[Federal Register Volume 62, Number 95 (Friday, May 16, 1997)]
[Notices]
[Pages 27033-27040]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-12907]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-734; FRL-5717-7]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-734, must
be received on or before June 16, 1997.
ADDRESSES: By mail submit written comments to: Public Response and
Program Resources Branch, Field Operations Divison (7505C), Office of
Pesticides Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person bring comments to: Rm. 1132, CM #2,
1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Joanne I. Miller, Product Manager,
(PM) 23, Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location, telephone number, and e-mail address: Rm. 237, CM#2
1921 Jefferson Davis
[[Page 27034]]
Hwy., Arlington, VA 22202, (703) 305-6224; e-mail:
[email protected].
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports grantinig of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-734] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number [PF-734] and appropriate petition
number. Electronic comments on this notice may be filed online at many
Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: May 7, 1997.
James Jones,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
1. E. I. DuPONT
PP 4F4367
EPA has received a pesticide petition (PP) 4F4367 pursuant to
section 408(d) of the Federal Food, Drug, and Cosmetic Act, as amended,
21 U.S.C. Section 346a(d), by the Food Quality Protection Act of 1996
(Pub. L. 104-170, 110 Stat. 1489) from E. I. DuPont de Nemours and Co.,
Inc. (DuPont), Barley Mill Plaza, P.O. Box 80083, Wilmington, DE 19880-
0038, proposing to amend 40 CFR 180.445 by establishing a tolerance for
residues of the herbicide bensulfuron methyl, (methyl-2[[[[[(4,6-
dimethoxy-pyrimidin-2-yl)amino] carbonyl]amino]
sulfonyl]methyl]benzoate) in or on crayfish at 0.05 ppm. The petitioner
has also proposed an amendment to the directions for use for Londax*
herbicide, to permit crayfish farming in treated rice fields. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2); 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.
An adequately validated analytical method is available for
enforcement purposes.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residues of
bensulfuron methyl in rice is adequately understood. Metabolism studies
with bensulfuron methyl indicate the major metabolic pathway being
oxidative o-dealkylation of the parent to a desmethyl metabolite. The
desmethyl metabolite is cleaved at the C-N bond to form sulfonamide
which quickly undergoes ring closure forming homosaccharin; the end
product. Hydroxylation of the 5 position of the pyrimidine ring forms a
hydroxyl metabolite which can also be cleaved to form sulfonamide. An
alternative pathway is the direct cleavage of the C-N bond in the
parent to sulfonamide. One side reaction may lead to the formation of a
free acid metabolite. CBTS previously concluded that due to the very
low level of total residue, the small percentage of the hydroxyl and
free acid metabolites present, and no expressed concerns over the low
levels of residue in rice plants for homosaccharin, sulfonamide, and
the desmethyl metabolite, the only residue of concern in rice plants
(grain and straw) was the parent herbicide, bensulfuron methyl. In
consideration of PP 4F4367 CBTS has again concluded that the nature of
the residue in crayfish is adequately understood and that the only
residue of concern is the parent, bensulfuron methyl.
2. Analytical method. There is an adequately validated practical
analytical method available using HPLC-UV with column and eluent
switching, to measure levels of bensulfuron methyl in or on crayfish
with a limit of quantitation that allows monitoring of crayfish at or
above the proposed tolerance level.
3. Magnitude of the residue. Crayfish field trial residue data show
that bensulfuron methyl residues will not exceed the proposed tolerance
of 0.05 ppm on crayfish. No detectable residues at a limit of
quantitation (LOQ) of 0.025 ppm were found in whole body or cooked
crayfish at 1, 3, 7, 14, or 21 days after bensulfuron methyl
application. In consideration of PP 4F4367 CBTS has concluded that
processing data for crayfish is not required.
B. Toxicological Profile
1. Acute toxicity. Bensulfuron methyl technical has been placed in
EPA Toxicity Category III for acute dermal toxicity based on the test
article being nonlethal and nonirritating at the limit dose of 2,000
mg/kg (highest dose tested). Bensulfuron methyl has been placed in
Category IV for the remaining acute toxicity tests based on the
following: A rat acute oral study with an LD50 of >5,000 mg/
kg; a rat acute inhalation study with an LC50 of >5.0 mg/l;
and primary eye and dermal irritation tests that demonstrated no
significant irritation in the rabbit. A dermal sensitization test with
bensulfuron methyl technical in guinea pigs demonstrated no significant
effects. Based on these results, DuPont believes that bensulfuron
methyl represents a minimal acute toxicity risk.
