[Federal Register Volume 62, Number 242 (Wednesday, December 17, 1997)]
[Notices]
[Pages 66083-66091]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-32936]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-782; FRL-5759-1]


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-782, must 
be received on or before January 16, 1998.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch (7502C), Information Resources and Services 
Division, 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 to: opp-
[email protected]. Follow 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: The product manager listed in the 
table below:

------------------------------------------------------------------------
                                   Office location/                     
        Product Manager            telephone number          Address    
------------------------------------------------------------------------
Joanne Miller (PM 23).........  Rm. 237, CM #2, 703-    1921 Jefferson  
                                 305-6224, e-mail:       Davis Hwy,     
                                 miller.joanne@epamail   Arlington, VA  
                                 .epa.gov.                              
James Tompkins (PM 25)........  Rm. 239, CM #2, 703-    Do.             
                                 305-5697, e-mail:                      
                                 tompkins.james@epamai
l.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 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 granting 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-782] (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 5.1/6.1 or ASCII file 
format. All comments and data in electronic form must be identified by 
the docket control number [PF-782] 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: December 3, 1997.

Peter Caulkins,

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.


[[Page 66084]]



1. DowElanco

PP 6F4772

    EPA has received a pesticide petition (PP 6F4772) from DowElanco, 
9330 Zionsville Road, Indianapolis, IN 46268, 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 fluroxypyr methylheptyl ester (MHE) and its only 
significant metabolite fluroxypyr, free and conjugated, all expressed 
as fluroxypyr in or on the raw agricultural commodities wheat, barley, 
and oats as follows: 0.5 parts per million (ppm) (grain), 10 ppm (straw 
and forage), 20 ppm (hay), and 0.5 ppm (aspirated grain fractions, 
wheat). Because residues of fluroxypyr MHE or fluroxypyr, free or 
conjugated, may occur in animal feeds derived from wheat, barley, and 
oats, the following meat and milk tolerances are also being proposed: 
0.1 ppm (meat, fat, milk, and meat byproducts except for kidney) and 
0.5 ppm (kidney). The proposed analytical method is based on gas 
chomatography (GC) with mass spectral (MS) detection. EPA has 
determined that the petition contains data or information regarding the 
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has 
not fully evaluated the sufficiency of the submitted data at this time 
or whether the data supports granting of the petition. Additional data 
may be needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of fluroxypyr MHE in plants 
(wheat) and animals (goats and poultry) is adequately understood for 
the purposes of this tolerance. A rotational crop study showed no 
carryover of significant fluroxypyr MHE related residues in 
representative test crops except for cereal grains for which tolerances 
are being proposed.
    2. Analytical method. There is a practical method (GC with MS 
detection) for measuring levels of fluroxypyr MHE in or on food with a 
limit of detection that allows monitoring of food with residues at or 
above the levels set for the proposed tolerances. Fluroxypyr has been 
tested through the FDAs Multiresidue Methodology, Protocols C, D. and 
E. The results have been published in the FDA Pesticide Analytical 
Manual, Volume I.
    3. Magnitude of residues. Magnitude of residue studies were 
conducted for wheat, barley, and oats. Residues of fluroxypyr MHE did 
not concentrate in process fractions in samples treated at a 7.5 X 
application rate.

B. Toxicological Profile

    1. Acute toxicity. Fluroxypyr MHE has low acute toxicity. The rat 
oral LD50 is >5000 mg/kg, the rabbit dermal LD50 
is >2000 mg/kg, and the rat inhalation LC50 is >1.0 mg/l 
(1,000 mg/cubic meter), the maximum attainable concentration. In 
addition, fluroxypyr MHE is not a skin sensitizer in guinea pigs, has 
no dermal irritation in rabbits, and shows mild ocular irritation in 
rabbits. The end use formulation of fluroxypyr MHE has a similar low 
acute toxicity profile.
    2. Genotoxicity. Short term assays for genotoxicity consisting of a 
bacterial reverse mutation assay (Ames test), an in vitro assay for 
cytogenetic damage using the Chinese hamster ovary cells, an in 
vitrochromosomal aberration assay using rat lymphocytes, and an in vivo 
cytogenetic assay in the mouse bone marrow (micronucleus test) have 
been conducted with fluroxypyr MHE. DowElanco believes that these 
studies show a lack of genotoxicity. In addition, short term assays for 
genotoxicity consisting of an Ames metabolic activation test, point 
mutations at the HGPRT-Locus of Chinese hamster ovary cells, in vivo 
and in vitro chromosomal aberrations in the Chinese hamster ovary 
cells, unscheduled DNA synthesis in human embryonic cells, and an assay 
in mouse lymphoma cells have been conducted with fluroxypyr. DowElanco 
believes that the weight of evidence also indicates a lack of 
genotoxicity.
    3. Reproductive and developmental toxicity. Developmental studies 
in rats and rabbits were conducted with both fluroxypyr MHE and 
fluroxypyr. Studies with fluroxypyr MHE showed maternal and fetal no 
observed effect levels (NOELs) of 300 milligram/kilogram (mg/kg/day) 
(rat) and 500 mg/kg/day (rabbit). Studies with fluroxypyr showed no 
observed adverse effect levels (NOAELs) in the rat of 250 mg/kg/day for 
maternal effects and 500 mg/kg/day for fetal effects and a NOEL in the 
rabbit of 250 mg/kg/day for both maternal and fetal effects. DowElanco 
believes that these studies show that fluroxypyr and fluroxypyr MHE are 
not teratogenic nor will they interfere with in utero development. Two 
multi-generation reproduction studies were conducted with fluroxypyr in 
rats. The first in Wistar rats showed no effect on fertility or 
reproductive performance and had a NOAEL of 500 mg/kg/day (highest dose 
tested). The second study in Sprague-Dawley rats showed a parental NOEL 
for systemic effects of 100 mg/kg/day in male rats and 500 mg/kg/day in 
female rats. The NOEL for reproductive effects was 750 mg/kg/day for 
males and 1,000 mg/kg/day for females (highest dose tested). The NOEL 
for neonatal effects was 500 mg/kg/day.
    4. Subchronic toxicity. Fluroxypyr MHE showed a NOEL of 1,000 mg/
kg/day in a 90-day rat dietary study and a 21-day rabbit dermal study. 
Ninety day feeding studies with fluroxypyr showed NOELs of 80 mg/kg/day 
(Wistar rats), 700 mg/kg/day (Fischer 344 rats), 1342 mg/kg/day (male 
mice), and 1,748 mg/kg/day (female mice). In a 4-week dietary, range 
finding study with fluroxypyr in dogs the NOEL was >50 mg/kg/day.
    5. Chronic toxicity. Based on chronic testing with fluroxypyr in 
the mouse, dog, and rat (two studies), a reference dose (RfD) of 0.8 
mg/kg/day is proposed for fluroxypyr and fluroxypyr MHE. The RfD has 
incorporated a 100-fold safety factor to the NOEL found in the rat 
chronic test. NOELs found in the chronic dietary studies are as 
follows: 150 mg/kg/day (dog), 300 mg/kg/day (mouse), 80 mg/kg/day 
(Wistar rats), 100 mg/kg/day (male Fischer 344 rats), and 500 mg/kg/day 
(female Fischer 344 rats).
    6. Animal metabolism. Both fluroxypyr and fluroxypyr MHE have been 
evaluated in rat metabolism studies. In summary, these studies show 
that fluroxypyr MHE is rapidly hydrolyzed and the fate of the 
hydrolysis products, fluroxypyr and 1-methylheptanol, are independent 
of whether they were given as the ester or the acid. Fluroxypyr, per 
se, was extensively absorbed and rapidly excreted principally unchanged 
in the urine. 1-Methylheptanol also was rapidly absorbed and rapidly 
eliminated. Repeated administration of fluroxypyr MHE was not 
associated with accumulation in tissues. Also, the metabolism and 
pharmacokinetics of methylheptanol are comparable to that of the 
methylheptyl portion of fluroxypyr MHE.
    7. Metabolite toxicology. Administration of fluroxypyr, as the acid 
or methylheptyl ester, in a variety of toxicological studies has 
produced similar effects. The principal response to sufficiently high 
dosages, whether administered over the short-term or, in some cases, 
over a lifetime, was nephrosis. Fluroxypyr is an organic acid that is 
actively excreted into the urine by the kidney. Thus, the target organ 
and dose response relationship for fluroxypyr toxicity are entirely 
consistent with the data on the toxicokinetics of fluroxypyr. 
Metabolism studies have shown that fluroxypyr MHE is rapidly and 
completely hydrolyzed to fluroxypyr acid and methylheptanol.

