or have traveled to
areas with known geographic risk for Coccidioides and be aware that
those areas might be broader than previously recognized'' (Ref. 11).
    In the August 2015 final order, FDA used a disease prevalence rate
of 0.1 percent of the population in developed countries for aiding in
the determination of whether a ``significant market'' may exist for
treatment of a disease. For purposes of determining a reasonable
indicator for the number of cases of coccidioidomycosis that might be
considered for treatment in a given year annual incidence (new cases
appearing during a given year) was used by FDA. Based on the 2010 U.S.
census population of 308.7 million, and using an estimate of 150,000
total cases per year, the calculated annual incidence rate in the
United States would be approximately 0.048 percent (Refs. 4 and 20).
These estimates suggest the annual number of persons potentially
considered for treatment for coccidioidomycosis in the United States is
currently below 0.1 percent of the population. However, these estimates
should be considered with due regard to their inherent uncertainty and
also in the context of potential development of products for prevention
of infection or prevention of disease due to Coccidioides spp.
    Because of the ongoing environmental exposures and risk factors for
severe disease when infection occurs, the market for prevention
products such as vaccines could differ substantially from that for
treatment of clinically manifest illness. Data to support a market
estimate are limited, and discussions of potential vaccine cost-
effectiveness have used widely different assumptions regarding annual
target population size, from 90,000 (based on targeting birth cohorts
in highly endemic regions within California and Arizona) (Ref. 21), to
``many millions'' in a worldwide estimate (Ref. 22).
    An annual target population size estimate of 1,035,300 for a
coccidioidomycosis vaccine for use in the United States was presented
in an Institute of Medicine (IOM) committee report on ``Vaccines for
the 21st Century'' commissioned by the National Institutes of Health
(NIH), which utilized a quantitative model to provide decision makers
with a tool to aid in prioritizing vaccine development (Ref. 23). The
committee determined an estimate of annual target population for a
coccidioidomycosis vaccine based upon targeting birth cohorts in five
States where infections are ``most prominent'' plus persons who migrate
into that area. This methodology was used because persons who move into
the endemic part of the United States and were not previously
vaccinated could be at risk from environmental exposure in the endemic
area after their move. The committee report estimates that 90 percent
of newborns and 10 percent of persons moving into the targeted areas
would receive the vaccine.
    Given the purpose of the IOM committee report, the methodology
used, and the experts and stakeholders consulted in its development,
FDA considers it a reasonable estimate of a potential target population
for a licensed coccidioidomycosis vaccine. We acknowledge that there
are limitations to any hypothetical estimate of a recommended
population for a licensed coccidioidomycosis vaccine, and the true
population would depend upon multiple factors that include, but are not
limited to: The incidence and/or prevalence of disease, the extent of
exposure risks that may not be readily avoidable by means other than
vaccination, and the indication, safety profile, efficacy, and
durability of the immune response associated with a specific product.
However, the IOM analysis predicts a sizeable direct market for
products to prevent the disease, and no strong evidence has been found
that the potential market has become smaller since the time of the
committee report.
    A few efforts have been initiated to help facilitate development of
products targeting coccidioidomycosis. At present, FDA is aware of
funding for

coccidioidomycosis drug development by U.S. government sources,
including grants reported as being awarded by FDA and the NIH (Refs. 25
and 26). FDA's Office of Orphan Product Development has accorded orphan
product designation to several drugs intended to treat
coccidioidomycosis (Ref. 27). FDA added Coccidioides species to the
``list of ``qualifying pathogens'' that have the potential to pose a
serious threat to human health'' under the Generating Antibiotic
Incentives Now title of the Food and Drug Administration Safety and
Innovation Act, noting ``[i]t is estimated that up to 60 percent of
people living in the endemic areas of southwestern United States have
been exposed to the fungus'' (June 5, 2014, 79 FR 32464). C. immitis
and C. posadasii were previously on the HHS list of Select Agents and
Toxins but were removed in 2012 based on availability of treatment and
a lowered assessment of impact on human health (Ref. 28). Further,
Coccidioides species are not listed as a high priority threat in the
2017-2018 Public Health Emergency Medical Countermeasures Enterprise
Strategy and Implementation Plan (Ref. 29).
    In summary, based on the analyses outlined above focusing on the
estimated vaccination rates of infants born in endemic areas and
persons who may be exposed by moving into those areas, FDA has found a
significant potential direct market for products for prevention of
coccidioidomycosis.

