[Federal Register Volume 62, Number 195 (Wednesday, October 8, 1997)]
[Notices]
[Pages 52544-52552]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-26537]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-766; FRL 5746-9]


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-766, must 
be received on or before November 7, 1997.
ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Division 
(7506C), 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'' of this document. No Confidential Business Information 
(CBI) 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 
CBI. Information so marked 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    
------------------------------------------------------------------------
Cynthia Giles-Parker, (PM 22).  Rm. 247, CM #2, 703-    1921 Jefferson  
                                 305-7740; e-mail:       Davis Hwy,     
                                 giles-parker            Arlington, VA  
                                 [email protected]                  
                                 ov.                                    
                                                                        
Joanne Miller (PM 23).........  Rm. 237, CM #2, 703-    Do.             
                                 305-6224; e-mail:                      
                                 miller                                 
                                 [email protected]                  
                                 v.                                     
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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-766] (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-766) and appropriate petition 
number. Electronic comments on 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: September 29, 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. AgrEvo USA Company (AgrEvo)

PP 7F4910 and 7E4911

    EPA has received pesticide petitions (PP 7F4910 and 7E4911) from 
AgrEvo USA Company (AgrEvo), Wilmington, DE 19808 proposing pursuant to 
section 408(d) of the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 
346a(d), to amend 40 CFR 180.473(c) and part 186 by establishing 
tolerances for residues of glufosinate-ammonium in or on raw 
agricultural commodities derived from transgenic sugar beets and canola 
that are tolerant to the herbicide, glufosinate-ammonium: sugar beet 
roots at 0.7 ppm, sugar beet tops (leaves) at 1.3 ppm, canola seed at 
0.4 ppm and the processed feeds: canola meal at 2.0 ppm and sugar beet 
molasses at 5.0 ppm. AgrEvo has also proposed to amend 40 CFR 
180.473(a)(1) and part 185 by establishing a tolerance for residues of 
the herbicide, glufosinate-ammonium: butanoic acid, 2-amino-4-
(hydroxymethylphosphinyl)-, monoammonium salt and its metabolite, 3-
methylphosphinico-propionic acid expressed as glufosinate free acid

[[Page 52545]]

equivalents in or on the following raw agricultural commodity: potatoes 
at 0.4 ppm and the processed foods: potato flakes at 1.3 ppm and 
processed potatoes (including potato chips) at 1.0 ppm. The proposed 
analytical method involves homogenization, filtration, partition and 
cleanup with analysis by gas chromatography. 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 support granting of the petition. Additional data may be 
needed before EPA rules on the petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of glufosinate-ammonium in 
plants is adequately understood for the purposes of these tolerances. 
The crop residue profile following selective use of glufosinate-
ammonium on transgenic crops is different than that found in 
conventional crops. The only crop residue found after non-selective use 
is the metabolite, 3-methylphosphinico-propionic acid, which is found 
in only trace amounts. The principal residue identified in the 
metabolism studies after selective use of glufosinate-ammonium on 
transgenic crops is the acetylated derivative of the parent material, 
2-acetamido-4-methylphosphinico-butanoic acid, with lesser amounts of 
glufosinate and 3-methylphosphinico-propionic acid.
    2. Analytical method. There is a practical analytical method 
utilizing gas chromatography for detecting and measuring levels of 
glufosinate-ammonium and its metabolites in or on food with a general 
limit of quantification of 0.05 ppm. This method allows monitoring of 
food with residues at or above the levels proposed in these tolerances. 
This method has been validated by an independent laboratory and the 
petitioner has been advised that the EPA concluded its own successful 
method try out.
    3. Magnitude of residues. Field residue trials with glufosinate-
ammonium tolerant sugar beets and canola have been conducted in 1995 
and 1996 and 1993 and 1994 respectively at several different use rates 
and timing intervals to represent the use patterns which would most 
likely result in the highest residue. In these trials, the primary 
residue in all samples was the combination of glufosinate and 2-
acetamido-4-methylphosphinico-butanoic acid which was typically found 
at higher levels than 3-methylphosphinico-propionic acid. In sugar 
beets, the mean glufosinate-ammonium derived residues in treated roots 
did not exceed 0.70 ppm in trials conducted at 13 different sites 
representing the 6 major sugar beet producing regions in the U.S. The 
mean glufosinate-ammonium derived residues in treated tops (leaves) in 
these trials did not exceed 1.29 ppm when sampled at 60 days or more 
after treatment.
    In canola, 11 out of 40 samples produced detectable residue levels 
above the limit of detection in harvested seed following treatment with 
glufosinate-ammonium at 14 trial locations. The highest level of 
residue found in these trials was 0.295 ppm and the total mean 
glufosinate derived residues in all samples containing detectable 
residues was 0.136 ppm.
    For both sugar beet and canola, the tolerances levels have been 
proposed assuming the following: (1) a seasonal maximum rate of 1.1 
pounds of active ingredient per acre for sugar beets and 0.9 pound of 
active ingredient per acre for canola and (2) a pre-harvest interval of 
60 days for sugar beets and 65 days for canola.
    Total residues of glufosinate-ammonium and its metabolite in 
potatoes desiccated with glufosinate-ammonium were determined in more 
than 40 trials conducted over approximately 13 locations during the 
period from 1987 to 1994. Within the pre-harvest interval of 7 to 56 
days, all residue values (with one exception) did not exceed 0.4 ppm. A 
pre-harvest interval of 9 days is specified on the product label for 
potato desiccation and the seasonal maximum use rate is 0.4 pound of 
active ingredient per acre.
    4. Residue in processed commodities. Studies have been conducted to 
determine the level of glufosinate derived residues found in or on the 
processed commodities from glufosinate tolerant sugar beet roots, 
canola seed and potatoes. The studies utilized treatments at 
significantly exaggerated rates to provide the necessary test 
sensitivity. In the sugar beet processing study, a concentration factor 
of 6.3x was determined for sugar beet molasses whereas there was no 
concentration of residues in either refined sugar or dried pulp.
    In the canola processing study, a concentration factor of 
approximately 4 times was observed for the meal when the levels of 
terminal residues were compared between the seed and the toasted meal. 
There was no concentration of residues in the canola oil.
    In the potato processing study, glufosinate residues appear to 
concentrate 2.3 fold in chips and 3.1 fold in flakes. Glufosinate 
residues do not appear to concentrate in the peel.