[[Page 66085]]

    8. Carcinogenicity. Using the Guidelines for Carcinogen Risk 
Assessment published September 24, 1986 (51 FR 33992), it is proposed 
that fluroxypyr and fluroxypyr MHE be classified as Group E for 
carcinogenicity (no evidence of carcinogenicity) based on the results 
of carcinogenicity studies in two species. DowElanco believes that 
there was no evidence of carcinogenicity in an 18-month mouse feeding 
study and a 24-month rat feeding study at all dosages tested. The NOELs 
shown in the mouse and rat oncogenicity studies were 1,000 and 320 mg/
kg/day, respectively. A maximum tolerated dose was achieved at the top 
dosage level tested in both of these studies based on excessive renal 
toxicity. Thus, the doses tested are adequate for identifying a cancer 
risk. Accordingly, DowElanco believes that a cancer risk assessment is 
not needed.
    9. Endocrine effects. There is no evidence to suggest that 
fluroxypyr and fluroxypyr HME have an effect on any endocrine system.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. An over estimation of dietary 
exposure from use of fluroxypyr MHE on wheat, barley, oats is 
determined by basing the TMRC on the conservative assumptions that all 
cereal grain commodities will have tolerance level residues of 
fluroxypyr and that 100% of the wheat, barley, and oat crops grown in 
the U.S. are treated with fluroxypyr MHE. The TMRC is obtained by 
multiplying the tolerance residue levels by the consumption data which 
estimates the amount of crops and related foodstuffs consumed by 
various population subgroups. There are no other established U.S. 
tolerances or exemption from tolerances for fluroxypyr MHE and no other 
registered uses for fluroxypyr MHE on food or feed crops in the United 
States. The use of a tolerance level and 100% of crop treated clearly 
results in an overestimate of human exposure and a safety determination 
for the use of fluroxypyr MHE on wheat, barley, and oats that is based 
on a conservative exposure assessment.
    ii. Drinking water. Another potential source of dietary exposure 
are residues in drinking water. Based on the available environmental 
studies conducted with fluroxypyr MHE and fluroxypyr wherein the 
properties of these materials show little persistence in the soil 
environment, there is no anticipated exposure to residues of fluroxypyr 
MHE and fluroxypyr in drinking water. In addition, there is no 
established Maximum Concentration Level for residues of fluroxypyr MHE 
and fluroxypyr in drinking water.
    2. Non-dietary exposure. There are no other uses currently 
registered for fluroxypyr MHE and fluroxypyr. The proposed use on 
wheat, barley, and oats involves application of fluroxypyr MHE to crops 
grown in an agriculture environment. Thus, the potential for non-
occupational exposure to the general population is not expected to be 
significant.

