Notice of Filing of Pesticide Petition for Cyflufenamid

ENVIRONMENTAL PROTECTION AGENCY

EPA-HQ-OPP-2009- 0029; FRL-(TO BE INSERTED)

Notice of Filing of a Pesticide Petition for Establishment of a
Regulation for Residues of Cyflufenamid in or on Various Commodities

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice

SUMMARY-:  This notice announces the initial filing of a pesticide
petition proposing the establishment of a regulation for residues of
cyflufenamid in or on cucurbit vegetables, pome fruit, wet apple pomace,
grapes (and other climbing vine small fruit except fuzzy kiwifruit),
raisins, and strawberries (and other low growing berries).

DATES-:  Comments must be received on or before (insert date 30 days
after date of publication in Federal Register).

ADDRESSES-:  Submit your comments, identified by docket identification
(ID) number (insert docket ID)  by one of the following methods:

Federal eRulemaking Portal:  HYPERLINK "http://www.regulations.gov"
http://www.regulations.gov . Follow the on-line instructions for
submitting comments.

	Mail: Office of Pesticide Programs (OPP) Regulatory Public Docket
(7502P), Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC  20460-0001

Delivery: OPP Regulatory Public Docket (7502P), Environmental Protection
Agency, Rm-S4400, One Potomac Yard (South Bldg.), 2777 S. Crystal Drive,
Arlington, VA.  Deliveries are only accepted during the Docket’s
normal hours of operation 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.  Special arrangements should be made for
deliveries of boxed information.  The Docket telephone number is (703)
305-5805.

Instructions: Direct your comments to docket ID number (insect docket
number here).  EPA’s policy is that all comments received will be
included in the docket without change and may be available on-line at 
HYPERLINK "http://www.regulations.gov" http://www.regulations.gov ,
including any personal information provided, unless the comment includes
information claimed to be Confidential Business Information (CBI) or
other information whose disclosure is restricted by statute.  Do not
submit information that you consider to be CBI or otherwise protected
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is an “anonymous access” system, which means EPA will not know your
identity or contact information unless you provide it in the body of
your comment.  If you send an e-mail comment directly to EPA without
going through regulations.gov, your e-mail address will be automatically
captured and included as part of the comment that is placed in the
docket and made available on the Internet.  If you submit an electronic
comment, EPA recommends that you include your name and other contact
information in the body of you comment and with any disk or CD-ROM you
submit.  If EPA cannot read your comment due to technical difficulties
and cannot contact you for clarification, EPA may not be able to
consider your comment.  Electronic files should avoid the use of special
characters, any form of encryption, and be free of any defects or
viruses.

Docket: All documents in the docket are listed in the docket index. 
Although listed in the index, some information is not publicly
available, e.g., CBI or other information whose disclosure is restricted
by statute.  Certain other material, such as copyrighted material, is
not placed on the Internet and will be publicly available only in hard
copy form.  Publicly available docket materials are available either in
the electronic docket at  HYPERLINK "http://www.regulations.gov"
http://www.regulations.gov , or if only available in hard copy, at the
OPP Regulatory Public Docket in Rm. S-4400, One Potomac Yard (South
Bldg.), 2777 S. Crystal Drive, Arlington, VA.  The hours of operation of
this Docket Facility are from 8:30 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays.  The Docket telephone number is (703)
305-5805.

FOR FURTHER INFORMATION CONTACT:

Cynthia Giles-Parker, Registration Division (7505P), Office of Pesticide
Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001; telephone number (703) 305-7740; e-mail:
giles-parker.cynthia@epa.gov.

SUPPLEMENTARY INFORMATION:

General Information

Does This Action Apply to Me?

You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer. 
Potentially affect entities may include, but are not limited to:

	Crop production (NAICS code 111).

	Animal production (NAICS code 112).

	Food manufacturing (NAICS code 311).

	Pesticide manufacturing (NAICS code32 532).

	This listing is not intended to be exhaustive, but rather provides a
guide for readers regarding entities likely to be affected by this
action.  Other types of entities not listed in this unit could also be
affected.  The North American Industrial Classification System (NAICS)
codes have been provided to assist you and other in determining whether
this action might apply to certain entities.  If you have any questions
regarding the applicability of the action to a particular entity,
consult the person listed under FOR FURTHER INFORMATION CONTACT.  

