Document ID: EPA-HQ-OPP-2007-0189-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-10-24T04:00Z

<EPA Registration Division Contact: Sidney Jackson 703-305-7610

Docket ID: EPA-HQ-OPP-2007-0189>

 

<>

<Interregional Research Project Number 4 (IR-4)>

<PP#: 7E7238>

	EPA has received a pesticide petition (PP 7E7238) from the IR-4 Project
Headquarters, 500 College Road East, Suite 201 W, Princeton, NJ 08540
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.317 
by establishing a tolerance for residues of propyzamide (pronamide) and
its metabolite containing the 3,5-dichlorobenzoyl moiety and calculated
as 3,5-dichloro-N-(1,1-dimethyl-2-propynyl) benzamide] in or on the raw
agricultural commodity bearberry at 1.0 parts per million (ppm),
bilberry at 1.0 ppm, blueberry, lowbush at 1.0 ppm, cloudberry at 1.0
ppm, cranberry at 1.0 ppm, lingonberry at 1.0 ppm, muntries at 1.0 ppm,
and partridgeberry at 1.0 ppm..  EPA has determined that the petition
contains data or information regarding the elements set forth in section
408 (d)(2) of  FDDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
support granting of the petition. Additional data may be needed before
EPA rules on the petition.

<A. Residue Chemistry>

<	1. Plant metabolism. [The nature of the residue in plants is
adequately understood.  The residues of concern are the parent compound
and its metabolites containing the 3,5-dichlorobenzoyl moiety,
calculated as 3,5-dichloro-N-(1,1-dimethyl-2-propynyl) benzamide (as
specified in CFR 180.317). ]

>

<	2. Analytical method. [Adequate enforcement methodology (gas
chromatography using electron capture detection) is available to enforce
the tolerance expression, this method is published in PAM II, as method
I.]>

<	3. Magnitude of residues. [i.  Cranberry, Crop Group 13H.  IR-4
received a request for the minor use of pronamide on cranberry for
control of dodder (Cusuta gronovii), cutgrass and summer grass.  To
support this request, magnitude of residue data were collected from 5
field trials located in Region 1 (Massachusetts), Region 2 (New Jersey),
Region 5 (2 trials in Wisconsin) and Region 12 (Oregon).  

There were two treatments at each trial site.  For treatment 02, two
broadcast applications were applied at 1.0 lb a.i./A.  There were 19 to
22 day intervals between applications with the last application 75 to 77
days before harvest.  For treatment 03, one broadcast application was
applied at 2.0 lb a.i./A, 75 to 77 days before harvest. 

Residues of pronamide and/or its metabolites are determined by digesting
the sample with sulfuric acid and methanol to convert pronamide to
methyl 3,5-dichlorobenzoate (MDCB).  This compound is codistilled from
the reaction medium and extracted with petroleum ether.  The samples
were then analyzed for MDCB by GC/Electron Capture detection. 

The results from these trials show that for treatment 02, the maximum
residue of pronamide was 0.36 ppm after two applications, each at 1.0 lb
a.i./A, and a PHI of 75 to 77 days (Treatment 02).  The results from
these trials also show that for treatment 03, the maximum residue of
pronamide was 0.90 ppm after a single application of 2.0 lb a.i./A, and
a PHI of 75 to 77 days ().]>

<B. Toxicological Profile>

EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk.  EPA has also considered the
available information concerning the variability of the sensitivities of
major identifiable subgroups of consumers, including infants and
children.  The nature of the toxic effects caused by propyzamide are
discussed below.

<	1. Acute toxicity.  [Pronamide technical has a low order of acute
toxicity via the oral, dermal, and inhalation routes of exposure
(Toxicity Category III or IV), produces mild irritation to the eyes and
skin (Toxicity category IV), and is not a dermal sensitizer.]>

<	2. Genotoxicty. [Mutagenicity: Pronamide was not mutagenic in
Salmonella typhimurium, Escherichia coli or in cultured Chinese hamster
lung cells and did not produce a genotoxic response in Bacillus
subtiltis or in cultured primary rat hepatocytes.  There was also no
evidence of clastogenicity in cultured Chinese hamster ovary cells and
pronamide administration did not result in the induction of
micronucleated polychromatic erythrocytes in bone marrow of mice. 
Overall, the data suggest that pronamide is negative for mutagenicity in
vitro and in vivo.]>

