Document ID: EPA-HQ-OPP-2008-0887-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-20T04:00Z

COMPANY FEDERAL REGISTER NOTICE OF FILING 

EPA Registration Division contact: Susan Stanton (703) 305-5218

Interregional Research Project No. 4 (IR-4)

PP #8E7473

	EPA has received a pesticide petition (PP#8E7473) from Interregional
Research Project No. 4, Rutgers University, 500 College Road East, Suite
201W, 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

by establishing a tolerance for residues of propamocarb hydrochloride;
propyl[3-(dimethylamino)propyl]carbamate mono-hydrochloride, in or on
the raw agricultural commodity bean, lima, succulent at 2.0 parts per
million (ppm).  EPA has determined that the petition contains data or
information regarding the elements set forth in section 408 (d)(2) of
the FDDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of the
petition. Additional data may be needed before EPA rules on the
petition.

A. Residue Chemistry

	1. Plant metabolism. The fate of propamocarb hydrochloride in plants is
clearly understood.  Metabolism studies in cucumbers, potatoes and
spinach demonstrated that propamocarb is degraded to carbon dioxide
which is reincorporated into natural plant constituents.  The primary
residue found in all crops, and the only residue of concern, is the
parent, propamocarb hydrochloride.

	2. Analytical method. A practical analytical method utilizing
gas/liquid chromatography and N-FID or MSD is available and has been
validated for detecting and measuring levels of propamocarb
hydrochloride in or on food. The limit of quantification (LOQ) is 0.05
mg/kg (ppm).

	3. Magnitude of residues. Five residue trails were conducted in the US
over a two-year period in accordance with the proposed label use
directions. The maximum residue detected in/on lima beans was 1.20 ppm.

B. Toxicological Profile

	1. Acute toxicity.  There are no acute toxicity concerns with
propamocarb hydrochloride. The acute rat oral LD50 is 2900 mg/kg in
males and 2000 mg/kg in females. The acute rat dermal LD50 is >3000
mg/kg. The acute (4-hour) inhalation LC50 in rats is >7.9 mg/l. 
Propamocarb hydrochloride is not considered a skin sensitizer.
Propamocarb hydrochloride has been classified as Toxicity Category III
for acute oral and dermal toxicity and eye irritation and Category IV
for acute inhalation toxicity and skin irritation. An acute
neurotoxicity study was performed in rats at dose levels of 0, 20, 200
and 2000 mg/kg of propamocarb hydrochloride. The overall NOAEL for this
study was determined to be 200 mg/kg based on decreased weight gain,
soiled fur and decreased motor activity in males and/or females at 2000
mg/kg.

	2. Genotoxicty. No evidence of genotoxicity was observed in a battery
of studies including Salmonella and E. Coli gene mutation assays, two
mouse micronucleus assays, an in vitro mammalian cytogenetic assay using
cultured human lymphocytes, a yeast mitotic gene conversion assay and a
yeast mitotic recombination assay.

	3. Reproductive and developmental toxicity. In a developmental toxicity
study, rats were administered propamocarb hydrochloride by gavage at
dose levels of 0, 74, 221, 740, or 2210 mg/kg/day on gestation days
6-19. The NOAEL for maternal toxicity was 740 mg/kg/day based on
mortality, clinical observations and decreased body weight gain at 221
mg/kg/day. The NOAEL for developmental toxicity was 221 mg/kg/day based
on increased post-implantation loss, decreased fetal weights and
increased incidence of minor skeletal anomalies (retarded ossification)
at 740 and/or 2210 mg/kg/day.

In another developmental toxicity study, rabbits were administered
propamocarb hydrochloride by gavage at dose levels of 0, 15, 45, 150,
300 or 600 mg/kg/day on gestation days 6-18. The NOAEL for both maternal
toxicity and developmental toxicity was 150 mg/kg/day, based on
decreased maternal body weight gain and increased post-implantation loss
at 300 mg/kg/day.

A three-generation reproduction study was conducted using rats fed diet
containing propamocarb hydrochloride at dietary concentrations of 0, 40,
200, and 1000 ppm for 100 days and then continuously through three
successive generations. No treatment-related effects were noted on
either the parents or offspring.