2. Coccidioides spp. Disproportionately Affects Poor and Marginalized
Populations

    Illnesses caused by Coccidioides spp. cause significant morbidity
with a disproportionate impact on poor and marginalized populations. In
addition to the well-known endemic regions of the United States, cases
and outbreaks of coccidioidomycosis have been reported in Mexico,
Guatemala, Honduras, Nicaragua, Colombia, Venezuela, Argentina, Brazil,
Paraguay, and Bolivia (Ref. 30). With the exception of the United
States and Argentina, none of these countries is on the World Bank list
of high-income economies, which in the August 2015 final order FDA
determined would be used as evidence that the country should be
considered a ``developed nation'' for tropical disease determination
(Ref. 15). While coccidioidal skin test antigens do not distinguish
subclinical infection from symptomatic disease, and recent data from
skin test surveys are sparse (Ref. 31), available information indicates
that coccidioidomycosis may be as prevalent in parts of Latin America
as in parts of the United States (Refs. 30 and 32). Coccidioidin skin
test surveys in Mexico some decades ago were reported as demonstrating
positivity ranging from 10 percent in Tijuana, to 40 percent in
Torreon, to as high as 93 percent in 12 communities in Coahuila (Ref.
30). In Brazil, by one estimate, 7.12 of 1,000 hospital admissions were
due to coccidioidomycosis (Ref. 33). Treatment options are more limited
in Latin America than in the United States, as lipid formulations of
amphotericin have restricted availability due to the high cost (Ref.
34).
    In the United States, several racial and ethnic minority groups
have been reported to have increased risk of severe disease; genetic,
socioeconomic, occupational, and geographic factors have been suggested
as potentially contributory factors. Analyses of hospitalizations from
2000 to 2011 and deaths from 2000 to 2013 in California have reported
higher rates in African-Americans, Hispanics, and older persons
compared to the general population (Refs. 35 and 36). Among
immunocompromised or immunosuppressed populations, persons with HIV
infection were reported to be strikingly vulnerable during the early
years of the HIV pandemic. While effective antiretroviral therapy has
decreased the disease burden in individuals with HIV, affected patients
lacking access to treatment, or with poorly-controlled disease, are at
higher risk for severe or disseminated disease (Ref. 37).
    While adults over the age of 60 have the highest incidence of
coccidioidomycosis (Ref. 38), children under the age of 17 and their
caretakers bear a substantial burden of the disease in endemic regions,
experiencing delays in diagnosis, prolonged symptoms, hospitalizations,
and missed school and work (Ref. 39). In California, for example,
during a period when reported cases and hospitalizations in the general
population increased 4.5-fold and 2.7-fold, respectively, cases and
hospitalizations in children increased almost 6-fold (Ref. 40).
    Prison inmates in endemic regions are at particularly high risk of
symptomatic disease. One study in California found that the risk of
primary disease was highest in prisoners over the age of 40 and in non-
white ethnic groups (Ref. 41). A significant increase in
coccidioidomycosis that was observed in two California prisons led to a
court ruling excluding inmates from incarceration at those locations if
they were in risk groups identified by the American Thoracic Society
for high risk of severe coccidioidomycosis (Ref. 42).
    Coccidioidomycosis is not currently designated by WHO as a
Neglected Tropical Disease and no data were found on Disability-
Adjusted Life Years distinguishing the burden attributable to
coccidioidomycoses in developing versus developed countries. However,
patients with coccidioidomycosis often experience prolonged symptoms,
delays in diagnosis, and unnecessary antibacterial therapy (Ref. 43).
Due to greater barriers to medical care for diagnosis and treatment,
poor and marginalized patents in both developing and developed
countries experience a significant burden of disease. Resolution of
symptoms may take months, thus resulting in significant impairment of
activities of daily living and loss of productivity (Ref. 44).
    The above information demonstrates it is reasonable to conclude
that coccidioidomycosis disproportionately affects poor and
marginalized populations.

B. FDA Determination

    Given the factors described above, FDA has determined that
coccidioidomycoses meets the statutory criteria of ``disproportionately
affects poor and marginalized populations,'' but it does not meet the
criteria of ``no significant market in developed nations'' due to the
potentially significant direct market for products to prevent the
disease. Therefore, FDA declines to designate coccidioidomycosis as an
addition to the tropical disease list under section 524 of the FD&C
Act.

III. Process for Requesting Additional Diseases To Be Added to the List

    FDA's current determination regarding coccidioidomycoses does not
prevent interested persons from requesting its consideration in the
future. To facilitate the consideration of future additions to the
list, FDA established a public docket (see https://www.regulations.gov,
Docket No. FDA-2008-N-0567) through which interested persons may submit
requests for additional diseases to be added to the list. Such requests
should be accompanied by information to document that the disease meets
the criteria set forth in section 524(a)(3)(S) of the FD&C Act. FDA
will periodically review these requests, and, when appropriate, expand
the list. For further information, see FDA's Tropical Disease Priority
Review Voucher Program web page at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/tropical-disease-priority-review-voucher-program.

IV. Paperwork Reduction Act

    This notice reiterates the ``open'' status of the previously
established public docket through which interested persons may submit
requests for additional diseases to be added to the list of tropical
diseases that FDA has found to meet the criteria in section
524(a)(3)(S) of the FD&C Act. Such a request for information is exempt
from Office of Management and Budget review under 5 CFR 1320.3(h)(4) of
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521).
Specifically, ``[f]acts or opinions submitted in response to general
solicitations of comments from the public, published in the Federal
Register or other publications, regardless of the form or format
thereof'' are exempt, ``provided that no person is required to supply
specific information pertaining to the commenter, other than that
necessary for self-identification, as a condition of the full
consideration of the comment.''

V. References

    The following references marked with an asterisk (*) have been
placed on display at the Dockets Management Staff (see ADDRESSES). They
may be seen by interested persons between 9 a.m. and 4 p.m., Monday
through Friday, and are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses but is
not responsible for any subsequent changes to the websites after this
document publishes in the Federal Register.

