UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES

MEMORANDUM							DATE:  	12/05/2006

SUBJECT: N6-Benzyladenine: Review of Information for an Exemption from
the Requirement of a Tolerance

Pesticide Petition #: 6F7035, PC code: 116901

Decision # 364874, 364878, DP # 329586, 329587 Reg # 73049-59, 73049-407

MRIDs: 46388302, 45551004, 45551005, 45551006, 45551007, 45551008,
45551009

FROM:	Kent R. Carlson, Ph.D., Biologist   /s/  12/05/06

Biochemical Pesticides Branch

Biopesticide and Pollution Prevention Division (7511P)

THRU:	Roger Gardner, Senior Scientist   /s/  12/05/06

Biochemical Pesticides Branch

Biopesticide and Pollution Prevention Division (7511P)

TO:		Denise Greenway, Regulatory Action Leader

Biochemical Pesticides Branch

Biopesticide and Pollution Prevention Division (7511P)

ACTION REQUESTED:

	Valent Biosciences Corporation has submitted a petition for exemption
from the requirements of a tolerance for the use of the plant regulator
N6-Benzyladenine in/on pears. The food commodity affected by the
proposed use is fresh and processed pears. Supporting documents have
been provided by the registrant and EPA. Application of N6-Benzyladenine
to pear king fruitlets 5-15mm in diameter is intended to reduce the
number of immature fruit on orchard trees (a thinning agent).

EXECUTIVE SUMMARY:

	Data provided by Valent Biosciences Corporation for N6-Benzyladenine
support the exemption from a requirement of a tolerance for use in/on
pears, provided application rates and preharvest interval (PHI) are
identical to that currently in apples (≤ 182 grams of active
ingredient per acre per season, PHI of 86 days).

PRODUCT NAME and PROPOSED USE:

	The end-use product, MaxCel®, contains the active ingredient
N6-Benzyladenine (1.9%) and other inert ingredients (89.1%).
MaxCel®’s proposed use is as a thinning agent in pear orchards
(identical to that in apples at ≤ 182 grams of active ingredient per
acre per season). The proposed use for pears also requires a preharvest
interval of 86 days.

	MaxCel® is a liquid formulation that is diluted to 75-200 ppm prior to
use and then sprayed (via airblast, groundboom, or handwand) on pear
trees when the average diameter of king fruitlets are between 5 and 15
mm. When applying, eighty percent of the spray is to be directed into
the upper two-thirds of the orchard canopy. One application in this
manner is expected to sufficiently reduce the amount of small, immature
fruit in the orchard. A second application can be used for additional
thinning and should be applied before the average king fruitlet diameter
exceeds 20 mm diameter. In either case, application amounts should not
exceed a total of 182 grams of N6-Benzyladenine per acre of pear trees
per season.

A. PRODUCT CHEMISTRY and MANUFACTURING PROCESS:

	N6-Benzyladenine (N-(phenylmethyl)-1H-purine-6-amine; CAS number
1214-39-7; C12H11N5) is a white powder that has a molecular weight of
225.25, a melting point of 230(C, an octanol-water partition coefficient
of 1.57, a bulk density of 0.42 g/ml, a vapor pressure of 1.79E-11, a
Henry’s Law Constant of 8.84E-14, and an Atmospheric OH rate constant
of 2.14E-10. It also is slightly soluble in water (60 mg/L at 20(C, 76
mg/l at 25-26(C), but more soluble in chloroform (288 mg/L) and
isopropanol (3960 mg/L).

	Information on the manufacturing process for N6-Benzyladenine was not
summarized in the EPA RED (1994), but has been reported in MRIDs
41895201, 42360301, and 42360302.

B. PRODUCT IDENTITY/CHEMISTRY:

1) Nature of the Pesticide and Residue Identity:

N6-Benzyladenine is a synthetic plant growth regulator in the general
classification of cytokinins. It works similarly to cytokinin B, a
natural plant growth hormone. N6-Benzyladenine actively increases
ethylene biosynthesis in fruitlets and stems, possibly by enhancing
concentrations of 1-aminocyclopropane-1-carboxylate (ACC) synthase. The
increase in ethylene stimulates stem abscission and drop in immature
fruit. N6-Benzyladenine also has a variety of other actions such as
enhancing fruit color, encouraging plant shoot and calyx growth, and
enhancing fruit size. These effects are dependent on the fruit variety
and timing of application.

9-β-D-glucopyranosyl-benzyladenine, 9-β-D-ribofuranosyl-benzyladenine,
7-β-D-glucopyranosyl-benzyladenine, 3-β-glucopyranosyl-benzyladenine,
and 9- β-D-(ribosylglucoside)-benzyladenine (Blakesley, 1991; Blakesley
and Constantine, 1992; Centeno et al., 2003). The amount and timing of
these metabolites differs substantially among plant species.

