Environmental Protection Agency (EPA).
This notice announces the initial filing of pesticide petitions proposing the establishment of regulations for residues of a certain pesticide chemical in or on various food commodities.
Comments, identified by docket ID number OPP-2003-0009, must be received on or before April 4, 2003.
Comments may be submitted electronically, by mail, or through hand delivery/courier. Follow the detailed instructions as provided in Unit I. of the SUPPLEMENTARY INFORMATION.Start Further Info
FOR FURTHER INFORMATION CONTACT:
Mary L. Waller, Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone number: (703) 308-9354; e-mail address: email@example.com.End Further Info End Preamble Start Supplemental Information
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected entities may include, but are not limited to:
- Crop production (NAICS 111)
- Animal production (NAICS 112)
- Food manufacturing (NAICS 311)
- Pesticide manufacturing (NAICS 32532)
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 this unit could also be affected. The North American Industrial Classification System (NAICS) codes have been provided to assist you and others in determining whether this action might apply to certain entities. To determine whether you or your business may be affected by this action, you should carefully examine the applicability provisions in OPP-2003-0009. If you have any 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 Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this action under docket identification (ID) number OPP-2003-0009. The official public docket consists of the documents specifically referenced in this action, any public comments received, and other information related to this action. Although a part of the official docket, the public docket does not include Confidential Business Information (CBI) or other information whose disclosure is restricted by statute. The official public docket is the collection of materials that is available for public viewing at the Public Information and Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA. This docket facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The docket telephone number is (703) 305-5805.
2. Electronic access. You may access this Federal Register document electronically through the EPA Internet under the “Federal Register” listings at http://www.epa.gov/fedrgstr/.
An electronic version of the public docket is available through EPA's electronic public docket and comment system, EPA Dockets. You may use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public comments, access the index listing of the contents of the official public docket, and to access those documents in the public docket that are available electronically. Although not all docket materials may be available electronically, you may still access any of the publicly available docket materials through the docket facility identified in Unit I.B.1. Once in the system, select “search,” then key in the appropriate docket ID number.
Certain types of information will not be placed in the EPA Dockets. Information claimed as CBI and other information whose disclosure is restricted by statute, which is not included in the official public docket, will not be available for public viewing in EPA's electronic public docket. EPA's policy is that copyrighted material will not be placed in EPA's electronic public docket but will be available only in printed, paper form in the official public docket. To the extent feasible, publicly available docket materials will be made available in EPA's electronic public docket. When a document is selected from the index list in EPA Dockets, the system will identify whether the document is available for viewing in EPA's electronic public docket. Although not all docket materials may be available electronically, you may still access any of the publicly available docket materials through the docket facility identified in Unit I.B. EPA intends to work towards providing electronic access to all of the publicly available docket materials through EPA's electronic public docket.
For public commenters, it is important to note that EPA's policy is that public comments, whether submitted electronically or in paper, will be made available for public viewing in EPA's electronic public docket as EPA receives them and without change, unless the comment contains copyrighted material, CBI, or other information whose disclosure is restricted by statute. When EPA identifies a comment containing copyrighted material, EPA will provide a reference to that material in the version of the comment that is placed in EPA's electronic public docket. The entire printed comment, including the copyrighted material, will be available in the public docket.
Public comments submitted on computer disks that are mailed or delivered to the docket will be transferred to EPA's electronic public Start Printed Page 10459docket. Public comments that are mailed or delivered to the docket will be scanned and placed in EPA's electronic public docket. Where practical, physical objects will be photographed, and the photograph will be placed in EPA's electronic public docket along with a brief description written by the docket staff.
C. How and To Whom Do I Submit Comments?
You may submit comments electronically, by mail, or through hand delivery/courier. To ensure proper receipt by EPA, identify the appropriate docket ID number in the subject line on the first page of your comment. Please ensure that your comments are submitted within the specified comment period. Comments received after the close of the comment period will be marked “late.” EPA is not required to consider these late comments. If you wish to submit CBI or information that is otherwise protected by statute, please follow the instructions in Unit I.D. Do not use EPA Dockets or e-mail to submit CBI or information protected by statute.
1. Electronically. If you submit an electronic comment as prescribed in this unit, EPA recommends that you include your name, mailing address, and an e-mail address or other contact information in the body of your comment. Also include this contact information on the outside of any disk or CD ROM you submit, and in any cover letter accompanying the disk or CD ROM. This ensures that you can be identified as the submitter of the comment and allows EPA to contact you in case EPA cannot read your comment due to technical difficulties or needs further information on the substance of your comment. EPA's policy is that EPA will not edit your comment, and any identifying or contact information provided in the body of a comment will be included as part of the comment that is placed in the official public docket, and made available in EPA's electronic public docket. If EPA cannot read your comment due to technical difficulties and cannot contact you for clarification, EPA may not be able to consider your comment.