1. Saubolle, M.A., P.P. McKellar, and D. Sussland, 2007,
``Epidemiologic, Clinical, and Diagnostic Aspects of
Coccidioidomycosis,'' Journal of Clinical Microbiology, epub ahead
of print November 15, 2006, doi: 10.1128/JCM.02230-06.
2. *U.S. Centers for Disease Control and Prevention (CDC), 2013,
``Increase in Reported Coccidioidomycosis--United States, 1998-
2011,'' Morbitity and Mortality Weekly Report (MMWR), 62(12):217-
221.
3. Galgiani, J.N., N.M. Ampel, J.E. Blair, et al., and the
Infectious Diseases Society of America, 2005,
``Coccidioidomycosis,'' Clinical Infectious Diseases, epub ahead of
print September 20, 2005, doi: 10.1086/496991.
4. Galgiani, J.N., N.M. Ampel, J.E. Blair, et al., 2016, ``Executive
Summary: 2016 Infectious Diseases Society of America (IDSA) Clinical
Practice Guideline for the Treatment of Coccidioidomycosis,''
Clinical Infectious Diseases, 63(6):717-722.
5. Valdivia, L., D. Nix, M. Wright, et al., 2006,
``Coccidioidomycosis as a Common Cause of Community-Acquired
Pneumonia,'' Emerging Infectious Diseases, 12(6):958-962.
6. Bergstrom, L., D.E. Yocum, N.M. Ampel, et al., 2004, ``Increased
Risk of Coccidioidomycosis in Patients Treated with Tumor Necrosis
Factor Alpha Antagonists,'' Arthritis & Rheumatology, 50(6):1959-
1966.
7. Miller, M.B., R. Hendren, and P.H. Gilligan, 2004,
``Posttransplantation Disseminated Coccidioidomycosis Acquired From
Donor Lungs,'' Journal of Clinical Microbiology, 42(5):2347-2349.
8. Bercovitch, R.S., A. Catanzaro, B.S. Schwartz, et al., 2011,
``Coccidioidomycosis During Pregnancy: A Review and Recommendations
for Management,'' Clinical Infectious Diseases, 53(4)363-368.
9. *CDC, 2009, ``Increase in Coccidioidomycosis--California, 2000-
2007,'' MMWR Morb Mortal Wkly Rep, 58(5):105-109.
10. Johnson, R.H. and H.E. Einstein, 2006, ``Coccidioidal
Meningitis,'' Clinical Infectious Diseases, epub ahead of print
November 29, 2005, doi: 10.1086/497596.
11. *CDC, 2019, ``Valley Fever (Coccidioidomycosis) Statistics,''
cited May 3, 2019, https://www.cdc.gov/fungal/diseases/coccidioidomycosis/statistics.html.
12. Galgiani, J.N. 2019, ``Valley Fever (Coccidioidomycosis):
Tutorial for Primary Care Professionals,'' cited January 15, 2019,
https://vfce.arizona.edu/sites/default/files/9-valley_fever_tutorial.pdf.
13. Galgiani, J.N., N.M. Ampel, J.E. Blair, et al., 2016, ``2016
Infectious Diseases Society of America (IDSA) Clinical Practice
Guideline for the Treatment of Coccidioidomycosis,'' Clinical
Infectious Diseases, epub ahead of print July 27, 2016, doi:
10.1093/cid/ciw360.
14. *FDA, 2017, ``FDA Drug Safety Communication: FDA Limits Usage of
Nizoral (Ketoconazole) Oral Tablets Due to Potentially Fatal Liver
Injury and Risk of Drug Interactions and Adrenal Gland Problems,''
cited May 10, 2019, https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-limits-usage-nizoral-ketoconazole-oral-tablets-due-potentially.
15. The World Bank, 2018, World Bank Country and Lending Groups,
cited April 29, 2019, https://datahelpdesk.worldbank.org/knowledgebase/articles/906519-world-bank-country-and-lending-groups.
16. Chang, D.C., S. Anderson, K. Wannemuehler, et al., 2008,
``Testing for Coccidioidomycosis Among Patients With Community-
Acquired Pneumonia,'' Emerging Infectious Diseases, 14(7):1053-1059.
17. Marsden-Haug, N., M. Goldoft, C. Ralston, et al., 2013,
``Coccidioidomycosis Acquired in Washington State,'' Clinical
Infectious Diseases, epub ahead of print December 7, 2012, doi:
10.1093/cid/cis1028.
18. Engelthaler, D.M., C.C. Roe, C.M. Hepp, et al., 2016, ``Local
Population Structure and Patterns of Western Hemisphere Dispersal
for Coccidioides spp., the Fungal Cause of Valley Fever,'' mBio,
7(2):e00550-16.
19. Hector, R.F. and R. Laniado-Laborin, 2005,
``Coccidioidomycosis--A Fungal Disease of the Americas,'' PLoS Med,
2(1):e2.
20. * U.S. Census Bureau, 2011, ``Population Distribution and
Change: 2000 to 2010,'' 2010 Census Briefs, accessed January 10,
2020, https://www.census.gov/prod/cen2010/briefs/c2010br-01.pdf.
21. Barnato, A.E., G.D. Sanders, and D.K. Owens, 2001, ``Cost-
Effectiveness of a Potential Vaccine for Coccidioides Immitis,''
Emerging Infectious Diseases, 7(5):797-806.
22. Galgiani, J.N. 2008, ``Vaccines to Prevent Systemic Mycoses:
Holy Grails Meet Translational Realities,'' Journal Infectious
Diseases 197(7):938-940.
23. Stratton, K R., J.S. Durch, and R.S. Lawrence, 2000, ``Vaccines
for the 21st Century: A Toll for Decisionmaking,'' Washington, DC:
National Academies Press.
24. Galgiani, J N. 2019, ``Vaccines to Prevent Coccidioidomycosis:
60 Years and Counting,'' cited September 25, 2019, https://custom.cvent.com/5ED8172A3B414619A18F31932AAB4C72/files/39a4663417b84176bcbe678ab3c0259a.pdf.
25. University of Arizona, 2016, ``The Search for the Cure for
Valley Fever--Nikkomycin Z Development at the University of
Arizona,'' cited May 3, 2019, https://vfce.arizona.edu/sites/vfce/files/bio5_summary_nikz_development_plan_1.pdf.
26. * NIH, National Institutes of Allergy and Infectious Diseases,
2018, ``Two Clinical Trials Focus on Serious Fungal Disease Valley
Fever,'' cited May 2, 2019, https://www.niaid.nih.gov/news-events/two-clinical-trials-focus-serious-fungal-disease-valley-fever.
27. * FDA, 2002, ``Cumulative List of All Products That Have
Received Orphan Designation: Total Active Designations,'' effective
May 5, 2009, cited June 4, 2019, https://www.fda.gov/media/76409/download.
28. * CDC, U.S. Department of Health and Human Services (HHS),
January 19, 2017, ``Possession, Use, and Transfer of Select Agents
and Toxins; Biennial Review,'' final rule, Federal Register, 82 FR
6278.
29. * HHS, 2017, ``2017-2018 Public Health Emergency Medical
Countermeasures Enterprise (PHEMCE) Strategy and Implementation
Plan,'' accessed January 15, 2020, https://www.phe.gov/Preparedness/mcm/phemce/Documents/2017-phemce-sip.pdf.
30. Laniado-Laborin, R., 2007, ``Expanding