2. Genotoxicity. Bensulfuron methyl technical was negative (non-
mutagenic) in the Ames microbial mutation assay using four strains of
Salmonella typhimurium and in a hypoxanthine-guanine phosphoribosyl
transferase gene mutation assay using Chinese hamster ovary cells. In
an in vivo bone marrow chromosome study in which
[[Page 27035]]
rats were dosed with 0, 500, 1,500 or 5,000 mg/kg of bensulfuron methyl
technical, no dose related toxicity or effects on mitotic index or
chromosome aberrations were observed. In an in vitro sister chromatid
exchange assay Chinese hamster ovary cells were dosed with bensulfuron
methyl technical at concentrations ranging from 0.135 to 2.7 mM. A
slight (1.4 fold) increase in sister chromatid exchanges was observed
in the nonactivated system at the maximum concentration however, a
negative response was observed in the activated system at the same
concentration. In an in vitro assay to assess unscheduled DNA synthesis
in primary rat hepatocytes, bensulfuron methyl technical was negative.
Based on the weight of these data, DuPont believes that bensulfuron
methyl is neither genotoxic nor mutagenic.
3. Reproductive and developmental toxicity. A two generation, 4
litter reproduction study with CD rats treated at dietary levels of 0,
50, 750, or 7,500 ppm of bensulfuron methyl failed to reveal any
evidence suggestive of an adverse effect on reproductive potential. A
reproductive NOEL was demonstrated at the highest dose tested of 7,500
ppm (309 and 405 mg/kg/day in males and females respectively). In a
developmental toxicity study with bensulfuron methyl technical,
pregnant rats were administered oral doses of 0, 50, 500 or 2,000 mg/
kg/day on gestation days 7-16. There were no indications of compound
related teratogenicity or maternal effects at any dose. Fetuses from
the 200 mg/kg group exhibited signs of minimal toxicity, which included
an increased incidence of minor skeletal variations. These consisted of
extra ossification centers in the lumbar region and incompletely
ossified sternebrae and hyoid. The fetal NOEL was 500 mg/kg/day based
on these observations at the high dose. In a developmental toxicity
study with bensulfuron methyl technical, pregnant rabbits were
administered oral doses of 0, 30, 300 or 1,500 mg/kg/day on gestation
days 7-19. Clinical signs of maternal toxicity and some decrease in
fetal weight gain at the high dose defined maternal and fetotoxic
NOEL's at 300 mg/kg/day. There were no dose related fetal malformations
or variations. A teratogenic NOEL of 1,500 mg/kg/day was defined. Based
on the weight of these data, DuPont believes that bensulfuron methyl is
not a reproductive toxicant. Developmental effects observed in the
absence of maternal toxicity were minimal, were only observed in the
rat and had a clearly defined NOEL. This NOEL, 500 mg/kg/day, far
exceeds any expected human occupational or consumer exposure.
4. Subchronic toxicity. In a 90-day feeding study in rats conducted
with bensulfuron methyl technical at dietary levels of 0, 100, 1,500,
and 7,500 ppm, the NOEL was 1,500 ppm (93 and 111 mg/kg/day, M/F) and
the LEL was 7,500 ppm (474 and 567 mg/kg/day, M/F) based on increased
cholesterol, slight reductions in erythrocytes among males, slightly
elevated liver weights, and reduced uptake of stain in the cytoplasm of
liver cells fixed for histological evaluation in both sexes. The latter
was not considered to be associated with an adverse effect. In a 90-day
feeding study in mice conducted with bensulfuron methyl technical at
dietary levels of 0, 300, 1,000, 3,000 and 10,000 ppm, the NOEL was
1,000 ppm (132 and 133 mg/kg/day, M/F) and the LEL was 3,000 ppm (387
and 407 mg/kg/day, M/F) based on fatty deposition in the cortico-
medullary junction of the adrenals in females, and centrilobular
hepatocyte swelling and increased liver weights in males and females.
In a 90-day feeding study in dogs conducted with bensulfuron methyl
technical at dietary levels of 0, 100, 1,000, and 10,000 ppm, the NOEL
was 1,000 ppm (32.1 and 36.3 mg/kg/day, M/F) and the LEL was 10,000 ppm
(340 and 360 mg/kg/day, M/F) based on elevated alkaline phosphatase and
alanine aminotransferase (ALT or SGPT), elevated liver weights, gross
liver enlargement and discoloration, and microscopic findings of gall
bladder calculus, bile stasis, centrilobular hepatocyte swelling, and
vacuolation of the seminiferous tubules at the highest dose tested.
5. Chronic toxicity/oncogenicity. A 1-year feeding study in dogs
was conducted with bensulfuron methyl technical at dietary levels of 0,
50, 750, and 7,500 ppm. Very little toxicity and no mortality were
observed in this study. Gross findings suggest that bensulfuron methyl
may have directly irritated the oral mucosa, especially in the high
dose males and females. The major target organ was the liver as
demonstrated by elevated alkaline phosphatase and SGPT (ALT), elevated
liver weights, and microscopic findings of brown pigment in the biliary
canaliculi of the liver at the highest dose tested. The defined
systemic NOEL is 750 ppm (21.4 and 19.9 mg/kg/day, M/F) and the
systemic LEL is 7,500 ppm (237.3 and 222.6 mg/kg/day, M/F). A 2-year
combined chronic toxicity and oncogenicity study in mice was conducted
with bensulfuron methyl technical at dietary levels of 0, 10, 150,
2,500 and 5,000 ppm. Very little toxicity was observed in this study.