i. EPA Dockets. Your use of EPA's electronic public docket to submit comments to EPA electronically is EPA's preferred method for receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket, and follow the online instructions for submitting comments. Once in the system, select “search,” and then key in docket ID number OPP-2003-0009. The system is an “anonymous access” system, which means EPA will not know your identity, e-mail address, or other contact information unless you provide it in the body of your comment.
ii. E-mail. Comments may be sent by e-mail to firstname.lastname@example.org, Attention: Docket ID number OPP-2003-0009. In contrast to EPA's electronic public docket, EPA's e-mail system is not an “anonymous access” system. If you send an e-mail comment directly to the docket without going through EPA's electronic public docket, EPA's e-mail system automatically captures your e-mail address. E-mail addresses that are automatically captured by EPA's e-mail system are included as part of the comment that is placed in the official public docket, and made available in EPA's electronic public docket.
iii. Disk or CD ROM. You may submit comments on a disk or CD ROM that you mail to the mailing address identified in Unit I.C.2. These electronic submissions will be accepted in WordPerfect or ASCII file format. Avoid the use of special characters and any form of encryption.
2. By mail. Send your comments to: Public Information and Records Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP), Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-0001, Attention: Docket ID Number OPP-20032-0009.
3. By hand delivery or courier. Deliver your comments to: Public Information and Records Integrity Branch (PIRIB), Office of Pesticide Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket ID Number OPP-2003-0009. Such deliveries are only accepted during the docket's normal hours of operation as identified in Unit I.B.1.
D. How Should I Submit CBI to the Agency?
Do not submit information that you consider to be CBI electronically through EPA's electronic public docket or by e-mail. You may claim information that you submit to EPA as CBI by marking any part or all of that information as CBI (if you submit CBI on disk or CD ROM, mark the outside of the disk or CD ROM as CBI and then identify electronically within the disk or CD ROM the specific information that is 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 docket and EPA's electronic public docket. If you submit the copy that does not contain CBI on disk or CD ROM, mark the outside of the disk or CD ROM clearly that it does not contain CBI. Information not marked as CBI will be included in the public docket and EPA's electronic public docket without prior notice. If you have any questions about CBI or the procedures for claiming CBI, please consult the person listed 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 ID 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 Cosmetic Act (FFDCA), 21 U.S.C. 346a. EPA has determined that this petition contains data or information regarding the elements set forth in FFDCA section 408(d)(2); 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.Start List of Subjects
List of Subjects
- Environmental protection
- Agricultural commodities
- Feed additives
- Food additives
- Pesticides and pests
- Reporting and recordkeeping requirements
Dated: February 20, 2003.
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
The petitioner summaries of the pesticide petitions are printed below as required by FFDCA section 408(d)(3). The summaries of the petitions were prepared by the petitioners and represent the views of the petitioners. 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.
2F6439 and 9E6054
EPA has received pesticide petitions (2F6439) from Bayer Crop Science, 2 T.W. Alexander Drive, Research Triangle Park, NC 27709 proposing, pursuant to section 408(d) of the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR 180.518 by establishing tolerances for residues of pyrimethanil (4,6-dimethyl-N-phenyl-2-pyrimidinamine) in or on the Raw Agricultural Commodities (RAC): Tree nut, nutmeat, group at 0.25 parts per million (ppm), tree nut, hulls, group at 12 ppm, fruit, pome, group at 0.20 ppm, apple, wet pomace at 0.75 ppm, fruit, stone, group at 3.0 ppm, grape at 3.0 ppm, grape, dry pomace at 20 ppm, grape, wet pomace at 7.0 ppm, grape, raisin waste at 50 ppm, grape, raisin at 5.0 ppm, vegetable, bulb, group at 2.0 ppm, vegetable, tuberous and corm, subgroup at 0.05 ppm, strawberry at 3.0 ppm, tomato at 0.50 ppm, wheat, rotational at 0.05 ppm, cattle, meat at 0.1 ppm, cattle, meat byproducts at 0.1 ppm, and milk at 0.03 ppm. EPA also received a pesticide petition (9E6054) from AgrEvo USA Company, now owned by Bayer Crop Science, proposing, pursuant to section 408(d) of the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR 180.518 by establishing a tolerance for residues of pyrimethanil in or on the RAC: Banana at 0.10 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 pyrimethanil has been investigated following application to five different crops (apple, carrots, grapes, lettuce and tomatoes) and is well understood. In plants, pyrimethanil is the only significant residue ranging from essentially all of the Total Radioactive Residues (TRR) in carrots and tomatoes to 44% in lettuce. Limited metabolism of pyrimethanil occurs with minor amounts (less than 10%) of the phenyl and pyrimidyl hydroxylated metabolites (AE C614276, AE C614277, AE C614278, and AE C621312) being released after acid hydrolysis. Analysis of the foliage from apples and carrots confirmed that the metabolism of pyrimethanil in plants proceeded primarily via hydroxylation of the aromatic ring structures as well as the methyl groups.