What should I Consider as I Prepare My Comments for EPA?

Submitting CBI.  Do not submit this information to EPA through
regulations.gov or e-mail.  Clearly mark the part of all of the
information that you claim to be CBI.  For CBI information in a disk or
CD ROM that you mail to EPA, mark the outside of the disk or CD ROM as
CBI and then identify electronically within the disk or DC ROM the
specific information that is claimed as CBI.  In addition to one
complete version of the comment that includes information claimed as
CBI, a copy of the comment that does not contain the information claimed
as CBI must be submitted for inclusion in the public docket. 
Information so marked will not be disclosed except in accordance with
procedures set forth in 40 CFR Part 2.	

Tips for preparing your comments.

Identify the document by docket ID number and other identifying
information subject heading, Federal Register date and page number.

Follow directions. The Agency may ask you to respond to specific
questions or organize comments by referencing a Code of Federal
Regulations (CFR) part or section number.

Explain why you agree or disagree; suggest alternatives and substitute
language for you requested changes.

Describe any assumptions and provide any technical information and/or
data that you used.

If you estimate potential costs or burdens, explain how you arrived at
your estimate in sufficient detail to allow for it to be reproduced.

Provide specific examples to illustrate you concerns and suggest
alternatives.

Explain your views as clearly as possible, avoiding the use of profanity
or personal threats.

Make sure to submit your comments by the comment period deadline
identified.  

What Action is the Agency Taking?

	

EPA is printing a summary of each pesticide petition received under
section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21
U.S.C. 346a, proposing the establishment or amendment of regulations in
40 CFR part 180 for residues of pesticide chemical cyflufenamid in or on
cucurbit vegetables, pome fruit, wet apple pomace, grapes (and other
climbing vine small fruit except fuzzy kiwifruit), raisins, and
strawberries (and other low growing berries).  EPA has determined that
this pesticide petition contains data or information regarding the
elements set forth in FFDCA section 408(d)(2); however, EPA has not
fully evaluated the sufficiency of the submitted data at this time or
whether the data support granting of the pesticide petitions. 
Additional data may be needed before EPA rules on this pesticide
petition.

Pursuant to 40 CFR 180.7(f), a summary of the petition included in this
notice prepared by the petitioner along with a description of the
analytical method available for the detection and measurement of the
pesticide chemical residues is available on EPA’s Electronic Docket at
 HYPERLINK "http://www.regulations.gov/" http://www.regulations.gov/ . 
To locate this information on the home page of EPA’s Electronic
Docket, select “Quick Search” and type the OPP docket ID number. 
Once the search has located the docket, clicking on the “Docket ID”
will bring up a list of all documents in the docket for the pesticide
including the petition summary.

Pursuant to section 408(d)(2) of the FFDCA, as amended by the Food
Quality Protection Act (FQPA), Nippon Soda Co., Ltd. has submitted the
following summary of information, data and rationales in support of this
pesticide petition and authorization for the summary to be published in
the Federal Register in a notice of receipt of the petition.

Residue Chemistry-

1.  Plant Metabolism-  The metabolism of cyflufenamid in plants is well
understood having been investigated in apples, cucumbers, and wheat. 
The metabolic pathway was similar in all crops tested.  The major
residue in each case was cyflufenamid itself.

The plant metabolism of cyflufenamid proceeds via hydoxylation at either
the N’ position, removing the cyclopropylmethyloxy moiety, or the
4-position of the phenylacetyl moiety followed by conjugation with
glucose.  

2. Analytical Method-  Based upon the metabolism of cyflufenamid in
plants (i.e., parent cyflufenamid as the major residue) and the
toxicology of the parent compound, quantification of the parent
cyflufenamid is sufficient to determine toxic residues.  As a result, a
method was developed using solvent extraction of cyflufenamid from crops
and analyzing sample extracts by LC/MS/MS.  The limit of quantification
(LOQ) for the method was calculated to be 0.01 ppm.