There were no dose-related effects on mortality, clinical signs, body
weights, food consumption, or food efficiency. The systemic NOEL was
2,500 ppm (226 and 227 mg/kg/day, M/F) and the systemic LEL was 5,000
ppm (455 and 460 mg/kg/day, M/F) based on reduced water consumption;
increased alkaline phosphatase, SGOT, SGPT, and total cholesterol;
enlarged liver, abdominal cavity ascites, and benign nodules and masses
in the liver; increased liver weights; centrilobular hepatocyte
swelling, focal hepatocellular necrosis, and increased brown pigment
deposition of stellate cells in the liver. There were no oncogenic
effects found at the maximum dose of 5,000 ppm (455 and 460 mg/kg/day,
M/F). A 2-year combined chronic toxicity and oncogenicity study in rats
was conducted with bensulfuron methyl technical at dietary levels of 0,
50, 750 and 7,500 ppm. Bensulfuron methyl caused little toxicity at the
doses used in this study. The systemic NOEL was 750 ppm (30 and 40 mg/
kg/day, M/F) and the systemic LEL was 7,500 ppm (309 and 405 mg/kg/day,
M/F) based on decreased body weight gain in females, increased BUN and
creatinine in males, diffuse fatty changes in male livers, and
centrilobular hepatocellular hypertrophy and centrilobular hepatocyte
cytoplasmic basophilia margination in both sexes. Although effects were
minimal to mild for chronic feeding/oncogenicity studies with
bensulfuron methyl, these studies have been found acceptable by EPA as
noted in the New Chemical Standard Toxicology Chapter for DPX-F5384
(bensulfuron methyl) -``because of the mild toxicity and lack of
oncogenic response at substantial maximum doses in the chronic and
subchronic studies in rats and mice. There was also a lack of an
oncogenic response in structurally related chemicals.''
6. Animal metabolism. Disposition and metabolism of bensulfuron
methyl were tested in male and female rats at oral doses of 16 an 2,000
mg/kg. Absorption of the radiolabelled test article from the gut was
nearly total at both dose levels. The major elimination route was urine
for the low-dose groups and feces for the high-dose groups. No
measurable quantities of CO2 or volatile metabolites were
released from the lungs. Minute quantities of radioactivity (2.1%) were
distributed to the body tissues, chiefly the gastrointestinal tract.
Approximately half the administered radioactivity was eliminated by 24
hours in the low-dose groups, and 48
[[Page 27036]]
hours in the high dose groups. Nearly 99% was eliminated by the time of
sacrifice at 96 hours. This study indicates that bensulfuron methyl has
low toxicity and does not accumulate within the body. The major
compound eliminated in urine and feces was ODS DPX-F5384 (desmethyl
metabolite), formed by demethylation of the pyrimidine ring. The parent
compound was found in feces but not in urine.
7. Metabolite toxicology. There is no evidence that the metabolites
of bensulfuron methyl as identified in either the plant or animal
metabolism studies are of any toxicological significance.
8. Endocrine effects. No special studies investigating potential
estrogenic or other endocrine effects of bensulfuron methyl have been
conducted. However, the standard battery of required toxicology studies
has been completed. These 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 to doses that far exceed likely human exposures. Based on
these studies there is no evidence to suggest that bensulfuron methyl
has an adverse effect on the endocrine system.
C. Aggregate Exposure
1. Dietary exposure--(i) food. For purposes of assessing the
potential dietary exposure under these tolerances, an estimate of
aggregate exposure is made using the tolerance on rice grain at 0.02
ppm and crayfish at 0.05 ppm. The potential exposure is obtained by
multiplying the tolerance level residues by the consumption data which
estimates the amount of rice, rice products and crayfish eaten by
various population subgroups. Rice straw is fed to animals, thus
exposure of humans to residues of rice straw might result if such
residues are transferred to meat, milk, poultry, or eggs. However,
based on the results of livestock metabolism studies in which no
quantifiable residues were reported when feeding levels were
approximately 500X the potential dietary burden from feeding
bensulfuron methyl treated rice straw, the EPA has concluded that there
is no reasonable expectation that measurable residues of bensulfuron
methyl will occur in meat or milk. Rice straw is not a poultry feed
item, thus no residues are expected in poultry or eggs. In
consideration of pesticide petition 4F4367 CBTS has concluded that
crayfish do not constitute a significant livestock feed item, and that
no additional secondary residues in animal commodities are anticipated
from the proposed use. There are no other established tolerances or
registered uses for bensulfuron methyl in the United States. Based on a
NOEL of 750 ppm (21.4 and 19.9 mg/kg/day, M/F) from the chronic dog
toxicity study and a 100-fold safety factor, the reference dose (RfD)
is 0.20 mg/kg/day. Assuming residues at tolerance levels and that 100%
of the crop is being treated, a theoretical maximum residue
contribution (TMRC) of <0.00001 mg/kg/day is estimated. With the above
assumptions which clearly overestimate potential human exposure and are
a most conservative assessment of risk, dietary (food) exposure to
bensulfuron methyl will utilize <0.01% of the RfD.