2. Analytical method. The plant metabolism studies indicated that analysis for the parent compound, pyrimethanil was sufficient to enable the assessment of the relevant residues in crop commodities. Following a dichloromethane surface wash and extraction of the crop matrix and sample cleanup, the analytical enforcement method relies on the use of NMR, High Performance Liquid Chromotography (HPLC), or Thin Layer Chromotography (TLC) for determination of the residue levels and metabolite identification. These methods allow detection and measurement of residues in or on agricultural commodities at or above the proposed tolerance level.
3. Magnitude of residues. Magnitude of residue trials were conducted for pyrimethanil on almonds, apples, apricots, grapes, onions, peaches, pears, plums, potatoes, strawberries, and tomatoes. Trials were conducted in the various required regions across the United States. Samples were collected at harvest according to good agricultural practices. The preharvest interval (PHI) ranged from 1-day to 72 days depending on the crop. Samples harvested at maturity were analyzed with a method having a level of quantitation (LOQ) of 0.05 ppm pyrimethanil. Residues in the RAC samples (range, maximum and average) are given below.
i. Tree nuts (almonds, pistachios, beechnuts, chestnuts, and chinquapins). Six trials were conducted on almonds during 2001. An end use formulation containing 400 g/l or 3.34 lbs active ingredient/gallon of pyrimethanil was applied three times as a broadcast application at a maximum rate of 0.70 lbs active ingredient/acre. Applications were made approximately every 7 days. In almond hull RAC samples collected, the maximum residues were 10.2 ppm for pyrimethanil at a 30 ± 1-day preharvest interval. In almond nutmeat RAC samples collected, the maximum residues were 0.135 ppm for pyrimethanil at a 30 ± 1-day preharvest interval. According to Agency standard operating procedure 2000.1, residue trials on almonds will support the use of this product on pistachios, beechnuts, chestnuts and chinquapins.
ii. Bulb vegetables (onions, green onions, dry bulb onions, welsh onions, garlic, great-headed garlic, leeks, and shallots). Dry bulb and green onions were treated with pyrimethanil, a 400 g/l or 3.34 lbs active ingredient/gallon end use product. Nine trials were established for the study, three in California, two in Texas and one each in, New York, Michigan, Colorado, and Oregon. Each trial was conducted under typical cropping practices for its location. Pyrimethanil was applied to onion plants three times prior to harvest. Applications were made at a nominal rate of 0.71 lb active ingredient/acre, with 7 days between applications, the last application being made 7 days prior to harvest. A control (non-treated) plot was included in each trial. Mean pyrimethanil residue levels found in or on the non-decline trial samples ranged from 0.10 ppm to <LOQ for dry bulb onions and 1.62 ppm to 0.26 ppm for green onions. Pyrimethanil residues declined rapidly in dry bulb onions, with residues of 0.168 at 0 day PHI, 0.074 ppm at 7-day PHI (normal harvest), and <LOQ at 10-day PHI and thereafter. These trials will support registrations on the entire bulb vegetable crop groups.
iii. Grapes. Grapes were treated with pyrimethanil, a 400 g/l or 3.34 lb active ingredient/gallon formulation. Twelve RAC residue trials were established for the study, 8 in California, 2 in New York, and 1 each in Washington and Oregon. Pyrimethanil was applied to the grape vines two times, once at 35 days and once at 7 days prior to harvest. Applications were made at a nominal rate of 0.71 lb active ingredient/acre. Mean pyrimethanil residue levels found in or on the grapes sampled at 7 days PHI ranged from 0.13 ppm to 0.47 ppm. At the decline trial, mean pyrimethanil residues declined from 0.51 ppm at 1-day PHI to 0.20 ppm at 28 days PHI. Ground applications of pyrimethanil at a nominal rate of 1 kg active ingredient/hectare at flowering, grape closure, color change and 21 days prior to harvest results in residues of 0.51 ppm in the whole fruit. Processing of the fruit into Start Printed Page 10461commodities results in residues of 0.34 ppm in the juice, 1.18 ppm in wet pomace, 3.31 ppm in dry pomace, 0.80 ppm in raisins, and 9.25 ppm in raisin waste. No concentration of the residue occurs in the juice, a 2.3 fold concentration occurs in the wet pomace, a 6.5 fold concentration occurs in the dry pomace, a 1.6 fold concentration occurs in the raisins, and an 18.1 fold concentration occurs in raisin waste.