A two-generation reproduction study was conducted with albino rats.
Animals received propamocarb hydrochloride at dietary concentration of
0, 200, 1250 and 8000 ppm. Reduced body weights were observed in the F0
and Fl parental animals and the F1 and F2 offspring at 8000 ppm. Based
on these findings, the NOAEL is 1250 ppm for parental and neonatal
toxicity (65.41 mg/kg/day for males and 76.78 mg/kg/day for females) and
8000 ppm for reproductive toxicity.

	4. Subchronic toxicity. In a 90-day feeding study, propamocarb
hydrochloride was administered to albino rats at concentrations of 0,
20, 50, 100, and 500/1000 ppm in the diet. The only effects noted were
slightly reduced food efficiency and body weight gains at 1000 ppm.

In a 90-day feeding study in beagle dogs, propamocarb was administered
in the diet at concentrations of 0, 50, 100, 500, and 1000/2000 ppm. No
treatment-related findings were observed. In a 90-day feeding study with
albino mice, propamocarb was administered at concentrations of 0, 1404,
2808, 5616 and 11,232 ppm in the diet. No treatment-related findings
were observed.

A 21-day dermal toxicity study was performed with propamocarb in
Sprague-Dawley rats at dose levels of 0, 100, 500 and 1000 mg/kg/day,
six hours per day, five days per week over a 21-day period. No treatment
related effects were observed.

A 21-day dermal toxicity study was performed with propamocarb
hydrochloride in rabbits at dose levels of 0, 150, 525 and 1500
mg/kg/day, six hours per day, five days per week, over a 21-day period. 
EPA assessed the NOAEL to be 150 mg/kg/day based on dose-related skin
irritation in mid- and high-dose animals and a decrease in weight gain
in mid-dose females.

A 90-day neurotoxicity study was conducted in rats at dietary
concentrations of propamocarb hydrochloride of 0, 200, 2,000 and 20,000
ppm. No evidence of neurotoxicity (FOB, motor activity or
neuropathology) was observed at any dose level. Plasma, red blood cell
and brain cholinesterase levels were also not affected. The NOAEL was
determined to be 2000 ppm (142 mg/kg/day) based on decreased weight gain
at 20,000 ppm.

	5. Chronic toxicity. A two-year feeding chronic
toxicity/carcinogenicity study was performed in Sprague- Dawley rats
with propamocarb hydrochloride at dietary concentrations of 0, 40, 200
or 1000 ppm.  There was no evidence of carcinogenicity or other
treatment-related effect except for a possible reduction in food intake
in female rats at the highest level tested. Thus, 1000 ppm (41
mg/kg/day) was considered to be the NOAEL. However, this study did not
satisfy the EPA's criteria for a Maximum Tolerated Dose (MTD). In a
second two-year chronic toxicity/ oncogenicity study, albino rats
received diets containing propamocarb hydrochloride at concentrations of
0, 350, 2800 and 22,400 ppm. Animals receiving 22,400 ppm exhibited
decreased body weights, body weight gain and food consumption.
Additionally, these animals revealed moderate vacuolation of the choroid
plexis ependymal cells. There was no evidence of oncogenicity. Based on
these findings, EPA assessed the NOAEL to be 2800 ppm (84 mg/kg/day in
males and 112 mg/kg/day in females).

A two-year feeding chronic toxicity/carcinogenicity study was performed
in CD-1 mice with propamocarb hydrochloride at dietary concentrations of
0, 20, 100 and 500 ppm. No evidence of carcinogenicity or toxicity was
noted at any dose level. 

An 18-month mouse oncogenicity study was conducted in CD-1 mice exposed
to propamocarb hydrochloride at dietary concentrations of 0, 105, 840
and 6720 ppm. Reduced body weights were reported for animals in the 840
and 6720 ppm groups. There was no evidence of oncogenicity. Based on
these findings, EPA assessed the NOAEL to be (12 mg/kg/day) based on the
body weight effects in females.