2) Magnitude of the Residue:

		Apple and pistachio residue data derived from magnitude of the residue
studies were used to estimate chronic dietary exposure (MRIDs 45551004,
45551005, 45551006, 45551007, 45551008, 45551009; reviewed by R.S.
Jones; 10/02/02; DP Barcode# D281806 and D281813).

		Three pistachio field trials were performed in CA in 2000. Two
treatments at 30 g ai/A were applied at 90 and 60 days, respectively,
before harvest (1X). Double the treatment concentration (60 g ai/A) was
also utilized on the same treatment schedule (2X). Residues in pistachio
nut meat ranged from undetectable to 1.5 μg/kg sixty days following the
last treatment. Residues in pistachios in between the limit of detection
(LOD) and limit of quantitation (LOQ; at ½ LOQ for each) were averaged
with residues less than the LOD (at ½ LOD for each). This method
yielded a final anticipated residue concentration for pistachios of 5.41
μg/kg.

		Six apple field trials were conducted in NY, PA, VA, MI, OR, and WA in
2000. Field trials were comprised of 4 applications (15, 15, 80, 80 g
ai/A; 1.04X) at 6-9 day intervals with the final application occurring
71-86 days prior to harvest. Double concentration applications (30, 30,
160, and 160 g ai/A; 2.04X) were also used at the same schedule. A
residue decline study was also performed on the WA site, with a one-time
160 g ai/A application with sampling at time 0, 1, 2, 3, 5, and 10 days
before harvest. Samples for processing into wet pomace and juice were
also taken at the 2.04X site in WA. Residues declined from 135-159
µg/kg (time 0) to 101-112 µg/kg (day 10) in the residue decline study.
Residues in the studies ranged from 0.7-7.0 µg/kg (1X), 1.7-12.3 µg/kg
(2X), and 0.1 and 3.3 µg/kg (wet apple pomace and juice). Residues in
apples at or above the LOQ were modified by using the average
fortification recovery (97%), and then averaged with residues in between
the LOD and LOQ (at ½ the LOQ for each). This method yielded a final
residue concentration for apples of 3.43 μg/kg. One-half the LOD, or
0.1 μg/kg, was used as the residue concentration for apple juice, since
no residues were detected in this processed commodity.

3) Analytical Method:

	The submitted method for detecting N6-Benzyladenine residues in apples
(MRID 45551006; and pears) involved extraction and then gas
chromatography with a nitrogen phosphorous detector. Method validation
included untreated matrices, fortified controls (5, 50, or 500 mg/kg),
and a N6-Benzyladenine calibration curve (0.125-0.50 mg/kg). The LOQ and
LOD for apples (and pears) were 0.005 and 0.0002 mg/kg, respectively.

	The submitted method for detecting N6-Benzyladenine residues in
pistachio (MRID 45551007) involved extraction and then gas
chromatography with a nitrogen phosphorous detector. Method validation
included untreated matrices, fortified controls (0.05, 0.5, or 5.0
mg/kg), and a N6-Benzyladenine calibration curve (0.025-0.50 mg/kg). The
LOQ and LOD for pistachios were 0.05 and 0.003 mg/kg, respectively.

	4) Storage Stability:

	Storage stability in freshly fortified pistachios and pistachios stored
at -20(C was determined at 48 and 96 days. At 48 days, freshly fortified
samples had 95% recovery, while the frozen fortified samples had
recoveries ranging between 87-90%. At 96 days, freshly fortified sample
recovery ranged between 90-98%, while the frozen fortified samples had
recoveries ranging between 88-93%. Data suggested that no significant
degradation in N6-Benzyladenine residues occurred over 96 days in
storage at -20(C.

C. MAMMALIAN TOXICOLOGY DATABASE:

1) Acute, Genotoxicity/Mutagenicity, Developmental Toxicity, Subchronic
Toxicity, Immunotoxicity:

	Acute toxicity, subchronic oral toxicity, developmental toxicity, and
genotoxicity of N6-Benzyladenine have been discussed in detail in the
EPA Reregistration Eligibility Decision (RED; 1994). A summary of this
information can be seen in Table 1 below.