iv. Stone fruits (apricots, nectarines, peaches, plums, chickasaw plums, damson plums, japanese plums, plumcots, and prunes) (except cherries). Five RAC residue trials were established on apricots, four in California, and one in Washington. Pyrimethanil was applied to the apricot trees three times prior to harvest. Applications were made at a nominal rate of 0.71 lb active ingredient/acre, approximately 69, 9, and 2 days prior to normal harvest. Mean pyrimethanil residue levels found in or on the apricot fruit from the non-decline trials ranged from 0.60 ppm to 1.66 ppm. Mean pyrimethanil residue levels found in or on the fruit from the decline trial ranged, from 1.39 ppm at 0 day PHI to 0.74 ppm at 21 days PHI. In addition, RAC residue trials were established on peaches in Pennsylvania, Georgia, South Carolina, North Carolina, Virginia, Arkansas, Michigan, Oklahoma, and California (four trials). Pyrimethanil was applied to the peach trees times times prior to harvest. Applications were made at a nominal rate of 0.71 lb ai/acre, 69, 9, and 2 days prior to normal harvest. Mean pyrimethanil residue levels found in or on the peach fruit from the non-decline trials ranged from 0.38 ppm to 1.63 ppm. At the decline trial mean pyrimethanil residue levels found in or on the peach fruit ranged from 2.61 ppm at 2 days to 0.95 at 21 days PHI. The apricot and peach trials are sufficient to support registrations on all stone fruits with the exception of cherries.
v. Pome fruit (apples, pears, oriental pears, crabapples, loquats, mayhew, and quince). Twelve trials were established for this study, 3 in Washington, 2 in New York, and 1 each in Pennsylvania, Virginia, Michigan, Ohio, Colorado, California, and Idaho. Pyrimethanil was applied to the apple trees four times prior to harvest. Applications were made at a nominal rate of 0.40 lb ai, with 7 days between applications. Mean pyrimethanil residue levels found in or on the apple fruit ranged from less than the 0.05 ppm LOQ to 0.16 ppm. No decline of the residue was seen between 65 and 93 days PHI at the decline trial. A single trial was established in Washington as a processing study. Pyrimethanil was applied to apple trees four times prior to harvest. Applications were made at a nominal rate of 2.0 lb ai/acre, with 7 days between applications. This rate is approximately five times the proposed label application rate. Mean pyrimethanil residue levels found in or on the samples were: Whole apple fruit 0.17 ppm, wet pomace 0.69 ppm, and juice 0.06 ppm. No pyrimethanil-derived residue concentrated from the whole fruit into the apple juice. However, the pyrimethanil residues concentrated from the whole apples into the wet pomace by a factor of 4.
vi. Tuberous and corm vegetables (potatoes, sweet potatoes, arracacha, arrowroot, artichokes, Chinese artichokes, Jerusalem artichokes, edible canna, cassava, bitter cassava, sweet cassava, chayote root, chufa, dasheen, ginger, leren, tanier, tumeric, yam bean, true yam). Sixteen trials were established for the study, 4 in Idaho, 2 in Washington, and 1 each in New York, Pennsylvania, North Carolina, Wisconsin, Ohio, Michigan, Minnesota, California, Florida, and Colorado. Pyrimethanil was applied to potato plants five times prior to harvest. Applications were made at a nominal rate of 0.27 lb active ingredient/acre, with 7 days between applications. No pyrimethanil residues at or above the 0.05 ppm LQO of the analytical method were found in or on any samples in the study. Thus, no decline could be determined from the samples taken from the decline trials. A single trial was established in Idaho for the purposes of conducting a potato processing study. Pyrimethanil was applied to the potato plants five times prior to harvest. Applications were made at a nominal rate of 1.34 lb active ingredient/acre, with 7 days between applications. This rate is approximately five times the proposed label application rate. It is also the theoretical concentration factor for potatoes. No pyrimethanil-derived residues (0.05 ppm LOQ) were detected in or on the whole tuber samples. Therefore, it can be stated that no concentration of residues would occur into the processed fractions. For this reason, the processed fractions were not analyzed. According to the crop subgrouping 1C, potatoes will support the use of this product on additional minor crops mentioned above.
vii. Strawberries. Eight trials were established for the strawberries RAC residue study. Three trials in California, and one each in Pennsylvania, Wisconsin, Oregon, New Jersey, and Florida. Pyrimethanil was applied to strawberry plants three times prior to harvest. Applications were made at a nominal rate of 0.80 kg active ingredient/hectare (approximately 0.71 lb active ingredient/acre) with 7 days between applications, the last application being made 1-day prior to harvest. Mean pyrimethanil residue levels found in or on the non-decline trial samples ranged from 0.36 ppm (3 days PHI) to 2.33 ppm (1-day PHI). Mean pyrimethanil residue levels in or on samples from the decline trial ranged from 1.33 ppm (1 day PHI) to 0.19 ppm (21 days PHI).