B. Toxicological Profile

    1. Acute toxicity. The acute oral LD50 values for 
glufosinate-ammonium technical ranged from 1,510 to 2,000 mg/kg in rats 
and from 200 to 464 mg/kg in mice and dogs. The acute dermal 
LD50 was 2,000 mg/kg in rabbits and  4,000 mg/kg 
in rats. The 4-hour rat inhalation LC50 was 1.26 mg/L in 
males and 2.6 mg/L in females. Glufosinate-ammonium was not irritating 
to rabbit skin but was slightly irritating to the eyes. Glufosinate-
ammonium did not cause skin sensitization in guinea pigs. Glufosinate-
ammonium should be classified as Tox Category II for oral toxicity, Tox 
Category III for inhalation and dermal toxicity and Tox Category IV for 
skin irritation and eye irritation.
    2. Genotoxicty. No evidence of genotoxicity was noted in an 
extensive battery of in vitro and in vivo studies. The petitioner has 
been advised by the EPA that negative studies determined acceptable 
included Salmonella, E. Coli and mouse lymphoma gene mutation assays, a 
mouse micronucleus assay, and an in vitro UDS assay.
    3. Reproductive and developmental toxicity. Three developmental 
toxicity studies were conducted with rats, at dose levels ranging from 
0.5 to 250 mg/kg/day. The No Observed Effect Levels (NOEL's) for 
maternal and developmental effects were determined to be 10 mg/kg/day 
for maternal toxicity and 50 mg/kg/day for developmental toxicity, 
based on the findings of hyperactivity and vaginal bleeding in dams at 
50 mg/kg/day and increased incidence of arrested renal and ureter 
development in fetuses at 250 mg/kg/day.
    A developmental toxicity study was conducted in rabbits at dose 
levels of 0, 2, 6.3 and 20 mg/kg/day. The maternal NOEL for this study 
was determined to be 6.3 mg/kg/day, based on increases in abortion and 
premature delivery, and decreases in food consumption and weight gain 
at 20 mg/kg/day. No evidence of developmental toxicity was noted at any 
dose level; thus the developmental NOEL was determined to be 20 mg/kg/
day.
    A 2-generation rat reproduction study was conducted at dietary 
concentrations of 0, 40, 120 and 360 ppm. The parental NOEL was 
determined to be 40 ppm (4 mg/kg/day) based on increased kidney weights 
at 120 ppm. The NOEL for reproductive effects was determined to be 120 
ppm (12 mg/kg/day) based on reduced numbers of pups at 360 ppm.
    4. Subchronic toxicity. A 90-day feeding study was conducted in 
Fisher

[[Page 52546]]

344 rats at dietary concentrations of 0, 8, 64, 500 and 4,000 ppm. 
Although slight evidence of toxicity was observed, there were no 
treatment-related histopathological findings at any dose level. The 
NOEL for this study was determined to be 8 ppm, based on increased 
kidney weights at 64 ppm.
    A 90-day feeding study was conducted in NMRI mice at dietary 
concentrations of 0, 80, 320 and 1,280 ppm. There were no treatment-
related pathological findings at any dose level but increases in 
absolute and relative liver weights, serum AST, and serum potassium 
levels were noted at 320 and/or 1,280 ppm. Based on these findings, the 
NOEL for this study was determined to be 80 ppm (16.6 mg/kg/day).
    A 90-day feeding study was conducted in beagle dogs at dietary 
concentrations of 0, 4, 8, 16, 64 and 256 ppm. There were no treatment-
related histopathological findings at any dose level. However, because 
of reduced weight gain and decreased thyroid weights at 64 and/or 256 
ppm, the NOEL was determined to be 16 ppm (0.53 mg/kg/day).
    5. Chronic toxicity. A 12-month feeding study was conducted in 
beagle dogs at dose levels of 0, 2, 5 and 8.5 mg/kg/day. The NOEL was 5 
mg/kg/day based on clinical signs of toxicity, reduced weight gain and 
mortality at 8.5 mg/kg/day.
    A 2-year mouse oncogenicity study was conducted in NMRI mice at 
dietary concentrations of 0, 20, 80 and 160 (males) or 320 (females) 
ppm. The NOEL was determined to be 80 ppm (10.8 and 16.2 mg/kg/day for 
males and females, respectively) based on increased blood glucose, 
decreased glutathione levels and increased mortality in the high-dose 
males and/or females. No evidence of oncogenicity was noted at any dose 
level.
    A combined chronic toxicity/oncogenicity study was conducted in 
Wistar rats for up to 130 weeks at dietary concentrations of 0, 40, 140 
and 500 ppm. A dose-related increase in mortality was noted in females 
at 140 and 500 ppm, while increased absolute and relative kidney 
weights were noted in 140 and 500 ppm males. Thus, the NOEL for this 
study was determined to be 40 ppm (2.1 mg/kg/day). No treatment-related 
oncogenic response was noted. However, the high-dose level in this 
study did not satisfy the EPA criteria for a Maximum Tolerated Dose and 
thus a data gap currently exists for a rat carcinogenicity study. All 
glufosinate-ammonium tolerances previously established by the EPA are 
time-limited because of this gap. A new rat oncogenicity study is 
currently being conducted and is due to the EPA by July 1, 1998.
    6. Animal metabolism. Numerous studies have been conducted to 
evaluate the absorption, distribution, metabolism and/or excretion of 
glufosinate-ammonium in rats. These studies indicate that glufosinate-
ammonium is poorly absorbed (5-10%) after oral administration and is 
rapidly eliminated, primarily as parent compound. Small amounts of the 
metabolites 3-methylphosphinico-propionic acid and 2-acetamido-4-
methylphosphinico-butanoic acid were found in the excreta, although the 
latter is believed to be a result of a revisable acetylation and 
decetylation process by intestinal bacteria.
    7. Metabolite toxicology . The primary residue resulting from the 
use of glufosinate-ammonium in genetically transformed sugar beets and 
canola that are tolerant to the herbicide, glufosinate-ammonium, 
consists of the metabolites, 2-acetamido-4-methylphosphinico-butanoic 
acid and 3-methylphosphinico-propionic acid. Only the latter metabolite 
is formed in conventional crops. A considerable number of toxicity 
studies have been conducted with these metabolites, including 
developmental toxicity studies in rats and rabbits with both 
metabolites and a 2-generation rat reproduction study with 2-acetamido-
4-methylphosphinico-butanoic acid. Neither metabolite presents an acute 
toxicity hazard and both were determined to be non-genotoxic in an 
extensive battery of in vitro and in vivo genotoxicity studies. Neither 
metabolite demonstrated significant developmental toxicity to either 
rats or rabbits. Subchronic studies in rats, mice and dogs were 
conducted with both metabolites with no clear evidence for any specific 
target organ toxicity and with NOEL's or No Observed Adverse Effects 
Levels (NOAEL's) substantially higher than those seen with glufosinate-
ammonium. Thus, these studies indicate that both metabolites are less 
toxic than the parent compound and do not pose any reproductive or 
developmental concerns.

