[Federal Register Volume 65, Number 120 (Wednesday, June 21, 2000)]
[Notices]
[Pages 38543-38549]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-15382]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-942; FRL-6557-3]


Notice of Filing a Pesticide Petition to Establish a Tolerance 
for Certain Pesticide Chemicals in or on Food

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 docket control number PF-942, must be 
received on or before July 21, 2000.

ADDRESSES: Comments may be submitted by mail, electronically, or in 
person. Please follow the detailed instructions for each method as 
provided in Unit I.C. of the ``SUPPLEMENTARY INFORMATION.'' To ensure 
proper receipt by EPA, it is imperative that you identify docket 
control number PF-942 in the subject line on the first page of your 
response.

FOR FURTHER INFORMATION CONTACT:  By mail: Richard J. Gebken, 
Registration Support Branch, Registration Division (7505C), Office of 
Pesticide Programs, Environmental Protection Agency, Ariel Rios Bldg., 
1200 Pennsylvania Ave., NW., Washington, DC 20460; telephone number: 
(703) 305-6701; e-mail address: [email protected].

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be affected by this action if you are an agricultural 
producer, food manufacturer or pesticide manufacturer. Potentially 
affected categories and entities may include, but are not limited to:

------------------------------------------------------------------------
                                                          Examples of
           Categories                    NAICS            potentially
                                                       affected entities
------------------------------------------------------------------------
Industry                          111                 Crop production
                                  112                 Animal production
                                  311                 Food manufacturing
                                  32532               Pesticide
                                                       manufacturing
------------------------------------------------------------------------

    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities likely to be affected by this 
action. Other types of entities not listed in the table could also be 
affected. The North American Industrial Classification System (NAICS) 
codes have been provided to assist you and others in determining 
whether or not this action might apply to certain entities. If you have 
questions regarding the applicability of this action to a particular 
entity, consult the person listed under ``FOR FURTHER INFORMATION 
CONTACT.''

B. How Can I Get Additional Information, Including Copies of this 
Document and Other Related Documents?

    1. Electronically. You may obtain electronic copies of this 
document, and certain other related documents that might be available 
electronically, from the EPA Internet Home Page at http://www.epa.gov/. 
To access this document, on the Home Page select ``Laws and 
Regulations'' and then look up the entry for this document under the 
``Federal Register--Environmental Documents.'' You can also go directly 
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
    2. In person. The Agency has established an official record for 
this action under docket control number PF-942. The official record 
consists of the documents specifically referenced in this action, any 
public comments received during an applicable comment period, and other 
information related to this action, including any information claimed 
as confidential business information (CBI). This official record 
includes the documents that are physically located in the docket, as 
well as the documents that are referenced in those documents. The 
public version of the official record does not include any information 
claimed as CBI. The public version of the official record, which 
includes printed, paper versions of any electronic comments submitted 
during an applicable comment period, is available for inspection in the 
Public Information and Records Integrity Branch (PIRIB), Rm. 119, 
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30 
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The 
PIRIB telephone number is (703) 305-5805.

C. How and to Whom Do I Submit Comments?

    You may submit comments through the mail, in person, or 
electronically. To ensure proper receipt by EPA, it is imperative that 
you identify docket control number PF-942 in the subject line on the 
first page of your response.
    1. By mail. Submit your comments to: Public Information and Records 
Integrity Branch (PIRIB), Information Resources and Services Division 
(7502C), Office of Pesticide Programs (OPP), Environmental Protection 
Agency, Ariel Rios Bldg., 1200 Pennsylvania Ave., NW., Washington, DC 
20460.
    2. In person or by courier. Deliver your comments to: Public 
Information and Records Integrity Branch (PIRIB), Information Resources 
and Services

[[Page 38544]]

Division (7502C), Office of Pesticide Programs (OPP), Environmental 
Protection Agency, Rm. 119, Crystal Mall #2, 1921 Jefferson Davis 
Highway, Arlington, VA. The PIRIB is open from 8:30 a.m. to 4 p.m., 
Monday through Friday, excluding legal holidays. The PIRIB telephone 
number is (703) 305-5805.
    3. Electronically. You may submit your comments electronically by 
e-mail to: ``[email protected],'' or you can submit a computer disk as 
described above. Do not submit any information electronically that you 
consider to be CBI. Avoid the use of special characters and any form of 
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be 
identified by docket control number PF-942. Electronic comments may 
also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want to Submit to the Agency?

    Do not submit any information electronically that you consider to 
be CBI. You may claim information that you submit to EPA in response to 
this document as CBI 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. In addition to one complete 
version of the comment that includes any information claimed as CBI, a 
copy of the comment that does not contain the information claimed as 
CBI must be submitted for inclusion in the public version of the 
official record. Information not marked confidential will be included 
in the public version of the official record without prior notice. If 
you have any questions about CBI or the procedures for claiming CBI, 
please consult the person identified under ``FOR FURTHER INFORMATION 
CONTACT.''

