Document ID: EPA-HQ-OPP-2006-0205-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-12-26T05:00Z

1. Gowan Company 

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

(7/1/2004)

EPA Registration Division contact: James A. Tompkins, (703) 305-5697

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PP2F6429

Summary of Petitions

	EPA has received a pesticide petition (PP2F6429) from Gowan Company,
370 S. Main Street 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

halosulfuron-methyl:methyl 5-{[(4,6-dimethoxy-2-pyrimidinyl)amino]
carbonyl aminosulfonyl}-

3-chloro-l-methyl-l H-pyrazole-4-carboxylate] in or on the raw
agricultural commodity alfalfa, forage at 1 parts per million (ppm) and
alfalfa, hay at 2 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 FFDCA; 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 metabolism of halosulfuron-methyl as well as
the nature of the residues in plants is adequately understood for
purposes of this tolerance. Metabolism studies were

conducted in three crops, viz.; field com, sugarcane and soybeans.
Metabolism depends on the mode of application. Preemergent applications
result in rapid soil degradation halosulfuron-methyl followed by crop
uptake of the resulting pyrazole moiety. The pyrimidine ring binds
tightly to soil and is eventually converted to carbon dioxide by
microbial degradation. In postemergent applications, little metabolism
and translocation take place resulting in unmetabolized parent compound
as the major residue on the directly treated Joliar surfaces. Very low
residue levels of the metabolite
3-chloro-I-methyl-5-sulfamoylpyrazole-4-carboxylic acid (3-CSA) are
found in the grain.

	2. Analytical method. A practical analytical method, gas chromatography
with a nitrogen

specific detector (TSD) which detects and measures residues
halosulfuron-methyl, is

available for enforcement purposes with a limit of detection that allows
monitoring of food with

residues at or above the levels set in these tolerances. This
enforcement method has been

submitted to the Food and Drug Administration for publication in the
Pesticide Analytical

Manual (PAM II). It has undergone independent laboratory validation and
validation at the

Beltsville laboratory. The Analytical Chemistry Section of the EPA
concluded that the method is

adequate for enforcement. The analytical method is also available for
analyzing meat by products,

which also underwent successful independent laboratory and Beltsville
laboratory

validations.

	3. Magnitude of residues. In alfalfa, maximum forage and hay residues
were approximately 0.6 and 1.1 ppm with a 14 day PHI, respectively.

B. Toxicological Profile

	1. Acute toxicity.  Acute toxicological studies placed the
technical-grade halosulfuron-methyl in Toxicity Category III. A 90-day
feeding study in rats resulted in a lowest-observed-adverse-
effect-level (LOAEL) of 497 milligrams/kilograms/day (mg/kg/day) in
males and 640 mg/kg/day in females, and a no-observed-effect-level
(NOAEL) of 116 mg/kg/day in males and 147

mg/kg/day in females.

	2. Genotoxicty.  Bacterial/mammalian microsomal mutagenicity assays
were performed and found not to be mutagenic. Two mutagenicity studies
were performed to test gene mutation and

found to produce no chromosomal aberrations or gene mutations in
cultured Chinese hamster

ovary cells. An in vivo mouse micronucleus assay did not cause a
significant increase in the

frequency of micronucleated polychromatic erythrocytes in bone marrow
cells. A mutagenicity

study was performed on rats and found not to induce unscheduled DNA
synthesis in primary

rat hepatocytes.

	3. Reproductive and developmental toxicity.  A developmental toxicity
study in rats resulted in a developmental LOAEL of 750 mg/kg/day, based
on decreases in mean litter size and fetal bodyweight, and increases in
resorptions, resorptions/dam, post-implantation loss and in fetal and
litter incidences or soft tissue and skeletal variations, and a
developmental NOAEL of 250

kg/kg/day. Maternal LOAEL was 750 mg/kg/day based on increased incidence
of clinical

observations, reduced body weight gains, and reduced food consumption
and food efficiency.