D. Cumulative Effects

    The potential for cumulative effects of fluroxypyr MHE and 
fluroxypyr and other substances that have a common mechanism of 
toxicity is also considered. There is no reliable information to 
indicate that toxic effects produced by fluroxypyr MHE and fluroxypyr 
would be cumulative with those of any other pesticide chemical. Thus, 
it is appropriate to consider only the potential risks of fluroxypyr 
MHE and fluroxypyr in an aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Using the conservative exposure assumptions and 
the proposed RfD, the dietary exposure to fluroxypyr MHE use on wheat, 
barley, and oats will utilize 0.2% of the RfD for the U.S. population. 
EPA generally has no concern for exposures 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 risks to 
human health. Since there are no anticipated residues in drinking water 
or from other non-occupational sources and no reliable information 
exists on cumulative effects due to common mechanism of toxicity, the 
aggregate exposure to fluroxypyr MHE is adequately represented by the 
dietary route. Thus, DowElanco believes that there is reasonable 
certainty that no harm will result from aggregate exposure to 
fluroxypyr MHE residues on wheat, barley, and oats.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of fluroxypyr MHE, data 
from developmental toxicity studies in rats and rabbits and a 2-
generation reproduction study in the rat are considered. The 
developmental toxicity studies are designed to evaluate adverse effects 
on the developing organism resulting from pesticide exposure during 
prenatal development. Reproduction studies provide information relating 
to effects from exposure to the pesticide on the reproductive 
capability and potential systemic toxicity of mating animals and on 
various parameters associated with the well-being of pups.
    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 the current toxicological data requirements, the 
database for fluroxypyr MHE relative to pre- and post-natal effects for 
children is complete. Further, for fluroxypyr MHE, the NOEL in the 
chronic feeding studies which was used to calculate the RfD (0.8 mg/kg/
day) is already lower than the NOELs from the developmental studies in 
rats and rabbits by a factor of more than three.
    Concerning the reproduction studies in rats, the pup effects shown 
at the highest dose tested (1,000 mg/kg/day) were attributed to 
maternal toxicity. Therefore, DowElanco concludes that an additional 
uncertainty factor is not needed and that the RfD at 0.8 mg/kg/day is 
appropriate for assessing risk to infants and children.
    As noted above for the general U.S. population, aggregate exposure 
for infants and children will result from the dietary (i.e. not 
drinking water or non-occupational) route of exposure. In addition, 
there is no reliable information that shows cumulative effects based on 
a common mechanism of toxicity for infants and children. Using the 
conservative exposure assumptions previously described, the percent RfD 
utilized by the aggregate dietary exposure to residues of fluroxypyr 
MHE on wheat, barley, and oats is 0.6% for children 1 to 6 years old, 
the most sensitive population subgroup. Thus, based on the completeness 
and reliability of the toxicity data and the conservative exposure 
assessment, DowElanco believes that there is a reasonable certainty 
that no harm will result to infants and children from aggregate 
exposure to fluroxypyr MHE residues on wheat, barley, and oats.

F. International Tolerances

    There are no Codex maximum residue levels established for residues 
of fluroxypyr MHE and fluroxypyr on any food or feed crop. (J. Miller)

2. E.I. du Pont de Nemours and Company

PP 1F4032

    EPA has received a pesticide petition (PP 1F4032) from E.I. du Pont 
de Nemours and Company, Barley Mill Plaza, Walker's Mill Bldg. 37, 
Wilmington, DE 19880-0038, proposing

[[Page 66086]]

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 ethametsulfuron in or on the raw agricultural commodity 
canola at 0.1 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 
ethametsulfuron methyl is adequately understood. The unmetabolized 
parent compound was the major residue found in a canola metabolism 
study up to 30 days after application. The principal route of metabolic 
breakdown of ethametsulfuron methyl in canola is dealkylation from the 
triazine ring. The initial step in the metabolic breakdown is 
deethylation to form O-deethyl ethametsulfuron methyl. Further 
metabolism forms N-demethyl-O-deethyl ethametsulfuron methyl and more 
minor polar metabolites. For purposes of establishing the proposed 
tolerance, the parent compound ethametsulfuron methyl is the only 
residue of concern.
    The available metabolism studies indicate that total radioactive 
residues found in mature seeds, when rapeseed was treated at a rate 
equivalent to the proposed application rate, ranged from 0.008 to 0.012 
ppm. These terminal residues may consist of the parent compound, O-
deethyl ethametsulfuron methyl, O-deethyl-N-demethyl ethametsulfuron 
methyl and other minor metabolites.
    2. Analytical method. Analytical methods are available to measure 
the parent compound in oil seeds, and in oil seed processing fractions. 
The quantification of ethametsulfuron methyl is by normal phase high 
performance liquid chromatography (HPLC) using a photoconductivity 
detector. The Limit of Quantitation (LOQ) for the analytical method is 
0.02 ppm.
    3. Magnitude of residues--i. Magnitude of the residue in plants.  
The results of the seed analyses from canola/seed show that no 
detectable residues of ethametsulfuron methyl were found in canola/seed 
harvested 60 to 137 days after treatment at exaggerated rates of 3X of 
the normal application rate.
    ii. Magnitude of the residue in processed commodities. Analyses of 
canola processed fractions (whole seed, pressed cake, desolventized 
meal, crude oil, pressed oil, solvent extracted oil, degummed oil, 
refined washed oil, refined bleached oil, and deodorized oil) show that 
levels of ethametsulfuron methyl were found to be less than 0.02 ppm, 
the limit of quantitation of the method in all of the fractions 
evaluated. All of the processed fractions were obtained from seed 
harvested 92 days after application at proposed use rates and 
exaggerated rates.