Understanding of Epidemiology of Coccidioidomycosis in the Western
Hemisphere,'' Annals of the New York Academy of Sciences, epub ahead
of print March 29, 2007, doi: 10.1196/annals.1406.004.
31. Wack, E.E., N.M. Ampel, R.H. Sunenshine, and J.N. Galgiani,
2015, ``The Return of Delayed-Type Hypersensitivity Skin Testing for
Coccidioidomycosis,'' Clinical Infectious Diseaes, epub ahead of
print May 15, 2015, doi: 10.1093/cid/civ388.
32. Laniado-Laborin, R., E.G. Arathoon, C. Canteros, et al.,
``Coccidioidomycosis in Latin America,'' Medical Mycology, 57(1
Suppl):S46-S55.
33. Giacomazzi, J., L. Baethgen, L.C. Carneiro, et al., in
association with the LIFE Program, 2016, ``The Burden of Serious
Human Fungal Infections in Brazil,'' Mycoses, epub ahead of print
December 22, 2015, doi: 10.1111/myc.12427.
34. Gonz[aacute]lez-Benavides, J., 1991, ``The Panorama of
Coccidioidomycosis in Nuevo Leon from 1978 to 1988,'' Gaceta Medica
de Mexico, 127(5):427-432.
35. Sondermeyer Cooksey, G., L.A. Lee, D. Gilliss, et al., 2013,
``Coccidioidomycosis-Associated Hospitalizations, California, USA,
2000-2011,'' Emerging Infectious Diseases, 10:1590-1597.
36. Sondermeyer Cooksey, G., L.A. Lee, D. Gilliss, and D.J. Vugia,
2016, ``Coccidioidomycosis-Associated Deaths in California, 2000-
2013,'' Public Health Reports, 131(4):531-535.
37. Ampel, N.M. 2005, ``Coccidioidomycosis in Persons Infected With
HIV Type 1,'' Clinical Infectious Diseases, epub ahead of print
September 12, 2005, doi: 10.1086/444502.
38. Benedict, K., O.Z. McCotter, S. Brady, et al., 2019,
``Surveillance for Coccidioidomycosis--United States, 2011-2017,''
MMWR Surveillance Summaries, 68(7):1-15.
39. Lee, L.A., G. Sondermeyer Cooksey, J.J. Kim, et al., 2019,
``Pediatric Coccidioidomycosis: Case Series From a California
Pediatric Infectious Diseases Clinic,'' Pediatric Infectious Disease
Journal, 38(2):115-121.
40. Sondermeyer Cooksey, G., L.A. Lee, D. Gilliss, et al.,
``Epidemiology of Pediatric Coccidioidomycosis in California, 2000-
2012,'' Pediatric Infectious Disease Journal, 35(2):166-171.
41. Wheeler, C., K.D. Lucas, and J.C. Mohle-Boetani, 2015, ``Rates
and Risk Factors for Coccidioidomycosis Among Prison Inmates,
California, USA, 2011,'' Emerging Infectious Diseases, 21(1):70-75.
42. U.S. District Court for the Northern District of California,
2013, Plata v. Brown, No. C01-1351 TEH, s.l.
43. Benedict, K., M. Ireland, M.P. Weinberg, et al., 2018,
``Enhanced Surveillance for Coccidioidomycosis, 14 U.S. States,''
Emerging Infectious Diseases, 242(8)1444-1452.
44. Garrett, A.L., Y.H. Chang, K. Ganley, and J.E. Blair, 2016,
``Uphill Both Ways: Fatigue and Quality of Life in Valley Fever,''
Medical Mycology, epub ahead of print November 26, 2015, doi:
10.1093/mmy/myv097.

    Dated: July 8, 2020.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2020-15255 Filed 7-14-20; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register Volume 82, Number 157 (Wednesday, August 16, 2017)]
[Notices]
[Pages 38911-38912]
[FR Doc No: 2017-17301]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2017-N-3966]

Upsher-Smith Laboratories, Inc.; Withdrawal of Approval of an
Abbreviated New Drug Application for ZALEPLON

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
withdrawing approval of an abbreviated new drug application (ANDA) for
ZALEPLON Capsules, 5 milligrams (mg) and 10 mg, held by Upsher-Smith
Laboratories, Inc. (Upsher-Smith), 6701 Evenstad Dr., Maple Grove, MN
55369. Upsher-Smith has voluntarily requested that approval of this
application be withdrawn, and has waived its opportunity for a hearing.

DATES: Effective August 16, 2017.

FOR FURTHER INFORMATION CONTACT: Stefanie Kraus, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6215, Silver Spring, MD 20993-0002, 301-
796-9585.

SUPPLEMENTARY INFORMATION: On June 6, 2008, FDA approved ANDA 078706
for ZALEPLON Capsules, 5 mg and 10 mg, submitted by Upsher-Smith.
According to annual reports Upsher-Smith filed with the Agency, Upsher-
Smith stopped distributing these products by April 6, 2010. In a letter
dated August 9, 2011, FDA informed Upsher-Smith that it had concerns
about the validity of bioequivalence data submitted with ANDA 078706
from studies conducted by a certain contract research organization,
establishing bioequivalence of Upsher-Smith's product to the reference
listed drug, SONATA (ZALEPLON) Capsules, 5 mg and 10 mg. In that
letter, FDA directed Upsher-Smith to supplement its ANDA with either:
(1) New bioequivalence studies or (2) re-assays of the samples from the
original bioequivalence studies. Upsher-Smith did not respond to this
letter. FDA then sent another letter to Upsher-Smith on August 19,

2016, requesting that Upsher-Smith provide the requested bioequivalence
data within 30 calendar days or voluntarily seek withdrawal of ANDA
078706 under section 314.150(d) (21 CFR 314.150(d)).
    In a letter dated September 15, 2016, Upsher-Smith informed FDA
that it did not intend to submit the requested bioequivalence data and
requested that the Agency withdraw approval of ANDA 078706 for ZALEPLON
Capsules under section 314.150(d). In that letter, Upsher-Smith also
waived any opportunity for a hearing otherwise provided under section
314.150(a).
    Therefore, under section 505(e) of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) (21 U.S.C. 355(e)) and 314.150(d), approval of
ANDA 078706, and all amendments and supplements thereto, is withdrawn
(see DATES). Distribution of this product in interstate commerce
without an approved application is illegal and subject to regulatory
action (see sections 505(a) and 301(d) of the FD&C Act (21 U.S.C.
355(a) and 331(d)).