The maternal NOAEL was 250 mg/kg/day.  A developmental toxicity study in
rabbits resulted in a developmental LOAEL of 150 mg/kg/day, based on
decreased mean litter size and increases in resorptions, resorptions/dam
and postimplantation loss, and a developmental NOAEL of 50 mg/kg/day.
The maternal LOAEL was 150 mg/kg/day based on reduced body weight gain
and reduced food consumption and food efficiency. The maternal NOAEL was
50 mg/kg/day.

A dietary 2-generation reproduction study in rats resulted in parental
toxicity at 223.2 mg/kg/day

in males and 261.4 mg/kg/day in females in the form of decreased body
weights, decreased body

weight gains, and reduced food consumption during the premating period.
Very light effects

were noted in body weight of the offspring at this dose. This effect was
considered to be

developmental toxicity (developmental delay) rather than a reproductive
effect. No effects were

noted on reproductive or other developmental toxicity parameters. The
systemic/ developmental

toxicity LOAEL was 223.2 mg/kg/day in males and 261.4 mg/kg/day in
females; the

systemic/ developmental toxicity NOAEL was 50.4 mg/kg/day in males and
58.7 mg/kg/day in

females. The reproductive LOAEL was greater than 223.2 mg/kg/day in
males and 261.4

mglkg/day in females; the reproductive NOAEL was equal to or greater
than 223.2 mg/kg/day in

males and 261.4 mg/kg/day in females.

	4. Subchronic toxicity.  A 21-day dermal toxicity study in rats
resulted in a NOAEL of 100

mg/kg/day in males and greater than 1,000 mg/kg/day in females. The only
treatment-related

effect was a decrease in body weight gain of the 1,000mg/kglday group in
males.

	5. Chronic toxicity. A 1-year chronic oral study in dogs resulted in a
LOAEL of 40 mg/kg/day based on decreased weight gain and a NOAEL of 10
mg/kg/day for systemic toxicity. A 78-week carcinogenicity study was
performed on mice. Males in the 971.6 mg/kg/day group had

decreased body weight gains and an increased incidence of
microconcretion/mineralization in the

testis and epididymis. No treatment-related effects were noted in
females. Based on these results,

a LOAEL of971.9 mg/kg/day was established in males and NOAELs of 410
mg/kg/day in males

and 1,214.6 mg/kg/day in females were established. The study showed no
evidence of

carcinogenicity. A combined chronic toxicity/carcinogenicity study in
rats resulted in a LOAEL

of 225.2 mg/kg/day in males and 138.6 mg/kg/day in females based on
decreased body weight

gains, and a NOAEL of 108.3 mg/kg/day in males and 56.3 mg/kg/day in
females. The study

showed no evidence of carcinogenicity.

	6. Animal metabolism. EPA stated that the nature of the residue in
ruminants was determined to be adequately understood. In the tissues and
milk of goats, the major extractable residue was the unmetabolized
parent compound. Based on the low residues of the parent compound in
corn grain and the low transfer of residues in the metabolism study,
tolerances on poultry products were not required. In the rat metabolism
study, parent compound was absorbed rapidly but incompletely. Excretion
was relatively rapid at all doses tested with majority of radioactivity
eliminated in the urine and feces by 72 hours. Fecal elimination of
parent was apparently the result of unabsorbed parent.

	7. Metabolite toxicology. The toxicology studies listed below were
conducted with the 3-CSA metabolite. Based on the toxicological data of
the 3-CSA metabolite, EPA concluded that it has

lower toxicity compared to the parent compound and that it should not be
included in the

tolerance expression. The residue of concern is the parent compound
only.

i. A 90-day rat feeding study resulted in a LOAEL in males of >20,000
ppm and a NOAEL of

20,000 ppm (1,400 mg/kg/day). In females, the LOAEL is 10,000ppm (772.8
mg/kg/day) based

on decreased body weight gains and a NOAEL of 1,000ppm (75.8 mg/kg/day).

ii. A developmental toxicity resulted in a LOEL for maternal toxicity
of> 1.000 mg/kg/day based

on the absence of systemic toxicity, a NOAEL of 1,000 mg/kg/day. The
developmental LOEL is

>1,000 mg/kg/day and the NOAEL is 1,000mg/kg/day.

iii. The microbial reverse gene mutation did not produce any mutagenic
effect while the

mammalian cell gene mutation/Chinese hamster ovary cells did not show a
clear evidence of

mutagenic effect in the Chinese hamster ovary cells.

iv. The mouse micronucleus assay did not show any clastogenic or
aneugenic effect.