B. Toxicological Profile

    1. Acute toxicity. Based on EPA criteria, ethametsulfuron methyl is 
relatively non-toxic, and be categorized as Toxicity Category IV (oral 
and inhalation routes) and Category III (dermal exposure). 
LD50s are >5,000 mg/kg for acute oral toxicity in rats, 
>2,000 mg/kg for acute dermal toxicity in rabbits, and >5.7 mg/L for 
acute inhalation toxicity in rats. For technical grade active 
ingredient, primary eye irritation in rabbits is classified as Tox Cat 
II. For formulated product, primary eye irritation in rabbits is 
classified as Tox Cat IV. Primary dermal irritation in rabbits is 
classified as Tox Cat IV. Dermal sensitization in guinea pigs is 
classified as ``Not a skin sensitizer.''
    2. Genotoxicity. This compound was negative in the following tests 
that have been conducted to determine the genotoxic and mutagenic 
potential of ethametsulfuron methyl: Mutagenicity assays conducted in 
bacteria (Ames test) and in cultured Chinese Hamster Ovary cells; a 
test that measures the induction of chromosomal aberrations in bone 
marrow cells isolated from rats treated with ethametsulfuron methyl; 
micronuclei induction in bone marrow cells from mice; and negative in a 
text that measures DNA damage in cultured rat liver cells. Based on the 
weight of these data, E.I du Pont concludes that ethametsulfuron methyl 
is neither genotoxic or mutagenic.
    3. Reproductive and developmental toxicity. A 2-generation, four 
litter reproduction study with CD rats treated with dietary levels of 
0, 250, 5,000, 20,000 ppm of ethametsulfuron methyl failed to reveal 
any evidence suggestive of an adverse effect on reproductive potential. 
A NOEL was indicated at the mid dose level of 5,000 ppm (equivalent to 
approx. 433 mg/kg b.w./day, actual intake) based on significantly 
(p<0.5) decreased body weights in the high dose treated F0 and F1 
generation males.
    A developmental toxicity study of ethametsulfuron methyl in rabbits 
indicated that dams administered 4,000 mg/kg (highest dose tested) had 
a higher mortality rate, lower food consumption and body weight gains, 
increased incidences of gross clinical signs of toxicity and of 
abortions, and increased absolute and relative liver weights. Absolute 
and relative liver weights were also slightly greater for dams 
administered 1,000 mg/kg. There were no compound-related effects 
observed for dams administered 250 mg/kg.
    Dams administered 4,000 mg/kg also had a decrease in the number of 
live fetuses. This was related to an increase in the number of early 
resorptions. There were no other compound-related effects on the dams, 
nor were there any effects on fetal weights, malformations or 
variations incidences. The NOELs for this study were 250 mg/kg for the 
dams and 1,000 mg/kg for the fetus. Ethametsulfuron methyl was neither 
teratogenic in rabbits nor uniquely toxic to the conceptus.
    A developmental toxicity study was also conducted in rats treated 
at doses of 0, 60, 250, 1,000, or 4,000 mg/kg. Among the dams of the 
groups given ethametsulfuron methyl, no compound-related mortality or 
clinical abnormalities were observed. For the treatment period, the 
high dose group had a lower weight gain and significantly decreased 
food consumption compared to the control group. No other significant 
differences in body weight changes or food consumption were observed. A 
significant trend was indicated for mean fetal weight and the mean 
fetal weight of the high dose group was lower than that of the control 
group. No significant differences were observed in the rates of 
malformations or developmental variations. Under the conditions of the 
study, the apparent no effect level for the dam and fetus was 1,000 mg/
kg/day. Thus ethametsulfuron methyl was not uniquely toxic to the 
conceptus nor was it teratogenic in rats.
    4. Subchronic toxicity--i. Rat. A 90-day feeding study followed by 
a 1-generation reproduction phase in rats at dietary levels of 0, 100, 
1,000, and 5,000 ppm of ethametsulfuron methyl failed to elicit any 
signs of overt toxicity or any adverse effect on reproductive 
performance at levels as high as 5,000 ppm (equivalent to 0.5% of the 
diet or approximately 409 mg/kg b.w./day, actual intake). The No 
Observed Adverse Effect Level (NOAEL) for this study was, therefore, 
the high dose level of 5,000 ppm.
    ii. Mouse. A 90-day dietary feeding study in CD-1 mice at levels of 
0, 50, 500, 2,500 and 5,000 ppm indicated a No Observed Effect Level 
(NOEL) for females and a NOAEL for males set at

[[Page 66087]]