E. What Should I Consider as I Prepare My Comments for EPA?

    You may find the following suggestions helpful for preparing your 
comments:
    1. Explain your views as clearly as possible
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used 
that support your views.
    4. If you estimate potential burden or costs, explain how you 
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Make sure to submit your comments by the deadline in this 
notice.
    7. To ensure proper receipt by EPA, be sure to identify the docket 
control number assigned to this action in the subject line on the first 
page of your response. You may also provide the name, date, and Federal 
Register citation.

II. What Action is the Agency Taking?

    EPA has received a pesticide petition as follows proposing the 
establishment and/or amendment of regulations for residues of a 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.

List of Subjects

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

    Dated: June 7, 2000.
James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The 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 represent the views of the 
petitioner. EPA is publishing the petition summary verbatim without 
editing it 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

0F6087

    EPA has received a pesticide petition [0F6087] from Aventis 
CropScience (fomerly AgrEvo USA Company), Aventis CropScience USA LP, 
2, T.W. Alexander Drive, Research Triangle Park, NC 27709 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 buprofezin in or on the following raw 
agricultural commodities: almonds, nutmeats at 0.05 part per million 
(ppm); almonds, hulls, at 0.7 ppm; bananas at 0.1 ppm; the citrus crop 
group, fruit, at 0.7 ppm; cotton seed at 1.0 ppm; grapes at 0.4 ppm; 
and tomatoes, fruit at 0.8 ppm; in or on the following processed 
commodities: citrus oil at 26 ppm; citrus pulp, dried, at 2.5 ppm; 
cotton gin by-products at 23 ppm; and raisins at 1.0 ppm; and in or on 
the following meat and milk commodities: the fat, meat and meat 
byproducts of cattle, goats, hogs, horses, and sheep at 0.05 ppm; and 
milk at 0.01 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 metabolic profile of buprofezin has been 
elucidated in a wide range of crops, including tomatoes, lettuce, 
cotton, and citrus. For convenience, buprofezin metabolites are 
identified in this document by an internal code, BF 1 through 13. 
Corresponding structures are available in the tolerance petition. In 
tomatoes, lettuce, and cotton unchanged buprofezin was the only 
significant residue. In citrus, although buprofezin was a major 
component of the residue, a chromatographically well-defined region of 
radioactivity, clearly associated with polar conjugates, was observed. 
Mass spectrometry identified the principal polar residue as a hexose 
conjugate of BF4 (buprofezin hydroxylated in the t-butyl group). 
Although the conjugate was resistant to enzyme hydrolysis, acid 
hydrolysis of the polar fraction released predominantly BF26 with minor 
amounts of BF9 and BF12. The same compounds were observed following 
acid hydrolysis of a standard of BF4 clearly indicating that BF4 is the 
conjugated metabolite existing in citrus. Although only limited 
metabolism was observed in lettuce and cotton, trace levels of BF4/
BF26, BF9 and BF12 were observed indicating that the metabolic pathway 
does not differ with plant species. In the tomato study, which was run 
prior to the citrus, cotton, and metabolism studies, these trace level 
metabolites were not specifically looked for due to the high percentage 
of the residue accounted for by the parent;

[[Page 38545]]