    Dated: August 11, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-17301 Filed 8-15-17; 8:45 am]
 BILLING CODE 4164-01-P


[Federal Register Volume 81, Number 251 (Friday, December 30, 2016)]
[Rules and Regulations]
[Pages 96362-96364]
[FR Doc No: 2016-31695]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2015-3753; Directorate Identifier 2015-NE-26-AD;
Amendment 39-18739; AD 2016-25-13]
RIN 2120-AA64

Airworthiness Directives; Safran Helicopter Engines, S.A.
(Formerly Turbomeca S.A.) Turboshaft Engines

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Final rule.

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

SUMMARY: We are superseding airworthiness directive (AD) 2016-04-12,
that applies to certain Safran Helicopter Engines, S.A. (formerly
Turbomeca S.A.) Arriel 2B, 2B1, 2C, 2C1, 2C2, 2D, 2E, 2S1, and 2S2
turboshaft engines. AD 2016-04-12 required spectrometric oil analysis
(SOA) inspection of the engine accessory gearbox (AGB), and, depending
on the results, removal of the engine AGB. This AD requires initial and
repetitive wear inspections of the engine AGB cover. This AD was
prompted by a report of an uncommanded in-flight shutdown (IFSD) of an
Arriel 2S2 engine caused by rupture of the 41-tooth gear, which forms
part of the bevel gear in the engine AGB. We are issuing this AD to
correct the unsafe condition on these products.

DATES: This AD is effective February 3, 2017.
    The Director of the Federal Register approved the incorporation by
reference of a certain publication listed in this AD as of February 3,
2017.

ADDRESSES: For service information identified in this final rule,
contact Safran Helicopter Engines, S.A. 40220 Tarnos, France; phone: 33
0 5 59 74 40 00; fax: 33 0 5 59 74 45 15. You may view this service
information at the FAA, Engine & Propeller Directorate, 1200 District
Avenue, Burlington, MA. For information on the availability of this
material at the FAA, call<PHONE_NUMBER>. It is also available on the
Internet at http://www.regulations.gov by

searching for and locating Docket No. FAA-2015-3753.

Examining the AD Docket

    You may examine the AD docket on the Internet at http://www.regulations.gov by searching for and locating Docket No. FAA-2015-
3753; or in person at the Docket Management Facility between 9 a.m. and
5 p.m., Monday through Friday, except Federal holidays. The AD docket
contains this AD, the mandatory continuing airworthiness information
(MCAI), regulatory evaluation, any comments received, and other
information. The address for the Docket Office (phone:<PHONE_NUMBER>) is
Document Management Facility, U.S. Department of Transportation, Docket
Operations, M-30, West Building Ground Floor, Room W12-140, 1200 New
Jersey Avenue SE., Washington, DC 20590.

FOR FURTHER INFORMATION CONTACT: Philip Haberlen, Aerospace Engineer,
Engine Certification Office, FAA, Engine & Propeller Directorate, 1200
District Avenue, Burlington, MA 01803; phone:<PHONE_NUMBER>; fax: 781-
238-7199; email<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

Discussion

    We issued a notice of proposed rulemaking (NPRM) to amend 14 CFR
part 39 to supersede AD 2016-04-12, Amendment 39-18406 (81 FR 12583,
March 10, 2016), (``AD 2016-04-12''). AD 2016-04-12 applied to the
specified products. The NPRM published in the Federal Register on June
17, 2016 (81 FR 39601). The NPRM proposed to require initial and
repetitive spectrometric oil analysis (SOA) of the AGB, and wear
inspections of the engine AGB cover. However, this AD only mandates
wear inspections of the engine AGB cover and does not add requirements
beyond the scope of the NPRM.

Comments

    We gave the public the opportunity to participate in developing
this AD. We received no comments on the NPRM (81 FR 39601, June 17,
2016).
    Since we issued AD 2016-04-12, the European Aviation Safety Agency
(EASA) has issued MCAI European Aviation Safety Agency AD 2016-0055R1,
dated October 11, 2016, to only specify that periodic wear inspections
of the engine AGB cover are necessary. This AD removes the proposed
requirements for initial and repetitive SOA of the AGB, which reduces
the costs of compliance in this AD.
    Also since we issued AD 2016-04-12, Safran Helicopter Engines, S.A.
has issued Mandatory Service Bulletin (MSB) No. 292 72 2861, Version D,
dated September 23, 2016. The MSB only requires performing periodic
wear inspections of the engine AGB cover.

Conclusion

    We reviewed the available data and determined that air safety and
the public interest require adopting this AD with the changes described
previously. We determined that these changes will not increase the
economic burden on any operator or increase the scope of this AD.

Related Service Information Under 1 CFR Part 51

    Safran Helicopter Engines, S.A. has issued MSB No. 292 72 2861,
Version D, dated September 23, 2016. The MSB describes procedures for
performing periodic wear inspections of the engine AGB cover. This
service information is reasonably available because the interested
parties have access to it through their normal course of business or by
the means identified in the ADDRESSES section.

Costs of Compliance

    We estimate that this AD affects 250 engines installed on
helicopters of U.S. registry. We also estimate that it will take 1 hour
to perform the engine AGB cover wear inspection. The average labor rate
is $85 per hour. Required parts for the wear inspection cost about
$3,100 per engine. We estimate that 5 engines will require AGB
replacement at a cost of $44,397 per engine. We also estimate that it
will take about 2 hours to replace the engine AGB. Based on these
figures, we estimate the cost of this AD on U.S. operators to be
$1,019,085.

Authority for This Rulemaking

    Title 49 of the United States Code specifies the FAA's authority to
issue rules on aviation safety. Subtitle I, Section 106, describes the
authority of the FAA Administrator. Subtitle VII, Aviation Programs,
describes in more detail the scope of the Agency's authority.
    We are issuing this rulemaking under the authority described in
Subtitle VII, Part A, Subpart III, Section 44701, ``General
requirements.'' Under that section, Congress charges the FAA with
promoting safe flight of civil aircraft in air commerce by prescribing
regulations for practices, methods, and procedures the Administrator
finds necessary for safety in air commerce. This regulation is within
the scope of that authority because it addresses an unsafe condition
that is likely to exist or develop on products identified in this
rulemaking action.