the high dose level of 5,000 ppm (equivalent to approximate 687 mg/kg 
b.w./day, actual intake for males).
    iii. Dog. Dietary administration of technical ethametsulfuron 
methyl to dogs for 90 days at levels of 0, 100, 3,500 or 10,000 ppm 
failed to reveal any evidence of treatment-related toxicity at levels 
as high as 10,000 ppm (equivalent to 1% of the diet or approximately 
386 mg/kg b.w./day, based on actual intake).
    5. Chronic toxicity--i. Rat. Administration of ethametsulfuron 
methyl to Sprague-Dawley rats for up to 24 months at dietary levels of 
0, 50, 500 and 5,000 ppm revealed a NOAEL for in-life parameters of 
5,000 ppm (equivalent to 238.5 mg/kg b.w./day, actual intake), based on 
questionable toxicological significance of decreased (p<0.05) serum 
sodium levels in both the 5,000 ppm treated males and females during 
the first 12 months of treatment. The effects on serum sodium levels in 
the high dose groups were described as mild (representing a decrease in 
2-6% of the control values) and occurring in the absence of any 
associated pathological changes in the kidney. Treatment with the test 
material at dietary levels as high as 5,000 ppm (equivalent to 0.5% of 
the diet) failed to elicit any evidence of treatment-related neoplastic 
potential.
    ii. Dogs. Chronic dietary administration of the test material to 
dogs at levels of 0, 250, 3,000 and 15,000 ppm for 1-year indicated a 
NOEL of 3,000 ppm, equivalent to approximately 87 mg/kg b.w./day actual 
intake, based on compound-related effects expressed in the 15,000 ppm 
treated group as decreased body weight gain and food efficiency values 
in the males. Significantly decreased serum sodium levels in both sexes 
at the high dose treated level were not associated with any evidence of 
renal pathology. In the absence of any collaborative clinical or 
pathological findings differences in organ weights relative to body or 
brain weight were considered to be of doubtful biological significance.
    iii. Mouse. Administration of the test material to CD-1 mice at 
dietary levels of 0, 25, 500, and 5,000 ppm for the period of up to 78 
weeks failed to reveal any overt signs of treatment-related toxicity of 
dietary levels of up to 5,000 ppm (equivalent to 818 mg/kg bwt/day, 
actual intake). Although a direct effect of treatment on body weights 
or weight gains could not be established, overall body weight gain in 
the 5,000 ppm treated male mice was depressed (non-significant, p>0.05) 
by 10% when compared to the controls. There was no evidence of any 
treatment-related oncogenic potential.
    6. Animal metabolism. When administered via oral gavage to rats, 
ethametsulfuron methyl was rapidly metabolized and excreted in the 
urine and feces. Within 3 days, greater than 90% of the administered 
dose was excreted by male rats and greater than 80% was excreted by 
females. Approximately 50% of the administered dose was excreted as 
unchanged ethametsulfuron methyl. The remainder was converted 
predominately to N-demethyl ethametsulfuron methyl and O-deethyl 
ethametsulfuron methyl, which are considered by by-products of 
cytochrome P450-mediated reactions. Less than 0.02% of the administered 
dose remained in the carcass or tissues. There was no significant or 
preferential accumulation of ethametsulfuron methyl or its metabolites 
in any tissue. Because of the short excretion half-life, repeated daily 
exposures are not expected to result in significant body burdens of 
ethametsulfuron methyl.
    7. Metabolite toxicology. There is no evidence that the metabolites 
of ethametsulfuron methyl as identified as either the plant or animal 
metabolism studies are of any toxicological significance.
    8. Endocrine effects. No special studies investigating potential 
estrogenic or endocrine effects of ethametsulfuron methyl have been 
conducted. However, the standard battery of required toxicology studies 
have 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. Based on these studies there is no evidence to suggest that 
ethametsulfuron methyl has an effect on the endocrine system.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Based on the residue data and the 
proposed single-crop use, potential for dietary exposure of 
ethametsulfuron methyl from food sources is extremely low. Residue 
studies have shown no residues above the LOQ (residues <0.02 ppm) in 
any canola seed samples evaluated, including the canola oil processed 
fractions. No dietary exposure is anticipated from secondary residues 
in meat or milk. Although canola meal is considered a minor feedstuff 
for cattle and poultry (representing a maximum of 15% of an animal's 
diet), field residue studies showed ethametsulfuron methyl residues 
were all below the LOQ (<0.02 ppm) in all of the canola RACs and 
processed fractions, including meal, even when the crop was treated at 
2-3X the proposed maximum use rate.
    Direct human consumption of canola as a food commodity in the 
United States is extremely low. Canola is a minor crop in the U.S., and 
the only canola fraction used as a food product is the refined canola 
oil. A dietary risk evaluation (DRES) was conducted to determine the 
theoretical maximum residue contribution of ethametsulfuron methyl in 
the diet as a result of agricultural use on canola. Unfortunately, 
consumption data for canola oil does not exist in the 1977-1979 food 
consumption database used in EPA's DRES system, since at that time, 
canola oil was not a significant part of the U.S. diet. Since 1977 more 
canola oil is used in U.S. homes, although total production and usage 
are still minor when compared to other edible oils such as soybean oil.
    Conservative assumptions were used to estimate canola consumption 
in the United States. The USDA's Oilseed Analysis Division has 
indicated that an average of 1.1 billion pounds of canola oil was used 
in the United States annually over the past 5 years. The dietary 
exposures that might occur by way of canola oil consumption can be 
estimated by taking the average annual use of canola oil in the United 
States (includes both domestically produced and imported canola oils) 
and dividing it by the approximate US population of 266.3 million 
people. This provides a per-capita consumption estimate for the general 
population. Using this approach, total canola oil consumption on a 
grams per kg body weight per day was calculated by dividing by the 
average days in a year and average body weight of a person (60 kg). The 
60 kg value is used by the US EPA as part of their ``Food Factor'' 
system, and is also supported by taking the average weight of children 
between the ages of 6 months to 19 years (36 kg) and the average weight 
of adults of 70 kg and assuming a 69 year life span (as proposed in the 
review draft of the US EPA's Exposure Factors Handbook). Using these 
assumptions, canola oil consumption was calculated to be 0.088 g/kg bw/
day.
    While this method provides a useful approximation of canola 
consumption, this is clearly a conservative estimate for risk 
assessment purposes, since this estimate assumes that all of the canola 
oil used in the US is indeed ingested. In reality, not all the oil that 
is used in cooking or deep-fat frying is consumed but instead, is 
discarded or recycled. Another indication that the consumption value of 
0.088 g/kg bw/day is an over-estimate is from the USDA's 1989-1992 food 
survey (not yet included in the EPA's DRES system),

[[Page 66088]]

 which indicates canola oil consumption is 0.00023 g/kg/day for the 
general U.S. population.
    Using the consumption estimate of 0.088 g canola oil/ kg bw/day for 
the general US population, and assuming that 100% of the canola crop is 
treated with ethametsulfuron methyl and all canola consumed contains 
residues at the proposed tolerance level of 0.1 ppm, the theoretical 
maximum residue contribution of ethametsulfuron methyl in the diet is 
calculated to be 0.00001 mg/kg/day or <0.01% of the RfD of 0.87 mg/kg/
day.
    ii. Drinking water. Another potential source of dietary exposure to 
pesticides are residues in drinking water. There is no established 
Maximum Concentration Level (MCL) for ethametsulfuron methyl in water. 
Based on the low use rate of ethametsulfuron methyl, and a use pattern 
that is not widespread (since the only proposed use is on a minor 
crop), DuPont does not anticipate residues of ethametsulfuron in 
drinking water and exposure from this route is unlikely.
    2. Non-dietary exposure. Ethametsulfuron methyl is not registered 
for any use which could result in non-occupational, non-dietary 
exposure to the general population. Ethametsulfuron methyl is a 
herbicide with proposed use only on canola. There are no other food 
uses, nor are there any residential or non-crop uses of this active 
ingredient. Therefore, the only potential for non-occupational 
aggregate exposure would come from dietary intake.