C. Endocrine Effects

    No special studies investigating potential estrogenic or endocrine 
effects of glufosinate-ammonium have been conducted. However, the 
standard battery of required studies has been completed. These studies 
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. These studies are generally 
considered to be sufficient to detect any endocrine effects but no such 
effects were noted in any of the studies with either glufosinate-
ammonium or its metabolites.

D. Aggregate Exposure

    Glufosinate-ammonium is a non-selective, post-emergent herbicide 
with both food and non-food uses. As such, aggregate non-occupational 
exposure would include exposures resulting from consumption of 
potential residues in food and water, as well as from residue exposure 
resulting from non-crop use around trees, shrubs, lawns, walks, 
driveways, etc. Thus, the possible human exposure from food, drinking 
water and residential uses has been assessed below.
    1. Food. For purposes of assessing the potential dietary exposure 
from food under the proposed tolerances, the petitioner has been 
advised that the EPA has estimated exposure based on the Theoretical 
Maximum Residue Contribution (TMRC) derived from the initially 
established tolerances for glufosinate-ammonium on apples, grapes, tree 
nuts, bananas, milk and the fat, meat and meat-by-products of cattle, 
goats, hogs, horses and sheep as well as the subsequently established 
tolerances for glufosinate-ammonium on field corn, soybeans, aspirated 
grain fractions, and the eggs, fat, meat and meat-by-products of 
poultry. The TMRC is obtained by using a model which multiplies the 
tolerance level residue for each commodity by consumption data which 
estimate the amount of each commodity and products derived from the 
commodity that are eaten by the U.S. population and various population 
subgroups. In conducting this exposure assessment, the EPA has made 
very conservative assumptions--100% of all commodities will contain 
glufosinate-ammonium residues and those residues would be at the level 
of the tolerance--which result in a large overestimate of human 
exposure. Thus, in making a safety determination for these tolerances, 
the Agency took into account this very conservative exposure 
assessment. In 62 FR 5333 (February 5, 1997), the Agency concluded that 
the original tolerances for apples, nuts, grapes and the secondary 
tolerances in animal commodities utilize 2.07% of the Reference Dose 
(RfD) and that the subsequent tolerances for the corn and soybean 
commodities will utilize 3.7% of the RfD.
    2. Drinking water. There is presently no EPA Lifetime Health 
Advisory level or Maximum Contaminant Level established for residues of 
glufosinate-ammonium in water. The petitioner has

[[Page 52547]]

been advised by the EPA that all environmental fate data requirements 
for glufosinate-ammonium have been satisfied. The potential for 
glufosinate-ammonium to leach into groundwater has been assessed in a 
total of nine terrestrial field dissipation studies conducted in 
several states and in varying soil types. The degradation of 
glufosinate-ammonium in these studies was rapid, with half-lives 
ranging from a low of 6 to a high of 23 days. Despite the relatively 
high water solubility of glufosinate-ammonium, this compound did not 
appear to leach under typical test conditions. This is a result of the 
combination of its rapid degradation and its tendency to bind to 
certain soil elements such as clay or organic matter. Based on these 
studies and the expected conditions of use, the potential for finding 
significant glufosinate-ammonium residues in water is minimal and the 
contribution of any such residues to the total dietary intake of 
glufosinate-ammonium will be negligible.
    3. Non-dietary exposure. As a non-selective, post-emergent 
herbicide, homeowner use of glufosinate-ammonium will consist primarily 
of spot spraying of weeds around trees, shrubs, walks, driveways, 
flower beds, etc. There will be minimal opportunity for post-
application exposure since contact with the treated weeds will rarely 
occur. Thus, any exposures to glufosinate-ammonium resulting from 
homeowner use will result from dermal exposure during the application 
and will be limited to adults, not to infants or children. These 
exposures are not expected to pose any acute toxicity concerns. 
Furthermore, based on the US EPA National Home and Garden Pesticide Use 
Survey (RTI/5100/17-01F, March 1992), the average homeowner is expected 
to use non-selective herbicides only about 4 times a year. Thus, these 
exposures would not normally be factored into a chronic exposure 
assessment.

E. Cumulative Effects

    The potential for cumulative effects of glufosinate-ammonium and 
other substances that have a common mechanism of toxicity must also be 
considered. The precise mechanism of action for the toxic effects of 
glufosinate-ammonium in animals is not known but is believed to result, 
at least in part, from interference with the neurotransmitter function 
of glutamate, to which it is a close structural analog. No other 
registered active ingredients are known to have a similar mechanism of 
action. Thus, no cumulative effects with other substances are 
anticipated. Furthermore, the residues in or on transgenic crops will 
consist primarily of the metabolites of glufosinate-ammonium, not 
glufosinate-ammonium itself. These metabolites are less toxic than 
glufosinate-ammonium and, because they are not structural analogs of 
glutamate, they should not cause the same effects. Thus, consideration 
of a common mechanism of toxicity is not appropriate at this time and 
only the potential risks of glufosinate-ammonium need to be considered 
in its aggregate exposure assessment.

F. Safety Determinations

    1. U.S. population. Based on a complete and reliable toxicity 
database, the EPA has adopted an RfD value of 0.02 mg/kg/day using the 
NOEL of 2.1 mg/kg/day from the chronic rat toxicity study and a 100-
fold safety factor. Using the Dietary Risk Evaluation System (DRES) 
with raw agricultural commodity residue values set at the established 
and proposed tolerance levels and with reasonable maximum market share 
estimates applied (``realistic'' case assessment), AgrEvo has 
calculated that aggregate dietary exposure to glufosinate-ammonium from 
the previously established tolerances and the proposed tolerances on 
sugar beets, canola and potatoes will utilize 2.1% of the RfD for the 
U.S. population (48 states). There is generally 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. Therefore, there is a 
reasonable certainty that no harm will result from aggregate exposure 
to glufosinate-ammonium residues to the U.S. population in general.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of glufosinate-
ammonium, one should consider data from developmental toxicity studies 
in the rat and rabbit and a 2-generation reproduction study in the rat. 
The developmental toxicity 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.
    Three developmental toxicity studies in rats (including pre- and 
post-natal phases), a developmental toxicity study in rabbits, and a 2-
generation rat reproduction study have been conducted with glufosinate-
ammonium. No evidence of developmental toxicity was noted in rabbits, 
even at the maternally toxic dose level of 20 mg/kg/day. No 
developmental or reproductive effects were noted in rats except at 
parentally toxic dose levels. The NOEL's for maternal and developmental 
toxicity in the rat developmental toxicity studies were determined to 
be 10 mg/kg/day and 50 mg/kg/day, respectively, based on findings of 
hyperactivity and vaginal bleeding in dams at 50 mg/kg/day and 
increased incidence of arrested renal and ureter development in fetuses 
at 250 mg/kg/day. The parental and reproductive NOEL's in the 2-
generation rat reproduction study were determined to be 40 ppm (4 mg/
kg/day) and 120 ppm (12 mg/kg/day), respectively, based on increased 
parental kidney weights at 120 ppm and decreased numbers of pups at 360 
ppm. In all cases, the reproductive and developmental NOEL's were 
greater than or equal to the parental NOEL's, thus indicating that 
glufosinate-ammonium does not pose any increased risk to infants or 
children.
    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 relative to pre- and post-natal effects for children is 
complete. Further, the NOEL at 2.1 mg/kg/day from the chronic rat study 
with glufosinate-ammonium, which was used to calculate the RfD 
(discussed above), is already lower than the NOEL's from the 
reproductive and developmental studies with glufosinate-ammonium by a 
factor of at least 6-fold. Therefore, an additional safety factor is 
not warranted and an RfD of 0.02 mg/kg/day is appropriate for assessing 
aggregate risk to infants and children.
    Using the DRES analysis with raw agricultural commodity residue 
values set at the established and proposed tolerance levels and with 
reasonable maximum market share estimates applied (``realistic'' case 
assessment), AgrEvo has calculated that aggregate dietary exposure to 
glufosinate-ammonium from the previously established tolerances and the 
proposed tolerances on sugar beets, canola and potatoes will utilize 
5.5% of the RfD for non-nursing infants (1- year old), the most 
sensitive population sub-group and 5.3% of the RfD for children (1-6 
year old), the second most sensitive population sub-group. Therefore, 
based on the completeness and reliability of the toxicity data and a 
comprehensive exposure assessment, it may be concluded that there is a 
reasonable certainty that no harm will result to