they may however have existed in trace amounts.
    2. Analytical method--i. Background. Metabolism studies on lettuce 
and tomatoes have shown that the only significant residue in these 
crops is buprofezin. Development of the analytical method took place in 
parallel with the metabolism studies and the method was designed to 
quantify two metabolites (BF9 and BF12) in addition to the parent 
compound. This method was used for analysis of samples from the field 
trials on all crops except citrus, but for tolerance enforcement only 
the parent compound is considered.
    In the case of citrus, the conjugate of another metabolite (BF4) 
was significant, and intensive efforts were made to include it in the 
analytical method. The technical problems proved to be very severe 
however and the effort was abandoned. As in all other crops, the parent 
compound is by far the largest component of the residue and this 
together with the aforementioned metabolites (BF9 and BF12) were the 
only residues quantified. The only modification made to the method for 
citrus was to add an amino column cleanup to take out some of the co-
extractives unique to citrus.
    ii. Data collection method. Samples are extracted with acetone. The 
extracts are filtered and the acetone removed by rotary evaporation. 
The remaining aqueous extract is acidified with hydrochloric acid and 
partitioned with hexane. The hexane is applied to a Florisil column and 
the residues are then eluted from the column with ether/hexane (50/50). 
The acidic aqueous phase is adjusted to pH 7 and partitioned with ethyl 
acetate/hexane (50/50). This organic extract is combined with the 
eluate from the Florisil column, evaporated to dryness, taken up in 
toluene and analyzed by gas chromatography (GC) with NP detection. The 
limit of quantitation (LOQ) of this method is 0.01 ppm in the sample.
    iii. Tolerance enforcement method. The metabolism work and field 
sample analyses indicated that the only significant residue in treated 
crops was buprofezin. Accordingly, the method proposed for tolerance 
enforcement quantifies only buprofezin. The method is identical to the 
data collection method except that the acid partition step was omitted. 
The method was validated by an independent laboratory using lettuce, 
tomato, and cucumber as the test matrices. Since the method used for 
citrus differs so little from that used for the other crops, no 
separate ILV was performed for that method.
    iv. Multiresidue methods. Buprofezin was tested through protocols D 
and F using tomatoes (a representative non-fatty food) and cottonseed 
(a representative fatty food). Recoveries were satisfactory such that 
the multiresidue methods could be used for tolerance enforcement or as 
confirmatory methods.
    v. Animal methods. Because of the complexity of the metabolism 
picture in ruminants, methods were developed to separately quantify 
buprofezin and three metabolites (BF02, BF12 and BF23) in milk and 
cattle tissues. The methods were validated to a LOQ of 0.01 ppm in milk 
and to an LOQ of 0.05 ppm in tissues. These methods were used to 
analyze the samples from a cattle feeding study. On completion of the 
study, only buprofezin could be detected in any of the samples and 
accordingly, the method for determination of buprofezin in milk and 
tissues is proposed for tolerance enforcement. This method was 
validated at an external laboratory.
    3. Magnitude of residues. Field trials were conducted on almonds, 
bananas, citrus, cotton, grapes, and tomatoes. In all crops buprofezin 
was the principal residue and in all crops except citrus, it was the 
only residue. Decline trials conducted in every crop demonstrated that 
the residue declined with time. In most cases, the residues declined 
approximately 50% in 3 to 7 days. In addition, processing studies were 
performed on tomatoes, grapes, citrus, and cotton. Residues 
concentrated significantly in orange oil, dry orange pulp, wet and dry 
tomato pomace, and in raisins, Two different formulations were used in 
the field trials, a 40SC and a 70WP. Bridging trials demonstrated that 
there was no difference in the residues produced by these two 
formulations.
    i. Residues in tomatoes. Field grown tomatoes were treated with 
sequential applications of APPLAUD 40 SC or APPLAUD 70 WP at the 
maximum and the minimum application and preharvest intervals. (This is 
twice the seasonal maximum on the proposed label.) A total of 20 sites 
were used, distributed throughout the United States.
    In the samples collected 7 days after treatment, the residues of 
buprofezin ranged from 0.02 ppm to 0.64 ppm. There was no apparent 
difference between tomatoes treated with the 70WP formulation and those 
treated with the 40SC formulation.
    ii. Residues in processed tomato commodities. Tomatoes at one trial 
site in California were treated four times with APPLAUD 40 SC at 2.4 
times the proposed maximum rate and at the minimum application and 
preharvest intervals. After the final application, whole tomatoes were 
harvested and processed into wet pomace, dry pomace, juice, puree, and 
paste.
    The results indicate that following typical commercial processing 
of APPLAUD 40 SC-treated tomatoes, buprofezin residues concentrated 
slightly in the processed commodity, tomato paste, relative to the 
whole unwashed tomatoes. Buprofezin was detected in paste at 0.68 ppm. 
This value represents a concentration factor of 1.26x for paste; 
however this factor does not trigger a separate tolerance for paste. No 
concentration was observed for buprofezin in the other processed 
commodity, puree.
    iii. Residues in almonds. Almonds at 6 sites in California were 
given a single treatment of APPLAUD 70 WP at the maximum application 
rate and minimum application and preharvest intervals. No residues 
above the LOQ (0.05 ppm) were present in any of the nut meat samples. 
The residues in the hulls ranged from  0.05 ppm to 0.55 ppm. Only 
buprofezin was detected.
    iv. Residues in grapes. Trials were conducted at 15 different 
sites, which represent 5 major grape producing regions within the 
United States. APPLAUD was applied twice to grapevines at the maximum 
application rate and minimum application and preharvest intervals.
    Results showed that the residues for parent buprofezin ranged 
between 0.01 ppm and 0.27 ppm.
    v. Residues in processed grape commodities. A single trial was 
conducted in California representing a major grape-producing region 
within the United States. APPLAUD 70WP was applied twice to grape vines 
at an exaggerated (5x) rate at the minimum application and preharvest 
intervals. Samples of treated grapes were harvested after the final 
application of APPLAUD and were processed into grape juice and raisins.
    Buprofezin residues were observed to concentrate (2.41x) in raisins 
relative to those found in whole grapes. No concentration was observed 
for any analyte in grape juice.
    vi. Residues in cotton. Trials were conducted at 15 different sites 
that represent 5 major cotton producing regions within the United 
States. APPLAUD 70WP was applied four times to plots of cotton at the 
maximum application rate, and minimum application and preharvest 
intervals. (This is twice the seasonal maximum on the proposed label). 
Duplicate samples of treated cottonseed were harvested

