[Federal Register: March 19, 1998 (Volume 63, Number 53)]
[Notices]               
[Page 13401-13404]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19mr98-55]

-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[PF-797; FRL-5776-7]

 
Notice of Filing of Pesticide Petitions

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

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 agricultural commodities.

DATES: Comments, identified by the docket control number PF-797, must 
be received on or before April 20, 1998.

ADDRESSES: By mail submit written comments to: Information and Records 
Integrity Branch, Public Information and Services Divison (7502C), 
Office of Pesticides Programs, Environmental Protection Agency, 401 M 
St., SW., Washington, DC 20460. In person bring comments to: Rm. 119, 
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. 119 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: James A. Tompkins, Product 
Manager (PM) 25, Registration Division, (7505C), Office of Pesticide 
Programs, Environmental Protection Agency, 401 M St., SW., Washington, 
DC 20460. Office location and telephone number: Rm. 239, 1921 Jefferson 
Davis Hwy., Arlington, VA., (703) 305-5697; e-mail: 
Tompkins.jim@epamail.epa.gov.

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 raw 
agricultural 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, as well as the public version, 
has been established for this notice of filing under docket control 
number PF-797 (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:
    opp-docket@epamail.epa.gov


    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 5.1/6.1 file format or 
ASCII file format. All comments and data in electronic form must be 
identified by the docket control number PF-797 and appropriate petition 
number. Electronic comments on this notice may be filed online at many 
Federal Depository Libraries.

    Authority: 21 U.S.C. 346a.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives, 
Feed additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: March 3, 1998.

James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

E.I. du Pont de Nemours & Company, Agricultural Products

PP 3F4215

    EPA has received a pesticide petition (PP 3F4215) from E.I. du Pont 
de Nemours & Company, Agricultural Products, P.O. Box 80038, 
Wilmington, DE 19880-0038, proposing pursuant to section 408(d) of the 
Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR 
part 180 by establishing a tolerance for residues of metsulfuron methyl 
(methyl-2-[[[[(4-methoxy-6-methyl-1-3, 5-triazin-2-yl)amino]carbonyl] 
amino]sulfonyl]benzoate) in or on the raw agricultural commodities 
sorghum grain at 0.1 parts per million (ppm), sorghum forage at 0.2 
ppm, and sorghum fodder at 0.2 ppm. EPA has determined that the 
petition contains data or information regarding the elements set forth 
in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated 
the sufficiency of the submitted data at this time or whether the data 
supports granting of the petition. Additional data may be needed before 
EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The qualitative nature of the residues of 
metsulfuron methyl is adequately understood. Metabolism studies 
conducted with radioactive 14C-metsulfuron methyl on wheat and barley 
under field conditions and on wheat under greenhouse conditions showed 
that residues dissipate rapidly in plants, primarily due to growth 
dilution. In these metabolism studies conducted at exaggerated rates, 
wheat and barley grain did not contain any detectable level of 
metsulfuron methyl or its metabolites (<0.01 mg/kg). Residues of 
individual metabolites were very low in straw in studies conducted at 
35 g a.i./ha (0.5 oz a.i./acre, <0.01 to 0.02 mg/kg). The only 
situation where residues of an

[[Page 13402]]