[[Page 52548]]

infants and children from aggregate exposure to glufosinate-ammonium 
residues.

G. International Tolerances

    An analysis of the Codex Alimentarius Commission (Codex) tolerances 
has been conducted. While no international Codex tolerances for 
selective uses of tolerances for glufosinate-ammonium in the 
desiccation use pattern have been established for conventional canola 
(rapeseed) at 5 ppm, crude rapeseed oil at 0.05 ppm and potatoes at 0.5 
ppm. These tolerances are established for the sum of glufosinate-
ammonium and 3-methylphosphinico-propionic acid, calculated as 
glufosinate (free acid). The U.S. proposal for a 0.4 ppm tolerance for 
residues of glufosinate-ammonium in potatoes will be harmonized with 
the Canadian tolerance which has already been established at this 
level.
    The Codex tolerances for glufosinate-ammonium in or on sugar beets 
have been established at 0.05 ppm in the beet and 0.1 ppm in the tops 
(leaves). AgrEvo intends to propose higher tolerances to the Codex 
commission for glufosinate-ammonium use on transgenic sugar beets in 
order to harmonize these tolerances with those proposed in the U.S. and 
elsewhere. (Joanne Miller)

2. K-I Chemical U.S.A., Inc.

PP 7F4821

    EPA has received an amendment to pesticide petition (PP 7F4821) 
from K-I Chemical U.S.A., Inc. , White Plains, New York 10606, 
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 herbicide, fluthiacet-methyl 
in or on the raw agricultural commodity popcorn grain at 0.02 ppm.
    On April 14, l997, EPA announces receipt of a pesticide petition 
(PP 7F4821) from K-I Chemical U.S.A., Inc., 11 Martine Avenue, 9th 
Floor, White Plains, NY 10606, 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 the herbicide 
fluthiacet-methyl: Acetic acid, [[2-chloro-4-fluoro-5-[(tetrahydro-3-
oxo-1H,3H-[1,3,4]thiadiazolo[3,4-a] pyridazin-1-
ylidene)amino]phenyl]thio]-methylester in or on the raw agricultural 
commodities field corn grain and sweet corn grain (K + CWHR) at 0.02 
ppm and corn forage and fodder at 0.05 ppm.
    On September 4, 1997 K-I Chemical, U.S.A., Inc., amended PP 7F4821 
to include a proposed tolerance for popcorn grain at 0.02 ppm. EPA has 
determined that the amended 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 nature of the residues in corn is 
adequately understood following application of fluthiacet-methyl. 
Residue levels and the metabolic pathway are consistent with those in 
soybeans. Parent fluthiacet-methyl was the primary component of the 
residue seen in corn grain, forage, fodder and silage. Results of these 
studies have been submitted to the EPA.
    2. Analytical method. K-I Chemical has submitted practical 
analytical methods (AG-603B and AG-624) for detecting and measuring the 
level of fluthiacet-methyl in or on corn and corn commodities and in 
animal tissues with a limit of detection that allows monitoring 
residues at or above the levels set for the proposed tolerance. The 
limit of quantitation of the crop method is 0.01 ppm in corn and corn 
commodities, 0.05 ppm in animal tissues and 0.01 ppm in milk. The crop 
method involves extraction, filtration, and solid phase clean up. 
Residue levels of fluthiacet-methyl are determined by gas 
chromatographic analysis utilizing a nitrogen phosphorus detector and a 
fused-silica column. The animal tissue method involves extraction, 
filtration, and partition. Determination of residue levels in animal 
tissues is by HPLC with UV detection via column switching using C1 and 
C18 columns. The analyte of interest in animal tissues and milk is the 
major animal metabolite CGA-300403. Residues of fluthiacet-methyl in 
corn are determined by gas chromatography.
    3. Magnitude of residues. The residue of concern in corn is 
fluthiacet-methyl per se. Twenty-one field residue studies were 
conducted with corn grown in nineteen states. Fifteen of the studies 
were on field corn and six on sweet corn. No studies were conducted 
with popcorn, however K-I believes that the data on field and sweet 
corn support a tolerance in popcorn as well. Because the proposed use 
rate and pattern is the same for popcorn, it is reasonable to conclude 
that residues in popcorn grain will not exceed the proposed tolerance 
of 0.02 ppm. Residues in field and sweet corn forage after the day of 
application were less than the proposed tolerance of 0.05 ppm. Popcorn 
forage is not a fed commodity. Nonetheless, residues in popcorn forage 
or fodder are not expected to exceed the proposed tolerance of 0.05 
ppm. The proposed tolerances of 0.02 ppm in field corn, sweet corn, and 
popcorn grain and 0.05 ppm in field corn and sweet corn forage and 
fodder are adequate to cover residues likely to occur when Action 
herbicide is applied to corn as directed.
    This position is based on section 180.34(d) of the CFR which states 
that ``If the pesticide chemical is not absorbed into the living plant 
or animal when applied (is not systemic), it may be possible to make a 
reliable estimate of the residues to be expected on each commodity in a 
group of related commodities on the basis of less data than would be 
required for each commodity in the group, considered separately.'' And, 
section 180.34(e) states that ``Each of the following groups of crops 
lists raw agricultural commodities that are considered to be related 
for the purpose of paragraph (d) of this section; field corn, popcorn, 
sweet corn (each in grain form).''
    Residues of fluthiacet-methyl in treated field and sweet corn grain 
and sweet corn ears were less than the method LOQ (<0.01 ppm). Because 
the proposed use rate and pattern is the same for popcorn, it is 
reasonable to conclude that residues in popcorn grain will not exceed 
the proposed tolerance of 0.02 ppm. Residues in field and sweet corn 
forage after the day of application were less than the proposed 
tolerance of 0.05 ppm. Popcorn forage is not a feed commodity. 
Nonetheless, residues in popcorn forage or fodder are not expected to 
exceed the proposed tolerance of 0.05 ppm. The proposed tolerances of 
0.02 ppm in field corn, sweet corn, and popcorn grain and 0.05 ppm in 
field corn and sweet corn forage and fodder are adequate to cover 
residues likely to occur when Action herbicide is applied to corn as 
directed.

