[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

[[Page 27039]]

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