A two-year feeding study was performed in beagle dogs with propamocarb
hydrochloride at dietary concentrations of 0, 1000, 3000, 10000 ppm.
Decreased weight gain, decreased food efficiency and an increased
incidence of acute gastric mucosal erosions and/or chronic erosive
gastritis were noted in all treated groups. Thus, a NOAEL for this study
was not determined but was considered to be slightly lower than the
lowest dose level tested (22.75 mg/kg/day).

	6. Animal metabolism. The absorption, distribution, metabolism and
excretion of propamocarb hydrochloride have been evaluated in rats.
Propamocarb hydrochloride was rapidly absorbed, extensively metabolized
and rapidly eliminated, primarily via the urine (>90% excreted within 24
hours), following oral administration. Metabolite profiles were similar
following single and repeated oral dosing and following intravenous
dosing. The primary route of metabolism was oxidative degradation with
hydrolytic cleavage occurring as a secondary pathway. 

The metabolism of propamocarb hydrochloride has been evaluated in
ruminants. The majority of the orally administered dose was excreted via
the urine and feces. Total radioactive residues in tissues and bile
accounted for 0.7% of the administered dose. The majority of the residue
was comprised of propamocarb, an N-oxide metabolite, an oxazolidine
metabolite, and a 2-hydroxy metabolite.

	7. Metabolite toxicology. NA 

	8. Endocrine disruption. No special studies have been conducted to
investigate the potential of propamocarb hydrochloride to induce
estrogenic or other endocrine effects. However, the standard battery of
required toxicity studies has been completed. These studies include an
evaluation of the potential effects on reproduction and development, and
an evaluation of the pathology of the endocrine organs following
repeated or long-term exposure. These studies are generally considered
to be sufficient to detect any endocrine effects yet no such effects
were detected. Thus, the potential for propamocarb hydrochloride to
produce any significant endocrine effects is considered to be minimal.

C. Aggregate Exposure

	1. Dietary exposure. For acute dietary analysis, an acute reference
dose (aRfD) of 1.5 mg/kg/day was derived for females 13 - 50 based on
increased post implantation loss in a rabbit developmental study and an
uncertainty factor of 100. For the general U.S. population including
infants and children the aRfD of 2.0 mg/kg/day was derived from
decreased body weight gain and decreased motor activity in the acute
neurotoxicity screening battery in the rat and an uncertainty factor of
100. For chronic dietary analysis, a chronic reference dose (cRfD) of
0.12 mg/kg/day was derived from body weight changes in the mouse
carcinogenicity study and an uncertainty factor of 100. EPA has
evaluated the potential for increased susceptibility of infants and
children from exposure to propamocarb hydrochloride and concluded that
the toxicology database is complete for FQPA purposes and that there are
no residual uncertainties for pre-/post-natal toxicity. The special FQPA
SF has been reduced to 1X. Acute and chronic Population Adjusted Doses
(aPAD and cPAD) are, therefore, the same as the reference doses for the
populations and subpopulations of interest.

was estimated from potential residues on food using the DEEM-FCID™
software. The Tier One assessments for acute and chronic analyses used
100% crop treated and tolerance level residue values. Established
tolerances for propamocarb hydrochloride include the cucurbit vegetable
crop group 9 (1.5 ppm), the fruiting vegetable crop group 8 (2.0 ppm)
with tomato paste at 5.0 ppm, head lettuce (50 ppm), leaf lettuce (90
ppm) and potatoes (0.06 ppm).  The proposed tolerance for lima beans is
2.0 ppm.  Secondary tolerances are established for meat and meat
by-products (0.15ppm), liver (0.65 ppm), kidney (0.2 ppm), fat (0.05ppm)
and milk (0.85 ppm). Acute exposure utilizes 6.1% of the aPAD for
Females 13-50 (aPAD=1.5 mg/kg bw/day) and 4.2% and 5.4% of the aPAD for
the US Population and Children 1-2 respectively (aPAD=2.0 mg/kg bw/day).
  Chronic exposure (cPAD=0.12 mg/kg bw/day) utilizes 17.5% for the US
Population and 36.3% for Children 1-2, the most highly exposed
subpopulation. These are conservative estimates and actual exposures are
likely to be much less.