B. Toxicological Profile

    1. Acute toxicity.
    \A rat acute oral study with an LD50 > 5,000 mg/kg.
    \A rabbit acute dermal study with an LD50 > 2,000 mg/kg.
    \A rat inhalation study with an LC50 > 5.05 mg/liter.
    \A primary eye irritation study in the rabbit showing moderate eye 
irritation.
    \A primary dermal irritation study in the rabbit showing no skin 
irritation.
    \A primary dermal sensitization study in the Guinea pig showing no 
sensitization.

[[Page 52549]]

    \Acute neurotoxicity study in rats. Neurotoxic effects were not 
observed. The NOEL was 2,000 mg/kg.
    2. Genotoxicity. In vitro gene mutation tests: Ames test - 
negative; Chinese hamster V79 test - negative; rat hepatocyte DNA 
repair test - negative; E. Coli letal DNA damage test - negative. In 
vitro chromosomal aberration tests: Chinese hamster ovary - positive at 
cytotoxic doses; Chinese hamster lung - positive at cytotoxic doses; 
human lymphocyes - positive at cytotoxic doses. In vivo chromosome 
aberration tests: Micronucleus assays in rat liver - negative; mouse 
bone marrow test - negative.
    3. Reproductive and developmental toxicity. Reproductive and 
developmental toxicity. Teratology study in rats with a maternal and 
developmental NOEL equal to or greater than 1,000 mg/kg/day.
    Teratology study in rabbits with a maternal NOEL greater than or 
equal to 1,000 mg/kg/day and a fetal NOEL of 300 mg/kg based on a 
slight delay in fetal maturation. 2-generation reproduction study in 
rats with a NOEL of 36 mg/kg/day, based on liver lesions in parental 
animals and slightly reduced body weight development in parental 
animals and pups. [The treatment had no effect on reproduction or 
fertility.]
    4. Subchronic toxicity. 90-day subchronic neurotoxicity study in 
rats. The NOEL was 0.5 mg/kg/day based on reduced body weight gain. No 
clinical or morphological signs of neurotoxicity were detected at any 
dose level. 28-day dermal toxicity study in rats with a NOEL equal to 
or higher than the limit dose of 1,000 mg/kg.
    6-week dietary toxicity study in dogs with a NOEL of 162 mg/kg/day 
in males and 50 mg/kg/day in females based on decreased body weight 
gain and modest hematological changes.
    90-day subchronic dietary toxicity study in rats with a NOEL of 6.2 
mg/kg/day based on liver changes and hematological effects.
    5. Chronic toxicity. 24-month combined chronic toxicity/
carcinogenicity study in rats with a NOEL of 2.1 mg/kg/day. Based on 
reduced body weight development and changes in bone marrow, liver, 
pancreas and uterus the MTD was exceeded at 130 mg/kg/day. A positive 
trend of adenomas of the pancreas in male rats treated at 130 mg/kg/day 
and above may be attributable to the increased survival of the rats 
treated at high doses. 18-month oncogenicity study in mice with a NOEL 
of 0.14 mg/kg/day. Based on liver changes, the MTD was reached at 1.2 
mg/kg/day. The incidence of hepatocellular tumors was increased in 
males treated at 12 and 37 mg/kg/day.

C. Endocrine effects

    Based on the results of short-term, chronic, and reproductive 
toxicity studies there is no indication that fluthiacet-methyl might 
interfere with the endocrine system. Considering further the low 
environmental concentrations and the lack of bioaccumulation, there is 
no risk of endocrine disruption in humans or wildlife.
    Animal metabolism. The results from hen and goat metabolism 
studies, wherein fluthiacet-methyl was fed at exaggerated rates, showed 
that the transfer of fluthiacet-methyl residues from feed to tissues, 
milk and eggs is extremely low. No detectable residues of fluthiacet-
methyl (or metabolite CGA-300403) would be expected in meat, milk, 
poultry, or eggs after feeding the maximum allowable amount of treated 
corn and soybeans. This conclusion is based on residue data from the 
corn and soybean metabolism and field residue chemistry studies coupled 
with the residue transfer from feed to tissues, milk and eggs obtained 
in the goat and hen metabolism studies.

D. Aggregate Exposure

    Aggregate exposure includes exposure from dietary exposure from 
food and drinking water; and non-dietary exposure from non-dietary uses 
of pesticides products containing the active ingredient, fluthiacet-
methyl.
    1. Dietary exposure. Dietary exposure consists of exposures from 
food and drinking water.
    2. Food. In this assessment, K-I Chemical has conservatively 
assumed that 100% of all soybeans and corn used for human consumption 
would contain residues of fluthiacet-methyl and all residues would be 
at the level of the proposed tolerances. The potential dietary exposure 
to fluthiacet-methyl was calculated on the basis of the proposed 
tolerance which is based on an LOQ of 0.01 ppm in soybeans and 0.02 ppm 
in corn (2 x LOQ). The anticipated residues in milk, meat and eggs 
resulting from feeding the maximum allowable amount of soybean and corn 
commodities to cattle and poultry were calculated, and the resulting 
quantities were well below the analytical method LOQ. Therefore, 
tolerances for milk, meat and eggs are not required. Assuming 100% crop 
treated values, the chronic dietary exposure of the general U.S. 
population to fluthiacet-methyl would correspond to 2.3% of the RfD.
    3. Drinking water. Although fluthiacet-methyl has a slight to 
medium leaching potential; the risk of the parent compound to leach to 
deeper soil layers is negligible under practical conditions in view of 
the fast degradation of the product. For example, the soil metabolism 
half-life was extremely short, ranging from 1.1 days under aerobic 
conditions to 1.6 days under an aerobic conditions. Even in the event 
of very heavy rainfalls immediately after application, which could lead 
to a certain downward movement of the parent compound, parent 
fluthiacet-methyl continues to be degraded during the transport into 
deeper soil zones. Considering the low application rate of fluthiacet-
methyl, the strong soil binding characteristics of fluthiacet-methyl 
and its degradates, and the rapid degradation of fluthiacet-methyl in 
the soil, there is no risk of ground water contamination with 
fluthiacet-methyl or its metabolites. Thus, aggregate risk of exposure 
to fluthiacet-methyl does not include drinking water
    4. Non-dietary exposure. Fluthiacet-methyl is not registered for 
any other use and is only proposed for use on agricultural crops. Thus, 
there is no potential for non-occupational exposure other than 
consumption of treated commodities containing fluthiacet-methyl 
residue.