Table 1. Toxicity Data Base for N6-Benzyladenine from the 1994 RED

Study	Species	Results	Category

Acute Oral Toxicity	Rat	LD50 = 1.3 g/kg	III

Acute Dermal Toxicity	Rabbit	LD50 > 5g/kg	IV

Acute Inhalation Toxicity	Rat	LC50 = 5.2 mg/L	IV

Eye Irritation	Rabbit	Moderate Irritant	III

Dermal Irritation	Rabbit	Slight Irritant	IV

Dermal Sensitization	Guinea pig	Not a Sensitizer	N/A

Subchronic Oral Toxicity	Rat	LOAEL = 304 mg/kg-day (M&F) based on
decreaed body weight gain, food consumption, increased clinical
chemistry and histopathological changes in the kidneys:

NOAEL = 111 mg/kg-day (M&F)	N/A

Developmental Toxicity	Rat	LOAEL = 175 mg/kg-day (maternal and
developmental) based on decreased body weight, increased hydrocephalus
and unossified sternebrae, and incompletely ossified phalanges, and
malaligned sternebrae (fetus); and decreased body weight, weight gain,
and food consumption (maternal):

NOAEL = 50 mg/kg-day (maternal and developmental).	N/A

Mutagenicity - Ames	Salmonella	Not Mutagenic	N/A

Mutagenicity - Micronucleus	Mouse	Not Mutagenic	N/A

Unscheduled DNA Synthesis	Rat Hepatocytes	Not Mutagenic	N/A

Immune Response	N/A	waived	N/A

2) 2 Generation Rat Reproductive Toxicity:

		A two generation rat reproductive toxicity study was submitted
subsequent to the 1994 RED and has not been reviewed previously. In this
study (MRID 46388302), ABG-3191 (6-benzyladenine technical) (99.6%,
a.i., batch/lot 65-375-H8) was administered in feed to groups of 28 male
and 29 female F0 rats and 24 male and 24 female F1 rats at dietary
concentrations of 0, 400, 750, or 1500 ppm.

		No treatment related deaths or clinical signs occurred in parental
animals of either generation. Although absolute body weight was within
10% of that of controls for mid and high-dose F0 males, the magnitude of
the decrease in weight gain was considered to be toxicologically
significant. Mean body weight of high-dose F1 males was significantly
decreased during the early phase of  premating, possibly due to the
decrease in pup body weight at weaning. A second decrease in body weight
in mid and high-dose F1 males occurred primarily during the postmating
period. There was a marginal decrease in weight gain associated with the
decreased body weight of mid high-dose F1 males, suggesting that the
decrease in body weight was toxicologically significant. Food
consumption was not significantly reduced in high-dose males except
during 2 weekly intervals in the F0 generation and the first 4 weeks and
week 13 of premating in the F1 generation; therefore, food consumption
appeared to have no significant impact on weight gain.

		High-dose F0 females gained significantly less weight than controls
resulting in a significantly decrease in mean body weight. Decreased
weight and weight gain was at least partly dependent on the
significantly reduced food consumption seen in high-dose F0 females.
Body weight of high-dose F1 females was significantly reduced throughout
premating, but weight gain was not significantly decreased, suggesting
that the decreased body weight was not toxicologically significant. As
with F0 females, reduced food consumption probably contributed to these
weight changes. The decrease in mean body weight in low-dose F0 females
during premating was not considered treatment-related because a
dose-dependent effect was not observed in the mid-dose group. Overall,
the data showed no treatment-related effects on body weight or weight
gain in low- or mid-dose females or low-dose males of either generation.

		Mean body weight, weight gain, and food consumption were not
significantly affected in F0 or F1 females during gestation or
lactation.

		Statistically significant changes in absolute and covariance-adjusted
(to body weight) organ weight (especially the liver) were observed in
female rats in both generations. Histopathologic changes were also
evident in the livers of high dose F0 and F1 female rats. Although not
thought to be pathologically significant, these pathologies included
clear cell foci, bile duct hyperplasia, and glycogen vacoulation. The
thyroid gland in high-dose F0 males was the only organ that showed a
statistically significant change in absolute weight in males, but no
treatment-related microscopic thyroid lesions were observed in males. No
treatment-related gross lesions were observed in any organ in male or
female rats in either generation.

		The lowest-observed-adverse-effect level (LOAEL) for parental systemic
toxicity of ABG-3191 (6-benzyladenine technical) is 750 ppm (58.6-70.4
mg/kg bw-day) and is based on reduced body weight and weight gain in F0
and F1 male rats.  The no-observed-adverse-effect level (NOAEL) is 400
ppm (31.5-37.5 mg/kg bw-day). This systemic adult endpoint was used in
the dietary risk assessment presented in an additional report (Carlson
to Greenway memo, 11/21/06). Although the pathological endpoint is
similar to that used in previous occupational risk assessments, the
previous numerical endpoint (40 mg/kg-day) has been modified to more
precisely account for the dietary composition of N6-Benzyladenine,
respective rat weights, and food consumption estimates.

		No treatment-related effects was observed on reproductive performance
as evidenced by changes in fertility and gestation indices, estrous
cycle length and periodicity, coital interval, gestation length, sperm
measures (sperm and spermatid count, sperm motility, progressive sperm
motility, sperm velocity, and morphological abnormalities), or
pathological lesions in reproductive organs.