D. Cumulative Effects

    Ethametsulfuron 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 ethametsulfuron 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 species chronic NOEL of 
87 mg/kg and a Reference Dose (RfD) of 0.87 mg/kg/day, the proposed use 
of ethametsulfuron methyl on canola is expected to utilize 0.001% of 
the RfD for the general U.S. population. Generally, exposures below 100 
percent 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. Thus, DuPont concludes 
that there is a reasonable certainty that no harm will result from 
aggregate exposure to ethametsulfuron methyl resulting from proposed 
agricultural use on canola.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of ethametsulfuron 
methyl, data were considered from developmental toxicity studies in the 
rat and rabbit, and a multi-generation reproduction study in rats. The 
developmental toxicity studies demonstrated that even at the high oral 
doses used in these studies (up to 4,000 mg/kg in rabbits and rats), no 
teratogenic effects were found in either species nor was the compound 
found to be uniquely toxic to the conceptus.
    The 2-generation reproduction study in rats treated at dietary 
levels as high as 20,000 ppm on a daily basis throughout 2 generations 
(equivalent to 1,582 mg/kg/day for males and 1817 mg/kg/day for 
females), showed no evidence of effects on reproductive performance in 
the adults, or evidence of gross or histopathological effects in the 
adult or weanling rats in any test group. This study indicates that 
ethametsulfuron methyl is not a reproductive toxicant.
    As mentioned previously, canola oil is a very minor component of 
the diet, and thus had not been included as part of the 1977-79 food 
survey used in EPA's DRES system. DuPont is not aware of specific food 
survey data concerning consumption of canola oil by infants and 
children. However, the 1977-79 food survey database does provide 
consumption data for other edible oils for each of the population 
subgroups, including infants and children. This data indicate that non-
nursing infants consume more soybean and coconut oil than any of the 
other 22 population subgroups, specifically consuming 4.2 times more 
soybean oil and 49.1 times more coconut oil than the consumption by the 
general US population. The data also show that children 1-6 consume 
more corn, cottonseed, peanut and sunflower oil than any other subgroup 
listed, to a maximum of 2 times more than the general U.S. population. 
Using these data and making the most conservative assumption to 
extrapolate to canola oil, we can estimate that infants and children 
consume 49 times more canola oil than does the U.S. population, and 
calculate an approximate daily consumption of 4.3 g canola oil/kg body 
weight. If we use the additional conservative assumptions that all the 
canola oil consumed contains ethametsulfuron methyl residues at 
tolerance levels of 0.1 ppm, we calculate that the maximum theoretical 
residue concentration of ethametsulfuron methyl in the infants' and 
children's diets would be 0.00049 mg/kg/day or <0.05% of the RfD.
    As indicated above, DuPont concludes that infants and children have 
a low potential for ethametsulfuron methyl exposure because of both the 
low level of canola oil in the diet, and the absence of detectable 
residues in field-treated canola. The toxicology profile of 
ethametsulfuron methyl demonstrates low mammalian toxicity, and results 
from the developmental and reproduction studies indicate that there is 
no additional sensitivity for infants and children. Therefore, DuPont 
concludes that an additional safety (uncertainty) factor is not 
warranted and the RfD of 0.87 mg/kg body weight/day, which utilizes a 
100-fold safety factor, is appropriate to assure a reasonable certainty 
of no harm to infants and children from aggregate exposure to 
ethametsulfuron methyl.

F. International Tolerances

    Ethametsulfuron methyl and its end-use product Muster are 
registered only in Canada on canola/rape and mustard with a MRL value 
of 0.1 ppm. A CODEX tolerance for ethametsulfuron methyl has not been 
established. (Jim Tompkins)

3. Monsanto

PP 7F4840

    EPA has received a pesticide petition (PP 7F4840) from Monsanto, 
Suite 1100, 700 14th St., NW., Washington, DC 2005, 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 sulfosulfuron 1-(4,6-dimethoxypyrimidin-2-yl)-3-[(2-
ethanesulfonyl-imdazo[1,2-a]pyridine-3-yl)sulfony]urea in or on the raw 
agricultural commodities. The proposed analytical method involves 
hydrolyzing sulfosulfuron and its imadazopyridine-containing 
metabolites under acidic conditions to the common chemophore, ethyl 
sulfone. Ethyl sulfone is then separated and quantitated by High 
Performance Liquid Chromatography (HPLC) with fluorescence detection. 
EPA has determined that the petition

[[Page 66089]]

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. Metabolism of sulfosulfuron in plants is 
negligible. The nature of the major sulfosulfuron residues in wheat 
matrices depends primarily on the mode of application with reliance 
upon metabolism in the soil.
    Postemergence applications result in residues that are mostly made 
up of parent compound, with small amounts of five to six metabolites 
that together make up less than 15% of the total radioactive residue.
    Preemergence application result in soil degradation of the parent 
compound followed by uptake primarily of the imidazopyridine ring-
containing metabolites and small amounts of the parent compound. The 
pyrimidine ring-containing metabolites under these conditions are 
tightly bound to the soil, resulting in negligible uptake of these 
residues. Little further metabolism of the imidazopyridine metabolites 
takes place in the plant. The predominant residues resulting from 
preemergence applications were sulfonamide (22% TRR) and guanidine 
(18.3% TRR).
    In both cases, translocation of residue to the grain is negligible. 
The highest residues are observed following postemergence applications 
and the residues are primarily parent compound.
    In rotational crops, residues were low, with the TRR's not 
exceeding 0.01 ppm in most crops. The most abundant metabolite was 
sulfonamide, with low levels of a sulfonamide-sugar conjugate and 
parent compound also observed.
    2. Analytical method. The primary crop (wheat) residue and the 
secondary (animal products) residues are analyzed as total residue by 
hydrolyzing sulfosulfuron and its imadazopyridine-containing 
metabolites under acidic conditions to the common chemophore, ethyl 
sulfone. Ethyl sulfone is then separated and quantitated by High 
Performance Liquid Chromatography (HPLC) with fluorescence detection.
    3. Magnitude of residues. EPA has received a pesticide petition 
from Monsanto Company proposing to amend 40 CFR part 180 by 
establishing a tolerance for residues of the herbicide sulfosulfuron in 
or on the following:


                                                                        
------------------------------------------------------------------------
                 Commodity                      Part per million (ppm)  
------------------------------------------------------------------------
Wheat                                                                   
                                                                        
grain                                       0.01 ppm (limit of          
                                             quantitation 0.008 ppm)    
straw                                       0.1 ppm                     
hay                                         0.3 ppm                     
forage                                      3.0 ppm                     
                                                                        
Animal Products                                                         
                                                                        
milk                                         0.004 ppm                  
fat                                          0.004 ppm                  
meat                                         0.004 ppm                  
muscle                                      0.004 ppm                   
meat by-products                            0.1 ppm                     
kidney                                      0.1 ppm                     
liver                                        0.1 ppm                    
------------------------------------------------------------------------