[[Page 38546]]

after the final application of APPLAUD and ginned at six sites to 
produce gin trash.
    Five of the six samples of gin trash harvested 14 days after the 
last application of APPLAUD had residues which ranged between 2.38 ppm 
and 6.12 ppm. The sixth sample had a residue of 22.52 ppm.
    Residues in cottonseed at 14 days after the last application ranged 
between 0.06 ppm and 0.82 ppm. Residues were observed to decline 
significantly for the two sites randomly selected to be used to 
generate decline data.
    vii. Residues in processed cotton commodities. A single trial was 
conducted in California representing a major cotton-producing region 
within the United States. APPLAUD 70WP was applied four times to cotton 
plants at an exaggerated (5x) rate, and minimum application and 
preharvest interval.
    Samples of treated cotton were harvested after the final 
application of APPLAUD and were processed into cottonseed, cottonseed 
by-products (gin trash), meal, hulls, crude oil, refined oil, and 
soapstock.
    Following typical commercial processing of cotton treated with 
APPLAUD 70WP, at an exaggerated rate, buprofezin residues were observed 
to be 37.99x higher in gin trash relative to those found in cottonseed. 
No concentration was observed for buprofezin in any other cottonseed 
fraction.
    viii. Residues in citrus. A total of 30 citrus trials were 
conducted throughout the major citrus producing regions within the 
United States. The trials consisted of orange, grapefruit, and lemon 
sites. APPLAUD 70WP was applied twice to the citrus trees at the 
maximum rate and minimum application and preharvest intervals. 
Duplicate samples of treated oranges were harvested after the final 
application of APPLAUD, including samples taken to observe residue 
decline.
    The highest of the citrus residues were found in grapefruit (2.20 
ppm) harvested 60 days after the last application of APPLAUD. This 
result is inconsistent with the rest of the samples in the study and no 
explanation can be offered for it. The 2.20 ppm result appears to be an 
outlier and if it is excluded the range of the grapefruit results is  
0.01 to 0.11, which is consistent with the other results in the study. 
Residues in oranges ranged from below 0.01 ppm to 0.47 ppm. Residues in 
lemons ranged between 0.01 ppm and 0.51 ppm.
    Residues in citrus declined with time after the last application.
    ix. Residues in processed citrus commodities. A single trial was 
conducted in California representing a major citrus producing region 
within the United States. APPLAUD 70WP was applied twice to orange 
trees at an exaggerated (5x) rate and minimum application and 
preharvest intervals.
    Samples of treated oranges were harvested after the final 
application of APPLAUD and were processed into orange oil, juice and 
dry pomace.
    Following typical commercial processing of oranges treated with 
APPLAUD 70WP at 5x the highest recommended application rate, buprofezin 
residue was detected and observed to concentrate (43.34x) in citrus oil 
relative to that found in whole fruit. The maximum average detected 
residue consisting of buprofezin was observed in orange oil at 15.17 
ppm. Concentration was also observed for buprofezin at 4.14x in dry 
pulp relative to that found in the whole fruit. No concentration was 
observed for any analyte in orange juice.
    x. Residues in bananas. Trials were conducted at one site in Puerto 
Rico and four sites on the island of Hawaii. Bananas were treated with 
four foliar applications of APPLAUD 70WP at the maximum application 
rate and minimum application and preharvest intervals. One half of the 
bananas site was protected with plastic bags and the other half was 
not. Samples were collected from both bagged and unbagged bananas at 
normal harvest. At one site, samples were also collected to develop 
data for a decline curve. Residues were determined in both peeled and 
unpeeled bananas.
    Residues of buprofezin ranged from  0.01 ppm (the LOQ) to 0.077 ppm 
in the 1-day PHI bananas. Residues were detected only in the unbagged, 
unpeeled bananas, indicating that these are strictly surface residues. 
No residues were detected in/on any bagged bananas nor in/on any peeled 
bananas.
    xi. Residues in milk and meat. Twelve Holstein dairy cows were 
randomly assigned to four groups consisting of three cows each. 
Following quarantine, each cow was orally dosed twice daily for 28 
consecutive days with one gelatin capsule containing a known amount of 
buprofezin. The control (T-0) group received capsules containing no 
buprofezin. Cattle in the T-I group received 119 mg of buprofezin per 
cow per day. Cattle in the T-II group received 357 mg per cow per day, 
and cattle in the T-III group, 1,190 mg per cow per day. These doses 
are equivalent to consumption of diets containing 0, 5, 15, and 50 ppm 
buprofezin (0, 1x, 3x, and 10x the maximum theoretical intake).
    Milk was sampled on the day prior to the first dosing (day 1), on 
the day of the first dosing (day 1), and on days 2, 4, 7, 10, 14, 17, 
21, 24, and 28. Cream and skim milk samples were prepared from whole 
milk collected on day 28. All cows were sacrificed on day 29 within 24 
hours of the last dose. Sub-samples of muscle (hind-quarter), fat 
(perinephric), liver, and kidney were taken for analysis.
    Milk and tissues were analyzed by methods that separately quantify 
buprofezin and the metabolites BF02, BF12, and BF23. The methods were 
validated to an LOQ of 0.01 ppm in milk and 0.05 ppm in tissues.
    No buprofezin-derived residues were found in meat or milk 
commodities in the ruminant feeding study at a feeding level equivalent 
to the maximum theoretical intake of buprofezin.