viii. Tomatoes. Sixteen trials were established for the tomato RAC residue study, 11 in California, 2 in Florida, and 1 each in Pennsylvania, North Carolina, and Ohio. Pyrimethanil was applied to tomato plants five times prior to harvest, with 7 days between applications. Applications were made at a nominal rate of 0.27 lb active ingredient/acre, the last application being made 1 day prior to harvest. Mean pyrimethanil residue levels found in or on samples from the non-decline trials ranged from less than the 0.05 ppm LOQ of the analytical method to 0.37 ppm. Mean pyrimethanil residue levels found in or on samples from the decline trials ranged from less than the 0.05 ppm LOQI of the analytical method to 0.37 ppm. One trial was conducted in California for the purposes of establishing tomato processing commodities residues. Pyrimethanil was applied to the tomato plants five times prior to harvest. Applications were made at a nominal rate of 1.34 lbs ai/acre, with 7 days between applications, the last application being made 1-day prior to harvest. The mean uncorrected pyrimethanil derived residue in or on the unwashed tomatoes from the trial was 1.35 ppm. The mean uncorrected pyrimethanil derived residue in the tomato puree was 0.45 ppm and 1.57 ppm in the tomato paste. Concentration factors relative to the unwashed tomatoes were 0.33 and 1.16 for the puree and paste respectively. These factors are significantly less than the theoretical concentration factors of 1.4 for the puree and 5.5 for the paste.
ix. Magnitude of residue trials were conducted on bananas using aerial application equipment that would result in the highest possible residues. Residues in whole fruit, edible pulp and peel fractions from bagged banana samples were all below the method LOQ. In one unbagged sample, a residue of 0.09 ppm was reported. The proposed tolerance of 0.10 ppm will adequately cover any potential residues in/on banana.
B. Toxicological Profile
1. Acute toxicity. Pyrimethanil is of low acute toxicity placing the active Start Printed Page 10462ingredient in Toxicity Category II, III and IV. Pyrimethanil is non-irritating to the eyes and skin and is not a skin sensitizer.
2. Genotoxicity. Pyrimethanil is not mutagenic or genotoxic in any assay in either the presence or absence of metabolic activation.
3. Reproductive and developmental toxicity. Pyrimethanil is not a developmental or reproductive toxicant.
i. Teratology—Rat. Thirty Sprague Dawley rats/group received doses of 0, 7, 85, 1,000 milligrams/kilogram (mg/kg) of pyrimethanil by gavage from gestation days 6-15. At the highest dose tested (HDT), reduced maternal body weight gain was observed during gestation days 6-15, along with a slight but statistically significant decrease in food consumption, hair loss, hunched posture, slight emaciation, and slightly reduced mean fetal body weight. The maternal and developmental no observed adverse effect level (NOAEL) was 85 mg/kg.
ii. Teratology—Rabbit. Groups of at least 18 time-mated New Zealand white rabbits received oral gavage doses of 0, 7, 45 or 300 mg/kg/day pyrimethanil over gestation days 7-19. At the HDT, there was a decrease in body weight gain, production of feces and food consumption. Three females were euthanized due to severe emaciation. The HDT, 300 mg/kg/day exceeded the maternal maximum tolerated dose (MTD). The maternal NOAEL was 45 mg/kg/day due to reduced fecal production in 1/3 of the animals. The HDT resulted in reduced mean fetal body weight, increased incidence of runts, delayed skeletal ossification and incidence of fetuses with 13 thoracic vertebrae and ribs. The maternal NOAEL was 7 mg/kg/day. The developmental NOAEL was 45 mg/kg/day.
iii. Two-generation reproduction—Rat. Three groups of 30 Sprague-Dawley rats per sex received dietary exposure to pyrimethanil at levels of 0, 1.7, 20.9 or 266.7 mg/kg/day. In the parental generation at the highest dose tested there was a statistically significant decrease in mean body weight gain in both sexes. Mean pup weights, observed on postnatal day (PND1) through weaning, were reduced, though were within the range of historical controls. In the F1 generation at the HDT, mean body weights and mean food consumption were reduced. Though the mean score for the combined sexes was the same as the controls, a marginally different air-righting reflex at PND11 associated with reduced body weight was seen in high dose male pups. The NOAEL for maternal and developmental toxicity was 20.9 mg/kg/day. The reproductive NOAEL was 266.7 mg/kg/day.
4. Subchronic toxicity—28-day dietary—i. Rat. Five Sprague-Dawley rats/sex/group received dietary exposure to pyrimethanil for 28 days at 0, 844, 1,161, 1,500, and 2,710 mg/kg/day. All doses exceeded the maximum tolerated dose. Severe emaciation was observed at all dose levels. Body weight gains and food consumption were reduced. Liver and thyroid histopathology were observed, along with reduced hemoglobin, Maxium Concentration Volume (MCV), and Mean Corpuscular Hematocrit (MCH). Kidney, adrenal and liver weights were altered. No NOEL or NOAEL was achieved.
ii. 90-Day dietary—Rat. Ten Sprague-Dawley rats/sex/group received pyrimethanil in the diet at dose levels of 0, 5.4-6.8, 54.5-66.7, 545-667 mg/kg/day (males and females, respectively). High dose animals had reduced body weight gain and food consumption, increased urinary protein in males, colored urine (not blood or bilirubin) and minimal hepatocellular hypertrophy. The NOAEL in males was 54.5-66.7 (males and females, respectively) due to colored urine and a low incidence of minimal centrilobular hepatocellular hypertrophy. The NOAEL was 5.4 mg/kg/day (males) −6.8 mg/kg/day (females).