3.  Magnitude of Residues-  Magnitude of residue studies were conducted
in representative crops in the cucurbit, pome fruit, grape (and other
small climbing vine fruit (except fuzzy kiwifruit)), and strawberry (and
other low growing berries) crop groups.  Trials were conducted in all of
the major use areas for the crops as specified in the Residue Chemistry
Guidelines OPPTS 860.1500 with applications at 2x greater than the
proposed label maximum seasonal use rate for each crop.  Residues of
cyflufenamid in grape and apple processed commodities were also
determined.

4.  New Tolerances

PP (insert petition number here).  Nippon Soda Co., Ltd., Shin-Ohtemachi
Bldg., 2-1,2-Chome Ohtemachi, Chiyoda-ku, Tokyo, 100-8165, Japan,
proposes to establish tolerances for residues of the insecticide
cyflufenamid in or on the following raw agricultural commodities:
cucurbit crop group – 0.05 ppm, pome fruit crop group – 0.05 ppm,
apple wet pomace – 0.1 ppm, grape (and other small climbing vine fruit
(except fuzzy kiwifruit)) crop group – 0.015 ppm, raisin – 0.3 ppm,
and strawberry (and other low growing berries) crop group – 0.2 ppm.

Toxicological Profile-

1.  Acute Toxicity for Technical Cyflufenamid -  Cyflufenamid is of low
acute toxicity irrespective of the route of exposure (oral LD50: >5000
mg/kg; dermal LD50: >2000 mg/kg; inhalation LC50: >4.76 mg/l.  It was
not irritant to rabbit skin but caused transient ocular irritancy
(conjunctival irritancy in all animals and opacity and iridial
inflammation in one rabbit) and all reactions had resolved by Day 7.
Cyflufenamid showed no potential to cause skin sensitisation.

Acute Toxicity for Formulated Cyflufenamid 10 SC Fungicide - The acute
oral and acute dermal LD50 of the 10% w/w suspension concentrate (10 SC)
formulation of cyflufenamid is >2000 mg/kg in the rat.  The acute
inhalation LC50 of the 10SC was determined to be >2.64 mg/liter in the
rat following a 4-hour nose-only exposure period.  The formulation was
considered to be minimally irritating to the eye with conjuntiva
clearing within 3 days following application.  No dermal reaction was
noted throughout the duration of a dermal irritation study and the 10 SC
formulation is considered a non-sensitizer.

2.  Genetic Toxicity for Technical Cyflufenamid – Cyflufenamid was
evaluated in a battery of tests including gene mutation in bacteria and
mammalian cells, chromosome damage in vitro and in vivo and DNA damage
in mammalian cells in vivo/in vitro.  No evidence of genotoxic activity
was observed.

3.  Reproductive and Developmental Toxicity -  A two-generation
reproduction study in rats and oral developmental toxicity studies in
rats and rabbits were conducted with cyflufenamid.

No effect on rat reproductive performance and capacity was seen at any
dose level.  The NOAEL for general toxicity was 250 ppm (corresponding
to achieved intakes of 18 to 23 mg/kg/day in males and 20 to 41
mg/kg/day in females).  However, the NOAEL for effects on reproduction
was 800 ppm (corresponding to 57 to 75 mg/kg/day in males and to 66 to
125 mg/kg/day in females).

There was no evidence of an increase in malformations (teratogenicity)
in either the rat or rabbit developmental toxicity studies, even at
maternally toxic dose levels.

In rabbits, marked maternal toxicity (abortion, non-specific clinical
signs and reduced body weight gain and food intake) was induced at the
highest dose level, 300 mg/kg/day and a NOEL/NOAEL was not identified in
the study.  However, a second study assessing maternal and litter data
but not including skeletal and visceral evaluations, confirmed that 10
mg/kg/day was the overall maternal NOAEL.  The developmental NOAEL/NOEL
was 10 mg/kg/day.

In rats, there was no effect on embryofetal development at any dose
level.  Pregnant rats were less sensitive to cyflufenamid since the only
evidence of maternal toxicity at the intermediate and high dose levels
(300 and 1000 mg/kg/day) was brown staining of the fur.  A dose-related
increase in liver weight was considered adaptive.  The maternal NOAEL
was 100 mg/kg/day and the developmental NOEL was 1000 mg/kg/day.

