[Federal Register Volume 64, Number 110 (Wednesday, June 9, 1999)]
[Notices]
[Pages 30997-31000]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-14362]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-876; FRL-6082-6]


Notice of Filing Pesticide Petition

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of a pesticide 
petition proposing the establishment of regulations for residues of a 
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by the docket control number PF-876, must 
be received on or before July 9, 1999.
ADDRESSES: By mail submit written comments to: Information and Records 
Integrity Branch, Public Information and Services Division (7502C), 
Office of Pesticides Programs, Environmental Protection Agency, 401 M 
St., SW., Washington, DC 20460. In person bring comments to: Rm. 1132, 
CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential 
business information (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. 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: Vera Soltero, Registration Support 
Branch, Registration Division (7505C), Office of Pesticide Programs, 
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. 
Office location, telephone number, and e-mail address: Rm. 713G, 
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, 
(703) 308-9359; e-mail: [email protected].
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemical 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 this petition 
contains data or information regarding the elements set forth in 
section 408(d)(2); however, EPA has not fully evaluated the sufficiency 
of the submitted data at this time or whether the data supports 
granting of the petition. Additional data may be needed before EPA 
rules on the petition.
    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-876] (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 control number (PF-876) 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, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: May 27, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petition

    Petitioner summary of the pesticide petition is printed below as 
required by section 408(d)(3) of the FFDCA. The summary of the petition 
was prepared by the petitioner and represents the views of the 
petitioner. EPA is publishing the petition summary 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.

 AgrEvo USA Company

PP 9E5060

    EPA has received a pesticide petition (9E5060) from AgrEvo USA 
Company, Little Falls Centre One, 2711 Centerville Road, Wilmington, 
Delaware 19808 proposing, pursuant to section 408(d) of the Federal 
Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 
CFR part 180 by establishing a tolerance for residues of ethyl 5,5-
diphenyl-2-isoxazoline-3-carboxylate (CAS 163520-33-0) herbicide 
safener AE F122006 in or on the raw agricultural commodities (RAC) rice 
grain at 0.05 parts per million (ppm) and rice straw

[[Page 30998]]

at 0.2 ppm. EPA has determined that the petition contains data or 
information regarding the elements set forth in section 408(d)(2) of 
the FFDCA; however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data 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 AE F122006 (ethyl 5,5-
diphenyl-2-isoxazoline-3-carboxylate) in rice has been investigated and 
is understood. Total residue levels in animal and rice commodities 
(particularly grain) were very low. The initial metabolic 
transformation of AE F122006 in plants is hydrolysis of the prominent 
ester function, yielding the carboxylic acid, AE F129431 (4,5-dihydro-
5,5-diphenyl-3-isoxazolecarboxylic acid). In rice grain, the primary 
metabolite identified was AE C637375 (-hydroxy--
benzenepropanenitrile), which was found only in trace amounts. AE 
F129431 and its hydroxylated analog AE F162241 (4,5-dihydro-5-(4-
hydroxyphenyl)-5-phenyl-3-isoxazolecarboxylic acid) comprised the major 
metabolic residues in rice straw.
    2. Analytical method. Based on the results of the metabolism 
studies, the analytical targets selected were parent compound (AE 
F122006), and the metabolites AE F129431, AE F162241, and AE C637375. A 
practical analytical method utilizing capillary gas chromatography and 
a mass spectrometer detector is available for detecting and measuring 
levels of these residue targets. The limit of quantification (LOQ) is 
0.02 ppm in rice grain and 0.05 ppm in rice straw.
    3. Magnitude of residues. Eighteen residue trials were conducted in 
the major United States rice growing areas over 2-years (1996 to 1997). 
When applied twice at a single application rate of 0.071 pound of the 
safener per acre (80 g/ha) with the second application made at 65-days 
before harvest, combined residues in rice grain did not exceed the LOQ 
(0.02 ppm) with the exception of the results from one trial where the 
residues were 0.03 and 0.04 ppm for AE F122006 and AE C637375, 
respectively. In rice straw, the combined maximum residues did not 
exceed 0.2 ppm. Thus, the tolerances are proposed at 0.05 ppm in rice 
grain and 0.2 ppm in rice straw. Based on the results of the animal 
metabolism studies, no residues are anticipated in milk, meat, and eggs 
due to feeding rice grain or straw. Therefore, tolerances for these 
commodities are not required.