E. Cumulative Effects

    A cumulative exposure assessment is not appropriate at this time 
because there is no information available to indicate that effects of 
fluthiacet-methyl in mammals would be cumulative with those of another 
chemical compound.

F. Safety Determination

    1. U.S. population. Using the very conservative exposure 
assumptions described above coupled with toxicity data for fluthiacet-
methyl, K-I Chemical calculated that aggregate, chronic exposure to 
fluthiacet-methyl will utilize no more than 2.3% of the RfD for the 
U.S. population. Because the actual anticipated residues are well below 
tolerance levels and the percent crop treated with fluthiacet-methyl is 
expected to be less than 25% of planted corn or soybeans, a more 
realistic estimate is that dietary exposure will likely be at least 20 
times less than the conservative estimate previously noted (the margins 
of exposure will be accordingly higher). Exposures below 100% of the 
RfD are generally not of concern 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.

[[Page 52550]]

    Also the acute dietary risk to consumers will be far below any 
significant level; the lowest NOEL from a short term exposure scenario 
comes from the teratology study in rabbits with a NOEL of 300 mg/kg. 
This NOEL is 2,000-fold higher than the chronic NOEL which provides the 
basis for the RfD (see above). Acute dietary exposure estimates which 
are based on a combined food survey from 1989 to 1992 predict margins 
of exposure of at least one million for 99.9% of the general population 
and for women of child bearing age. Margins of exposure of 100 or more 
are generally considered satisfactory. Therefore, K-I Chemical 
concludes that there is a reasonable certainty that no harm will result 
from aggregate exposure to fluthiacet-methyl residues.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of fluthiacet-methyl, 
K-I Chemical considered data from developmental toxicity studies in the 
rat and rabbit and a 2-generation reproduction study in the rat. A 
slight delay in fetal maturation was observed in a teratology study in 
rabbits at a daily dose of 1,000 mg/kg. In a 2-generation reproduction 
study fluthiacet-methyl did not affect the reproductive performance of 
the parental animals or the physiological development of the pups. The 
NOEL was 500 ppm for maternal animals and their offspring, which is 
50,000 fold higher than the RfD.
    3. Reference dose. Using the same conservative exposure assumptions 
as was used for the general population, the percent of the RfD that 
will be utilized by aggregate exposure to residues of fluthiacet-methyl 
is as follows: 1.5% for nursing infants less than 1 year old, 5.9% for 
non-nursing infants, and 5.2% for children 1-6 years old. K-I Chemical 
concludes that there is a reasonable certainty that no harm will result 
to infants and children from aggregate exposure to residues of 
fluthiacet-methyl.

G. International Tolerances

     No international tolerances have been established under CODEX for 
fluthiacet-methyl. (Joanne Miller)

3. Zeneca Ag Products

PP 7F4864

    EPA has received a pesticide petition (PP 7F4864) from Zeneca Ag 
Products, 1800 Concord Pike, P.O. Box 15458, Wilmington, DE 19850-5458] 
proposing pursuant to section 408(d) of the Federal Food, Drug and 
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR 180.507 by 
establishing a tolerance for residues of azoxystrobin (methyl(E)-2-(2-
(6-(2-cyanophenoxy)pyrimidin-4-yloxy)phenyl)-3- methoxyacrylate) and 
the Z-isomer of azoxystrobin (methyl(Z)-2-(2-(6-(2-cyanophenoxy) 
pyrimidin-4-yloxy)phenyl)-3-methoxyacrylate)] in or on the raw 
agricultural commodities almond hulls at 4.0 ppm, cucurbits (chayotes, 
Chinese waxgourds, citron melons, cucumbers, gherkins, edible gourds, 
Mordica spp., cantaloupes, casabas, crenshaw melons, golden pershaw 
melons, honeydew melons, honey balls, mango melons, Persian melons, 
summer squashes, winter squashes, and watermelons) at 0.3 ppm, peanut 
hay at 1.5 ppm, pistachios at 0.01 ppm, rice grain at 4.0 ppm, rice 
hulls at 20 ppm, rice straw at 11 ppm, tree nuts (almonds, beech nuts, 
Brazil nuts, butternuts, cashews, chestnuts, chinquapins, filberts, 
hickory nuts, macadamia nuts, pecans, and walnuts) at 0.01 ppm, wheat 
bran at 0.12 ppm, wheat grain at 0.04 ppm, wheat hay at 13.0 ppm, and 
wheat straw at 4.0 ppm. It is also proposed that 40 CFR 180.507 be 
amended by establishment of a tolerance for the residues of 
azoxystrobin (methyl (E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-
yloxy]phenyl]-3-methoxyacrylate) in or on the following animal 
products: eggs at 0.4 ppm, cattle kidney at 0.06 ppm, liver of cattle, 
goat, horse, and sheep at 0.3 ppm, hog liver at 0.2 ppm, poultry liver 
at 0.4 ppm, meat and fat of cattle, goat, horse, sheep, poultry and 
swine at 0.01 ppm, and milk at 0.006 ppm. The proposed analytical 
methods use gas chromatography with nitrogen-phosphorous detection (GC-
NPD) or, in mobile phase, high performance liquid chromatography with 
ultraviolet detection (HPLC-UV). 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 azoxystrobin as well as the 
nature of the residues is adequately understood for purposes of the 
tolerances. Plant metabolism has been evaluated in three diverse crops, 
grapes, wheat, and peanuts, which should serve to define the similar 
metabolism of azoxystrobin in a wide range of crops. Parent 
azoxystrobin is the major component found in crops. Azoxystrobin does 
not accumulate in crop seeds or fruits. Metabolism of azoxystrobin in 
plants is complex, with more than 15 metabolites identified. These 
metabolites are present at low levels, typically much less than 5% of 
the TRR.
    2. Analytical method. An adequate analytical method, gas 
chromatography with nitrogen-phosphorous detection (GC-NDP) or, in 
mobile phase, by high performance liquid chromatography with 
ultraviolet detection (HPLC-UV), is available for enforcement purposes 
with a limit of detection that allows monitoring of food with residues 
at or above the levels set in these tolerances. The Analytical 
Chemistry Section of the EPA concluded that the method(s) are adequate 
for enforcement. Analytical methods are also available for analyzing 
meat, milk, poultry, and eggs and also underwent successful independent 
laboratory validations.