2. Dietary exposure--(ii) drinking water. Other potential dietary
sources of exposure of the general population to residues of pesticides
are residues in drinking water. There is no Maximum Contaminant Level
established for residues of bensulfuron methyl. The petitioner has been
advised by the EPA that all environmental fate data requirements for
bensulfuron methyl have been satisfied and based on these studies and
the conditions of use, the potential for finding significant
bensulfuron methyl residues in water, with the exception of flooded
rice fields, is minimal. However, for purposes of assessing a potential
dietary exposure from water an estimated exposure may be made using
information from a prior Experimental Use Permit (EUP) which has since
been withdrawn without prejudice. Under this EUP bensulfuron methyl was
evaluated as an aquatic vegetation management herbicide applied
directly to water at a rate identical to it's current registered use in
rice. With this prior EUP, a temporary tolerance for bensulfuron methyl
residues in potable water of 0.1 ppm was established. Assuming this
extreme case scenario with residues at this tolerance level and using a
consumption figure of 2 liters per day of drinking water (consistent
with the National Primary Drinking Water Regulations --Synthetic
Organic and Inorganic Chemicals, (56 FR 3526, January 30, 1991)), a
theoretical maximum residue contribution (TMRC) of <0.000004 mg/kg/day
was calculated (calculated and reported by the California Department of
Food and Agriculture, Division of Pest Management, April, 1989). With
the above assumptions which would now reflect an off-label use of
bensulfuron methyl, and therefore clearly overestimate potential human
exposure, dietary (drinking water) exposure to bensulfuron methyl would
still only utilize <0.01% of the RfD.
3. Non-dietary exposure. Bensulfuron methyl is not registered for
any use which could result in non-occupational, non-dietary exposure to
the general population.
D. Cumulative Effects
Bensulfuron methyl belongs to the sulfonylurea class of compounds.
Other compounds in this class are registered herbicides. However, the
herbicidal activity of the sulfonylureas is due to the inhibition of
acetolactase synthase (ALS), an enzyme only found in plants. ALS is
part of the biosynthetic pathway leading to the formation of branched
chain amino acids. Animals lack ALS and this biosynthetic pathway. This
lack of ALS contributes to the low toxicity of the sulfonylurea
compounds in animals. There is no evidence to indicate or suggest that
bensulfuron methyl has any toxic effects on mammals that would be
cumulative with those of any other chemical.
E. Safety Determination
1. U S population in general. Based on a complete and reliable
toxicity database, the EPA has adopted an RfD value of 0.20 mg/kg/day
using the NOEL of 750 ppm (21.4 and 19.9 mg/kg/day, M/F) from the
chronic dog toxicity study and a hundredfold safety factor. Using crop
tolerance levels, assuming 100% of the crop being treated, a drinking
water estimate which is clearly an overestimate based on off-label use,
and a complete battery of toxicity data, it is concluded that aggregate
exposure to bensulfuron methyl will utilize significantly less than
0.1% of the RfD for either the entire U.S. population or any of the
population subgroups for which consumption data is available, including
infants and children. EPA generally has no concern for exposure below
100% of the RfD because the RfD represents the level at or below which
daily aggregate dietary exposure over a lifetime will not pose
appreciable risk to human health. Thus, DuPont believes that there is a
reasonable certainty that no harm will result from aggregate exposure
to bensulfuron methyl residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of bensulfuron methyl,
data from the previously discussed developmental and reproduction
toxicity studies were considered. Developmental studies are designed to
evaluate adverse effects on the developing organism resulting from
pesticide exposure during pre-natal development. Reproduction studies
provide information relating to reproductive and other effects on
adults
[[Page 27037]]
and offspring from pre-natal and post-natal exposure to the pesticide.
Based on the weight of these data, DuPont believes that bensulfuron
methyl is not a reproductive toxicant. Developmental effects observed
in the absence of maternal toxicity were minimal, and were only
observed in the rat and at a dose that far exceeds any expected human
exposure. FFDCA section 408 provides that EPA may apply an additional
safety factor for infants and children in the case of threshold effects
to account for pre- and post-natal toxicity and the completeness of the
database. Based on current toxicological data requirements, the
database for bensulfuron methyl relative to pre-and post-natal effects
for children is complete. Further, as the NOEL of 20 mg/kg/day from the
1-year dog study with bensulfuron methyl which was used to calculate
the RfD (discussed above), is already lower than any of the NOEL's
defined in the developmental and reproductive toxicity studies with
bensulfuron methyl, an additional safety factor is not warranted. As
stated above, aggregate exposure assessments utilized significantly
less than 0.1% of the RfD for either the entire U.S. population or any
of the population subgroups for which consumption data was available,
including infants and children. Therefore, DuPont believes that it may
be concluded that there is reasonable certainty that no harm will
result to infants and children from aggregate exposure to bensulfuron
methyl residues.