B. Toxicological Profile

    1. Acute toxicity. AE F122006 is slightly toxic following acute 
oral exposure, no more than slightly toxic following acute dermal 
exposure and practically non-toxic following acute inhalation exposure. 
The acute rat oral LD50 of AE F122006 was 1,740 milligrams/
kilograms (mg/kg). The acute rat dermal LD50 was greater 
than 2,000 mg/kg and the 4-hour rat inhalation LC50 was > 5 
milligrams per liter (mg/l). AE F122006 was slightly irritating to 
rabbit eyes and non-irritating to rabbit skin. Based on these results, 
AE F122006 would be classified as EPA Category III for oral and dermal 
toxicity and eye irritation, and EPA Category IV for inhalation 
toxicity and dermal irritation. Technical AE F122006 was shown to be a 
dermal sensitizer in a guinea pig maximization assay, but no evidence 
of sensitization has been observed in a Buehler assay when formulated 
into a commercial product.
    2. Genotoxicity. No evidence of genotoxicity was noted in 
Salmonella and E. coli reverse bacterial mutation assays, an in vitro 
mammalian gene mutation assay in Chinese hamster lung (V79) cells, an 
in vivo unscheduled DNA synthesis assay in rat hepatocytes, or a mouse 
micronucleus assay. An increase in chromosomal aberrations was observed 
in an in vitro assay in Chinese hamster lung (V79) cells, but only at 
toxic concentrations. Thus, the overall weight of evidence indicates 
that AE F122006 does not possess significant genotoxic activity.
    3. Reproductive and developmental toxicity. A rat developmental 
toxicity study was conducted at dose levels of 0, 15, 120, and 1,000 
mg/kg/day. Maternal toxicity (including one death) was noted at 1,000 
mg/kg/day. Slight developmental toxicity (an increase in resorptions) 
but no evidence of teratogenicity was also noted at this level. No 
effects were noted at 120 mg/kg/day, which was considered to be the no-
observed adverse effect level (NOAEL) for both maternal and 
developmental toxicity.
    A rabbit developmental toxicity study was conducted at dose levels 
of 0, 5, 50, and 500 mg/kg/day. Maternal effects at 500 mg/kg/day 
consisted of decreased food consumption, slight weight loss during 
gestation days 6-8, and one death. In addition, one animal at 500 mg/
kg/day had only two empty implantation sites. No evidence of 
teratogenicity or developmental toxicity was noted. Thus, 50 mg/kg/day 
was considered to be the NOAEL for maternal toxicity while 500 mg/kg/
day was the NOAEL for developmental effects.
    Although generally not a prerequisite for the establishment of 
tolerances for an inert safener, a 2-generation rat reproduction study 
with AE F122006 is in progress. In this study, AE F122006 was 
administered at dietary concentrations of 0, 20, 200, and 4,000 ppm. 
Although histopathology is still in progress, the preliminary results 
from the in-life data indicate that the NOAEL will likely be 200 ppm, 
based on decreased body weight (bwt) gain in both adults and weanlings 
(beginning at day 21) at 4,000 ppm. No reproductive effects have been 
observed at any dose level.
    4. Subchronic toxicity. In a 90-day rat feeding study, AE F122006 
was administered at dietary concentrations of 0, 20, 200, 2,000, and 
4,000 ppm. The NOAEL for this study was considered to be 200 ppm 
(approximately 15.3 mg/kg/day) based on decreased weight gain at 2,000 
ppm, and decreased weight gain, increased liver weights, and 
centrilobular hepatocyte enlargement at 4,000 ppm.
    In a 90-day feeding study in mice, AE F122006 was administered at 
dietary concentrations of 13, 125, 1,250, and 2,500 ppm. Decreased 
kidney weights, increased liver weights, and histopathological changes 
in the liver (centrilobular hepatocyte enlargement and vacuolation) 
were noted at 1,250, and 2,500 ppm. The NOAEL for this study was 125 
ppm (approximately 23 mg/kg/day).
    In a 90-day dog feeding study, AE F122006 was administered to 
beagle dogs at dietary concentrations of 0, 25, 125, and 1,000 ppm. The 
NOAEL for this study was considered to be 25 ppm (approximately 1.3 mg/
kg/day) based on slight histopathological effects in the kidneys at 125 
ppm, and effects on the kidneys, spleen, liver, heart, and intestines 
at 1,000 ppm.
    5. Chronic toxicity. Long-term studies in rats, mice, and dogs have 
not yet been completed. However, these studies are generally not a 
prerequisite to the establishment of tolerances for inert safeners, and 
no preneoplastic lesions were observed in any of the 90-day studies. 
Furthermore, AE F122006 is not closely related to any known human or 
animal oncogen, and a structure activity assessment revealed no 
structural alerts for oncogenicity.
    6. Animal metabolism. AE F122006 was well absorbed and rapidly 
metabolized and excreted when administered to rats as a single oral 
dose in sesame oil. AE F122006 was poorly absorbed in dogs when 
administered as a single oral dose in 1% gum tragacanth.