		The LOAEL for reproductive toxicity of ABG-3191 (6-benzyladenine
technical) in rats could not be determined. The NOAEL, therefore, is
>1500 ppm (115.7-144.2 mg/kg bw-day for males and 133.0-139.2 mg/kg
bw-day for females).

		No treatment-related effect was observed on viability or survival
indices (birth, live birth, viability, lactation) or the overall
survival of pups in either generation during lactation. No
treatment-related clinical signs or abnormalities were reported. Mean
litter weights were substantially reduced in high dose groups. Body
weight and weight gain of mid- and high-dose F1 and F2 pups were
substantially reduced during lactation. Birth weight was not adversely
affected in male or female pups in either generation. In F1 male and
female pups, mean body weight was decreased in the high-dose group
starting at 7 days of age and in the mid-dose group starting at 4 days
of age. In F2 male and female pups, mean body weight was decreased
starting at 4 days of age in mid- and high-dose males and high-dose
females and at 7 days of age in mid-dose females. Weight gain was
decreased in mid- and high-dose male and female pups starting with the
PND 4-7 interval for the F1 generation and PND 1-4 interval for the F2
generation. Reduced pup weight gain in both generations when consuming
milk only and afterward suggests that both a lactational and systemic
effect occurs in pups.

		Sexual maturation was delayed in high-dose F1 male and female pups;
the delay appeared to be related to delayed growth in pre-pubertal
animals. Organ weight measurements in weanlings showed that spleen
weight in high-dose F1 male, spleen and thymus weight in high-dose F2
males, and brain, spleen, and thymus in mid- and high-dose F2 females
were significantly decreased compared with those of controls. The spleen
weight in low-dose F2 female offspring also was significantly decreased.
Decreased organ weight in weanlings was likely due to decreased body
weight. However, the organs were not examined microscopically to
determine if the decreased weights were accompanied by histopathological
lesions.

		The lowest-observed-adverse-effect level (LOAEL) for offspring
toxicity of ABG-3191 (6-benzyladenine technical) in rats is 750 ppm
(66.7-68.1 mg/kg bw-day) and is based on decreased body weight and
weight gain in F1 and F2 male and female pups. The
no-observed-adverse-effect level (NOAEL) is 400 ppm (35.8-36.0 mg/kg
bw-day).

		Uncertainty factors for inter- and intra-species variation (10X each)
and subchronic to chronic extrapolation (3X) were used to modify the
toxicity NOAEL. The FQPA factor was reduced from 10X to 3X because of
adequate data from: 1) a 2-generation rat reproduction study [MRID
4638802] and 2) a rat developmental toxicity study [MRID 41623703]. A
summary of toxicological findings relevant to this dietary assessment
can be seen in Table 3.

Table 3.  Summary of Toxicological Doses and Endpoints for
N6-Benzyladenine for Use in Dietary Exposure Assessment

Exposure

Scenario	Dose Used in Risk

Assessment, UF	Hazard and Exposure Based FQPA Safety Factor	Study and
Toxicological Effects

Chronic Dietary

all populations	NOAEL= 34.5 mg/kg bw-day    (31.5-37.5 mg/kg bw-day)

UF = 300                                      (10X interspecies, 10X
intraspecies, 3X subchronic to chronic)

Chronic RfD = 0.109 mg/kg bw-day

	FQPA SF = 3X

cPAD =0.0345 mg/kg bw-day	Rat 2 Generation Reproductive Toxicity; LOAEL
= 58.6-70.4 mg/kg bw-day; based on decreased body weight and weight gain
in F0 and F1 male rats.

D. AGGREGATE EXPOSURE:

1) Dietary Exposure:

dity Intake Database (DEEM-FCID™, Version 2.03), which incorporates
consumption data from USDA’s Continuing Surveys of Food Intakes by
Individuals (CSFII), 1994-1996 and 1998.  The 1994-96, 98 data are based
on the reported consumption of more than 20,000 individuals over two
non-consecutive survey days.  Foods “as consumed” (e.g., apple pie)
are linked to EPA-defined food commodities (e.g. apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA. For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events. Based on analysis of the 1994-96, 98
CSFII consumption data, which took into account dietary patterns and
survey respondents, HED concluded that it is most appropriate to report
risk for the following population subgroups: the general U.S.
population, all infants (<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

	For chronic dietary exposure assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form. The resulting residue
consumption estimate for each food/food form is summed with the residue
consumption estimates for all other food/food forms on the commodity
residue list to arrive at the total average estimated exposure.
Exposure is expressed in mg/kg body weight/day and as a percent of the
cPAD. This procedure is performed for each population subgroup.

Food:

N6-Benzyladenine residues that may be present in pistachios, apples,
apple juice, and pears after the required preharvest interval are
expected to contribute minimally to dietary exposure (Table 4).