	8. Endocrine disruption.  No specific tests have been conducted with
halosulfuron-methyl to determine whether the chemical may have an effect
in humans that is similar to an effect produced by a naturally occurring
estrogen or other endocrine effects. However, there were no

significant findings in other relevant toxicity tests, i.e., teratology
and multi-generation

reproduction studies, which would suggest that halosulfuron-methyl
produces effects characteristic of the disruption of the estrogenic
hormone.

C. Aggregate Exposure

	1. Dietary exposure. Tolerances have been established (40 CFR 180.479)
for residues of

halosulfuron-methyl in or on a variety of plant and animal RACs
including field corn at 0.05

ppm, grain sorghum (milo) at 0.05 ppm, sweet com (kernel + cobs with
husks removed) at 0.05

ppm), pop corn grain at 0.05 ppm, sugarcane cane at 0.05 ppm, tree nuts
nutmeat at 0.05 ppm,

pistachio nuts nutmeat at 0.05 ppm, cotton undelinted seed at 0.05 ppm,
rice grain al 0.05 ppm,

melons at 0.1 ppm, and cucurbits at 0.5 ppm; and secondary tolerances in
meat and meat

byproducts at 0.1 ppm (cattle, goats, hogs, horses, and sheep).
Additional tolerances are pending

for fruiting vegetables crop group 8 and beans (dry and snap) at 0.05
ppm, and for asparagus at

0.8 ppm. Tolerances are also established for corn forage and fodder at
0.2 ppm and 0.8 ppm,

respectively, sorghum fodder/stover at 0.1 ppm and rice straw at 0.2
ppm. Additional tolerances

for alfalfa forage and hay of 1 ppm and 2 ppm are being requested with
this petition.

	i. Food.  a. Acute exposure. For purposes of assessing the potential
dietary exposure from food under existing and proposed tolerances,
aggregate exposure is based on the Theoretical

Maximum Residue Contribution (TMRC) which is an estimate of the level of
residues consumed

daily if each food item contained pesticide residues equal to the
tolerance. The calculated TMRC

value using the 99.9111 percentile consumption data was 0.003367 mg/kg
body weight/day for the general US population. This value utilizes only
0.67% of the acute Reference Dose (ARfD) for

all established and proposed tolerances for halosulfuron-methyl. TMRC is
obtained by

multiplying the tolerance levels for each commodity by the daily
consumption of the food forms

of that commodity eaten by the U.S. population and various population
subgroups. In conducting

this exposure assessment, conservative assumptions were made, e.g., 100%
of all commodities

will contain halosulfuron-methyl residues and those residues would be at
the level of their

respective tolerances. This results in a large overestimate of human
exposure. Food consumption

data from DEEM software (Novigen Sciences, Inc.) were used in the
calculation. Field corn and

sorghum forage and fodder are fed to animals, thus exposure of humans to
residues from these

commodities might result if such residues are transferred to meat, milk,
poultry or eggs.

However, based on the results of animal metabolism and the amount of
halosulfuron-methyl

expected in animal feeds, it can be concluded that there is no
reasonable expectation that residues

of halosulfuron-methyl will exceed existing tolerances in meat.

b. Chronic exposure. The chronic Reference Dose (CRID)is 0.1 mg/kg/day.
The calculated

TMRC value using 99.91hpercentile consumption data was 0.000779 mg/kg
body weight/day for

children 1-6 years, the most exposed subpopulation group. This value
utilizes only 0.8% of the

CRfD for all established and proposed tolerances for
halosulfuron-methyl.