[[Page 30999]]

 A 2-fold increase in absorption was noted in dogs when administered 
via the diet. The primary metabolite in both rats and dogs was the 
carboxylic acid, AE F129431, which is the same as observed in plants.
    The metabolism of AE F122006 in ruminants is adequately understood. 
A dairy cow was dosed with the compound at a level equivalent to 10 ppm 
in the diet for 7 days. Total residue levels were very low. Parent 
compound was seen in fats and milk only. The carboxylic acid, AE 
F129431, was the major metabolite identified in all of the tissues, 
with traces also being found in the milk.
    The metabolism of AE F122006 in poultry is also adequately 
understood. Laying hens were fed the compound at a level equivalent to 
10 ppm in the diet for 14 days. Residue levels were low in all 
commodities. The vast majority of the dose was excreted as AE F129431, 
with smaller amounts of AE F162241 and AE F122006. AE F129431 was the 
major metabolite identified in all of the tissues and yolks. Trace 
amounts of AE F122006 and AE F162241 were detected in liver and eggs 
with AE F122006 also being detected in the muscle.
    7. Endocrine disruption. No special studies have been conducted to 
investigate the potential of AE F122006 to induce estrogenic or other 
endocrine effects. However, no evidence of estrogenic or other 
endocrine effects have been noted in any of the standard toxicology 
studies that have been conducted with this product, and there is no 
reason to suspect that any such effects would be likely.