Dietary Exposure Results and Characterization

Table 4.  Summary of Chronic Dietary Exposure and Risk for
N6-Benzyladenine

Population Subgroup	Dietary Exposure

(mg/kg/day)	% cPAD

General U.S. Population	0.000002	<1%

All Infants (< 1 year old)	0.000011	<1%

Children 1-2 years old	0.00008	<1%

Children 3-5 years old	0.00007	<1%

Children 6-12 years old	0.00004	<1%

Youth 13-19 years old	0.00001	<1%

Adults 20-49 years old	0.00001	<1%

Adults 50+ years old	0.00001	<1%

Females 13-49 years old	0.00001	<1%

		Chronic exposure and risk estimates for all populations did not exceed
100% of the cPAD. The risks to these populations from chronic exposure
to residues of N6-Benzyladenine found at 86 days (apples, apple juice,
pears) and 60 days (pistachios) following application, were therefore
below BPPD’s level of concern.

These estimates of dietary residue exposure were conservative since they
assumed that 100% of all pear crops were treated, that non-detected or
<LOQ residue concentrations were present, and that chronic exposure
could occur to N6-Benzyladenine which is only used a few times at most a
year, 60-86 days before harvest.

Drinking Water:

		N6-Benzyladenine residues that may be present in water are not
expected to contribute significantly to overall dietary exposure.
Dietary exposure to N6-Benzyladenine-contaminated water is not expected
because soil leaching studies show that free N6-Benzyladenine will
strongly adsorb to sediment particles (Federal Register, 2004). Residues
are therefore expected to be removed quickly from the water column. Soil
metabolism studies also show that bound N6-Benzyladenine residues have a
relatively short half-life (7 weeks in loamy sand and 9 weeks in clay),
further decreasing the ability of bound residues to repartition back
into the water column.

2) Non-dietary Exposure:

Occupational exposure and risk from application of N6-Benzyladenine to
apples has been previously assessed (MRID 46388301). Occupational
exposure and risk from application of MaxCel® to apples and pears was
determined using default values extracted from the Pesticide Handlers
Exposure Database (PHED, 1997). Assessments were made for mixer/loader,
applicator, mixer/loader/applicator, and post-application activities
with workers dressed in shoes with socks, long-sleeved shirts, and long
pant, personal protective equipment (PPE). Subchronic toxicological
endpoints from a 2-generation rat reproduction study were used in the
assessment. Overall, the risk to applicators from exposure to
6-benzyladenine was below BPPD’s threshold of concern (Margin of
Exposure=100; MOE). Risks to mixers and loaders were also below BPPD’s
threshold of concern (MOE=100) when chemical resistant gloves were added
to PPE requirements.

E. CUMULATIVE EXPOSURE:

N6-Benzyladenine has an unknown toxicological mode of cellular action
and there is no indication that the toxic effects of N6-Benzyladenine
are cumulative. Section 408(b)(2)(D)(v) of the FFDCA requires that, when
considering whether to establish, modify, or revoke a tolerance, EPA
consider available information concerning the cumulative effects of a
particular pesticide's residues and other substances that have a common
mechanism of toxicity.

EPA does not have, at this time, available data to determine whether
N6-Benzyladenine has a common mechanism of toxicity with other
substances. Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity, EPA
has not made a common mechanism of toxicity finding as to
N6-Benzyladenine and any other substances and N6-Benzyladenine does not
appear to produce a toxic metabolite produced by other substances. For
the purposes of this tolerance action, therefore, EPA has not assumed
that N6-Benzyladenine has a common mechanism of toxicity with other
substances. For information regarding EPA’s efforts to determine which
chemicals have a common mechanism of toxicity and to evaluate the
cumulative effects of such chemicals, see the policy statements released
by EPA’s Office of Pesticide Programs concerning common mechanism
determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

F. SAFETY DETERMINATION:

1) US Population:

Dietary exposure to N6-Benzyladenine residues in pears resulting from
the use of MaxCel® did not add significantly to the current dietary
exposure of N6-Benzyladenine from apples or pistachios. It is therefore
adequate to conclude that there is reasonable certainty that no dietary
harm will come from the use of MaxCel® in/on pears at the proposed
label rate and preharvest interval.

Consumption of N6-Benzyladenine residues in water from this application
is also not expected to result in unacceptable risks, since the chemical
is strongly bound and comparatively quickly degraded in the soil.
Migration to potable water resources, therefore, is highly improbable.

Conservative assumptions when performing dietary exposure and risk
assessments ensured that the risks from N6-Benzyladenine in food or
water were not underestimated.