F. International Tolerances
There are no Canadian, Mexican, or Codex MRLs/ tolerances for
bensulfuron methyl on rice straw. Compatibility is not a problem at
this time.
2. E. I. DuPONT
PP 5F4490
EPA has received a pesticide petition (PP) 5F4490 pursuant to
section 408(d) of the Federal Food, Drug, and Cosmetic Act, as amended,
21 U.S.C. Section 346a(d), by the Food Quality Protection Act of 1996
(Pub. L. 104-170, 110 Stat. 1489) from E. I. DuPont de Nemours and Co.,
Inc. (DuPont), Barley Mill Plaza, P.O. Box 80083, Wilmington, DE 19880-
0038, proposing to amend 40 CFR 180.445 by amending the existing
tolerance for residues of the herbicide bensulfuron methyl (methyl-
2[[[[[(4,6-dimethoxy- pyrimidin-2-yl)amino]carbonyl]
amino]sulfonyl]methyl]benzoate) in or on the raw agricultural commodity
rice straw from 0.05 ppm to 0.3 ppm. The petitioner has also proposed
an amendment to the directions for use for Londax* herbicide, to reduce
the herbicides application pre-harvest interval from 80 to 60 days. EPA
has determined that the petition contains data or information regarding
the elements set forth in section 408(d)(2); 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.
An adequately validated analytical method is available for
enforcement purposes.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residues of
bensulfuron methyl in rice is adequately understood. Metabolism studies
with bensulfuron methyl indicate the major metabolic pathway being
oxidative o-dealkylation of the parent to a desmethyl metabolite. The
desmethyl metabolite is cleaved at the C-N bond to form sulfonamide
which quickly undergoes ring closure forming homosaccharin; the end
product. Hydroxylation of the 5 position of the pyrimidine ring forms a
hydroxyl metabolite which can also be cleaved to form sulfonamide. An
alternative pathway is the direct cleavage of the C-N bond in the
parent to sulfonamide. One side reaction may lead to the formation of a
free acid metabolite. CBTS previously concluded that due to the very
low level of total residue, the small percentage of the hydroxyl and
free acid metabolites present, and no expressed concerns over the low
levels of residue in rice plants for homosaccharin, sulfonamide, and
the desmethyl metabolite, the only residue of concern in rice plants
(grain and straw) was the parent herbicide, bensulfuron methyl. In
consideration of PP 5F4490 CBTS has again concluded that the only
residue of concern is the parent, bensulfuron methyl.
2. Analytical method. There is an adequately validated practical
analytical method available using HPLC-UV with column and eluent
switching, to measure levels of bensulfuron methyl in or on rice with a
limit of quantitation that allows monitoring of rice grain and straw at
or above tolerance levels. EPA has provided information on this method
to the Food and Drug Administration for future publication in PAM II.
3. Magnitude of the residue. Crop field trial residue data from a
60-day PHI study shows that the established bensulfuron methyl
tolerance on rice grain of 0.02 ppm will not be exceeded when Londax*
is used as directed, and the tolerance need not be changed. An adequate
amount of geographically representative crop field trial residue data
support the amended registration request and show that with the 60-day
PHI, bensulfuron methyl residues will not exceed the proposed tolerance
of 0.3 ppm on rice straw. An adequate bensulfuron methyl rice
processing study using rice bearing detectable residues following an
exaggerated 5X application shows that bensulfuron methyl does not
concentrate in rice bran, hulls, and polished rice; thus no tolerances
on these commodities are required.
B. Toxicological Profile
1. Acute toxicity. Bensulfuron methyl technical has been placed in
EPA Toxicity Category III for acute dermal toxicity based on the test
article being nonlethal and nonirritating at the limit dose of 2,000
mg/kg (highest dose tested). Bensulfuron methyl has been placed in
Category IV for the remaining acute toxicity tests based on the
following: a rat acute oral study with an LD50 of > 5,000
mg/kg; a rat acute inhalation study with an LC50 of > 5.0
mg/l; and primary eye and dermal irritation tests that demonstrated no
significant irritation in the rabbit. A dermal sensitization test with
bensulfuron methyl technical in guinea pigs demonstrated no significant
effects. Based on these results, DuPont believes that bensulfuron
methyl represents a minimal acute toxicity risk.
2. Genotoxicity. Bensulfuron methyl technical was negative (non-
mutagenic) in the Ames microbial mutation assay using four strains of
Salmonella typhimurium and in a hypoxanthine-guanine phosphoribosyl
transferase gene mutation assay using Chinese hamster ovary cells. In
an in vivo bone marrow chromosome study in which rats were dosed with
0, 500, 1,500 or 5,000 mg/kg of bensulfuron methyl technical, no dose
related toxicity or effects on mitotic index or chromosome aberrations
were observed. In an in vitro sister chromatid exchange assay Chinese
hamster ovary cells were dosed with bensulfuron methyl technical at
concentrations ranging from 0.135 to 2.7 mM. A slight (1.4 fold)
increase in sister chromatid exchanges was observed in the nonactivated
system at the maximum concentration; however, a negative response was
observed in the activated system at the same concentration. In an in
vitro assay to assess unscheduled DNA synthesis in primary rat
hepatocytes, bensulfuron methyl technical was negative. Based on the
weight of these data, DuPont
[[Page 27038]]
believes that bensulfuron methyl is neither genotoxic nor mutagenic.