iii. 28-Day dietary—Mouse. Five CD-1 mice/sex/group received dietary doses of 0, 167-236, 567-667, 1,960-2,357 mg/kg/day males and females respectively, for 28 days (all the mice in one additional high dose group, 30,000 ppm, died within the first week of the study). At 1,960-2,357 mg/kg/day, animals experienced body weight loss (females), decreased body weight gain during the first 2 weeks (males), a statistically significant decrease in cholesterol, statistically significant decreases in relative liver weights (females), pigmentation of thyroid follicles, urolithiasis, moderate urothelial hyperplasia in urinary bladder, and slight kidney tubular degeneration (females). The NOAEL was 167-236 mg/kg/day.
iv. 90-Day dietary—Mouse. Twenty CD-1 mice/sex/group received pyrimethanil diet exposure at dose levels of 0, 12-18, 139-203, 1,864-2,545 mg/kg/day males-females for 90 days. At the high dose, animals had decreased body weight and increased food consumption, cholesterol and total bilirubin. High dose females had increased relative liver weights. Histopathology in the high dose animals was found in the kidneys, liver, thyroid, and urinary bladder. High dose males had slight urinary tract tubular dilation and slight to moderate hyperplasia of bladder epithelium. The NOAEL was determined to be 12 mg/kg/day (males) 18 mg/kg/day (females). Based on mild hepatic glycogen depletion, the NOAEL was 139-203 mg/kg/day (males and females, respectively).
v. 90-Day dietary—Dog. Four beagle dogs/sex/group received pyrimethanil by gavage for 90 days at doses of 0, 6, 80, 1,000 mg/kg/day. The high dose was lowered to 800 mg/kg/day on day 7 due to frequent and consistent vomiting. Decreased body weight, food and water consumption were observed. Males had a significant reduction in phosphate, while females experienced a slight reduction in sodium, anion gap and total protein. At 80 mg/kg/day, infrequent vomiting after dosing and decreased water consumption were observed. After 4 weeks of dosing at 80 mg/kg/day, males had significantly reduced phosphate. The NOEL was 80 mg/kg/day. The NOAEL was 6 mg/kg/day.
vi. Dermal toxicity evaluation. No dermal studies have been conducted for pyrimethanil.
5. Chronic toxicity—i. Chronic toxicity—Dog. Four beagle dogs/sex/group received pyrimethanil by gavage at levels of 0, 2, 30, or 250 mg/kg/day for 12 months. The high dose was reduced from 400 to 250 mg/kg/day on day 8 of treatment due to excessive vomiting during the first week of treatment. At the high dose, there was a decrease in mean body weight gain and mean consumption of food and water. The NOAEL for the study was 30 mg/kg/day, with the high dose of 250 mg/kg/day being the NOAEL.
ii. Combined chronic toxicity/oncogenicity—Rat. Seventy Sprague-Dawley rats/sex/group received pyrimethanil by diet at levels of 0, 1.3-1.8, 17-22, 221-291 mg/kg/day (males and females, respectively) for 2 years. At the HDT, body weight gain and food consumption were decreased. Absolute liver weights were increased. Histopathology revealed centrilobular hepatocyte hypertrophy, increased incidence of eosinophilic foci (males), thyroid follicular hyperplasia, hypertrophy and colloid depletion, and the presence of a brown pigment, identified as lipofuscin in thyroid follicular cell epithelium. There was a statistically significant, dose-dependent increase in the incidence of benign thyroid follicular cell adenomas. There was no increased incidence in any malignant tumor or increase in tumor multiplicity as a result of daily dietary ingestion of pyrimethanil at any dose Start Printed Page 10463level. The results of special studies, discussed below, demonstrate that the benign thyroid tumors are likely a secondary result of a disruption of thyroid-pituitary homeostasis, a well-known, threshold-mediated mechanism. The NOAEL was 17 mg/kg/day (males) and 22 mg/kg/day (females).
iii. Oncogenicity—Mouse. Fifty-one CD-1 mice/sex/group received pyrimethanil by diet at 0, 16, 160, and 1,600 ppm (corresponding to 0, 2-2.5, 20-24.9, 210.9-253.8 mg/kg/day in males and females, respectively). There was an increase in the number of high dose male deaths caused by urogenital tract lesions. Urinary bladder histopathology on those dying during the course of the study indicates an increase in the incidence of male urinary bladder distension, cystitis, urothelial hyperplasia and inflammation of the penis. These findings are consistent with the findings of both the 28-day and 90-day studies indicating that high dose administration of pyrimethanil resulted in urolith formation leading to irritation, distension and hyperplasia of the urinary bladder and urinary tract. Chronic dietary treatment with pyrimethanil produced no increased incidence of tumor-bearing mice nor of any specific tumor type suggestive of a carcinogenic effect. The NOAEL for both sexes was 20-24.9 mg/kg/day (males and females, respectively).
iv. Special studies. Since rodent thyroid tumors are fairly common, and since the EPA has established that five lines of evidence are required to prove the thyroid-pituitary disruption mode of action for rodent thyroid tumors, special studies were undertaken.