2) Infants and Children

FFDCA section 408 provides that EPA shall apply an additional tenfold
margin of exposure (safety) for infants and children in the case of
threshold effects to account for pre-natal and post-natal toxicity and
the completeness of the data base unless the EPA determines that a
different margin of exposure (safety) will be safe for infants and
children.

In the case of N6-Benzyladenine, the FQPA factor was reduced from 10X to
3X because of adequate data from: 1) a 2-generation rat reproduction
study [MRID 4638802], 2) a rat developmental toxicity study [MRID
41623703], and 3) the rationale discussed below. Residual uncertainties
for N6-Benzyladenine-induced pre-/post-natal toxicity were present,
however, because of the lack of a developmental toxicity study in a
second species. The lack of this study prohibited reduction of the FQPA
factor from 3X to 1X.

Hazard:  There is no evidence of unique fetal susceptibility in any of
the acceptable studies presented. In both the developmental rat toxicity
and two generation rat reproduction studies, fetal or neonatal effects
occurred only at maternally toxic doses. In addition, genotoxicity and
mutagenicity tests were negative.

Exposure:  Differential pre- and post-natal exposures have also been
considered in light of FQPA requirements. Both pre- and post-natal
populations have been taken into account when estimating dietary
exposure. Relevant assessed populations included infants less than 1
year old, toddlers 1-2, children 3-5, children 6-12, youth 13-19, and
women 13-49 years old.

In summary, pre- and post-natal exposure has been considered either
qualitatively or quantitatively in comparative dietary risk assessments.
Conservative assumptions used in these exposure assessments suggest that
special susceptibilities of these populations have been appropriately
accounted for.

G. EFFECTS on the IMMUNE and ENDOCRINE SYSTEMS:

No studies illustrating N6-Benzyladenine-induced immune and endocrine
toxicity have been reviewed.

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA),
as amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there was scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) and, to the
extent that effects in wildlife may help determine whether a substance
may have an effect in humans, FFDCA has authority to require the
wildlife evaluations.  As the science develops and resources allow,
screening of additional hormone systems may be added to the Endocrine
Disruptor Screening Program (EDSP).

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4ve been developed, N6-Benzyladenine may be subjected to additional
screening and/or testing to better characterize effects related to
endocrine disruption.

H. EXISTING TOLERANCES:

n rate of ≤ 182 grams of active ingredient per acre per season, and in
or on pistachio at an application rate of ≤ 60 grams of active
ingredient per acre per season” (40 CFR §180.1150). Pistachio and
apple have preharvest intervals of 60 and 86 days respectively, as
additional use constraints.

I. INTERNATIONAL TOLERANCES:

CODEX MRL’s have not been established for N6-Benzyladenine.
N6-Benzyladenine has, however, been registered for use in South Africa,
Denmark, Australia, New Zealand, and Canada.

J. REFERENCES

	Blakesley, D. 1991. Uptake and metabolism of 6-benzyladenine in shoot
cultures of Musa and Rhododendron. Plant cell, tissue and organ culture.
25(1): 69-74.

	Blakesley D. and D. Constantine. 1992. Uptake and metabolism of
6-benzyladenine in shoot cultures of a range of species. Plant cell,
tissue and organ culture. 28(2): 183-186.

	Centeno , M.L., Rodriguez, A., Feito, I., Sanchez-Tames, R., and B
Fernandez. 2003. Uptake and metabolism of N6-Benzyladenine and
1-naphthaleneacetic acid and dynamics of indole-3-acetic acid and
cytokinins in two callus lines of Actinidia deliciosa differing in
growth and shoot organogenesis. Physiologia Plantarum. 118: 579-588.

@

@

@

%EPA. 1994. Reregistration eligibility decision (RED); N6-Benzyladenine.
EPA 736R-94-0011. p 1-39.

	Federal Register. 2004. 6-benzyladenine; Exemption from the requirement
of a tolerance. 69 (64), pp 17304-17308.

MaxCel - N6-Benzyadenine	   	DP Barcode:	329586, 329587

EPA Reg No: 73049-59, 73049-407		Page:   PAGE  1  of 10

Apilife VAR (thymol, eucalyptol, menthol)	   	DP Barcode: 324676

EPA Reg No: 73291-R		Page:   PAGE  12  of 8


[Federal Register Volume 88, Number 96 (Thursday, May 18, 2023)]
[Notices]
[Pages 31764-31766]
[FR Doc No: 2023-10610]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2005-D-0460]

Pediatric Drug Development: Regulatory Considerations--Complying
With the Pediatric Research Equity Act and Qualifying for Pediatric
Exclusivity Under the Best Pharmaceuticals for Children Act; Draft
Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Pediatric Drug
Development: Regulatory Considerations--Complying With the Pediatric
Research Equity Act and Qualifying for Pediatric Exclusivity Under the
Best Pharmaceuticals for Children Act.'' This draft guidance, when
finalized, is intended to provide recommendations to industry on
complying with the pediatric study requirements under the Pediatric
Research Equity Act (PREA), and to describe the process for qualifying
for pediatric exclusivity and the protections that pediatric
exclusivity offers under the Best Pharmaceuticals for Children Act
(BPCA). Combining discussion of PREA and the BPCA together in
regulatory guidance emphasizes the sponsor's need to consider both laws
when developing pediatric drugs and biological products.