B. Toxicological Profile

    An extensive battery of toxicology studies has been conducted with 
buprofezin. These studies have been reviewed and summarized by the 
Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food 
and the Environment and the WHO Expert Group on Pesticide Residues 
(JMPR, 1991 and 1995). They have also been reviewed by the USEPA as 
part of the submission for an Experimental Use Permit. Supplemental 
information on several studies (acute dermal, acute inhalation, chronic 
dog, rat reproduction, and rat chronic toxicity/oncogenicity study) is 
being submitted with this petition. These studies indicate that 
buprofezin has a relatively low degree of toxicity, is neither 
genotoxic nor oncogenic, and does not cause any significant 
reproductive or developmental effects. Thus, the use of buprofezin on 
lettuce and cucurbits (as well as on cotton (Arizona and California) 
and citrus (California) under the current section 18 emergency 
exemptions) will not pose a significant risk to human health.
    1. Acute toxicity. The acute rat oral LD50 for 
buprofezin was 1,635 mg/kg in males and 2,015 mg/kg in females. The 
acute rat dermal LD50 was  5,000 mg/kg in both 
sexes. The 4-hour rat inhalation LC50 was > 4.57 milligram/
liter (mg/L). Buprofezin was slightly irritating to rabbit eyes and 
skin and did not induce dermal sensitization in guinea pigs.
    2. Genotoxicty. No evidence of genotoxicity was noted in a battery 
of in vitro and in vivo studies. Studies included Ames Salmonella and 
mouse lymphoma gene mutation assays, a

[[Page 38547]]