3. Reproductive and developmental toxicity. A two generation, 4
litter reproduction study with CD rats treated at dietary levels of 0,
50, 750, or 7,500 ppm of bensulfuron methyl failed to reveal any
evidence suggestive of an adverse effect on reproductive potential. A
reproductive NOEL was demonstrated at the highest dose tested of 7,500
ppm (309 and 405 mg/kg/day in males and females respectively). In a
developmental toxicity study with bensulfuron methyl technical,
pregnant rats were administered oral doses of 0, 50, 500 or 2,000 mg/
kg/day on gestation days 7-16. There were no indications of compound
related teratogenicity or maternal effects at any dose. Fetuses from
the 200 mg/kg group exhibited signs of minimal toxicity, which included
an increased incidence of minor skeletal variations. These consisted of
extra ossification centers in the lumbar region and incompletely
ossified sternebrae and hyoid. The fetal NOEL was 500 mg/kg/day based
on these observations at the high dose. In a developmental toxicity
study with bensulfuron methyl technical, pregnant rabbits were
administered oral doses of 0, 30, 300 or 1,500 mg/kg/day on gestation
days 7-19. Clinical signs of maternal toxicity and some decrease in
fetal weight gain at the high dose defined maternal and fetotoxic
NOEL's at 300 mg/kg/day. There were no dose related fetal malformations
or variations. A teratogenic NOEL of 1,500 mg/kg/day was defined. Based
on the weight of these data, DuPont believes that bensulfuron methyl
was not a reproductive toxicant. Developmental effects observed in the
absence of maternal toxicity were minimal, were only observed in the
rat and had a clearly defined NOEL. This NOEL, 500 mg/kg/day, far
exceeds any expected human occupational or consumer exposure.
4. Subchronic toxicity. In a 90-day feeding study in rats conducted
with bensulfuron methyl technical at dietary levels of 0, 100, 1,500,
and 7,500 ppm, the NOEL was 1,500 ppm (93 and 111 mg/kg/day, M/F) and
the LEL was 7,500 ppm (474 and 567 mg/kg/day, M/F) based on increased
cholesterol, slight reductions in erythrocytes among males, slightly
elevated liver weights, and reduced uptake of stain in the cytoplasm of
liver cells fixed for histological evaluation in both sexes. The latter
was not considered to be associated with an adverse effect. In a 90-day
feeding study in mice conducted with bensulfuron methyl technical at
dietary levels of 0, 300, 1,000, 3,000 and 10,000 ppm, the NOEL was
1,000 ppm (132 and 133 mg/kg/day, M/F) and the LEL was 3,000 ppm (387
and 407 mg/kg/day, M/F) based on fatty deposition in the cortico-
medullary junction of the adrenals in females, and centrilobular
hepatocyte swelling and increased liver weights in males and females.
In a 90-day feeding study in dogs conducted with bensulfuron methyl
technical at dietary levels of 0, 100, 1,000, and 10,000 ppm, the NOEL
was 1,000 ppm (32.1 and 36.3 mg/kg/day, M/F) and the LEL was 10,000 ppm
(340 and 360 mg/kg/day, M/F) based on elevated alkaline phosphatase and
alanine aminotransferase (ALT or SGPT), elevated liver weights, gross
liver enlargement and discoloration, and microscopic findings of gall
bladder calculus, bile stasis, centrilobular hepatocyte swelling, and
vacuolation of the seminiferous tubules at the highest dose tested.
5. Chronic toxicity/oncogenicity. A 1-year feeding study in dogs
was conducted with bensulfuron methyl technical at dietary levels of 0,
50, 750, and 7,500 ppm. Very little toxicity and no mortality were
observed in this study. Gross findings suggest that bensulfuron methyl
may have directly irritated the oral mucosa, especially in the high
dose males and females. The major target organ was the liver as
demonstrated by elevated alkaline phosphatase and SGPT (ALT), elevated
liver weights, and microscopic findings of brown pigment in the biliary
canaliculi of the liver at the highest dose tested. The defined
systemic NOEL is 750 ppm (21.4 and 19.9 mg/kg/day, M/F) and the
systemic LEL is 7,500 ppm (237.3 and 222.6 mg/kg/day, M/F). A 2-year
combined chronic toxicity and oncogenicity study in mice was conducted
with bensulfuron methyl technical at dietary levels of 0, 10, 150,
2,500 and 5,000 ppm. Very little toxicity was observed in this study.