<	3. Reproductive and developmental toxicity. [There was no qualitative
evidence of increased susceptibility in the fetuses or the offspring of
rats or rabbits following pre- and/or postnatal exposure to pronamide. 
Fetal/offspring effects in both of these species were observed at either
the same or higher dose levels which produced maternal/parental
toxicity.  In the developmental toxicity study in rabbits, abortions
were observed at a higher dose level (80 mg/kg/day) compared to the dose
(20 mg/kg/day) at which maternal toxicity (soiled anal area, anorexia
and punctate vacuolation of hepatocytes) was observed.  Also, no
evidence of increased susceptibility was demonstrated in the
two-generation reproduction study in rats.  Offspring toxicity
(decreased combined male/female pup weight/litter) was observed at the
same dose that caused parental toxicity (decreased body weight and food
consumption in both sexes, increased incidences of histopathology of the
liver, adrenal gland, thyroid gland, and anterior pituitary gland in
both P1 and P2 generations, and increased incidences of uterine gross
pathology in P2 females).  Parental and offspring toxicities were
observed at the same LOAEL of 1500 ppm (130.1 mg/kg/day for males and
120.7 mg/kg/day for females).]>

<	4. Subchronic toxicity. [The pronamide subchronic data base contain
two acceptable studies conducted in the rat: a 4-week oral toxicity
study (non-guideline) and a 13-week oral toxicity study (guideline).  In
the non-guideline, 4-week study, systemic toxicities were noted in males
treated with 37.24 or 74.05 mg/kg/day pronamide and in females treated
with 43.65 or 87.65 mg/kg/day pronamide.  These toxicities were limited
to the liver and included increases in absolute and relative (to body)
liver weights (males: both doses; females: high-dose) and a positive
trend in the increased incidence of centrilobular hypertrophy (males). 
When pronamide was administered in the diet for 13 consecutive weeks,
male rats treated with 60.0 mg/kg/day and females rats treated with 74.6
mg/kg/day presented with the following systemic toxicities in one or
both sexes: decreased body weight, body weight gain and food
consumption, increased blood cholesterol levels, increased relative (to
body) liver weights and incidence of hepatic centrilobular hypertrophy. 
At the highest dose tested (254.0 mg/kg/day for males and 289.2
mg/kg/day in females), many of these toxicities were observed in both
sexes and showed an increase in incidence and/or severity.  The
following additional changes were also observed in high-dose animals:
clinical signs (brown and/or yellow staining of the anogenital area
(males), increased enzyme activity (SGOT and alkaline phosphatase) in
males, triglyceride blood levels (females), increased absolute liver
weights (males and females), and increased incidences of thyroid
follicular cell hypertrophy (males and females) sexes and anterior
pituitary cellular hypertrophy (males).  After 4 weeks of recovery, most
of the adverse effects observed at the high-dose were partially or
completely reversed with the exception of the increase in incidence of
pituitary cellular hypertrophy (males only).]>

<	5. Chronic toxicity. [EPA has established the Reference Dose (RfD) for
propyzamide at 0.08 milligrams/kilogram body weight/day (mg/kg bwt/day).
 The RfD was established based on a 2-year feeding study in rats with a
NOEL of 8.46 mg/kg/day and using an uncertainty factor of 100.  The
Lowest Observed Effect Level (LOEL) of 42.6 mg/kg/day was based on
decreased mean body weight and decreased mean body weight gain,
increased relative liver weight, increased incidences of hepatic
centrilobular hypertrophy, as well as eosinophilic cell alterations and
thyroid follicular cell hypertrophy in both males and females.  In
females there was an increased incidence of ovarian hyperplasia.]>

<	6. Animal metabolism. [Pronamide is rapidly absorbed from the
gastrointestinal tract and extensively and rapidly metabolized; 93-103%
the radioactivity administered was recovered.  It is excreted (7 days
post-dosing) equally in both the urine (40-61%) and the feces (40-60%). 
No bioaccumulation was apparent; radioactivity recovered in all tissues
were consistently highest at the first sampling time (8 hours post-dose)
then gradually declined to insignificant levels 7 days after dosing. 
The elimination of radioactivity from the plasma of low dose rats was
biphasic [rapid phase = 12.6 hrs (males) and 12.7 hrs (females); slow
phase = 36.6 hrs (males) and 45.3 hrs (females] and that of the high
dose rats was monophasic [t½ = 24.1 hrs (males) and 24.8 hrs (females}.
 Tissues with the highest radioactivity contents were, in decreasing
order, the fat, adrenals, bone marrow, thyroids, liver, kidney, and
plasma.  Very little unchanged pronamide was recovered in the urine and
no significant difference in the urinary metabolite profile was observed
between the doses or the sexes.]>

<	7. Metabolite toxicology. [Approximately 27 unidentified metabolites
were found in the urine and none exceeded 3.3% of the dose whereas all
of the fecal metabolites were unidentified and comprised less than 1% of
the dose.  Two major urinary metabolites have been identified and
quantified; 2-(3,5-dichlorophenyl)-4,4-dimethyl-5-carboxyoxazoline
(metabolites SS47-70, 3.0-5.9% of the administered dose) and
N-carboxymethyl-3,5-dichlorobenzamide (metabolite 10, 12.7-18.9% of the
administered dose).]>

<	8. Endocrine disruption. [Evidence of endocrine effects from several
guideline toxicity studies as well as two special studies submitted to
the Agency by the Registrant include, in part: (i) histopathology of the
thyroid gland, pituitary gland, adrenal glands, testes and ovaries, (ii)
changes in hormone levels; decreased T4 and increased TSH, LH and FSH,
and (iii) the induction of enzymes such as cytochrome-P450 and -B5, and
NADPH-cytochrome-c-reductase in addition to those enzymes involved in
the oxidation of testosterone.