4.  Subchronic Toxicity - The general toxicity of cyflufenamid was
evaluated in 4-week and 13-week studies in rats, mice and dogs.  A
52-week study was also conducted in the dog.  In addition, in dogs, the
opportunity for reversibility of treatment-related findings was provided
in two further 13-week studies that incorporated a 13-week and a 26-week
off-dose recovery phase at the end of the treatment period.  The overall
NOAEL for the rodent and dog 13-week and dog 52-week studies was 6.5
mg/kg/day (150 ppm) based on slight liver changes in the dog 13-week
study.

Dermal treatment of rats for 28 days showed that cyflufenamid was well
tolerated with no systemic toxicity at a limit dose of 1000 mg/kg/day.

 

5.  Chronic Toxicity - Long-term studies comprised a rat combined
chronic toxicity and carcinogenicity study and a carcinogenicity study
in mice.  Achieved intakes in the chronic toxicity phase at the highest
dose levels were 277 mg/kg/day in male rats at 5000 ppm and 133
mg/kg/day in females at 2000 ppm in the chronic toxicity phase and 229
and 115 mg/kg/day, respectively in the carcinogenicity phase.  In the
mouse carcinogenicity study achieved intakes were 325 mg/kg/day in males
and 404 mg/kg/day in females at the 4000/2000 ppm high dose level.  The
NOAEL in the rat long-term study was 100 ppm (corresponding to 5.2
mg/kg/day in males and 6.7 mg/kg/day in females in the chronic toxicity
phase and to 4.4 mg/kg/day and 5.5 mg/kg/day, respectively, in the
carcinogenicity phase).  In the mouse carcinogenicity study, the NOAEL
was 500 ppm (63 mg/kg/day in males and 76 mg/kg/day in females).

6.  Animal metabolism-  Cyflufenamid, as the [fluorinated
phenyl-14C]-labelled compound, was well absorbed in rats after oral
administration with 70-85% being absorbed after a dose of 10 mg/kg and
41-51% after 200 mg/kg.  The compound was rapidly excreted with >95% of
the dose detected in the urine and faeces within 72 hours.  No
substantial differences in the pattern of excretion were observed after
either a single or 14 consecutive daily oral doses of 10 mg/kg. 
Cyflufenamid was extensively metabolised in rats to 18 urinary and 17
faecal components.  The metabolism of cyflufenamid is well understood
and three metabolic routes were identified.  

7.  Metabolite Toxicology - The acute oral toxicity in rats and
bacterial reverse mutation of the structural isomer of cyflufenamid
(149-(E)-FB), four identified metabolites (149-F, 149-F1, 149-F6 and
149-F11) were assessed.  149-F was of low acute oral toxicity in rats. 
Although LD50 values of more than 1000 mg/kg were recorded both sexes
after 149-F11, those for all other metabolites/potential metabolites and
for males dosed with 149-F11 ranged between 270 and 872 mg/kg.

None of the principal metabolites cyflufenamid (149-F, 149-F1, 149-F6,
149-F11 and 149-(E)-FB) showed any evidence of mutagenic potential in
the four strains of Salmonella typhimurium or the single strain of
Escherichia coli in the two independent Ames plate tests incorporating a
pre-incubation phase.

8.  Endocrine disruption - There is no evidence that cyflufenamid has
any estrogenic activity nor direct effect on male hormonal activity.

C. Aggregate Exposure

1. Dietary - For chronic dietary exposures, the proposed reference dose
is 0.04 mg/kg/day.  Chronic dietary exposures are quite low, ranging
from 0.000191 mg/kg/day for youth aged 13-19 years to 0.001196 mg/kg/day
for children aged 1-2 years.  The chronic dietary exposure for the U.S.
population is 0.000307 mg/kg/day.  Chronic dietary exposures correspond
to 3.0% of the chronic reference dose or less for all population
subgroups.

For acute dietary exposures, the proposed reference dose is 0.1
mg/kg/day.  At the 95th percentile (the appropriate level for a Tier 1
acute assessment), dietary exposures are quite low, ranging from
0.000663 mg/kg/day for youth aged 13-19 years to 0.003819 mg/kg/day for
children aged 1-2 years.  The acute dietary exposure for the U.S.
population is 0.001043 mg/kg/day.  Acute dietary exposures correspond to
3.8% of the acute reference dose or less for all population subgroups.