Thyroid mechanistic study (14-day). Sprague Dawley rats received 378.5 mg/kg/day of pyrimethanil for 14 days to study the effects of pyrimethanil on the thyroid and liver microsomal enzymes. An increase in the levels of UDPGT and a corresponding statistically significant increase in liver weight were observed. Thyroid hormones T4 and T3 were decreased, while TSH levels were significantly increased. All effects were shown to be reversible.
Dietary thyroid function test using perchlorate discharge (7-day). Sprague Dawley rats received 509 mg/kg/day pyrimethanil or 177 mg/kg/day propylthiouracil, or 109 mg/kg/day phenobarbital in order to study the function of the thyroid gland. The animals fed pyrimethanil had 43% decreased body weight gain, 21% decreased food consumption and a 150% increase in uptake of iodine-125. There was no significant discharge of radioactive iodine from the thyroid after administration of perchlorate.
The required five lines of evidence to support the threshold mode of action for thyroid pituitary disruption and rat thyroid tumors are satisfied in the pyrimethanil studies.
EPA's final rule establishing a tolerance for pyrimethanil in wine stated that “The Agency's Carcinogenicity Peer Review Committee (CPRC)” chose a non-linear approach MOE based on a NOAEL of 17 mg/kg/day for increased incidences of thyroid tumors in rats. The MOE methodology was selected because of thyroid tumors associated with administration of pyrimethanil in the rat, which may be due to a disruption in the thyroid-pituitary status. This chemical has been classified as a Group C chemical (possible human carcinogen) and a non-linear methodology MOE was applied for the estimation of human cancer risk. The estimated MOE does not exceed the Agency's level of concern and therefore, EPA has a reasonable certainty that no harm will result from exposures to residues of pyrimethanil.
6. Animal metabolism. Pyrimethanil is rapidly metabolized and excreted from lactating dairy cows. The observed total radioactive residues in edible tissues and milk were as follows: Milk maximum residue of 0.069 ppm; liver - 0.363 ppm; kidney 0.249 ppm, and muscle 0.017 ppm. The metabolic pathway is similar to that of plants involving hydroxylation of the phenyl and pyrimidine rings as well as hydroxylation of the methyl substituents. Further metabolic reactions occur including cleavage of the phenyl ring to produce substituted pyrimidines. The major metabolite was AE C614276 (46% of the kidney residues, 63% of the milk residues resulting from hydroxylation of the phenyl ring. Hydroxylation of the pyrimidinyl ring of pyrimethanil resulted in formation of minor amounts of AE C614277. Hydroxylation of the methyl groups of pyrimethanil resulted in formation of minor amounts of AE C614278. Hydroxylation of the methyl groups of AE C614276 resulted in formation of minor amounts of AE C614800.
7. Metabolite toxicology. The primary residue of concern in both crop and animal commodities is pyrimethanil. In the animal metabolism, since major metabolites are produced following the oral administration of pyrimethanil, toxicology data for metabolites are completely supported by data obtained for pyrimethanil.
8. Endocrine disruption. Chronic, life span, and multi-generational bioassays in mammals and acute and subchronic studies on aquatic organisms and wildlife did not reveal endocrine effects. Any endocrine related effects would have been detected in this definitive array of required tests. The probability of any such effect due to agricultural uses of pyrimethanil is negligible.
C. Aggregate Exposure
1. Dietary exposure. Tolerances are proposed under 40 CFR part 180 for pyrimethanil in or on tree nuts, bulb vegetables, grapes, stone fruits (except cherries), pome fruit, tuberous and corm vegetables, strawberries, and tomatoes. An import tolerance for wine grapes has been approved by the EPA. A petition for registration of pyrimethanil on bananas is pending at EPA. There are no residential uses proposed for pyrimethanil. Therefore, potential human risk scenarios cover aggregate exposure from food residues and drinking water.
i. Food. Refined estimates of acute dietary exposure from potential pyrimethanil residues on the proposed crops are all well under 100% of the acute reference dose (aRfD) at the 99.9th percentile. The most highly exposed sub population of children (1-6) utilizes 7.9% of the RfD, while the U.S. population utilizes 3.4%. These potential dietary exposures were estimated in a Tier 3 Monte Carlo risk assessment using the DEEMTM software, Version 7.76 (Novigen Sciences, Inc.). The 1994-96, 1998 Continuing Survey of Food Intake by Individuals (CSFII) consumption data from Department of Agriculture (USDA) was used which includes the Supplemental Children's Survey (1998). Residue values included in the assessment were distributions of the field trail values incorporating percent crop treated (PCT) as zeroes for all non-blended and partially blended items. Blended items were included as the average residue and adjusted for PCT. These PCT values are the anticipated market share of pyrimethanil for the crops at market maturity (5 years). Concentration factors derived from processing studies were included where appropriate. Secondary residues for meat and milk were included in the assessment. These were calculated using theoretical dietary burdens from sensible diets for beef and dairy cattle and tissue to feed ratios from the ruminant feeding study.