DATES: Submit either electronic or written comments on the draft
guidance by July 17, 2023 to ensure that the Agency considers your
comment on this draft guidance before it begins work on the final
version of the guidance.

ADDRESSES: You may submit comments on any guidance at any time as
follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2005-D-0460 for ``Pediatric Drug Development: Regulatory
Considerations--Complying With the Pediatric Research Equity Act and
Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for
Children Act.'' Received comments will be placed in the docket and,
except for those submitted as ``Confidential Submissions,'' publicly
viewable at https://www.regulations.gov or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.

    You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
    Submit written requests for single copies of the draft guidance to
the Division of Drug Information, Center for Drug Evaluation and
Research, Food and Drug Administration, 10001 New Hampshire Ave.,
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002, or the
Office of Communication, Outreach, and Development, Center for
Biologics Evaluation and Research, Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002.
Send one self-addressed adhesive label to assist that office in
processing your requests. See the SUPPLEMENTARY INFORMATION section for
electronic access to the draft guidance document.

FOR FURTHER INFORMATION CONTACT: Rosemary Addy, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 6430, Silver Spring, MD 20993-0002, 301-
796-1640, [email protected]; or Diane Maloney, 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:

I. Background

    FDA is announcing the availability of a draft guidance for industry
entitled ``Pediatric Drug Development: Regulatory Considerations--
Complying With the Pediatric Research Equity Act and Qualifying for
Pediatric Exclusivity Under the Best Pharmaceuticals for Children
Act.'' This draft guidance is intended to provide recommendations on
how to comply with the pediatric study requirements under sections 505B
of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355c)
(PREA), and to qualify for pediatric exclusivity under section 505A of
the FD&C Act (21 U.S.C. 355a) (BPCA). This guidance also incorporates
recommendations based on FDA's Retrospective Review.\1\
---------------------------------------------------------------------------

    \1\ This review was conducted pursuant to section 505B(f)(5) of
the FD&C Act and is described in more detail in a report available
at https://www.fda.gov/media/78050/download.
---------------------------------------------------------------------------

    PREA requires that certain applications (or supplements to
applications) submitted under section 505 of the FD&C Act (21 U.S.C.
355) or under section 351 of the Public Health Service Act (42 U.S.C.
262) (specifically, any application that is subject to PREA) must
either include pediatric assessments or reports on the molecularly
targeted pediatric cancer investigation (as appropriate), or a request
for waiver and/or deferral (see section 505B(a)(1), (a)(4), and (a)(5)
of the FD&C Act). To ensure that sponsors thoroughly consider a
pediatric clinical development program earlier in their overall
clinical development program, PREA requires sponsors to submit an
initial pediatric study plan during the investigational phase of
development (see section 505B(e) of the FD&C Act). PREA also authorizes
FDA to require holders of approved applications for drugs and
biological products, who are not seeking approval for one of the
changes specified, to submit pediatric assessments under certain
circumstances (see section 505B(b) of the FD&C Act).
    Under the BPCA, certain applications may qualify for 6 months of
exclusivity if the following conditions are met: (1) FDA determines
that information relating to the use of a drug in the pediatric
population may produce health benefits in that population; (2) FDA
issues a written request (WR) for studies of that drug in pediatric
populations and the applicant agrees to the request; (3) the studies
are completed using appropriate formulations for each age group and
within the requested time; and (4) the reports of the studies are
submitted and accepted by FDA (see section 505A(b)(1) and (c)(1) of the
FD&C Act). In accepting or rejecting the reports, FDA determines
whether the studies fairly respond to the WR, have been reported in
accordance with filing requirements, and otherwise qualify for
pediatric exclusivity (see section 505A(d)(4) of the FD&C Act).
    With respect to content, this draft guidance addresses pediatric
assessments, molecularly targeted pediatric cancer investigations,
pediatric study plans, waivers and deferrals (including deferral
extensions), labeling considerations, the noncompliance process, the
relationship of the PREA requirements to pediatric exclusivity, and the
reporting of adverse events for products subject to PREA and the BPCA.
Additionally, the draft guidance includes a description of the
mechanisms FDA uses to obtain pediatric studies, how industry can
obtain a WR and what it includes, how study reports should be submitted
to FDA for filing, the criteria to qualify for pediatric exclusivity,
the nature and scope of pediatric exclusivity, and the information that
should be submitted in support of a request for a pediatric exclusivity
determination.
    With respect to its discussion of PREA, this guidance, along with
the draft guidance for industry entitled ``Pediatric Drug Development
Under the Pediatric Research Equity Act and the Best Pharmaceuticals
for Children Act: Scientific Considerations,'' revises and replaces the
draft guidance for industry entitled ``How to Comply With the Pediatric
Research Equity Act'' (2005 draft guidance; 70 FR 53233, September 7,
2005).\2\ In addition to addressing certain PREA-related topics covered
in the 2005 draft guidance, this draft guidance also addresses certain
changes to PREA that have occurred since 2005.
---------------------------------------------------------------------------