	ii. Drinking Water. The surface water estimated drinking water
concentrations (EDWCs) were estimated using PRZM/EXAMS (Pesticide Root
Zone Model/Exposure Analysis Modeling System) for propamocarb
hydrochloride use on turf (Florida turf scenario) and lima beans
(Michigan bean scenario).   Ground water EDWCs, calculated using
SCI-GROW (Screening Concentration in Ground Water), model were lower
than the surface water EDWCs. The surface water estimates from the
Michigan bean scenario were slightly higher than the estimates from the
Florida turf scenario. Acute (peak) and chronic (annual average) EDWCs
representing the upper 1-in-10 year concentration were 153.5 and 10.4
ppb, respectively. These conservative single point values were added
directly to the Tier One acute and chronic dietary analyses described
above.  Acute exposure utilizes 6.4% of the aPAD for Females 13-50, 4.3%
for the US Population and 5.7% for Children 1-2, the most highly exposed
subpopulation.  Chronic exposure utilizes 17.7% of the cPAD for the US
Population and 36.6%% for Children 1-2, the most highly exposed
subpopulation. These conservative estimates indicate there is no concern
for dietary exposures from food and drinking water from potential
residues of propamocarb hydrochloride in food and drinking water. 

	2. Non-dietary exposure. EPA has determined that there is a potential
for short-term post-application exposures for the adult and adolescent
golfer. An MOE of 100 is adequate to ensure protection from propamocarb
hydrochloride via the dermal and inhalation routes for residential
exposures.  Golfer exposure is expected through minimal hand contact
with the golf ball and dermal contact to the lower legs from treated
plant surfaces. Since it is assumed that the adolescent golfer would
have a proportionally similar exposure to adults, a dermal
post-application assessment was performed for the adult golfer only. A
TC (transfer coefficient) of 500 cm2/hr has been used to estimate
post-application exposure and all exposure estimates were assessed on
the day of treatment. The appropriate endpoint for short term dermal
exposure is NOAEL of 150 mg/kg/day based on weight gain changes in the
rabbit in a 21-day dermal absorption study. The calculated MOE for the
golfer is 980 and, therefore, does not exceed EPA’s level of concern.

D. Cumulative Effects

	Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity.”   EPA has not made a common mechanism
of toxicity finding as to propamocarb hydrochloride and any other
substances and propamocarb hydrochloride does not appear to produce a
toxic metabolite produced by other substances.

E. Safety Determination

	1. U.S. population. Risk assessments for propamocarb hydrochloride are
based on based on a complete and reliable toxicity data package and
highly conservative assumptions. Chronic aggregate exposure (food and
water) from the proposed uses of propamocarb hydrochloride will utilize
less than 18% of the cPAD for the US Population. EPA generally has no
concern for exposures below 100% of the cPAD because the cPAD represents
the level at or below which daily aggregate exposure over a lifetime
will not pose appreciable risk to human health. For acute aggregate
exposure (food and water) females 13+ represent the most sensitive
subpopulation of the overall U.S. adult population but this group still
utilizes less than 7% of the aPAD using highly conservative assumptions.
 In addition to acute and chronic exposure, there is the potential for
short term aggregate exposure to adult and youth golfers. The proposed
uses on lima beans do not add significantly to aggregate dietary
exposure (food and water).  EPA has determined that MOEs for short term
aggregate exposure from food and residential exposure are greater than
100, and therefore below EPA’s level of concern. For surface and
ground water, the estimated average concentrations of propamocarb
hydrochloride are less than EPA's calculated DWLOCs (Drinking Water
Levels of Comparison) for propamocarb hydrochloride in drinking water as
a contribution to short-term aggregate exposure. Therefore, there is a
reasonable certainty that no harm will occur to the US Population from
aggregate exposure (food, drinking water and non-dietary) to residues of
propamocarb hydrochloride.

Ä

Æ

Ê

Å

Æ

Ê

Ü

Ý

옍)

옍)

옍)

ildren. Therefore, there is a reasonable certainty that no harm will
occur to infants and children from aggregate exposure to residues of
propamocarb hydrochloride.

F. International Tolerances

	Codex and other import tolerances are currently not available for
propamocarb hydrochloride on lima beans.