B. Toxicological Profile

    1. Acute toxicity. The acute oral toxicity study in rats of 
technical azoxystrobin resulted in an LD50 of >5,000 
milligrams/kilogram (limit test) for both males and females. The acute 
dermal toxicity study in rats of technical azoxystrobin resulted in an 
LD50 of >2,000 milligrams/kilogram (limit dose). The acute 
inhalation study of technical azoxystrobin in rats resulted in an 
LC50 of 0.962 milligrams/liter in males and 0.698 
milligrams/liter in females. In an acute oral neurotoxicity study in 
rats dosed once by gavage with 0, 200, 600, or 2,000 milligrams/ 
kilogram azoxystrobin, the systemic toxicity no observed effect level 
(NOEL) was 200 milligrams/kilogram and the systemic toxicity lowest 
observed effect level (LOEL) was 200 milligrams/kilogram, based on the 
occurrence of transient diarrhea in both sexes. There was no indication 
of neurotoxicity at the doses tested. This acute neurotoxicity study is 
considered supplementary (upgradable) but the data required are 
considered only to be confirmatory. Zeneca has submitted the required 
confirmatory data; these data have been scheduled for review by the 
Agency.
    2. Genotoxicty (mutagenicity). Azoxystrobin was negative for 
mutagenicity in the salmonella/mammalian activation gene mutation 
assay, the mouse micronucleus test, and the unscheduled DNA synthesis 
in rat hepatocytes/mammalian cells (in vivo/in vitro procedure study). 
In the forward mutation study using L5178 mouse lymphoma cells in 
culture, azoxystrobin tested positive for forward gene mutation at the 
TK locus. In the in vitro human lymphocytes cytogenetics assay of 
azoxystrobin, there was evidence of a concentration related induction 
of

[[Page 52551]]

chromosomal aberrations over background in the presence of moderate to 
severe cytotoxicity.
    3. Reproductive and developmental toxicity. In a prenatal 
development study in rats gavaged with azoxystrobin at dose levels of 
0, 25, 100, or 300 mg/kg/day during days 7 through 16 of gestation, 
lethality at the highest dose caused the discontinuation of dosing at 
that level. The developmental NOEL was greater than or equal to 100 mg/
kg/day and the developmental lowest observed effect level (LOEL) was 
>100 mg/kg/day because no significant adverse developmental effects 
were observed. In this same study, the maternal NOEL was not 
established; the maternal LOEL was 25 mg/kg/day, based on increased 
salivation.
    In a prenatal developmental study in rabbits gavaged with 0, 50, 
150, or 500 mg/kg/day during days 8 through 20 of gestation, the 
developmental NOEL was 500 mg/kg/day and the developmental LOEL was 
>500 mg/kg/day because no treatment-related adverse effects on 
development were seen. The maternal NOEL was 150 mg/kg/day and the 
maternal LOEL was 500 mg/kg/day, based on decreased body weight gain.
    In a 2-generation study, rats were fed 0, 60, 300, or 1,500 ppm of 
azoxystrobin. The reproductive NOEL was 32.2 mg/kg/day. The 
reproductive LOEL was 165.4 mg/kg/day. Reproductive toxicity was 
demonstrated as treatment-related reductions in adjusted pup body 
weights as observed in the F18 and F2. pups dosed at 1500 ppm (165.4 
mg/kg/day).
    4. Subchronic toxicity. In a 90-day rat feeding study the NOEL was 
20.4 mg/kg/day for males and females. The LOEL was 211.0 mg/kg/day 
based on decreased weight gain in both sexes, clinical observations of 
distended abdomens and reduced body size, and clinical pathology 
findings attributable to reduced nutritional status.
    In a subchronic toxicity study in which azoxystrobin was 
administered to dogs by capsule for 92 or 93 days, the NOEL for both 
males and females was 50 mg/kg/day. The LOEL was 250 mg/kg/day, based 
on treatment-related clinical observations and clinical chemistry 
alterations at this dose.
    In a 21-day repeated-dose dermal rat study using azoxystrobin, the 
NOEL for both males and females was greater than or equal to 1,000 mg/
kg/day (the highest dosing regimen); a LOEL was therefore not 
determined.
    5. Chronic toxicity and carcinogenicity. In a 2-year feeding study 
in rats fed diets containing 0, 60, 300, and 750/1,500 ppm (males/
females), the systemic toxicity NOEL was 18.2 mg/kg/day for males and 
22.3 mg/kg/day for females. The systemic toxicity LOEL for males was 34 
mg/kg/day, based on reduced body weights, food consumption, and food 
efficiency; and bile duct lesions. The systemic toxicity LOEL for 
females was 117.1 mg/kg/day, based on reduced body weights. There was 
no evidence of carcinogenic activity in this study.
    In a 1-year feeding study in dogs to which azoxystrobin was fed by 
capsule at doses of 0, 3, 25, or 200 mg/kg/day, the NOEL for both males 
and females was 25 mg/kg/day and the LOEL was 200 mg/kg/day for both 
sexes, based on clinical observations, clinical chemistry changes, and 
liver weight increases that were observed in both sexes.
    In a 2-year carcinogenicity feeding study in mice using dosing 
concentrations of 0, 50, 300, or 2,000 ppm, the systemic toxicity NOEL 
was 37.5 mg/kg/day for both males and females. The systemic toxicity 
LOEL was 272.4 mg/kg/day for both sexes, based on reduced body weights 
in both at this dose. There was no evidence of carcinogenicity at the 
dose levels tested.
    According to the new proposed guidelines for Carcinogen Risk 
Assessment (April, 1996), the appropriate descriptor for human 
carcinogenic potential of azoxystrobin is ``Not Likely''. The 
appropriate subdescriptor is ``has been evaluated in at least two well 
conducted studies in two appropriate species without demonstrating 
carcinogenic effects''.
    6. Animal metabolism. In the study of metabolism in the rat, 
azoxystrobin-- unlabeled or with a pyrimidinyl, phenylacrylate, or 
cyanophenyl label--was administered to rats by gavage as a single or 
14-day repeated doses. Less than 0.5% of the administered dose was 
detected in the tissues and carcass up to 7 days post-dosing and most 
of it was in excretion- related organs. There was no evidence of 
potential for bioaccumulation. The primary route of excretion was via 
the feces, though 9 to 18% was detected in the urine of the various 
dose groups. Absorbed azoxystrobin appeared to be extensively 
metabolized. A metabolic pathway was proposed showing hydrolysis and 
subsequent glucuronide conjugation as the major biotransformation 
process. This study was classified as supplementary but upgradable; the 
company has submitted data intended to upgrade the study and these data 
have been reviewed.