Regulatory Findings

    This AD will not have federalism implications under Executive Order
13132. This AD will not have 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.
    For the reasons discussed above, I certify that this AD:
    (1) Is not a ``significant regulatory action'' under Executive
Order 12866,
    (2) Is not a ``significant rule'' under DOT Regulatory Policies and
Procedures (44 FR 11034, February 26, 1979),
    (3) Will not affect intrastate aviation in Alaska to the extent
that it justifies making a regulatory distinction, and
    (4) Will not have a significant economic impact, positive or
negative, on a substantial number of small entities under the criteria
of the Regulatory Flexibility Act.

List of Subjects in 14 CFR Part 39

    Air transportation, Aircraft, Aviation safety, Incorporation by
reference, Safety.

Adoption of the Amendment

    Accordingly, under the authority delegated to me by the
Administrator, the FAA amends part 39 of the Federal Aviation
Regulations (14 CFR part 39) as follows:

PART 39--AIRWORTHINESS DIRECTIVES

0
1. The authority citation for part 39 continues to read as follows:

    Authority:  49 U.S.C. 106(g), 40113, 44701.

Sec.  39.13  [Amended]

0
2. The FAA amends Sec.  39.13 by removing airworthiness directive (AD)
AD 2016-04-12, Amendment 39-18406 (81 FR 12583, March 10, 2016), and
adding the following new AD:

2016-25-13 Safran Helicopter Engines, S.A. (Type Certificate
previously held by Turbomeca S.A.): Amendment 39-18739; Docket No.
FAA-2015-3753; Directorate Identifier 2015-NE-26-AD.

(a) Effective Date

    This AD is effective February 3, 2017.

(b) Affected ADs

    This AD supersedes AD 2016-04-12, Amendment 39-18406 (81 FR
12583, March 10, 2016).

(c) Applicability

    This AD applies to Safran Helicopter Engines, S.A. Arriel 2B,
2B1, 2C, 2C1, 2C2, 2D, 2E, 2S1, and 2S2 turboshaft engines with an
engine accessory gearbox (AGB), part number<PHONE_NUMBER>, with a
machined front casing.

(d) Unsafe Condition

    This AD was prompted by a report of an uncommanded in-flight
shutdown (IFSD) of an Arriel 2S2 engine caused by rupture of the 41-
tooth gear, which forms part of the bevel gear in the engine AGB. We
are issuing this AD to prevent failure of the engine AGB,
uncommanded IFSD, damage to the engine, and damage to the
helicopter.

(e) Compliance

    Comply with this AD within the compliance times specified,
unless already done.
    (1) Initial Wear Inspection
    (i) For all affected engines, perform a wear inspection of the
engine AGB cover before the engine AGB, module M01, exceeds 850
engine hours (EH) since new or since last overhaul (SLO), or within
50 EHs after April 14, 2016, or before the next flight after the
effective date of this AD, whichever occurs latest.
    (ii) Reserved.
    (2) Repetitive Wear Inspection Intervals
    (i) For Arriel 2E engines, repeat the engine AGB cover wear
inspection within every 800 EH since last inspection (SLI).
    (ii) For all affected engines, except for Arriel 2E engines,
repeat the engine AGB cover wear inspection within every 600 EH SLI.
    (3) Inspection Criteria
    (i) Use paragraph 2.4.2 of Safran Helicopter Engines, S.A.
Mandatory Service Bulletin (MSB) No. 292 72 2861, Version D, dated
September 23, 2016, to do the inspections required by paragraphs
(e)(1) and (e)(2) of this AD.
    (ii) Reserved.
    (4) Corrective Actions Based on the Results of the Most Recent
Wear Inspection
    (i) If the wear measured from the most recent wear inspection is
0.15 mm or less, no further action is required. However, you must
still comply with the repetitive inspection requirements of
paragraph (e)(2) of this AD.
    (ii) If the most recent wear inspection was performed while the
engine was in service, and the wear is greater than 0.15 mm, do the
following:
    (A) If the wear measured from the most recent wear inspection is
greater than 0.15 mm, but 0.30 mm or less, remove the engine AGB
from service within 200 EH SLI and replace with a part eligible for
installation.
    (B) If the wear measured from the most recent wear inspection is
greater than 0.30 mm, but 0.40 mm or less, remove the engine AGB
from service within 25 EH SLI and replace with a part eligible for
installation.
    (C) If the wear measured from the most recent wear inspection is
greater than 0.40 mm, remove the engine AGB from service before
further flight and replace with a part eligible for installation.
    (iii) If the most recent wear inspection was performed on the
engine during an engine shop visit, and the wear is greater than
0.15 mm, remove the engine AGB before further flight and replace
with a part eligible for installation.

(f) Credit for Previous Action

    If you have previously performed a wear inspection of the engine
AGB cover prior to the effective date of this AD in accordance with
the instructions given in Turbomeca MSB No. 292 72 2861, Version C,
dated March 9, 2016, or Turbomeca MSB No. 292 72 2861, Version B,
dated February 2, 2016, then you may take credit for that wear
inspection as the ``most recent'' wear inspection for the purposes
of paragraph (e)(4) of this AD.

(g) Definition

    For the purpose of this AD, an engine shop visit is defined as
the induction of an engine into the shop for maintenance involving
the separation of any major mating engine flanges, except that the
separation of engine flanges solely for the purposes of
transportation without subsequent engine maintenance does not
constitute an engine shop visit.

(h) Alternative Methods of Compliance (AMOCs)

    The Manager, Engine Certification Office, FAA, may approve AMOCs
for this AD. Use the procedures found in 14 CFR 39.19 to make your
request. You may email your request to<EMAIL_ADDRESS>
(i) Related Information

    (1) For more information about this AD, contact Philip Haberlen,
Aerospace Engineer, Engine Certification Office, FAA, Engine &
Propeller Directorate, 1200 District Avenue, Burlington, MA 01803;
phone:<PHONE_NUMBER>; fax:<PHONE_NUMBER>; email:
<EMAIL_ADDRESS>    (2) Refer to MCAI European Aviation Safety Agency AD 2016-
0055R1, dated October 11, 2016, for more information. You may
examine the MCAI in the AD docket on the Internet at http://www.regulations.gov/document?D=FAA-2015-3753-0006.