B. Toxicological Profile

    1. Acute toxicity. A rat acute oral study with an LD50 
of >5,000 mg/kg, EPA Category IV. A rabbit acute dermal study with an 
LD50 of >5,000 mg/kg, EPA Category IV. A rat inhalation 
study with and LC50 of >3.0 mg/l, the highest concentration 
generated, EPA Category IV. A primary eye irritation study in the 
rabbit showing moderate eye irritation, EPA Category III. A primary 
dermal irritation study in the rabbit showing essentially no 
irritation, EPA Category IV. A dermal sensitization study in the guinea 
pig showing no potential for sensitization. Acute and subchronic 
neurotoxicity studies in rats demonstrating no neurotoxicity potential. 
Sulfosulfuron has a low order of acute toxicity.
    2. Genotoxicity. An in vitro Ames/Salmonella mutagenicity assay in 
five commonly used strains was negative for mutagenic potential.
    An in vitro CHO/HGPRT Gene Mutation assay was negative for 
mutagenicity up to the limit of solubility.
    An in vitro chromosomal aberration test in cultured mammalian cells 
demonstrated the induction of chromosomal aberrations only under 
conditions of prolonged incubation at high dose levels that exceeded 
the solubility of the test material. The mechanism responsible for this 
induction and the biological relevance of the effect is not clear. 
Other, more relevant, chromosomal aberration tests (see below) were 
negative.
    An in vitro chromosome aberration study in human lymphocytes was 
negative for chromosomal aberrations.
    An in vivo bone marrow micronucleus assay in the mouse was negative 
for chromosomal effects.
    The weight of evidence demonstrates that sulfosulfuron does not 
produce significant genotoxic or mutagenic effects.
    3. Reproductive and developmental toxicity. A developmental study 
in the rat demonstrated no signs of maternal or developmental toxicity 
up to the maximum dose level of 1,000 mg/kg/day. The NOEL was 
considered to be 1,000 mg/kg/day.
    A developmental study in the rabbit demonstrated no signs of 
maternal or developmental toxicity up to the maximum dose level of 
1,000 mg/kg/day. The NOEL was considered to be 1,000 mg/kg/day.
    A 2-generation reproduction study in the rat demonstrated a 
subchronic toxicity NOEL of 5,000 ppm based on body weight and food 
consumption decreases, urinary bladder calculi formation and minor 
bladder and kidney pathology. There were no effects on reproduction or 
fertility up to 20,000 ppm, the highest dose tested. Sulfosulfuron 
demonstrates no reproductive effects in rats and no teratogenic or 
developmental effects in rats and rabbits.
    4. Subchronic toxicity. A 28-day dermal study in the rat with a 
NOEL of at least 1,000 mg/kg/day, the highest dose tested. A 90-day 
feeding study in the rat resulted in only mild body weight/weight gain 
effects at 20,000 ppm, the highest dose tested. The NOEL for both males 
and females was considered to be 6,000 ppm. A 90-day feeding study in 
the dog demonstrated subchronic toxicity, primarily in the urinary 
bladder, secondary to urinary crystal formation and urolithiasis at 
dose levels of 300 and 1,000 mg/kg/day in females and at 1,000 mg/kg/
day in males. The NOEL was considered to be 100 mg/kg/day in females 
and 300 mg/kg/day in males. Sulfosulfuron has a low order of subchronic 
toxicity, related only to the precipitation of test material in the 
urinary bladder of dogs at high doses.
    5. Chronic toxicity. A 1-year study in the dog demonstrated 
toxicity in the urinary bladder secondary to urinary crystal and 
calculus formation at 500 mg/kg/day in a single male animal. Urinary 
crystal formation was observed in females at 500 mg/kg/day with no 
subsequent pathology. The NOEL was considered to be 100 mg/kg/day for 
male and female dogs.
    A combined chronic toxicity/oncogenicity study in the rat 
demonstrated chronic toxicity, primarily in the urinary bladder, in 
males and females at 5,000 and females at 20,000 mg/kg/day. The NOEL 
for chronic toxicity was considered to be 500 ppm or 24.4 mg/kg/day. 
This is the

[[Page 66090]]

lowest NOEL and is used in the calculation of the Reference Dose (RfD).
    An 18-month oncogenicity study in the mouse demonstrated chronic 
toxicity, primarily in the urinary bladder, of male mice at 3,000 and 
7,000 ppm. No chronic toxicity was observed in females. The NOEL for 
chronic toxicity was considered to be 700 ppm for male mice and 7,000 
ppm for female mice. Sulfosulfuron demonstrates chronic toxicity 
related only to the formation of crystals and calculi of the compound 
in the urinary bladders of mice, rats and dogs.
    6. Carcinogenicity. An 18-month oncogenicity study in the mouse 
demonstrated a small increase in the incidence of benign mesenchymal 
tumors of the urinary bladder submucosa in male mice with urinary 
bladder calculi at 7,000 ppm. However, these tumors are reportedly 
unique to Swiss-derived mice and were considered to be of biological 
relevance only to the mouse by a Independent Working Group on Mouse 
Mesenchymal Tumors convened by the International Life Sciences 
Institute (ILSI).
    A combined chronic toxicity/oncogenicity study in the rat (same as 
above) demonstrated a urinary bladder transitional cell carcinoma and a 
urinary bladder transitional cell papilloma in two females at 5,000 mg/
kg/day, probably secondary to urinary system calculi formation and 
(chronic) irritation.
    The low incidences of oncogenicity observed in the oncogenicity 
studies conducted with sulfosulfuron are either considered to be 
relevant to the mouse only or a secondary threshold effect related to 
chronic irritation resulting from bladder stone formation at high 
doses. Sulfosulfuron is not considered to be a primary oncogen.
    Using the Guidelines for Carcinogenic Risk Assessment published 
September 24, 1986, Monsanto believes that the EPA would classify 
sulfosulfuron as a Group ``C'' carcinogen, without quantitative risk 
assessment, i.e., using the margin of exposure (MOE) approach for risk 
assessment. Under the proposed guidelines published April 10, 1996, 
however, Monsanto believes that sufosulfuron should be included in the 
``Not Likely Human Carcinogen'' category based upon mechanistic 
considerations. To quote the 1996 EPA guideline document discussing a 
similar effect in a rat study:
    ``A major uncertainty is whether the profound effects of (substance 
5) may be unique to the rat. Even if (substance 5) produced stones in 
humans, there is only limited evidence that humans with bladder stones 
develop cancer. Most often human bladder stones are either passed in 
the urine or lead to symptoms resulting in their removal.''
    In either case, a Margin of Exposure assessment or reference dose 
(RfD) approach would be utilized. Since the chronic NOEL for male rats 
is lower than the oncogenic NOEL for female rats (24 mg/kg/day vs 30 
mg/kg/day), the male rat chronic NOEL was used with a 100 fold safety 
factor for a reference dose of 0.24 mg/kg/day, for the quantitation of 
human risk.
    7. Animal metabolism. An animal metabolism study was conducted in 
the rat using sulfosulfuron radiolabeled in both the pyrimidine and 
iminodazopyridine rings to detect possible cleavage of the sulfonylurea 
bond. Following oral dosing of sulfosulfuron, absorption was found to 
be greater at low doses (>90%) than at the higher doses ( 40%). 
Sulfosulfuron was readily excreted, mostly unchanged, with urinary 
excretion the major route of elimination at low doses and fecal 
excretion the major route at high doses. Greater than 90% of the dose 
was excreted 3 days after administration. Expiration as carbon dioxide 
or volatiles was not a significant route of elimination. Metabolism of 
sulfosulfuron in the rat occurred to only a limited extent with 
demethylation and pyrimidine ring hydroxylation as the major metabolic 
routes, yielding desmethyl-sulfosulfuron and 5-hydroxy-sulfosulfuron as 
the major metabolites. There was no evidence of bio-retention of 
sulfosulfuron or its metabolites; tissue and blood levels were 
negligible, with no individual tissue showing levels exceeding 0.2% of 
the dose.
    8. Metabolite toxicology. Dietary residues are comprised almost 
entirely of parent sulfosulfuron and the imidazopyridine-containing 
metabolites sulfonamide and guanidine. Specific toxicology data is not 
available on these metabolites, but the structures do not suggest any 
specific toxicologic concern and the level of dietary exposure is low. 
These metabolites are not considered to present a significant 
toxicological risk.