Refined chronic dietary exposure estimates resulting from the proposed uses of pyrimethanil are well within acceptable limits for all population subgroups examined. The most highly exposed group of children (1-6) utilized 0.3% of the RfD with the .U.S Start Printed Page 10464population utilizing 0.1% of the RfD. A Tier 3 chronic analysis was done using the DEEMTM software, Version 7.76 (Novigen Sciences, Inc.). The 1994-96, 1998 CSFII consumption data from USDA were used. Average anticipated residue values were calculated from the appropriate field trial studies conducted for pyrimethanil. The average residue values were adjusted by the projected PCT at product maturity. Concentration factors derived from processing studies were included where appropriate. Secondary residues were calculated using theoretical dietary burdens derived from sensible diets for beef and dairy cattle and tissue to feed ratios from the ruminant feeding study.
ii. Drinking water. U.S. EPA's Standard Operating Procedure (SOP) for Drinking Water Exposure and Risk Assessments was followed to perform the Tier 1 drinking water assessment. This SOP uses a variety of tools to conduct drinking water assessments, including water models such as Screening Concentration in Ground Water (SCI-GROW), FIRST, Pesticide Root Zone Model (PRZMS)/EXAMS, and monitoring data. If monitoring data are not available then the models are used to predict potential residues in surface and ground water and the highest levels (whether ground or surface) are assumed to be the drinking water residue. In the case of pyrimethanil, monitoring data are not available. SCI-GROW and FIRST were used to estimate a drinking water residue. Calculation of the Drinking Water Estimate Concentration (DWEC) for surface water for the worst case pyrimethanil use scenario results in an acute DWEC of 122 parts per billion (ppb) and a chronic DWEC of 37 ppb. DWLOCs calculated based on the acute and chronic risk assessments described above are many fold higher than these conservative DWECs. The adult acute and chronic DWLOCs are 10,146 ppb and 5,944 ppb respectively. Children's acute and chronic DWLOCs are 2,762 ppb and 1,695 ppb respectively.
2. Non-dietary exposure. Pyrimethanil products are not labeled for residential uses (food or non-food), thereby eliminating the potential for residential exposure or non-occupational exposure.
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.” There are no available data to determine whether pyrimethanil 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, pyrimethanil does not appear to form a toxic metabolite produced by other substances. For the purposes of the tolerance petition and this reduced risk rationale, therefore, it has been assumed that pyrimethanil does not have a common mechanism of toxicity with other substances.
E. Safety Determination
1. U.S. population. Using the assumptions and data described above, based on the completeness and reliability of the toxicity data, it is concluded that dietary risk from the proposed uses of pyrimethanil are acceptable for all populations examined. Chronic exposure for the U.S. population utilizes 0.1% (0.00015 mg/kg bwt/day) of the cRfD. Acute exposure for the U.S. population utilizes 3.4% (0.01012 mg/kg bwt/day) of the aRfD. The most highly exposed population of children 1-6 utilizes only 0.3% of the cRfD and 7.9% of the aRfD. The actual exposures are likely to be much less as more realistic data and models are developed. EPA generally has no concern for exposures below 100% of the RfD (acute or chronic), because the RfD represents the level at or below which exposure will not pose appreciable risk to human health. DWLOC for adults both acute (10,146 ppb) and chronic (5,944 ppb) are several orders of magnitude above the conservative DWEC for acute (122 ppb) and chronic (37 ppb) worst case scenarios. Therefore, there is a reasonable certainty that no harm will occur to the U.S. population from aggregate exposure (food and drinking water) to residues of pyrimethanil.
2. Infants and children. The relevant toxicity studies as discussed in the toxicology section above show no extra sensitivity of infants and children to pyrimethanil, therefore, the FQPA safety factor can be removed. Using the assumptions and data described in the exposure section above, it is concluded that dietary risk from the proposed uses of pyrimethanil are acceptable for all infant and children sub-populations examined. The most highly exposed sub-population was children 1-6 for both the chronic and acute analyses. The sub-population children 1-6 utilizes 0.3% (0.00047 mg/kg bwt/day) of the cRfD and 7.9% (0.02377 mg/kg bwt/day) of the aRfD. All other infant and children populations have less exposure. The chronic and acute drinking water levels of concern for children (1,695 ppb and 2,762 ppb respectively) are well above the conservative DWEC for chronic and acute scenarios. The chronic DWEC is 37 ppb and the acute DWEC is 122 ppb. Therefore, there is a reasonable certainty that no harm will occur to infants and children from aggregate exposure to residues of pyrimethanil.
F. International Tolerances
Maximum residue limits for pyrimethanil have not been established by the Codex Alimentarius Commission.End Supplemental Information
[FR Doc. 03-5032 Filed 3-4-03; 8:45 am]
BILLING CODE 6560-50-S