individual substance was detected in straw above 0.1 mg/kg was under 
greenhouse conditions at 70 g a.i./ha (1 oz a.i./acre), ( 8 X maximum 
recommended rate), metsulfuron methyl residue level measured in straw 
at maturity was 0.44 mg/kg (other individual metabolites were below 0.1 
mg/kg).
    The initial step of the metabolic breakdown of metsulfuron methyl 
involves either hydroxylation of the phenyl ring and subsequent 
conjugation with glucose or cleavage of the sulfonylurea bridge. The 
latter process results in triazine amine derivatives from one side of 
the molecule and sulfonamide derivatives from the other side, which may 
further evolve to saccharin through cyclization.
    Plant/animal comparative metabolism showed two plant unique 
metabolites (4-hydroxy metsulfuron methyl and its glucose conjugate). 
However they do not occur at detectable levels (< 0.01 mg/kg) in cereal 
grain, even at exaggerated rates of application. For this reason they 
were not subject to any testing and were not of concern for the purpose 
of establishing the proposed tolerance.
    Based on the absence of detectable residue in food commodities 
(wheat and barley grain) and on the expected low residue levels of 
individual substances in feed items (straw) under normal use 
conditions, and the Residue Chemistry Guidelines (OPPTS 860-1300, D, 
ii) which states that; one metabolism study will be required for each 
of the crop groups defined in CFR 40 180.34(f) except for herbs and 
spices, a plant metabolism study in grain sorghum was not required.
    A confined crop rotation study was conducted using sugar beets, 
oats, rape and soybeans as following crops, an application rate of 16 g 
a.i./ha, (0.23 oz a.i./acre), (2  x  the maximum recommended rate) and 
a 120-day treatment-to-planting interval. A field crop rotation study 
was also conducted using oats, rape, sorghum and soybean as following 
crops, a 30 g a.s./ha, (0.86 oz a.i./acre), application rate and a 1-
year treatment-to-planting interval. Residues of metsulfuron methyl or 
its degradation products were not detected in any edible crop 
commodities (<0.01 mg/kg), suggesting that use of metsulfuron methyl 
should not expose consumers to detectable residues in food through 
following crops.
    2. Analytical method. The quantification of metsulfuron methyl is 
by HPLC/UV (high performance liquid chromatography/ultra violet) 
utilizing eluent and column switching with UV absorbance detection at 
254 nm. The LOQ (limits of quantitation) of the analytical method for 
sorghum is 0.10 ppm for metsulfuron methyl and its metabolite (4-
hydroxy metsulfuron methyl) in grain and fodder, 0.050 ppm for 
metsulfuron methyl and its metabolite in forage, 0.070 ppm for the 
glucose conjugate metabolite in grain and forage, and 0.14 ppm for the 
glucose conjugate metabolite in fodder. The LOQ of the analytical 
method for metsulfuron methyl and its metabolite in wheat and barley is 
0.05 ppm for wheat/barley forage or grain and 0.10 ppm for wheat/barley 
straw.
    3.--a. Magnitude of residues. The results of an analyses of sorghum 
grain, fodder and stover (at seed maturity), forage and hay (30 days), 
after application of metsulfuron methyl at the maximum proposed label 
rate and twice the rate, show that all residues of metsulfuron methyl 
and its metabolites (4-hydroxy metsulfuron methyl and its glucose 
conjugate) were below the limit of quantitation (0.05 or 0.1 ppm).
    b. Magnitude of residues in processed commodities. Sorghum was 
field treated with metsulfuron methyl at exaggerated rates and samples 
were analyzed for metsulfuron methyl and its metabolites in bran, large 