C. Dietary Exposure

    1. Food. The primary route of human exposure to azoxystrobin is 
expected to be dietary ingestion of both raw and processed agricultural 
commodities from bananas, grapes, peaches, peanuts, tomatoes, tree 
nuts, pistachios, rice, cucurbits, and wheat. A chronic dietary 
exposure analysis (combined years 1989 - 1992 U.S. Department of 
Agriculture's Nationwide Food Consumption Survey using the Technical 
Assessment Systems, Inc. ``EXPOSURE 1'' software) was conducted using 
tolerance level residues and 100% crop treated information to estimate 
the TMRC for the general population and 22 subgroups.
    2. Drinking water. There is no established Maximum Concentration 
Level for residues of azoxystrobin in drinking water. The potential 
exposures associated with azoxystrobin in water, even at the higher 
levels the Agency is considering as a conservative upper bound, would 
not prevent the Agency from determining that there is a reasonable 
certainty of no harm if the proposed uses were granted.
    3. Non-dietary exposure. The Agency evaluated the existing 
toxicological database for azoxystrobin and assessed appropriate 
toxicological endpoints and dose levels of concern that should be 
assessed for risk assessment purposes. Dermal absorption data indicate 
that absorption is less than or equal to 4%. No appropriate endpoints 
were identified for acute dietary or short term, intermediate term, and 
chronic term (noncancer) dermal and inhalation occupational or 
residential exposure. Therefore, risk assessments are not required for 
these exposure scenarios and there are no residential risk assessments 
to aggregate with the chronic dietary risk assessment.

D. Cumulative Effects

    Section 408(b)(2)(D)(v) requires that, when considering whether to 
establish, modify, or revoke a tolerance, the Agency consider 
``available information'' concerning the cumulative effects of a 
particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.'' EPA does not have, at this time, 
available data to determine whether azoxystrobin has a common mechanism 
of toxicity with other substances or how to include this pesticide in a 
cumulative risk assessment. Unlike other pesticides for which EPA has 
followed a cumulative risk approach based on a common mechanism of 
toxicity, azoxystrobin does not appear to be structurally similar to 
any other pesticide chemical at this time. No metabolites of 
azoxystrobin that are of toxicological concern are known to the Agency. 
Azoxystrobin appears to the only pesticide member of its class of

[[Page 52552]]

chemistry and there are no reliable data to indicate that this chemical 
is structurally or toxicologically similar to existing chemical 
substances at this time. Therefore, it appears unlikely that 
azoxystrobin bears a common mechanism of activity with other 
substances. For the purposes of this tolerance action, it is not 
appropriate to assume that azoxystrobin has a common mechanism of 
toxicity with other substances.

E. Safety Determination

    The chronic toxicity Reference Dose (RfD) for azoxystrobin is 0.18 
mg/kg/day, based on the NOEL of 18.2 mg/kg/day from the rat chronic 
toxicity/ carcinogenicity feeding study in which decreased body weight 
and bile duct lesions were observed in male rats at the LOEL of 34 mg/
kg/day. This NOEL was divided by an Uncertainty Factor of 100, to allow 
for interspecies sensitivity and intraspecies variability.
    1.As part of the hazard assessment process, the available 
toxicological database was reviewed to determine if there are 
toxicological endpoints of concern. For azoxystrobin, the Agency does 
not have a concern for acute dietary exposure since the available data 
do not indicate any evidence of significant toxicity from a 1-day or 
single event exposure by the oral route. Therefore, an acute dietary 
risk assessment is not required for azoxystrobin at this time.
    2. U.S. population. The chronic dietary exposure analysis showed 
that exposure from the proposed new tolerances in or on tree nuts, 
pistachios, cucurbits, rice, and wheat for the general U.S. population 
would be 1.1% of the RfD. This analysis used a value of 0.05 ppm for 
banana pulp rather than the value of 0.5 that has been established for 
banana (whole fruit including peel) because adequate data were 
submitted to support use of the lower value in the dietary risk 
analyses.
    3. Infants and children. The chronic dietary exposure analysis, 
using the same tolerances and commodities that were used for the same 
analysis for the general U.S. population showed that the exposure of 
Non-nursing Infants (the subgroup with the highest exposure) would be 
4.1% of the RfD.
    FFDCA section 408 provides that EPA shall apply an additional 
tenfold margin of safety for infants and children in the case of 
threshold effects to account for pre- and post-natal toxicity and the 
completeness of the database unless EPA determines that a different 
margin of safety will be safe for infants and children. Margins of 
safety are incorporated into EPA risk assessments either directly 
through use of a margin of exposure analysis or through using 
uncertainty (safety) factors in calculating a dose level that poses no 
appreciable risk to humans. In either case, EPA generally defines the 
level of appreciable risk as exposure that is greater than 1/100th of 
the no observed effect level in the animal study appropriate to the 
particular risk assessment. This hundredfold uncertainty (safety) 
factor/margin of exposure (safety) is designed to account for combined 
inter- and intraspecies variability. EPA believes that reliable data 
support using the standard hundredfold margin/factor not the additional 
tenfold margin/factor when EPA has a complete database under existing 
guidelines and when the severity of the effect in infants or children 
or the potency or unusual toxic properties of a compound do not raise 
concerns regarding the adequacy of the standard margin/factor. The 
database for azoxystrobin is complete except that the acute and 
subchronic neurotoxicity studies require upgrading. The upgrade data 
are confirmatory only, have been submitted by the company, and await 
review by the Agency.
    There was no evidence of increased susceptibility of infants or 
children to azoxystrobin. Therefore, no additional uncertainty factors 
are considered necessary at this time.

F. Endocrine Effects

    EPA is required to develop a screening program to determine whether 
certain substances (including all pesticides and inerts) ``may have an 
effect in humans that is similar to an effect produced by a naturally 
occurring estrogen, or such other endocrine effect...''. The Agency is 
currently working with interested shareholders, including other 
government agencies, public interest groups, industry, and research 
scientists, to develop a screening and testing program and a priority 
setting scheme to implement this program. Congress has allowed three 
(3) years from the passage pf FQPA (August 3, 1999) to implement this 
program. When this program is implemented, EPA may require further 
testing of azoxystrobin and end-use product formulations for endocrine 
disrupter effects. There are currently no data or information 
suggesting that azoxystrobin has any endocrine effects.

G. International Tolerances

    There are no Codex Maximum Residue Levels established for 
azoxystrobin. (Cynthia Giles-Parker)

[FR Doc. 97-26537 Filed 10-8-97; 8:45 am]
BILLING CODE 6560-50-F