    \2\ This guidance also addresses certain topics previously
addressed in the guidance for industry entitled ``Qualifying for
Pediatric Exclusivity Under Section 505A of the Federal Food, Drug,
and Cosmetic Act.'' That guidance was withdrawn August 7, 2013 (78
FR 48175).
---------------------------------------------------------------------------

    This draft guidance is being issued consistent with FDA's good
guidance practices regulation (21 CFR 10.115). The draft guidance, when
finalized, will represent the current thinking of FDA on ``Pediatric
Drug Development: Regulatory Considerations--Complying With the
Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity
Under the Best Pharmaceuticals for Children Act.'' It does not
establish any rights for any person and is not binding on FDA or the
public. You can use an alternative approach if it satisfies the
requirements of the applicable statutes and regulations.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. Therefore,
clearance by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not
required for this guidance. The previously approved collections of
information are subject to review by OMB under the PRA. The collections
of information in 21 CFR part 312 for investigational new drug
applications and 21 CFR part 314 for new drug applications and
abbreviated new drug applications have been approved under OMB control
numbers 0910-0014 and 0910-0001, respectively. The collections of
information in 21 CFR parts 601 and 610 pertaining to biologics license
applications have been approved under OMB control number 0910-0338. The
collections of information in 42 U.S.C. 262(k) for biosimilar
applications have been approved under OMB control number 0910-0718. The
collections of information in 21 CFR 201.56 and 201.57 regarding
labeling requirements for prescription drugs have been approved under
OMB control number 0910-0572. The collections of

information in 21 CFR part 201, subpart C regarding over-the-counter
products have been approved under OMB control number 0910-0340. The
collections of information in 21 CFR part 316 regarding orphan drug
product development have been approved under OMB control number 0910-
0167.

III. Electronic Access

    Persons with access to the internet may obtain the draft guidance
at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    Dated: May 15, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-10610 Filed 5-17-23; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register: February 12, 2007 (Volume 72, Number 28)]
[Notices]
[Page 6551]
[DOCID:fr12fe07-65]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Docket No. RP07-161-000]

National Fuel Gas Supply Corporation; Notice of Tariff Filing

February 5, 2007.
    Take notice that on January 31, 2007, National Fuel Gas Supply
Corporation (National) tendered for filing as part of its FERC Gas
Tariff, Fourth Revised Volume No. 1, Ninety Seventh Revised Sheet No.
9, to become effective February 1, 2007.
    Any person desiring to intervene or to protest this filing must
file in accordance with Rules 211 and 214 of the Commission's Rules of
Practice and Procedure (18 CFR 385.211 and 385.214). Protests will be
considered by the Commission in determining the appropriate action to
be taken, but will not serve to make protestants parties to the
proceeding. Any person wishing to become a party must file a notice of
intervention or motion to intervene, as appropriate. Such notices,
motions, or protests must be filed in accordance with the provisions of
Section 154.210 of the Commission's regulations (18 CFR 154.210).
Anyone filing an intervention or protest must serve a copy of that
document on the Applicant. Anyone filing an intervention or protest on
or before the intervention or protest date need not serve motions to
intervene or protests on persons other than the Applicant.
    The Commission encourages electronic submission of protests and
interventions in lieu of paper using the ``eFiling'' link at http://www.ferc.gov.
 Persons unable to file electronically should submit an

original and 14 copies of the protest or intervention to the Federal
Energy Regulatory Commission, 888 First Street, NE., Washington, DC
20426.
    This filing is accessible on-line at http://www.ferc.gov, using the

``eLibrary'' link and is available for review in the Commission's
Public Reference Room in Washington, DC. There is an ``eSubscription''
link on the Web site that enables subscribers to receive e-mail
notification when a document is added to a subscribed docket(s). For
assistance with any FERC Online service, please e-mail
<EMAIL_ADDRESS>or call<PHONE_NUMBER> (toll free). For

TTY, call<PHONE_NUMBER>.

Magalie R. Salas,
Secretary.
[FR Doc. E7-2274 Filed 2-9-07; 8:45 am]

BILLING CODE 6717-01-P