grits, small grits, flour, grain dust, starch and gluten. All residues 
of metsulfuron methyl and it's metabolites in sorghum seeds and its 
processed fractions were below the limit of quantitation (<0.02-0.05 
ppm).

B. Toxicological Profile

    1. Acute toxicity. Based on EPA criteria, technical metsulfuron 
methyl is in acute toxicity Category IV for oral and inhalation routes 
of exposure and for dermal irritation and Category III for the dermal 
route of exposure and for eye irritation. It is not a skin sensitizer.
    Acute oral toxicity in rats     LD50>5000 mg/kg
    Acute dermal toxicity in rabbits     LD50>2000 mg/kg
    Acute inhalation toxicity in rats     LD50>5.0 mg/L
    Primary eye irritation in rabbits     Effects reversed within 72 
hours.
    Primary dermal irritation in rabbits     No irritation observed.
    Dermal sensitization in guinea pigs     Non-sensitizer.
    2. Genotoxicty. Metsulfuron methyl has shown no genotoxic activity 
in the following listed in-vitro and in-vivo tests, except for in-vitro 
chromosomal aberration (CHO):
    Ames          Negative
    Mammalian gene mutation (CHO/HGPRT)     Negative
    Unscheduled DNA synthesis     Negative
    In-vivo bone marrow cytogenetics      Negative
    In-vivo mouse micronucleus      Negative
    In-vitro chromosomal aberration (CHO)     Positive
    Metsulfuron methyl was only positive at concentrations > 1,000 mg/L 
in an in vitro test for induction of chromosome aberrations in Chinese 
Hamster Ovary cells. In vivo studies included the assessment of 
chromosome aberrations by metaphase analysis in bone marrow of male and 
female rats and the evaluation of micronuclei in bone marrow 
polychromatic erythrocytes of male and female mice. The results of both 
studies were negative when exposures were conducted up to 5,000 mg/kg. 
The fact that no effects were observed in the more definitive in vivo 
tests and considering the negative results in all other genotoxicity 
studies, the weight-of-evidence indicates that metsulfuron methyl is 
neither genotoxic nor mutagenic.
    3. Reproductive and developmental toxicity. The results of a series 
of studies indicated that there were no reproductive, developmental or 
teratogenic hazards associated with the use of metsulfuron methyl. In a 
rat multigeneration reproduction study, reduced parental body weights 
were observed for both generations at the highest dose tested, 5,000 
ppm. There were no effects on fertility, lactation, litter size or pup 
survival. The NOEL was 500 ppm (or 34 to 43 mg/kg bw/day).
    In studies conducted to evaluate developmental toxicity potential, 
metsulfuron methyl was neither teratogenic nor uniquely toxic to the 
conceptus (i.e., not considered a developmental toxin). In the rat 
study, maternal toxicity, presented as reduced food consumption and 
body weight gain, was observed at 250 mg/kg bw and above. The systemic 
NOEL for the dams was 40 mg/kg/day. There were no effects on the 
conceptus at the highest dose tested, 1,000 mg/kg/day. Therefore, the 
fetal NOEL for rats is greater than 1000 mg/kg/day. In the rabbit 
developmental toxicity study, maternal mortality, reduced food 
consumption, and reduced body weights were observed at or above 100 mg/
kg bw. The NOEL for maternal toxicity in rabbits was 25 mg/kg, based on 
maternal mortality and body weight decreases. Impact on the fetuses was 
minimum at these maternally toxic doses and was characterized only by a 
non-statistically significant trend in incomplete ossification of 
frontal bones at 100 and 300 mg/kg bw and above. The NOEL for fetal 
toxicity in rabbits was >700 mg/kg, the highest dose tested.