Two special studies were conducted by the Registrant to evaluate
pronamide’s effect on hormonal balance in support of a threshold
mechanism for the induction of thyroid and testicular neoplasms.  The
results of these special endocrine studies are suggestive of a
pronamide-induced thyroid and testicular neoplastic effect via
disruption of the pituitary-thyroid and pituitary-testis hormone
balance.]>

<C. Aggregate Exposure>

FQPA requires an aggregate risk assessment to be conducted considering
all non-occupational sources, including exposure from water, food, and
residential use. Because there are no potential exposures to residential
treated turf, the aggregate exposure assessment for pronamide includes
exposure estimates from food and drinking water.

<	1. Dietary exposure. [Dietary exposure includes intakes from food
(crops and animal commodities), with and without drinking water
component.]>

<	i. Food. [Tolerances have been established (40CFR 180.317) for the
residues of propyzamide, 3,5-dichloro-N-(1,1-dimethyl-2-propynyl)
benzamide and its metabolites (containing the dichlorobenzoyl moiety and
calculated as 3,5-dichloro-N-(1,1-dimethyl-2-propynyl) benzamide in or
on a variety of raw agricultural commodities at levels ranging from 0.02
ppm in milk to 10 ppm in non-grass animal feeds.  EPA has reassessed the
pronamide tolerances.  Acute dietary risk assessments were not necessary
since there were no acute toxicological endpoints of concern for
pronamide.  Chronic and carcinogenic dietary risks were assessed,
however, due to exposure to pronamide.  The Dietary Exposure Evaluation
Model (DEEM) was used to estimate chronic dietary exposure.  A refined
Tier 3 analysis was performed using: 1) percent crop treated; 2) FDA and
PDP monitoring data; and, 3) tolerance level residues for 4 crops.

The cPAD is 0.03 mg/kg/day (chronic RfD 0.08 mg/kg/day ( 3x FQPA safety
factor).  Chronic risks for published and pending tolerances result in a
dietary exposure that is equivalent to <2% of the RfD for all population
subgroups.  Carcinogenic risks estimate for exposure to pronamide
through food were 1.5 X 10-6.]>

<	ii. Drinking water. [Chronic cancer and non-cancer risk assessment
from exposure through drinking water was conducted in addition to the
dietary exposure.  The Agency did not establish any acute and short-term
oral toxicological endpoint.   Cancer and non-cancer  chronic exposure
to pronamide through contaminated ground and surface water was based on
EECs calculated using USEPA water models. The chronic non-cancer EECs
range between 1.5 to 6.4 ppb.  Chronic EEC for cancer ranged from 0.54
to 4.3 ppb and was refined to 1.5 ppb using % crop area treated from
Doane Marketing Research.  Chronic drinking water exposure (cancer and
non-cancer) to pronamide did not result in a risk estimate of concern
for non-cancer risks.  There are cancer risk estimates which slightly
exceed the Agency’s level of concern.  However, the modeled
groundwater EECs are high-end estimates resultant from conservative
models and they are far below the chronic reference doses for both
adults and children.]>

<	2. Non-dietary exposure. [There are no residential uses of pronamide. 
Use is limited to turf grown for seed or sod and non-residential sites. 
These risk mitigation measures make children’s non-dietary exposure
unlikely.  To minimize adult non-occupational exposure, the pronamide
labels require a 24-hour restricted entry interval or require
watering-in as soon as possible after application.  The sole exposure
scenario for the non-occupational risk assessment is based on low
contact activity, which is represented and estimated by golf course
reentry.  The route of exposure is dermal.  The population at risk is
adults.  The short-term Margin of Exposure (MOE) for golf course reentry
using zero day after treatment (DAT 0) turf transferable residue data
from the turf study is 1000.  Therefore, the Agency is not concerned
about short-term non-residential exposure to pronamide.