C. Aggregate Exposure

    1. Dietary exposure. AE F122006 will be used only as a herbicide 
safener and, at this time, only for use on rice. No non-agricultural 
uses are anticipated. Thus, the only potential sources of non-
occupational exposure to AE F122006 would consist of any potential 
residues in food and drinking water. As previously indicated, in the 
absence of any acute toxicity concerns, only chronic exposures have 
been evaluated.
    i. Food. AE F122006 is being proposed for use only in rice. In the 
animal metabolism studies with ruminants and poultry, the concentration 
of AE F122006 and its metabolites in the edible tissues, milk and eggs 
were very low. Based on these results, no secondary residues of AE 
F122006 are expected in meat, milk and eggs as a result of using AE 
F122006 treated rice and/or rice commodities as animal feed. Thus, only 
potential exposures from direct human consumption of rice containing 
residues of AE F122006 were evaluated.
    The potential dietary exposures from consumption of treated rice 
have been assessed using the Exposure 1 software system (TAS, Inc.) and 
the 1977-78 USDA food consumption data. Two different dietary exposure 
scenarios were evaluated. In the first, worst-case scenario, it was 
assumed that 100% of the rice consumed contained residues of AE F122006 
at the proposed tolerance level of 0.05 ppm. However, it is anticipated 
that AE F122006 would be used on no more than 10% of the rice grown in 
the United States. Furthermore, rice is a nationally distributed crop. 
Rice treated with AE F122006 would be mixed in grain elevators and 
processing plants with other rice which was not treated with this 
product. Thus, a second, more realistic scenario assumed that only 10% 
of the commodities consumed contained residues of AE F122006, but that 
these residues remained at the proposed tolerance level of 0.05 ppm.
    ii. Drinking water. The potential for AE F122006 and its main acid 
metabolite AE F129431 to leach into ground water and reach surface 
water has been assessed in various laboratory studies. These studies 
clearly demonstrate that both compounds are rapidly degraded in the 
environment. AE F122006 is rapidly hydrolyzed in soil (half-life = 0.1-
day) to AE F129431 which is further metabolized to carbon dioxide and 
soil bound residue (half-life = 6.5 days).
    A screening evaluation of worst-case shallow ground water 
concentration was conducted using the EPA model SCIGROW and a simple 
calculation of worst-case long-term surface water concentrations 
following use in rice paddies. The results indicate that both compounds 
(parent and its primary degradate) will not contaminate shallow ground 
water or surface water. Concentrations of AE F122006 and its primary 
degradate, AE F129431 in ground or surface water were calculated to be 
< 0.01 ppb. Potential residues in drinking water would be even lower. 
Since the contribution of any potential residues of AE F122006 in water 
to the total dietary intake of AE F122006 would be negligible, these 
values were not included in the dietary exposure assessment.

D. Cumulative Effects

    There is no information to indicate that AE F122006 may share a 
common mechanism of toxicity with any other chemical. Thus, this 
assessment was limited strictly to AE F122006.

E. Safety Determination

    1. U.S. population. No acute toxicity concerns were noted in either 
the acute toxicity studies or the developmental toxicity studies in 
rats or rabbits. Since an acute toxicology endpoint has not been 
identified, an acute risk assessment with AE F122006 is not necessary 
and has not been conducted.
    Long-term studies in rats, mice and dogs, although generally not a 
prerequisite for issuance of tolerances for inert safeners, have not 
yet been completed. Based on the subchronic toxicity data, it appears 
that the dog is the species most sensitive to AE F122006. Therefore, a 
provisional RfD (ADI) of 0.0013 mg/kg/day has been proposed by using 
the NOAEL of 1.3 mg/kg/day from the 90-day dog study and a 1,000-fold 
(rather than 100-fold) margin of safety. The extra ten-fold safety 
factor is used to account for the fact that the RfD is calculated from 
the NOAEL of a subchronic rather than chronic toxicity study.
    Although there is no indication or expectation of any oncogenic 
effect from AE F122006, a worst-case Q1* can be estimated based on the 
potential worst-case results from the ongoing rodent oncogenicity 
studies. Using the linearized multistage model with hypothetical worst-
case tumor responses from the ongoing studies, a hypothetical worst-
case Q1* was calculated to be 1.2 x 10-2 (mg/kg/day)-
1. This hypothetical Q1* can be used to generate an upper 
bound on any potential oncogenic risk that might result from exposure 
to AE F122006.
    Under the most conservative, worst-case scenario, in which it is 
assumed that all rice commodities contain residues of AE F122006 at the 
proposed tolerance level, the potential exposures to the ``General U.S. 
Population'' and the most highly exposed adult subgroup, ``Non-Hispanic 
other Than Black or White,'' would utilize about 0.7% and 3.2%, 
respectively, of the proposed provisional RfD. In a more realistic 
scenario, in which the treated rice is assumed to represent only 10% of 
the rice consumed in the United States and is assumed to be blended 
with non-treated rice prior to consumption, the potential exposures to 
the ``General U.S. Population'' and ``Non-Hispanic Other Than Black or 
White'' subgroup would utilize about 0.1% and 0.3% of the proposed 
provisional RfD, respectively. For chronic exposures, there is 
generally no concern for exposures below 100% of the RfD because the 
RfD represents the level at or below which daily exposure over a 
lifetime would not pose