[[Page 13403]]

    4. Subchronic toxicity. Repeated dietary exposures to metsulfuron 
methyl presented low toxicity manifested as reduced food consumption 
and body weight gain in the rat and the dog. There were no adverse 
effects observed in mice in subchronic studies at the highest dose 
tested, 5,000 ppm. The NOEL for subchronic exposure in mice was >5000 
ppm (814 and 944 mg/kg/day, M/F). The rat was the most sensitive 
species tested in subchronic toxicity studies. The NOEL was 1,000 ppm 
(68 and 84 mg/kg/day for males amd females respectively) based on 
decreased body weights, body weight gains, and total serum protein in 
females, and decreased relative liver weights in males exposed at 7,500 
ppm. In a 90-day feeding study in dogs, the NOEL was 5,000 ppm (134 and 
129 mg/kg/day, M/F), the highest dose tested.
    A 21-day dermal study was conducted in rabbits at 0, 125, 500 or 
2,000 mg/kg/day. The NOEL was 125 mg/kg/day based on dermal effects at 
the application site; the NOEL for systemic toxicity was 2,000 mg/kg/
day.
    5. Chronic toxicity. Chronic Toxicity studies of metsulfuron methyl 
resulted in only minimal effects in the rat, mouse, or dog. Metsulfuron 
methyl was not oncogenic in the chronic rat and mouse bioassays.
    A 1-year feeding study in dogs, the NOEL for chronic toxicity in 
beagle dogs was 500 ppm (or 13 mg/kg/day) and 5,000 ppm (or 127 mg/kg/
day) in male and female dogs, respectively. Metsulfuron methyl produced 
minimal toxicity after 12 months administration to male beagle dogs, 
manifested as minimal interference with normal nutrition by decreasing 
food consumption toward the end of 1 year. This minimal interference 
was not considered adverse since it did not cause changes in body 
weights or body weight gains.
    In an 18-month study in mice, the NOEL was 5,000 ppm (666 and 836 
mg/kg/day for males and females, respectively), the highest dose 
tested. Metsulfuron methyl is not an oncogen in this study.
    A 2-year combined chronic toxicity and oncogenicity study in rats, 
the NOEL was 500 ppm (or 23 and 30 mg/kg/day for males and females, 
respectively). Metsulfuron methyl was not oncogenic in rats nor was 
target organ toxicity evident after two years administration. Chronic 
toxicity was manifested as minimal interference with normal nutrition 
and subsequent decreases in body weight gain that were more pronounced 
during the early growth phase of the animals life span and became less 
evident toward the end of the study.
    6. Animal metabolism. The metabolism of metsulfuron methyl in 
animals (rat, hen and goat) is adequately understood and similar among 
the species evaluated. The rat metabolism and disposition data 
indicated rapid absorption, metabolism and elimination. In the rat, 
approximately 90% of the administered dose of metsulfuron methyl was 
excreted in the feces and urine within 72 hours. The biological half-
lives were 9-16 hours for low-dose groups and 23-29 hours for high-dose 
groups. The major pathway was breakdown of the urea bridge to give rise 
to either aminosulfonyl benzoate or sulfonamide and the triazine amine 
derivative. The secondary biotransformation pathway was demethylation 
of aminosulfonyl benzoate to form saccharin. Preconditioning with low-
dose exposures did not affect the metabolism of metsulfuron methyl. 
There was no evidence of accumulation of metsulfuron methyl or its 
metabolites in any organ or tissue. A significant portion (85-95%) of 
the recovered radioactivity from urine, feces and tissues was intact 
metsulfuron methyl. There were two major plant specific metabolites 
identified, that were not detected in the rat. However, in residue 
studies, no detectable residues of parent or major plant unique 
metabolites, were found in the feed and food items of cereal crops 
treated at the maximum seasonal use rate. Hence, toxicity testing of 
other degradation products of metsulfuron methyl was not needed.
    Results from a metabolism study with two radioactive forms of 
metsulfuron methyl, (14C-Phenyl and 14C-Triazine) in the laying hens 
show that virtually all the radioactivity was eliminated in the 
excreta. The total radioactivity in edibale tissues and eggs 
represented </=0.2% of the total radioactivity administered for either 
radiolabel. Parent metsulfuron methyl was excreted largely unchanged, 
and a minor portion is metabolized to o- desmethyl metsulfuron methyl.
    The fate of metsulfuron methyl and its metabolite was investigated 
in the lactating goat. Metsulfuron methyl and the metabolite were 
eliminated mostly in the urine and feces. Traces of radioactivity were 
found in some tissues and in milk (0.008-0.009%) of the parent and no 
radioactivity of the metabolite was detected in the milk or any organ 
or tissue sample.
    In a cattle feeding study, metsulfuron methyl was rapidly excreted 
in the urine and feces of the treated cows. Less than 0.1% of the daily 
dose was excreted in the milk as metsulfuron methyl and <10% of the 
metsulfuron methyl residue level was found as the glucoronide 
conjugate. Residues (<0.1 ppm) were found in the kidney of cows 
slaughtered 12 hours after treatment stopped but not in cows 
slaughtered a week later.
    Tolerances for metsulfuron methyl in fat (0.1 ppm), meat (0.1 ppm), 
meat by products (0.1 ppm), and kidney (0.5 ppm) of cattle, goats, 
hogs, horses and sheep, and a tolerance of 0.05 ppm in milk have been 
posted in 40CFR 180.428.
    7. Metabolite toxicology. There is no evidence that the metabolites 
of metsulfuron methyl as identified in either the plant or animal 
metabolism studies are of any toxicological significance.
    8. Endocrine disruption. No special studies investigating potential 
estrogenic or other endocrine effects of metsulfuron 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 metsulfuron methyl 
has an adverse effect on the endocrine system.

C. Aggregate Exposure

    1. Dietary exposure. Tolerances have been established (40 CFR 
180.428) for the residues of metsulfuron methyl in or on various food 
commodities ranging from 0.05 ppm in milk to 0.5 in kidney. There are 
no potential sources of exposure of the general population to residues 
of metsulfuron methyl from drinking water or non-occupational sources 
such as in door and out door residential uses. There are no in door or 
out door residential uses registered for metsulfuron methyl. There are 
no acute dietary exposure or cancer risk endpoints of concern for 
metsulfuron methyl. Aggregate risk has been assessed from chronic 
exposure to food.
    2. Food. Tolerances have been established for metsulfuron methyl on 
the following food crops: barley, wheat, and sugar cane. A tolerance of 
0.1 ppm for sorghum grain was included in this assessment. Also 
included were tolerances for meat and milk commodities. The dietary 
exposure was estimated using the Dietary Exposure Evaluation Model 
(DEEM ver. 5.03) which utilizes the 1989-1991 CSFII food consumption 
database. In conducting this assessment the