No intermediate or long-term exposure scenarios (i.e.:  greater than 30
days) are anticipated based on the results of the turf transferable
residue (TTR) study which showed that residues dissipate to below the
level of quantification by day 14 following application.  The adult
golfer cancer risk is estimated at 1.15 x 10-7.  In order to exceed the
cancer risk (1.0 x 10-6), an exposure frequency of 8.7 days per year
would be needed for the activity of golf.  Because pronamide is applied
one time per year, the Agency does not believe this exposure frequency
will occur.  Therefore, the cancer risk for golfers does not exceed the
Agency’s level of concern.]>

<D. Cumulative Effects>

<	[Pronamide is a pre- and post-emergence herbicide used to control
annual grasses and broadleaf weeds.  At this time, the EPA has not made
a determination that pronamide and other substances that may have a
common mechanism of toxicity would have cumulative effects.  Therefore,
for these tolerance petitions, it is assumed that pronamide does not
have a common mechanism of toxicity with other substances and only the
potential risks of pronamide in its aggregate exposure are considered.]>

<E. Safety Determination>

<	1. U.S. population. [Acute risk.  Because no acute dietary endpoint
was identified, no acute risk assessment was conducted.

Chronic risk.  Using the ARC exposure assumptions described above, the
chronic dietary risk estimates are not of concern, <1% of the cPAD, for
the U.S. population and for all subgroups.  EPA has concluded that there
is a reasonable certainty that no harm will result from aggregate
exposure to pronamide residues.

Short- and intermediate-term risk.  The short-term Margin of Exposure
(MOE) for golf course reentry using zero day after treatment turf
transferable residue data from the turf study is 1000.  Therefore, the
Agency is not concerned about short-term non-residential exposure to
pronamide.  No intermediate or long-term exposure scenarios are
anticipated.

Cancer risk.  Pronamide is classified as a Group B2 chemical, probable
human carcinogen with inadequate evidence in humans.  The cancer risk
estimate for golfing a single day per year and chronic dietary exposure
risk estimate is about 1 X 10-7 and 2 X 10-6, respectively.  After
considering both dietary and non-dietary exposure, the cancer DWLOC is
26 ppb.  The Tier 2 PRZM-EXAMS 36 year mean EECs are 0.54 - 4.4 ppb. 
The modeled groundwater EEC using SCI-GROW is 3 ppb.  The modeled EEC
(4.4 ppb) is much lower than the cancer DWLOC (26 ppb).  The PRZM-EXAMS
assessment was based on the maximum label rates for pronamide, whereas
typical rates for many crops are 25% - 50% less.  The model also assumed
a Percent Crop Area (PCA) of 29%, which is an updated estimate for the
commodities being assessed.  Therefore, EPA concluded that there is a
reasonable certainty no harm in the form of cancer will result from
aggregate exposure to pronamide residues..]>

<	2. Infants and children. [In general, Section 408 of FFDCA provides
that EPA shall apply an additional tenfold margin of safety for infants
and children in the case of threshold effects to account for prenatal
and postnatal toxicity and the completeness of the data base on toxicity
and exposure unless EPA determines based on reliable data that a
different margin of safety will be safe for infants and children. 
Margins of safety are incorporated into EPA risk assessments either
directly through use of a MOE analysis or through using uncertainty
(safety) factors in calculating a dose level that poses no appreciable
risk to humans.  In applying this provision, EPA either retains the
default value of 10X when reliable data do not support the choice of a
different factor, or, if reliable data are available, EPA uses a
different additional safety factor value based on the use of traditional
uncertainty factors and/or special FQPA safety factors, as appropriate.

EPA has determined that the additional safety factor for the protection
of infants and children will be retained but reduced to 3X based on the
following weight of evidence consideration relating to potential
sensitivity and completeness of the data.

The toxicological database is adequate for FQPA assessment.

There was no quantitative or qualitative evidence of increased
susceptibility of rabbits to in utero exposure or to rats following
pre/post-natal exposure.  Although the developmental toxicity study was
unacceptable because a definitive NOAEL as well as a LOAEL were not
established, no increased susceptibility was seen at the highest dose
tested.

A developmental neurotoxicity study is not required.

The dietary (food and drinking water) and non-residential exposure
assessments will not underestimate the potential exposures for infants
and children.

A 3X was retained because of evidence of endocrine organ toxicity in the
thyroid, testes, ovaries, adrenal glands, pituitary gland, thymus.

Based on the exposure assessments described above, Dow AgroSciences has
concluded that the dietary exposure from all labeled and pending uses of
pronamide are about 2% of the cPAD for all subgroups.  Thus, Dow
AgroSciences has concluded there is a reasonable certainty that no harm
will result from aggregate exposure to pronamide residues.]>

<F. International Tolerances>

<	[Currently there are no Codex MRLs in place for propyzamide (or
pronamide).]>

 PAGE   

 PAGE   8 

	

 	Pronamide: Magnitude of Residue on Cranberry.  IR-4 PR No. A3152. 
January 7, 2007.