2.  Food - Dietary exposures associated with the proposed used of
cyflufenamid on pome fruit, grapes, strawberries and cucurbits were
conservatively estimated assuming tolerance-level residues and 100% crop
treated for all crops.  Field trial data were used in the MRL calculator
to estimate tolerances for raw agricultural commodities:  pome fruit
(0.05 ppm), cucurbits (0.05 ppm), strawberry (0.20 ppm) and grapes (0.15
ppm).  Residues do not concentrate in pome fruit juice or grape juice,
so separate tolerances are not required.  In wet apple pomace,
processing data indicate a processing factor (PF) of 2.88, and when the
residue in the highest average field trial (HAFT) of 0.026 ppm is
multiplied by the PF, an estimated residue of 0.075 ppm results, which
was subsequently rounded up to 0.1 ppm to set a conservative tolerance. 
Similarly, in raisins, processing data indicate a processing factor of
3.6, and when the HAFT residue (0.07495 ppm) is multiplied by the PF,
and estimated residue of 0.27 ppm results, which was subsequently
rounded up to 0.3 ppm to set a conservative tolerance.

Secondary residues in meat and milk are not anticipated.  According to
new guidance on calculating maximum reasonable balanced diets for
livestock, apple pomace is fed to dairy cattle from fall to spring only
in apple producing areas and will constitute no more than 10% of the
diet.  Therefore, with a proposed tolerance of 0.1 ppm for wet apple
pomace, it is unlikely that significant residues in cattle and dairy
products will result.  Apple pomace is not fed to poultry or swine. 
Therefore, no secondary tolerances are proposed for cyflufenamid.  

3.  Drinking Water - Screening-level estimates of drinking water
concentrations were generated using FIRST and SCI-GROW models and the
maximum estimates were included directly in the dietary exposure
assessment.  Based on the modeling, the worst-case residue estimate is
5.9 ppb (total residue) in ground water based on the maximum application
rate on pome fruit, strawberries and grapes.  To provide a conservative
estimate of dietary (food + water) exposures, cyflufenamid residues in
water are assumed to be 5.9 ppb in both the acute and chronic
assessments.

 4.  Non-dietary exposure - Cyflufenamid will be applied only by
professionals.  Therefore, residents will not be exposed while applying
products containing cyflufenamid.  However, as there are proposed uses
for outdoor landscape ornamentals, residential post-application
exposures may result when residents contact residues on treated plants. 
Residential post-application exposures are anticipated to be of
short-term (1 to 30 days) and intermediate-term (1 to 6 months)
duration.

Cyflufenamid is proposed for use on outdoor landscape ornamentals and
may therefore be used in residential areas and other areas where
residents may be exposed.  Therefore, potential post-application
exposures may be experienced by children and adult residents who come
into contact with treated landscape ornamentals.  Residential
post-application exposure scenarios for ornamentals in the Residential
SOPs apply only to trees, and the scenarios include dermal exposures for
adults and youths (aged 10-12 years).  There is no SOP for children
exposed to residues on ornamentals, so this scenario is not addressed. 
Exposures and risks for residential post-application scenarios were
conservatively estimated using the maximum application rate of 25 g
ai/ha (0.022 lb ai/A).  Using the proposed dermal NOAEL of 1000
mg/kg/day for short- and intermediate-term exposures, MOEs for
post-application exposures by residents are estimated to range from
211,000 to 474,000, which is much greater than 100, and therefore
residential are therefore not of concern.

 D.  Cumulative Effects - Since cyflufenamid is a compound that belongs
to a new class of chemistry with a new fungicidal mode of action it has
not been determined if a common mechanism of toxicity exists with
current chemical substances.  Therefore a cumulative risk assessment was
not performed for this submission.