C. Aggregate Exposure

    1. Dietary exposure--i. Food. Estimates of dietary exposure to 
residues of sulfosulfuron utilized the proposed tolerance-level 
residues for wheat grain (0.01 ppm) and for the following animal 
products: milk (0.004 ppm), fat (0.004 ppm), meat (0.004 ppm) and meat 
by-products (0.1 ppm, including kidney and liver). One-hundred percent 
market share was assumed as well as the assumption that no loss of 
residue would occur due to processing and cooking. A Reference Dose 
(RfD) of 0.24 mg/kg/day was assumed based on the low NOEL from the 
chronic/oncogenicity study in rats ( 24 mg/kg/day) with a 
safety factor of 100. Since the present label lists only wheat or 
fallow as approved rotations, no residues were entered for rotational 
crops. Using these conservative assumptions, dietary residues of 
sulfosulfuron contribute only 0.000149 mg/kg/day (0.006% of the RfD) 
for children 1-6 years, the most sensitive sub-population. For the U.S. 
Population as a whole, the exposure was only 0.000048 mg/kg/day (0.02% 
of the RfD).
    ii. Drinking water. Given the low use rates, rapid soil 
degradation, strong soil binding characteristics and low soil mobility 
of sulfosulfuron, the risk of significant ground and surface water 
contamination and exposure via drinking water is considered to be 
negligible. Assuming that 10% of the RfD is allocated to drinking water 
exposure (0.024 mg/kg/day), and the average, 70 kg human consumes 2 
liters of water per day, a Maximum Allowable Concentration value for 
drinking water of 0.84 mg/l is proposed for sulfosulfuron.
    2. Non-dietary exposure. Sulfosulfuron is proposed for a variety of 
non-crop uses including roadsides, fencerows, industrial sites, parks, 
apartment complexes, schools and other public areas. Exposure 
assessments have been made for mixer/loaders and applicators in these 
situations (occupational exposure) and the cumulative (amortized) daily 
exposure from both these activities has been estimated to be less than 
0.5 g/kg/day, or approximately 0.2% of the RfD. The non-
occupational exposure in these locations to the casual passer-by would 
be expected to be orders of magnitude less. The exposure in either 
instance does not present a significant exposure risk.

D. Cumulative Effects

    Sulfosulfuron falls into the common category of sulfonylurea (SU) 
herbicides; however there is no information to suggest that any of the 
SU's have a common mechanism of mammalian toxicity or even produce 
similar effects. It is not appropriate to combine exposures in this 
case, and Monsanto is considering only the potential risk of 
sulfosulfuron in its aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. As presented above, the exposure of the U.S. 
General population to sulfosulfuron is low, and the risks, based on 
comparisons to the reference dose, are negligible. Margins

[[Page 66091]]

of safety are expected to be considerable. Monsanto concludes that 
there is a reasonable certainty that no harm will result to the U.S. 
Population from aggregate exposure to sulfosulfuron residues.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of sulfosulfuron, 
Monsanto considered data from developmental toxicity studies in the rat 
and rabbit and a two-generation reproduction study in rats. No 
developmental or reproductive effects were observed up to the highest 
dose tested in each of the three studies. The Observed NOEL's were 
1,000 mg/kg/day, 1,000 mg/kg/day and 20,000 ppm, respectively. Using 
the same conservative assumptions that were made previously for the 
dietary exposure analysis for the U.S. General population, the percent 
of the RfD utilized by pre-adult sub-populations are: all infants-
0.03%; nursing infants-0.005%; non-nursing infants-0.04%; children, 1-6 
years-0.06%; children, 7-12 years-0.04%. Monsanto concludes that there 
is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to sulfosulfuron residues.

F. International Tolerances

    There are currently no international (Codex) tolerances established 
for sulfosulfuron. Sulfosulfuron is currently registered on wheat in 
Switzerland, Poland, the Czech Republic, Slovakia and South Africa. 
Petitions for tolerances for sulfosulfuron in/on wheat have been 
submitted in Canada, Australia and the European Union. (Jim Tompkins)

[FR Doc. 97-32936 Filed 12-16-97; 8:45 am]
BILLING CODE 6560-50-F