(j) Material Incorporated by Reference

    (1) The Director of the Federal Register approved the
incorporation by reference (IBR) of the service information listed
in this paragraph under 5 U.S.C. 552(a) and 1 CFR part 51.
    (2) You must use this service information as applicable to do
the actions required by this AD, unless the AD specifies otherwise.
    (i) Safran Helicopter Engines, S.A. Mandatory Service Bulletin
No. 292 72 2861, Version D, dated September 23, 2016.
    (ii) Reserved.
    (3) For Safran Helicopter Engines, S.A. service information
identified in this AD, contact Safran Helicopter Engines, S.A. 40220
Tarnos, France; phone: 33 0 5 59 74 40 00; fax: 33 0 5 59 74 45 15.
    (4) You may view this service information at FAA, Engine &
Propeller Directorate, 1200 District Avenue, Burlington, MA. For
information on the availability of this material at the FAA, call
781-238-7125.
    (5) You may view this service information at the National
Archives and Records Administration (NARA). For information on the
availability of this material at NARA, call<PHONE_NUMBER>, or go to:
http://www.archives.gov/federal-register/cfr/ibr-locations.html.

    Issued in Burlington, Massachusetts, on November 29, 2016.
Colleen M. D'Alessandro,
Manager, Engine & Propeller Directorate, Aircraft Certification
Service.
[FR Doc. 2016-31695 Filed 12-29-16; 8:45 am]
 BILLING CODE 4910-13-P


[Federal Register Volume 81, Number 13 (Thursday, January 21, 2016)]
[Rules and Regulations]
[Pages 3319-3320]
[FR Doc No: 2016-00945]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2015-1998; Directorate Identifier 2014-SW-035-AD;
Amendment 39-18379; AD 2016-01-19]
RIN 2120-AA64

Airworthiness Directives; MD Helicopters Inc.

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Final rule.

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

SUMMARY: We are adopting a new airworthiness directive (AD) for MD
Helicopters Inc. (MDHI) Model 500N and 600N helicopters with certain
rotating cone assemblies installed. This AD requires establishing a
life limit of 10,000 hours time-in-service (TIS) on these rotating cone
assemblies. This AD was prompted by the determination that MDHI created
rotating cone assemblies with new dash numbers but incorrectly failed
to identify them as life-limited parts. The actions are intended to
prevent operation of rotating cone assemblies past their life limits,
failure of the rotating cone assemblies, loss of directional control,
and subsequent loss of control of the helicopter.

DATES: This AD is effective February 25, 2016.

ADDRESSES: For service information identified in this final rule,
contact MD Helicopters, Inc., Attn: Customer Support Division, 4555 E.
McDowell Rd., Mail Stop M615, Mesa, AZ 85215-9734; telephone 1-800-388-
3378; fax<PHONE_NUMBER>; or at http://www.mdhelicopters.com. You may
review a copy of the referenced service information at the FAA, Office
of the Regional Counsel, Southwest Region, 10101 Hillwood Pkwy, Room
6N-321, Fort Worth, TX 76177.

Examining the AD Docket

    You may examine the AD docket on the Internet at http://www.regulations.gov by searching for and locating Docket No. FAA-2015-
1998; or in person at the Docket Operations Office between 9 a.m. and 5
p.m., Monday through Friday, except Federal holidays. The AD docket
contains this AD, the economic evaluation, any comments received, and
other information. The street address for the Docket Operations Office
(phone:<PHONE_NUMBER>) is U.S. Department of Transportation, Docket
Operations Office, M-30, West Building Ground Floor, Room W12-140, 1200
New Jersey Avenue SE., Washington, DC 20590.

FOR FURTHER INFORMATION CONTACT: Galib Abumeri, Aerospace Engineer, Los
Angeles Aircraft Certification Office, Transport Airplane Directorate,
FAA, 3960 Paramount Blvd., Lakewood, California 90712, telephone 562-
627-5324; email<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

Discussion

    On June 9, 2015, at 80 FR 32508, the Federal Register published our
notice of proposed rulemaking (NPRM), which proposed to amend 14 CFR
part 39 by adding an AD that would apply to MDHI Model 500N helicopters
with a rotating cone assembly part number (P/N) 500N3740-81 installed,
and Model 600N helicopters with a rotating cone assembly P/N 500N3740-
71 installed. The NPRM proposed to require establishing a life limit of
10,000 hours TIS on these rotating cone assemblies. Although these
parts have a life limit of 10,000 hours TIS, they were incorrectly
omitted from the Airworthiness Limitation Section of the Rotorcraft
Maintenance Manual. Some of the affected parts were sold as spares,
while others were installed on new helicopters in production. The
proposed requirements were intended to prevent operation of rotating
cone assemblies past their life limits, failure of the rotating cone
assemblies, loss of directional control, and subsequent loss of control
of the helicopter.
    Since the NPRM was issued, the FAA Southwest Regional Office has
relocated. This AD includes the current physical address of the FAA
Southwest Regional Office.

Comments

    We gave the public the opportunity to participate in developing
this AD, but we received no comments on the NPRM (80 FR 32508, June 9,
2015).

FAA's Determination

    We have reviewed the relevant information and determined that an
unsafe condition exists and is likely to exist or develop on other
products of these same type designs and that air safety and the public
interest require adopting the AD requirements as proposed.

Related Service Information

    MDHI issued Service Bulletin SB500N-046 and SB600N-054 (SB) as a
single bulletin on July 9, 2012. The SB calls for a one-time inspection
within 100 flight hours to determine the rotating cone assembly's part
number on MDHI Model 500N and 600N helicopters. The SB then states the
need to correct the component record for certain rotating cone
assemblies.
    The SB also specifies determining the rotating cone assembly's
total service time since new and recording this on the component
record. MDHI reports that failure to comply with the SB may result in
an aircraft exceeding the life limit of the rotating cone assembly and
that this could lead to component failure and loss of directional
control of the helicopter.

Differences Between This AD and the Service Information

    The SB calls for inspecting the rotating cone assembly to determine
its P/N. We make no requirement about how to determine the P/N. The
compliance time for the SB is within 100 flight hours, while this AD
requires compliance within 1 year or by the next annual inspection,
whichever comes later.