E.  Safety Determination 

1.  U.S. Population – For chronic dietary exposures, the proposed
reference dose is 0.04 mg/kg/day.  The chronic dietary exposure for the
U.S. population is 0.000307 mg/kg/day.  Chronic dietary exposures
correspond to 3.0% of the chronic reference dose or less for all
population subgroups including infants and children.  For acute dietary
exposures, the proposed reference dose is 0.1 mg/kg/day.  At the 95th
percentile (the appropriate level for a Tier 1 acute assessment),
dietary exposures are quite low, ranging from 0.000663 mg/kg/day for
youth aged 13-19 years to 0.003819 mg/kg/day for children aged 1-2
years.  The acute dietary exposure for the U.S. population is 0.001043
mg/kg/day.  Acute dietary exposures correspond to 3.8% of the acute
reference dose or less for all population subgroups including infants
and children. 

In an aggregate risk assessment, all sources of potential exposure are
combined.  As residents will not apply cyflufenamid, residential handler
exposures are not included.  Potential exposure sources include
post-application and dietary (i.e., food and drinking water) exposures
for cyflufenamid.  Adult and youth residents may be exposed to residues
on treated ornamentals following application.  Cyflufenamid is currently
proposed for crop use on pome fruit, grapes, strawberries and cucurbits.
 Dietary exposures were conservatively estimated assuming
tolerance-level residues on all crops, 100% crop treated for all crops
and conservatively estimated residue concentrations in drinking water. 
In short- and intermediate-term aggregate assessments, the chronic
dietary exposure is included as an estimate of the background exposure
experienced by the population.  Using conservative assumptions and based
on the completeness and reliability of the data, adult short-term
aggregate (food, drinking water, and residential exposure) total MOEs
are 18,700 and adult intermediate-term aggregate total MOEs are 13,400. 
Thus, the aggregate MOEs for adults are demonstrated to be significantly
greater than 100, indicating a reasonable certainty of no harm to the
adult US population associated with the proposed uses of cyflufenamid.

2.  Infants and Children-.  In a multi-generation reproduction study
with rats, no adverse effects on reproduction were observed in either
rats or rabbits.  In a rat teratology study, fetus survival, growth, and
development were unaffected at all doses tested.  Likewise, in a rabbit
developmental study, cyflufenamid was not considered teratogenic.  There
is also no indication of developmental neurotoxicity.  Therefore the
FQPA safety factor may be reduced to 1X.

For chronic dietary exposures, the proposed reference dose is 0.04
mg/kg/day.  Chronic dietary exposures are quite low, ranging from
0.000191 mg/kg/day for youth aged 13-19 years to 0.001196 mg/kg/day for
children aged 1-2 years.  Chronic dietary exposures correspond to 3.0%
of the chronic reference dose or less for all population subgroups
including infants and children.  For acute dietary exposures, the
proposed reference dose is 0.1 mg/kg/day.  At the 95th percentile (the
appropriate level for a Tier 1 acute assessment), dietary exposures are
quite low, ranging from 0.000663 mg/kg/day for youth aged 13-19 years to
0.003819 mg/kg/day for children aged 1-2 years.  Acute dietary exposures
correspond to 3.8% of the acute reference dose or less for all
population subgroups including infants and children.  

Among the child subpopulations included in the dietary assessment, the
subpopulation of children aged 1-2 years was determined to be the most
highly exposed, so this subpopulation was selected for the aggregate
exposure.  However, unlike adults and youths, the only source of
exposure for children aged 1-2 years is dietary (food + water). 
Short-term aggregate total MOEs are 5,270 for children and 15,900 for
youths while intermediate-term aggregate total MOEs are 3,680 for
children and 11,200 for youths.  Thus, the aggregate MOEs for infants
and children are demonstrated to be significantly greater than 100,
indicating a reasonable certainty of no harm to infants, children, and
any other population subgroup associated with the proposed uses of
cyflufenamid.  

F.  International Tolerances- Cyflufenamid is registered for use on food
crops in Japan, Europe, and other locations throughout the world.

Section G – 10

International Tolerances

Cyflufenamid is registered for use on food crops in Japan, Europe, and
other locations throughout the world.

Section G- 11

Conclusion

Establishment of cyflufenamid tolerances for the cucurbit, pome fruit,
grape (and other climbing vine small fruit), and strawberry (and other
low growing berries) crop groups will result in the use of a new
mode-of-action fungicide for the control of powdery mildew that has been
extensively evaluated and passes criteria established by the Food
Quality Protection Act. 