There were no dose-related effects on mortality, clinical signs, body
weights, food consumption, or food efficiency. The systemic NOEL was
2,500 ppm (226 and 227 mg/kg/day, M/F) and the systemic LEL was 5,000
ppm (455 and 460 mg/kg/day, M/F) based on reduced water consumption;
increased alkaline phosphatase, SGOT, SGPT, and total cholesterol;
enlarged liver, abdominal cavity ascites, and benign nodules and masses
in the liver; increased liver weights; centrilobular hepatocyte
swelling, focal hepatocellular necrosis, and increased brown pigment
deposition of stellate cells in the liver. There were no oncogenic
effects found at the maximum dose of 5,000 ppm (455 and 460 mg/kg/day,
M/F). A 2-year combined chronic toxicity and oncogenicity study in rats
was conducted with bensulfuron methyl technical at dietary levels of 0,
50, 750 and 7,500 ppm. Bensulfuron methyl caused little toxicity at the
doses used in this study. The systemic NOEL was 750 ppm (30 and 40 mg/
kg/day, M/F) and the systemic LEL was 7,500 ppm (309 and 405 mg/kg/day,
M/F) based on decreased body weight gain in females, increased BUN and
creatinine in males, diffuse fatty changes in male livers, and
centrilobular hepatocellular hypertrophy and centrilobular hepatocyte
cytoplasmic basophilia margination in both sexes. Although effects were
minimal to mild for chronic feeding/oncogenicity studies with
bensulfuron methyl, these studies have been found acceptable by EPA as
noted in the New Chemical Standard Toxicology Chapter for DPX-F5384
(bensulfuron methyl) - ``because of the mild toxicity and lack of
oncogenic response at substantial maximum doses in the chronic and
subchronic studies in rats and mice. There was also a lack of an
oncogenic response in structurally related chemicals.''
6. Animal metabolism. Disposition and metabolism of bensulfuron
methyl were tested in male and female rats at oral doses of 16 an 2,000
mg/kg. Absorption of the radiolabelled test article from the gut was
nearly total at both dose levels. The major elimination route was urine
for the low- dose groups and feces for the high-dose groups. No
measurable quantities of CO2 or volatile metabolites were
released from the lungs. Minute quantities of radioactivity (2.1%) were
distributed to the body tissues, chiefly the gastrointestinal tract.
Approximately half the administered radioactivity was eliminated by 24
hours in the low-dose groups, and 48 hours in the high dose groups.
Nearly 99% was eliminated by the time of sacrifice at 96 hours. This
study indicates that bensulfuron methyl has low toxicity and does not
accumulate within the body. The major compound eliminated in urine and
feces was ODS DPX-F5384 (desmethyl metabolite), formed by demethylation
of the pyrimidine ring. The parent compound was found in feces but not
in urine.
7. Metabolite toxicology. There is no evidence that the metabolites
of bensulfuron methyl as identified in either the plant or animal
metabolism studies are of any toxicological significance.
8. Endocrine effects. No special studies investigating potential
estrogenic or other endocrine effects of bensulfuron methyl have been
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conducted. However, the standard battery of required toxicology studies
has been completed. These 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 to doses that far exceed likely human exposures. Based on
these studies there is no evidence to suggest that bensulfuron methyl
has an adverse effect on the endocrine system.
C. Aggregate Exposure
1. Dietary exposure--(i) food. For purposes of assessing the
potential dietary exposure under these tolerances, an estimate of
aggregate exposure is made using the tolerance on rice grain at 0.02
ppm. The potential exposure is obtained by multiplying the tolerance
level residues by the consumption data which estimates the amount of
rice or rice products eaten by various population subgroups. Rice straw
is fed to animals, thus exposure of humans to residues of rice straw
might result if such residues are transferred to meat, milk, poultry,
or eggs. However, based on the results of livestock metabolism studies
in which no quantifiable residues were reported when feeding levels
were approximately 500X the potential dietary burden from feeding
bensulfuron methyl treated rice straw, the EPA has concluded that there
is no reasonable expectation that measurable residues of bensulfuron
methyl will occur in meat or milk. Rice straw is not a poultry feed
item, thus no residues are expected in poultry or eggs. There are no
other established tolerances or registered uses for bensulfuron methyl
in the United States. Based on a NOEL of 750 ppm (21.4 and 19.9 mg/kg/
day, M/F) from the chronic dog toxicity study and a hundredfold safety
factor, the reference dose (RfD) is 0.20 mg/kg/day. Assuming residues
at tolerance levels and that 100% of the crop is being treated, a
theoretical maximum residue contribution (TMRC) of <0.000001 mg/kg/day
is calculated. With the above assumptions which clearly overestimate
potential human exposure and are a most conservative assessment of
risk, dietary (food) exposure to bensulfuron methyl will utilize <0.01%
of the RfD.