mouse micronucleus assay, an in vitro human lymphocyte cytogenetics 
assay and an in vitro rat hepatocyte unscheduled DNA synthesis (UDS) 
assay.
    3. Reproductive and developmental toxicity. A developmental 
toxicity study was conducted in rats at dose levels of 0, 50, 200, or 
800 mg/kg/day. The (systemic) maternal no observed adverse effect level 
(NOAEL) for this study was 200 mg/kg/day based on weight loss, 
decreased food consumption, clinical signs, increased resorption rate, 
increased loss of entire litters and one maternal death at 800 mg/kg/
day. The developmental (fetal) NOAEL was also 200 mg/kg/day based on 
reduced fetal body weights and increased incidence of delayed 
ossification at 800 mg/kg/day. Slightly reduced ossification was also 
noted at 200 mg/kg/day but this was within historical control range and 
thus not considered to be significant.
    A developmental toxicity study was conducted in rabbits at dose 
levels of 0, 10, 50, or 250 mg/kg/day. The maternal (systemic) NOAEL 
was 50 mg/kg/day based on decreased weight gain, decreased food 
consumption and the complete resorption of 2 litters at 250 mg/kg/day. 
No evidence of developmental toxicity was noted; therefore, the 
developmental (fetal) NOAEL was 250 mg/kg/day, the highest dose tested 
(HDT).
    Two rat reproduction studies have been conducted at dietary 
concentrations of 0, 10, 100, or 1,000 ppm. One was a 2-generation 
study that included a teratological evaluation. The other was a 1-
generation reproduction study conducted to further evaluate some 
possible changes noted in the first study. Based on the results from 
both studies, the parental NOAEL was 1,000 ppm HDT. There were no 
effects on any reproductive parameters but pup weights were decreased 
at 1,000 ppm. Thus, the reproductive NOAEL was 100 ppm.
    4. Subchronic toxicity. A 90-day feeding study was conducted in 
rats at dietary concentrations of 0, 40, 200, 1,000, or 5,000 ppm. 
Effects noted at 1,000 and/or 5,000 ppm included decreased weight gain, 
clinical pathology changes, increased liver and thyroid weights, and 
gross and/or microscopic evidence of liver, thyroid and kidney lesions. 
Only marginal effects, consisting of slightly reduced feed intake and 
slightly decreased glucose levels, were noted at 200 ppm. Although the 
report conservatively concluded the NOAEL to be 40 ppm, the NOAEL was 
considered by the EPA to be 200 ppm (15 mg/kg/day).
    A 90-day study was conducted in which beagle dogs were administered 
buprofezin via capsule at dose levels of 0, 2, 10, 50, or 300 mg/kg/
day. Effects noted at 50, and/or 300 mg/kg/day included various 
clinical signs of toxicity, substantially decreased weight gain, 
clinical pathology changes, increased liver, kidney and thyroid 
weights, and microscopic liver lesions. The NOAEL was 10 mg/kg/day.
    5. Chronic toxicity. A 2-year study was conducted in which beagle 
dogs were administered buprofezin via capsule at dose levels of 0, 2, 
20, or 200 mg/kg/day. Effects noted at 20 and/or 200 mg/kg/day included 
decreased weight gain, clinical pathology changes, increased liver and 
thyroid weights, decreased liver function (measured by BSP clearance) 
and microscopic liver lesions. Although the report concluded that the 
NOAEL for this study was 2 mg/kg/day, marginal effects in females at 2 
mg/kg/day were considered to be a possible effect by the EPA reviewer 
pending receipt of additional historical control data. These data are 
being submitted with this petition and will establish that the dose of 
2 mg/kg/day is a NOAEL for this study.
    A 2-year rat feeding study was conducted at dietary concentrations 
of 0, 5, 20, 200, or 2,000 ppm. No evidence of oncogenicity was noted 
at any dose level. Effects noted at 2,000 ppm included decreased weight 
gain, increased liver and thyroid weights, and an increased incidence 
of non-neoplastic liver and thyroid lesions. A possible increase in 
thyroid lesions was also noted at 200 ppm. According to the EPA 
reviewer, the NOAEL for this study was 200 ppm (10 mg/kg/day). However, 
the conclusions of the original report and a subsequent 
histopathological reevaluation, not yet reviewed by the Agency, 
indicate that the NOAEL should be considered to be 20 ppm (1 mg/kg/
day).
    A 2-year mouse feeding study was conducted at dietary 
concentrations of 0, 20, 200, 2,000, and 5,000 ppm. Effects observed at 
2,000 and/or 5,000 ppm included decreased weight gain, minor clinical 
pathology changes, increased liver weights and an increased incidence 
of non-neoplastic liver lesions. Increased liver weights were also 
noted at 200 ppm. Thus, the NOAEL was considered to be 20 ppm (1.8 mg/
kg/day). There were slightly increased incidences of liver tumors in 
females at 5,000 ppm and of lung tumors in males at 200 and 5,000 ppm. 
The increased incidences of these common tumors were not considered to 
be treatment-related by either the study director or EPA reviewer but 
the study was referred to EPA Carcinogenicity Peer Review Group for 
further valuation.
    6. Animal metabolism. The metabolism of buprofezin has been 
extensively studied in various species of animals and fish. Buprofezin 
has several groups that can metabolize in a variety of ways thus 
potentially producing a very large number of metabolites. Indeed 
extensive metabolism to many minor metabolites was observed in all the 
animal species. Metabolism in fish was, however, much more limited and 
clearly defined. Although not all metabolic intermediates have been 
detected in all the species, the major routes of metabolism have been 
identified in animals and fish and a consistent pattern is observed 
throughout these species. The proposed metabolic pathway was provided 
in the tolerance petition. For convenience, degradates are referred to 
by an internal code: BF 1 through 13. Corresponding chemical structures 
were provided in the tolerance petition.
    i. Metabolism in rats. The major metabolite found in rat excreta 
was parent buprofezin in addition to several compounds formed after 
extensive metabolism. Whereas plant metabolism appeared restricted 
mainly to oxidation of the tertiary butyl group, oxidation of the butyl 
group and hydroxylation of the phenyl ring were both observed in rats. 
Oxidation of the t-butyl group proceeded beyond an alcohol to an acid 
and was accompanied by ring opening. The most extensively metabolized 
compound identified in rats was BF23 (acetylated p-aminophenol)
    ii. Metabolism in ruminants and hens. Residue levels were low ( 
0.05 ppm) in all ruminant and poultry tissues and commodities, 
following treatment at exaggerated rates (approximately 20x and 7,500x 
the anticipated dietary burden, respectively). The only exceptions were 
cow liver (1.21 ppm), cow kidney (0.41 ppm), hen liver (0.15 ppm), and 
egg yolk (0.11 ppm). Extensive metabolism was observed in both species 
with a large number of minor metabolites being produced.
    The principal metabolites identified in the cow were BF2 and BF23 
indicating that the major pathway of degradation in ruminants is 
hydroxylation of the phenyl ring followed by opening and degradation of 
the heterocyclic ring. The identification of trace levels of BF13 
confirms this pathway. As in rats, BF23 was the most extensively 
metabolized compound identified. Trace levels of BF12 were also 
detected. This indicates that the parallel pathway of heterocyclic ring 
opening without hydroxylation of the

[[Page 38548]]

phenyl ring is also in operation. Similarly in hens, the identified 
metabolites were derived from degradation of the heterocyclic ring 
either with (BF13) or without (BF9 and BF12) phenyl ring hydroxylation. 
No single unidentified compound accounted for more than 6% of the total 
residue in any animal tissue or commodity, with the exception of a 
component comprising 8.7% of egg white. The total residue in egg white 
was, however, only 0.02 ppm even at this highly exaggerated dose rate.
    iii. Metabolism in fish. Analysis of fish tissues, following a 
bioaccumulation study, found a much simpler metabolic profile. 
Buprofezin was present in both edible and non-edible tissues, but the 
principle metabolites were polar conjugates of BF4. Trace levels of 
BF12 were also detected.
    7. Endocrine disruption. No special studies have been conducted to 
investigate the potential of buprofezin to induce estrogenic or other 
endocrine effects. The standard battery of required toxicity 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. The only effect noted on endocrine organs 
was an increased incidence of follicular cell hypertrophy and C-cell 
hyperplasia of the thyroid gland in rats administered buprofezin at 
dietary concentrations of 2,000 ppm for 24 months. Buprofezin also 
caused mild to moderate hepatotoxic effects at this dietary 
concentration. AgrEvo believes that the effect on the thyroid most 
likely resulted from increased turnover of T3/T4 in the liver with a 
resultant rise in TSH secretion (due to the hepatotoxicity). The rat is 
known to be much more susceptible than humans to these effects due to 
the very rapid turnover of thyroxine in the blood in rats (12 hours vs. 
about 5-9 days in humans). Therefore, the thyroid pathological changes 
which have been noted following administration of high doses of 
buprofezin are considered to be of minimal relevance to human risk 
assessment, particularly considering the low levels of buprofezin to 
which humans are likely to be exposed.