c. Short- and intermediate- term exposure. The short-term NOAEL for
females 13+ years and

infants and children is 50 mg/kg/day. Comparing the NOAEL with the
chronic food exposure

from DEEM analysis of 0.000365 mg/kg/day for females 13+ and 0.000779
mg/kg/day for

infants and children results in food MOEs of 136,986 and 61,184
respectively. The

intermediate-term NOAEL is 10mg/kg/day, comparing the NOAEL with the
chronic food

exposure from DEEM analysis of 0.000779 mg/kg/day for children (1-6
years old) results in a

food MOE of 12,836.

d. Chronic risk-carcinogenic. Halosulfuron-methyl has been classified as
a Group E chemical

'based upon the lack of evidence of carcinogenicity in mice and rat, and
has been classified as a not likely human carcinogen.]

	ii. Drinking water. There is no Maximum Contaminant Level (MCL)
established for residues of halosulfuron-methy1. It is not listed for
MCL development or drinking water monitoring under the Safe Drinking
Water Act nor is it a target of EPA's National Survey of Wells for
Pesticides. Gowan is not aware of any halosulfuron-methyl detections in
any wells, ponds, lakes or streams resulting from its use in the United
States. The estimated drinking water environmental concentrations (DWEC)
in ground water (acute and chronic) is 0.008 µg/L. The estimated DWECs
(acute and chronic) for surface water are 4.3 µg/L and 1.1 µg/L,
respectively. These estimates are based on a maximum application rate of
0.063 lbs active per acre, which may be  applied twice per season.

a. Acute exposure and risk. Acute DWLOCs have been calculated for
exposure to halosulfuron-methyl in drinking water for the relevant
population subgroups of females 13+ years and infants and children. The
acute DWLOC is 15,000 µg/L for females 13+ years and 5,000 µg/L for
infants and children. The calculated DWLOCs are significantly higher
than the DWECs for ground water (0.008 µg/L)and surface water (4.3
µg/L).

b. Chronic exposure and risk. Chronic DWLOCs have been calculated for
exposure to

halosulfuron-methyl in drinking water for the US population (48 states)
and the relevant

subgroups of females 13+ years and infants and children. The chronic
DWLOC is 3,500 µg/L

for the U.S. population, 3,000 µ g/L for females 13+ years, and 1,000
µg/L for infants and

children. The calculated DWLOCs are significantly higher than the DWECs
for ground water (0.008 µg/L) and surface water (1.1 µg/L).

c. Short and intermediate term exposure and risk. Short-tern and
intermediate-term DWLOCs

have been calculated for exposure to halosulfuron-methyl in drinking
water for the relevant

population subgroups. The short-term DWLOC is 10,000 µg/L for females
13+ years and 3,700

µg/L for infants and children. The intermediate-term DWLOC is 590 µg/L
for adult males, 57

µg/L for females 13+ years, and 160 µg/L for infants and children. The
calculated intermediate-term DWLOCs are significantly higher than the
chronic DWECs for surface water (1.1 µg/L).

The calculated short-term DWLOCs are significantly higher than the acute
DWECs for ground

water (0.008 µg/L) and surface water (4.3 µg/L).

d. Conclusion. EPA has concluded that potential levels of
halosulfuron-methyl in soil and water

do not appear to have significant toxicological effects on humans or
animals and presents a

negligible risk. Based on the very low level of mammalian toxicity, lack
of other toxicological

concerns and low use rates, there is reasonable certainty that no harm
will result from exposure

to halosulfuron-methyl via drinking water sources.]

	2. Non-dietary exposure. [Halosulfuron-methyl is labeled for use on
commercial and residential turf and other non-crop sites. For
residential applicators, short- and intermediate exposure may occur.
Chronic exposure(>6 months of continuous exposure) are not expected.

a. Acute exposure and risk. There is potential for exposure to
halosulfuron-methyl by

homeowner. However, since endpoints for acute dermal or inhalation were
not identified, the

use of halosulfuron-methyl on residential non-food sites is not expected
to pose an unacceptable

acute risk.

b. Chronic exposure and risk. Chronic exposures for residential use of
halosulfuron-methyl are

not expected and a chronic non-dietary endpoint was not identified,
therefore the use on

residential non-food sites is not expected to pose an unacceptable
chronic risk.

c. Short- and intermediate-term exposure and risk. There is potential
for short- or intermediate-term dermal exposure to residential handlers,
therefore residential exposure assessments were conducted to assess the
following post-application exposure scenarios: (a) dermal exposure to

residues on turf; (b) children's incidental non-dietary ingestion of
residues on residential lawn

from hand-to-mouth transfer; (c) children's ingestion of
pesticide-treated turfgrass.