[[Page 31000]]

appreciable risks to human health. Therefore, these dietary exposures 
clearly would not pose a significant risk to the health of the overall 
U.S. population.
    As previously indicated, there is no indication that AE F122006 is 
likely to be oncogenic. Nevertheless, an upper bound on the potential 
oncogenic risks was estimated using the hypothetical Q1* of 1.2 x 10-
2 (mg/kg/day)-1. Under the worst-case scenario in 
which all rice contained tolerance level residues of AE F122006, the 
theoretical 95% upper bound estimates of potential oncogenic risk for 
the overall ``U.S. Population'' and ``Non-Hispanic Other Than Black or 
White'' subgroup would be 1 x 10-7 and 5 x 10-7, 
respectively. Taking into account the expected market share of AE 
F122006, the upper bounds on the potential oncogenic risks for these 2 
groups would be 1 x 10-8 and 5 x 10-8, 
respectively. Thus, regardless of the outcome of the ongoing 
oncogenicity studies, the potential oncogenic risks to the overall U.S. 
population from dietary exposure to AE F122006 following its use in 
rice are clearly negligible.
    2. Infants and children. Data from rat and rabbit developmental 
toxicity studies and rat multigeneration reproduction studies are 
generally used to assess the potential for increased sensitivity of 
infants and children. The developmental toxicity studies are designed 
to evaluate adverse effects on the developing organism resulting from 
potential exposure during prenatal development. Reproduction studies 
provide information relating to reproductive and other effects on 
adults and offspring from potential prenatal and postnatal exposure to 
the pesticide.
    FFDCA section 408 provides that EPA may apply an additional safety 
factor for infants and children to take into account possible increased 
sensitivity or based upon the completeness of the data base. No 
evidence of increased sensitivity to fetuses was noted in developmental 
toxicity studies in rats or rabbits. Although histopathology 
examinations from the 2-generation rat reproduction study have not yet 
been completed, there has been no indication of any reproductive 
effects or indication of increased sensitivity to the offspring. 
Furthermore, the proposed provisional RfD of 0.0013 mg/kg/day (which is 
derived from the NOAEL from the 90-day dog study and a 1,000-fold 
safety factor) is about 1,000-fold lower than the tentative (pending 
histopathology) NOAEL of 200 ppm (about 15 mg/kg/day) in the 
reproduction study. Thus, no additional safety factor to protect 
infants and children is deemed necessary.
    According to the results of the dietary assessment, the population 
subgroup with the highest potential exposures to AE F122006 under 
scenarios previously described would be non-nursing infants (<1-year 
old). In the first, worst-case scenario, in which all rice and rice 
commodities contained residues of AE F122006 at the proposed tolerance 
levels, the potential dietary exposure to AE F122006 would utilize 4.5% 
of the proposed provisional RfD. Taking into account the fact that less 
than 10% of the rice consumed will be treated with AE F122006, the 
potential exposure to infants and children would utilize no more than 
0.5% of the proposed provisional RfD. These values are substantially 
below the RfD and therefore would not pose an appreciable risk to human 
health.
    Regardless of the outcome of the ongoing oncogenicity studies, the 
hypothetical upper bound estimate of potential oncogenic risk to 
infants and children under the worst-case exposure scenario was 
estimated to be approximately 7 x 10-7. Under the more 
realistic scenario incorporating percent crop treated, the potential 
upper bound estimate of oncogenic risk would be no more than 7 x 10-
8. Thus, even under a worst-case scenario, the use of AE 
F122006 on rice would pose no more than a negligible risk of 
oncogenicity to infants and children.

F. International Tolerances

    There are no Codex Alimentarius Commission (CODEX) maximum residue 
levels (MRLs) established for residues of AE F122006.
[FR Doc. 99-14362 Filed 6-8-99; 8:45 am]
BILLING CODE 6560-50-F