C. Aggregate Exposure

    Buprofezin is an insect growth regulator, which is approved for use 
under a section 18 emergency exemption for control of red scale on 
citrus in California. Section 18 applications are pending at EPA for 
the control of whitefly on cotton in Arizona and California, on 
cucurbits in Arizona, and on tomatoes in Florida. Non-crop uses of 
buprofezin are limited to an Experimental Use Permit for use on 
ornamentals in greenhouses, thus only dietary exposures are being 
considered.
    1. Dietary exposure--i. Food. Potential dietary exposures from food 
commodities under the proposed food tolerances for buprofezin, 
including those in the previously submitted tolerance petition number 
7F4923, were estimated using the exposure I software system (TAS, Inc.) 
and the 1977-78 Department of Agriculture (USDA) consumption data. A 
single, worst-case scenario was evaluated.
    In this case, it was assumed that all uses contained residues at 
the proposed tolerance levels of: Leaf lettuce (13 ppm), head lettuce 
(5 ppm), the cucurbits crop group (0.5 ppm), almonds, nutmeats (0/05 
ppm), bananas (0.8 ppm), citrus (0.6 ppm), grapes (0.3 ppm), raisins 
(0.8 ppm), tomatoes (0.7 ppm), animal fat, meat and meat by-products 
(0.05 ppm), and milk (0.01 ppm). This very worst-case scenario also 
assumed 100% of the crop treated.
    ii. Drinking water. Exposure to buprofezin from drinking water is 
expected to be negligible. The potential for buprofezin to leach into 
ground water was assessed in various laboratory studies as well as 
terrestrial field dissipation studies conducted in two locations and in 
varying soil types. The degradation of buprofezin occurs rapidly with 
half-lives in soil ranging from 22 to 59 days. No evidence of leaching 
of parent or degradation products was observed in aged leaching or 
terrestrial field dissipation studies. The major routes of degradation 
result in mineralization to carbon dioxide and the formation of 
``bound'' residues. Buprofezin tends to bind to the top layers of soil 
with low mobility. The Koc for most soils fell in the range 2,100-
4,800. The solubility in water is low (0.382 mg/L).
    A screening evaluation of worst-case shallow ground water 
concentrations was conducted using EPA model SCI/GROW. A number of uses 
were compared and the results are summarized in the following table:

 
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                                         Screening
                Crop                   Annual application       Aerobic half-life            Koc              Relative Intrinsic      Concentration in
                                        rate (lbs./acre)             (days)                                   Leaching Potential     Ground water (ppb)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Almonds                              2                                                                                             0.036
Citrus                               4                       41 a                    3008b                  0.811c                 0.072
Grapes                               1                                                                                             0.018
Vegetables & cotton                  076                                                                                           0.014
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Average of laboratory aerobic soil metabolism studies
\b\ Average of all tested soils excluding one abnormally highly value (Koc = 18836)
\c\ Relative Intrinsic Leaching Potential = (log(t1/2 5))*(4-log(Koc + 5))

    The potential exposure of buprofezin in drinking water abstracted 
from surface water was assessed using a Tier 2, modeling approach. PRZM 
was used to generate potential runoff loads from a standardized 
agricultural field (10-ha) to a standardized aquatic system (1-ha 2-m 
deep pond) following application of buprofezin to citrus (the maximum 
proposed use rate for all crops). EXAMS was used to estimate the 
exposure concentration (EEC) in surface water. The ``once-in-10-year'' 
exceedance probability corresponded to a concentration at 0.52 part per 
billion (ppb). This value refers to the 56-day average estimated 
concentration in a farm pond draining agricultural land and must be 
considered a gross over-estimate of concentrations of buprofezin at the 
point of drinking water abstraction.
    The calculated worst-case maximum exposure of buprofezin in 
drinking water (assuming consumption of 2 liters per day) will be no 
more than 1.04 g per day. Exposure from drinking water 
abstracted from ground water will be an order of magnitude lower (> 
0.14 g per day). However, the contribution of any such residues to the 
total dietary intake of buprofezin will be negligible.

[[Page 38549]]

    2. Non-dietary exposure. There is a current Experimental Use Permit 
(EUP) for the use of buprofezin on ornamentals in greenhouses. Exposure 
to the general population would be minimal in this use and thus was not 
considered.