The short-term dermal MOE for residential handlers is 4,200 which is
significantly greater than

the minimum acceptable MOE of 100.

The short-term dermal MOE for exposure from treated lawns for adult
males, adult females, and

children are 390, 330, and 420, respectively, which are significantly
greater than the minimum

acceptable MOE of 100.The intermediate-term dermal MOE for exposure from
treated lawns for

adult males, adult females, and children are 120, 100, and 130,
respectively, which are

significantly greater than the minimum acceptable MOE of 100. Therefore
the use of

halosulfuron-methyl on residential non-food sites is not expected to
pose an unacceptable short or

intermediate-term risk.  The short-and intermediate-term oral MOE for
hand-to-mouth transfer for children are 4,900 and 1,500, respectively,
which are significantly greater than the minimum acceptable MOE of 100.
Therefore the use of halosulfuron-methyl on residential non-food sites
is not expected to

pose an unacceptable short- or intermediate- term risk. The short- and
intermediate- term oral MOE for incidental ingestion by children are
210,000 and 66,000, respectively, which are significantly greater than
the minimum acceptable MOE of 100. Therefore the use on residential
non-food sites is not expected to pose an unacceptable short- or
intermediate- term risk.

D. Cumulative Effects

	Halosulfuron-methyl belongs to the sulfonyl urea class of chemistry.
The mode of action of

halosulfuron-methyl is the inhibition of the plant enzyme acetolactase
synthetase (ALS), which

is essential for the production of required amino acid in plants.
Although other registered sulfonyl ureas may have similar herbicidal
mode of action, there is no information available to suggest that these
compounds exhibit a similar toxicity profile in the mammalian system
that would be cumulative with halosulfuron-methy1.Thus, consideration of
a common mechanism of toxicity is not appropriate at this time. Gowan is
considering only the potential risks of halosulfuron-methyl in its
aggregate exposure assessment.

E. Safety Determination

	1. U.S. population. 

i. Acute risk. Aggregate exposure risk includes exposure from food and
water. The risk from acute "food only" exposure is ≤ 1% of the RfD for
all population groups which is less than the EPA's level of concern. The
lowest DWLOC calculated was 5,000 µg/L for infants and children. The
calculated DWLOC for females (13+ years) was 15,000 µg/L. For both
subgroups, the DWLOC is significantly higher than the DWEC for acute
ground water (0.008 µg/L) and surface water (4.3 µg/L), therefore, the
risk from aggregate exposure to halosulfuron-methyl residues from all
anticipated dietary exposure routes does not pose appreciable risks to
human health.

ii. Chronic risk. Aggregate chronic exposure to halosulfuron-methyl from
"food only" utilities

less than 0.8% of the RfD for the most sensitive subgroup, children (1-6
years). The lowest

DWLOC calculated was 1,000 µg/L for infants and children, which is
significantly higher than

the DWEC for chronic ground water (0.008 µg/L) and surface water (1.1
µg/L). Therefore, the

aggregate risk from chronic exposure to halosulfuron-methyl residues
from all anticipated

dietary exposures does not pose appreciable risks to human health.

iii. Short- and intermediate- term risk-

a. Short-term aggregate exposure takes into account

chronic dietary food and water plus short-term residential exposure. For
halosulfuron-methyl,

the EPA has determined that it is appropriate to aggregate exposure via
oral exposure route (food

and water) with those via oral and dermal exposure routes from
residential uses. The MOEs for

"food only" and residential exposure routes are 13,859 and 310 for
females 13+ years. Short-term

DWLOC for females 13+ is 10,000 µg/L, which is substantially higher
than the DWEC for

acute surface water (4.3 µg/L).The food only and residential (oral and
dermal) MOEs are well

above the acceptable short-term aggregate MOE of 100. Therefore,
exposure to halosulfuron-methyl residues resulting from current and
proposed uses does not pose a short-term aggregate

risk.