2. Dietary exposure--(ii) drinking water. Other potential dietary
sources of exposure of the general population to residues of pesticides
are residues in drinking water. There is no Maximum Contaminant Level
established for residues of bensulfuron methyl. The petitioner has been
advised by the EPA that all environmental fate data requirements for
bensulfuron methyl have been satisfied and based on these studies and
the conditions of use, the potential for finding significant
bensulfuron methyl residues in water, with the exception of flooded
rice fields, is minimal. However, for purposes of assessing a potential
dietary exposure from water an estimated exposure may be made using
information from a prior Experimental Use Permit (EUP) which has since
been withdrawn without prejudice. Under this EUP bensulfuron methyl was
evaluated as an aquatic vegetation management herbicide applied
directly to water at a rate identical to it's current registered use in
rice. With this prior EUP, a temporary tolerance for bensulfuron methyl
residues in potable water of 0.1 ppm was established. Assuming this
extreme case scenario with residues at this tolerance level and using a
consumption figure of 2 liters per day of drinking water (consistent
with the National Primary Drinking Water Regulations --Synthetic
Organic and Inorganic Chemicals, (56 FR 3526, January 30, 1991)), a
theoretical maximum residue contribution (TMRC) of <0.000004 mg/kg/day
was calculated (calculated and reported by the California Department of
Food and Agriculture, Division of Pest Management, April, 1989). With
the above assumptions which would now reflect an off-label use of
bensulfuron methyl, and therefore clearly overestimate potential human
exposure, dietary (drinking water) exposure to bensulfuron methyl would
still only utilize <0.01% of the RfD.
3. Non-dietary exposure. Bensulfuron methyl is not registered for
any use which could result in non-occupational, non-dietary exposure to
the general population.
D. Cumulative Effects
Bensulfuron methyl belongs to the sulfonylurea class of compounds.
Other compounds in this class are registered herbicides. However, the
herbicidal activity of the sulfonylureas is due to the inhibition of
acetolactase synthase (ALS), an enzyme only found in plants. ALS is
part of the biosynthetic pathway leading to the formation of branched
chain amino acids. Animals lack ALS and this biosynthetic pathway. This
lack of ALS contributes to the low toxicity of the sulfonylurea
compounds in animals. There is no evidence to indicate or suggest that
bensulfuron methyl has any toxic effects on mammals that would be
cumulative with those of any other chemical.
E. Safety Determination
1. U.S. population in general. Based on a complete and reliable
toxicity database, the EPA has adopted an RfD value of 0.20 mg/kg/day
using the NOEL of 750 ppm (21.4 and 19.9 mg/kg/day, M/F) from the
chronic dog toxicity study and a hundredfold safety factor. Using crop
tolerance levels, assuming 100% of the crop being treated, a drinking
water estimate which is clearly an overestimate based on off-label use,
and a complete battery of toxicity data, it is concluded that aggregate
exposure to bensulfuron methyl will utilize significantly less than
0.1% of the RfD for either the entire U.S. population or any of the
population subgroups for which consumption data is available, including
infants and children. EPA generally has no concern for exposure below
100% of the RfD because the RfD represents the level at or below which
daily aggregate dietary exposure over a lifetime will not pose
appreciable risk to human health. Thus, DuPont believes that there is a
reasonable certainty that no harm will result from aggregate exposure
to bensulfuron methyl residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of bensulfuron methyl,
data from the previously discussed developmental and reproduction
toxicity studies were considered. Developmental studies are designed to
evaluate adverse effects on the developing organism resulting from
pesticide exposure during pre-natal development. Reproduction studies
provide information relating to reproductive and other effects on
adults and offspring from pre-natal and post-natal exposure to the
pesticide. Based on the weight of these data, DuPont believes that
bensulfuron methyl is not a reproductive toxicant. Developmental
effects observed in the absence of maternal toxicity were minimal, and
were only observed in the rat and at a dose that far exceeds any
expected human exposure. FFDCA section 408 provides that EPA may apply
an additional safety factor for infants and children in the case of
threshold effects to account for pre- and post-natal toxicity and the
completeness of the database. Based on current toxicological data
requirements, the database for bensulfuron methyl relative to pre- and
post-natal effects for children is complete. Further, as the NOEL of 20
mg/kg/day from the 1-year dog study with bensulfuron methyl which was
used to calculate the RfD (discussed above), is already lower than any
of the NOEL's defined in the developmental and reproductive toxicity
studies with bensulfuron methyl, an additional safety factor is not
warranted. As stated above,
[[Page 27040]]
aggregate exposure assessments utilized significantly less than 0.1% of
the RfD for either the entire U.S. population or any of the population
subgroups for which consumption data was available, including infants
and children. Therefore, DuPont believes that it may be concluded that
there is reasonable certainty that no harm will result to infants and
children from aggregate exposure to bensulfuron methyl residues.
F. International Tolerances
There are no Canadian, Mexican, or Codex MRLs/ tolerances for
bensulfuron methyl on rice straw. Compatibility is not a problem at
this time.
[FR Doc. 97-12907 Filed 5-15-97; 8:45 am]
BILLING CODE 6560-50-F