D. Cumulative Effects

    At the present time, there are insufficient data available to allow 
AgrEvo to properly evaluate the potential for cumulative effects with 
other pesticides to which an individual may be exposed. For the 
purposes of this assessment, therefore, AgrEvo has assumed that 
buprofezin does not have a common mechanism of toxicity with any other 
registered pesticides. Therefore, only exposure from buprofezin is 
being addressed at this time.

E. Safety Determination

    The toxicity and residue data bases for buprofezin are considered 
to be valid, reliable and essentially complete. The standard margin of 
safety approach is considered appropriate to assess the risk of adverse 
effects from exposure to buprofezin for both acute and chronic effects. 
EPA has adopted a temporary reference dose (RfD) for buprofezin at 
0.002 mg/kg/day. This RfD was based on the systemic lowest effect level 
(LEL) of 2.0 mg/kg/day limit dose tested (LDT) from a 2-year dog study 
and using a 1,000-fold uncertainty factor (UF). An extra factor of 10 
was added to the standard 100 fold safety factor since the RfD was 
based on a LEL (rather than a NOAEL) and the data base lacked an 
acceptable reproductive study. Additional data have been submitted to 
upgrade the reproduction study and to support the lowest dose in the 2-
year dog study as a NOAEL. With the upgrading of these studies, the 
critical study for the establishment of a permanent RfD would be the 
rat chronic/oncogenicity study. The NOAEL for this study is 1 mg/kg/
day. Applying a standard safety factor of 100 for this study, to 
account for interspecies extrapolation and intraspecies variation, 
would result in a RfD of 0.01 mg/kg/day. It is this proposed RfD which 
was used to assess risk to the public.
    1. U.S. population--i. Acute risk. EPA has previously selected, in 
their approval of the section 18 emergency exemption use, a 
developmental NOAEL of 200 mg/kg/day from a rat developmental study for 
the acute dietary endpoint. However, it appears that this is an 
inappropriate acute endpoint since the clinical effects noted at the 
higher dose (800 mg/kg/day) occurred only after at least 5 days of 
dosing and the fetal effects (reduced fetal body weight and delayed 
ossification) are not likely to be due to an acute (1-day) exposure.
    Based on this assessment, AgrEvo has not evaluated the risk from 
acute exposure to any subgroup of the population. Previously, EPA has 
assessed the acute risk from use of buprofezin on citrus and cotton to 
the population subgroup of females 13+ years of age. Using the 
developmental NOAEL of 200 mg/kg/day, the margin of exposure (MOE), 
according to EPA calculations, was 5,000 for this subgroup.
    ii. Chronic risk. Chronic dietary exposures for the U.S. population 
as a whole utilize 30% of the buprofezin RfD in the worst-case scenario 
of 100% of crop treated and all residues at the proposed tolerance 
levels. There is generally no concern for exposures below 100% of the 
RfD since it represents the level at or below which no appreciable 
risks to human health is posed. Therefore, there is reasonable 
certainty that no harm would result to the U.S. population from 
exposure to buprofezin.
    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 to 
infants and children. 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 reproductive and other effects on 
adults and offspring from prenatal and postnatal exposure to the 
pesticide.
    No indication of increased sensitivity to infants and children was 
noted in either of the developmental studies. However, in the 
reproduction studies, the NOAEL for pups (100 ppm) was lower than for 
adults (1,000 ppm). Based on the intake of buprofezin in pups up to 8 
weeks of age, the RfD for children, using a 1,000 fold safety factor, 
would be 0.01 mg/kg/day. This is the same RfD that is calculated for 
chronic exposure utilizing the rat chronic/oncogenicity study.
    Evaluation of the dietary exposure to infants and children was 
conducted utilizing the same assumptions as for the U.S. population as 
a whole. In the worst-case scenario, assuming residues at the proposed 
tolerance levels and with no adjustment for the percent crop treated, 
the dietary exposure for children, 1-6 years, was 50% of the RfD. There 
is generally no concern for exposures below 100% of the RfD since it 
represents the level at or below which no appreciable risks to human 
health is posed. Thus, there is a reasonable certainty that no harm 
will result to the most highly exposed population subgroup, children 
between 1 and 6 years of age, from exposure to buprofezin.

F. International Tolerances

    Buprofezin was reviewed by the Joint Meeting of the Food and 
Agriculture Organization Panel of Experts on Pesticide Residues in Food 
and the Environment and the World Health Organization Expert Group on 
Pesticide Residues (JMPR) to establish Codex maximum residue levels 
(MRLs) in 1991, 1995, and 1997. Permanent MRLs were granted for 
cucumbers and tomatoes and a temporary MRL was granted for oranges as 
described below. Additional residue trial data on oranges will be 
available for the 1999 JMPR meeting to determine if this MRL should 
also be made permanent.

 
------------------------------------------------------------------------
                 Commodity                               MRL
------------------------------------------------------------------------
Cucumber                                    0.3 ppm
Tomato                                      0.5 ppm
Oranges, Sweet, Sour                        0.3 ppm (temporary)
------------------------------------------------------------------------

[FR Doc. 00-15382 Filed 6-20-00; 8:45 am]
BILLING CODE 6560-50-F