b. Intermediate-term aggregate exposure takes into account chronic
dietary food and water plus

intermediate-term residential exposure. The MOEs for "food only" and
residential exposure

routes are 29,069 and 120 for adult males, and 28,985 and 102 for
females 13+ years. The

intermediate-term DWLOCs are 590 µg/L and 57 µg/L, respectively, for
adult males and

females 13+. Intermediate-term DWLOCs are substantially higher than the
DWEC for chronic

surface water (1.1 µg/L).The food only and residential (dermal) MOEs
are above the acceptable

short-term aggregate MOE of 100. Therefore, exposure to
halosulfuron-methyl residues

resulting from current and proposed uses does not pose a
intermediate-term aggregate risk.

iv. Aggregate cancer risk. Halosulfuron-methyl has been classified as a
Group E chemical based

upon the lack of evidence of carcinogenicity in mice and rats, and has
been classified as a not

likely human carcinogen.

v. Conclusion. Based upon these risk assessments, Gowan concluded that
there is a reasonable

certainty that no harm will result from aggregate exposure to
halosulfuron-methyl residues

resulting from current and proposed uses.]

	2. Infants and children.  Aggregate Risks for Infants and Chi1dren-

i. Safety factor. FFDCA section 408 provides that EPA may apply an
additional safety factor (up to 10) in the case of threshold effects for
infants and children to account for pre- and post-natal toxicity and the
completeness or the database. Except for the pending request for a
developmental neurotoxicity study, the toxicity data base is complete
for halosulfuron-methyl. Based upon reliable toxicity data, the use or
an additional 10x safety factor is not warranted. Dietary assessments do
not indicate a level of concern for potential risks to infants and
children based upon the low use rates of halosulfuron-methyl and that
the results of field and animal RAC studies conclude that detectable
residues are not expected in human foods.

ii. Acute risk. The acute RfD was determined to be 0.5 mg/kg/day based
upon the

developmental rabbit study. The percent of the RfD occupied is 0.67% for
the U.S. population,

0.72% for females 13+ years, and 1.03% for children 1-6 year, which was
the subpopulation with

the highest exposure. The drinking water level of comparison (DWLOC) for
acute exposure for

infants and children is 5,000 µg/L and is significantly greater than
the maximum concentration of

halosulfuron-methyl in drinking water (0.008 µg/L in ground water and
4.3 µg/L in surface

water). 

iii. Chronic risk. The chronic RfD was determined to be 0.1 mg/kg/day
based upon the chronic

dog study. The percent of RfD occupied is 0.8% for the most sensitive
subgroup, children (1-6

years old). The DWLOC for chronic exposure for infants and children is
1,000 µg/L and is

significantly greater than the maximum concentration of
halosulfuron-methyl in drinking water

(0.008 µg/L in ground water and 1.1 µg/L in surface water).

iv. Short- and intermediate- term risk. An aggregate exposure estimate
and risk assessment was

calculated for post-application exposure to halosulfuron-methyl from
treated lawns. Short- term

MOEs for food, residential oral, and residential dermal are 61,184,
4,900, and 420, respectively,

for infants and children. Intermediate-term MOEs for food, residential
oral, and residential

dermal are 12,836, 1,500, and 130, respectively, for children and
infants. The short- and

intermediate- term DWLOCs for infants and children were 3,700 and 160
µg/L, respectively,

which are substantially higher than the DWECs for acute surface water
(4.3 µg/L) and chronic

surface water (1.1 µg/L).

v. Conclusion. Therefore, based on complete and reliable toxicity data
and the conservative

exposure assessment, Gowan concludes that there is reasonable certainty
that no harm will result

to infants and children from aggregate exposure to halosulfuron-methyl
residues with respect to

the proposed new uses on the fruiting vegetable (except cucurbits) crop
group.]

F. International Tolerances

	Maximum residue levels have not been established for residues of
halosulfuron-methyl on alfalfa forage and hay by Canada, Mexico or the
Codex Alimentarius Commission.

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