[[Page 13404]]

conservative assumption was made that residues would be at the 
tolerance level. Use of the tolerances rather than actual field 
measurements will result in an overestimate of human dietary exposure. 
The existing metsulfuron methyl tolerances with the addition of the 
sorghum tolerance result in a theoretical maximum residue level (TMRC) 
that is equivalent to the following percentages of the RfD:
    U.S. Population        0.3%
    Nursing Infants (<1 year old)      0.1%
    Non-Nursing Infants (<1 year old)      0.4%
    Children (1-6 years old)      0.8%
    Children (7-12 years old)      0.5%
    Thus, the estimated exposure for the U.S. population and all 
subpopulation was less than 1% of the RfD. Metsulfuron methyl RfD (0.3 
mg/kg/day)is based on the NOEL for the 2-year rat study. The most 
sensitive chronic toxicity/oncogenicity study. The subpopulation with 
the highest exposure was children ages 1-6 years (0.8% of the RfD). 
Based on the residue data, potential for dietary exposure is extremely 
low. Residue studies have shown no residue above LOQ (0.05 or 0.02 ppm) 
in sorghum samples evaluated including the sorghum grain processed 
fractions. No dietary exposure is anticipated from secondary residues 
in meat or milk. Although sorghum is considered a major foodstuff for 
cattle and poultry, residue studies and metabolism studies in the 
laying hen and lactating goat and cattle feeding studies showed 
residues below LOQ of processed fractions and less than 2% of the 
administered concentration in edible meat and eggs. Only traces of 
metsulfuron methyl were found in some goat meat and milk (0.008-0.009).
    Direct human consumption of sorghum grain as a food commodity in 
the U.S. is extremely low. At the above levels of exposure, there is a 
reasonable certainty that no harm will result from dietary exposure to 
metsulfuron methyl.
    3. Drinking water. Another potential source of dietary exposure to 
pesticides are residues in drinking water. There is no established 
Maximum Contaminant Level (MCL) for metsulfuron methyl in water. Based 
on the low use rate of metsulfuron methyl and a use pattern that is not 
widespread, DuPont does not anticipate residues of metsulfuron methyl 
in drinking water and exposure from this route is unlikely.
    4. Non-dietary exposure. Metsulfuron methyl is registered for use 
in weed and brush control in non-crop situations including industrial, 
unimproved turf areas. Metsulfuron methyl is not to be used on lawns, 
walks, drive ways, tennis courts, golf courses, athletic fields, 
commercial sod operations, or other high maintenance, fine turf grass 
areas, or similar areas. Any non-occupational exposure to metsulfuron 
methyl in the unimproved areas is likely to be negligible.

D. Cumulative Effects

    Metsulfuron methyl belongs to the sulfonylurea class of compounds. 
The herbicidal activity of the sulfonylurea 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. We are aware of no information to indicate or 
suggest that metsulfuron methyl has any toxic effects on mammals that 
would be cumulative with those of any other chemicals.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions 
described above, and based on the most sensitive chronic NOEL of 25 mg/
kg/day and an RfD of 0.3 mg/kg/day, the aggregate dietary exposure will 
utilize less than 1% of the RfD for the U.S. population. Generally, 
exposure below 100% of the RfD are of no concern because the RfD 
represents the level at or below which daily aggregate dietary exposure 
over a lifetime will not pose risk to human health. We therefore 
conclude that there is a reasonable certainty that no harm will result 
from aggregate exposure to metsulfuron methyl residues.
    Although no formal acute dietary margin of exposure (MOE) 
determinations were made, it is highly unlikely that the MOE would 
exceed a level of concern due to the low acute mammalian toxicity of 
this compound].
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of metsulfuron methyl, 
data were considered from developmental toxicity studies in the rat and 
the rabbit, and a multi-generation reproduction study in the rats. 
These studies proved that metsulfuron methyl was not a teratogenic or a 
developmental toxin.
    Using the conservative exposure assessment described above, the 
percent of the RfD that will be utilized ranges from 0.1 to 0.8% for 
infants and young children. Based on this we conclude that there is a 
reasonable certainty that no harm will result to infants and children 
from aggregate exposure to metsulfuron methyl residues.
    Although no formal acute dietary margin of exposure determinations 
were made, it is highly unlikely that the MOE would exceed a level of 
concern due to the low mammalian toxicity of this compound.

F. International Tolerances

    There are no Canadian, Mexican, or Codex Maximum Residue Level 
(MRLs) for metsulfuron methyl on sorghum grain.

[FR Doc. 98-7141 Filed 3-18-98; 8:45 am]
BILLING CODE 6560-50-F