Costs of Compliance

    We estimate that this AD affects 8 helicopters of U.S. Registry and
that labor costs average $85 a work hour. We estimate that creating a
component history card and revising the appropriate records takes 1
work-hour. No parts are needed for a total cost of $85 per helicopter
and $680 for the U.S. fleet.

Authority for This Rulemaking

    Title 49 of the United States Code specifies the FAA's authority to
issue rules on aviation safety. Subtitle I, section 106, describes the
authority of the FAA Administrator. Subtitle VII: Aviation Programs,
describes in more

detail the scope of the Agency's authority.
    We are issuing this rulemaking under the authority described in
Subtitle VII, Part A, Subpart III, Section 44701: ``General
requirements.'' Under that section, Congress charges the FAA with
promoting safe flight of civil aircraft in air commerce by prescribing
regulations for practices, methods, and procedures the Administrator
finds necessary for safety in air commerce. This regulation is within
the scope of that authority because it addresses an unsafe condition
that is likely to exist or develop on products identified in this
rulemaking action.

Regulatory Findings

    This AD will not have federalism implications under Executive Order
13132. This AD will not have 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.
    For the reasons discussed above, I certify that this AD:
    (1) Is not a ``significant regulatory action'' under Executive
Order 12866;
    (2) Is not a ``significant rule'' under DOT Regulatory Policies and
Procedures (44 FR 11034, February 26, 1979);
    (3) Will not affect intrastate aviation in Alaska to the extent
that it justifies making a regulatory distinction; and
    (4) Will not have a significant economic impact, positive or
negative, on a substantial number of small entities under the criteria
of the Regulatory Flexibility Act.
    We prepared an economic evaluation of the estimated costs to comply
with this AD and placed it in the AD docket.

List of Subjects in 14 CFR Part 39

    Air transportation, Aircraft, Aviation safety, Incorporation by
reference, Safety.

Adoption of the Amendment

    Accordingly, under the authority delegated to me by the
Administrator, the FAA amends 14 CFR part 39 as follows:

PART 39--AIRWORTHINESS DIRECTIVES

0
1. The authority citation for part 39 continues to read as follows:

    Authority: 49 U.S.C. 106(g), 40113, 44701.

Sec.  39.13  [Amended]

0
2. The FAA amends Sec.  39.13 by adding the following new airworthiness
directive (AD):

2016-01-19 MD Helicopters Inc.: Amendment 39-18379; Docket No. FAA-
2015-1998; Directorate Identifier 2014-SW-035-AD.

(a) Applicability

    This AD applies to MD Helicopters Inc. (MDHI) Model 500N with a
rotating cone assembly part number (P/N) 500N3740-81 installed, and
Model 600N helicopters with a rotating cone assembly P/N 500N3740-71
installed, certificated in any category.

(b) Unsafe Condition

    This AD defines the unsafe condition as a rotating cone assembly
remaining in service beyond its fatigue life. This condition could
result in failure of the rotating cone assembly and loss of control
of the helicopter.

(c) Effective Date

    This AD becomes effective February 25, 2016.

(d) Compliance

    You are responsible for performing each action required by this
AD within the specified compliance time unless it has already been
accomplished prior to that time.

(e) Required Actions

    (1) Within 1 year or at the next annual inspection, whichever
comes later:
    (i) Create a component history card or equivalent record for
each rotating cone assembly, P/N 500N3740-81 and P/N 500N3740-71,
and record a life limit of 10,000 hours time-in-service (TIS).
    (ii) Revise the Airworthiness Limitations Section of the
applicable maintenance manual or Instructions for Continued
Airworthiness by establishing a new retirement life of 10,000 hours
TIS for each rotating cone assembly, P/N 500N3740-81 and P/N
500N3740-71, by making pen-and-ink changes or by inserting a copy of
this AD into the Airworthiness Limitations Section of the
maintenance manual or the Instructions for Continued Airworthiness.
    (iii) Remove from service any rotating cone assembly, P/N
500N3740-81 and P/N 500N3740-71, that has 10,000 or more hours TIS.
    (2) Do not install a rotating cone assembly, P/N 500N3740-81 or
P/N 500N3740-71, on any helicopter unless you have complied with the
requirements of this AD.

(f) Alternative Methods of Compliance (AMOCs)

    (1) The Manager, Los Angeles Aircraft Certification Office, FAA,
may approve AMOCs for this AD. Send your proposal to: Galib Abumeri,
Aerospace Engineer, Los Angeles Aircraft Certification Office,
Transport Airplane Directorate, FAA, 3960 Paramount Blvd., Lakewood,
California 90712, telephone<PHONE_NUMBER>; email<EMAIL_ADDRESS>    (2) For operations conducted under a 14 CFR part 119 operating
certificate or under 14 CFR part 91, subpart K, we suggest that you
notify your principal inspector, or lacking a principal inspector,
the manager of the local flight standards district office or
certificate holding district office before operating any aircraft
complying with this AD through an AMOC.

(g) Additional Information

    MD Helicopters Inc. Service Bulletin SB500N-046/SB600N-054,
dated July 9, 2012, which is not incorporated by reference, contains
additional information about the subject of this AD. For service
information identified in this AD, contact MD Helicopters, Inc.,
Attn: Customer Support Division, 4555 E. McDowell Rd., Mail Stop
M615, Mesa, AZ 85215-9734; telephone 1-800-388-3378; fax 480-346-
6813; or at http://www.mdhelicopters.com. You may review a copy of
this service information at the FAA, Office of the Regional Counsel,
Southwest Region, 10101 Hillwood Pkwy, Room 6N-321, Fort Worth, TX
76177.

(h) Subject

    Joint Aircraft Service Component (JASC) Code: 5302, Rotorcraft
Tail Boom.

    Issued in Fort Worth, Texas, on January 8, 2016.
Lance T. Gant,
Manager, Rotorcraft Directorate, Aircraft Certification Service.
[FR Doc. 2016-00945 Filed 1-20-16; 8:45 am]
 BILLING CODE 4910-13-P