E. I. DuPont de Nemours and Company Aminocyclopyrachlor

------------------------------------------------------------ -----------

ENVIRONMENTAL PROTECTION AGENCY

Notice of Filing of a Pesticide Petition for the Establishment of Tolerances for Residues of Aminocyclopyrachlor in or on Food Commodities

AGENCY: Environmental Pr otection Agency (EPA).

ACTION: Notice.

------------------------------------------------------------ -----------

SUMMARY: This notice announces the init ial filing of a pesticide petition proposing the establishment of tolerances for residues of aminocyclopyrachlor in

or on food commodities under the Fede ral Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act of 1996 (FQPA).

FOR FURTHER INFORMATI ON CONTACT: By mail: Kable Bo Davis, Product Manager (PM 25), Registration Di vision, (7505P), Office of Pesticide Programs, Environmental Protecti on Agency, Ariel Rios Building 1200 Pennsylvania Avenue, N. W., Wash ington, DC 20460. Office location and telephone number: Arlington, VA., (703) 306-0415. Email: davis.kable@epa.gov

SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as follows proposing the establishment and/or amendment of regulations for residues of certain pesticide chemicals in or on various raw agricultural commodities under section 408(d) of the Federal Food, Drug, a nd Cosmetic Act (FFDCA), 21 U.S.C. 346a (d). EPA has determined that this petition contains data or information regarding the elements set forth in sec tion 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, Food Additives, Feed Additives, Pesticides and Pests, Repo rting and Recordkeeping Requirements.

Summary of Petition

A summary of the pesticide pe tition is given below. The petitioner prepared the summary of the petition.

EPA Registration Division c ontact: Kable Bo Davis, Pr oduct Manager 25, (703) 306-

0415.

Page 1 of 8E. I. DuPont de Nemours and Company Aminocyclopyrachlor

E. I. DuPont de Ne mours and Company, DuPo nt Crop Protection

0F7817

EPA has received a pesticide petition (0F7817) from E. I. DuPont de Nemours and Company, DuPont Crop Protection, Wilmington, Delaware, 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 to establish tolerances for residues of aminocyclopyrachlor [6-amino-5- chloro-2-cyclopropyl-4-pyrimidinecarboxylic acid] and aminocyclopyrachlor methyl ester [methyl 6-amino-5-chloro-2-cyclopropyl-4-pyrimidinecarboxylate], expressed as aminocyclopyrachlor in or on grass forage at 65 parts per million (ppm), grass hay at 125 ppm, fat (of cattle, goat, horse and sheep) at 0.07 ppm, meat (of cattle, goat, horse and sheep) at 0.02 ppm, meat byproducts - excluding liver (of cattle, goat, horse and sheep) at 0.4 ppm, liver (of cattle, goat, horse and sheep) at 0.06 ppm and milk at 0.035 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 ha s not fully evaluated the sufficiency of the

submitted data at this time or whether the da ta supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant and animal metabolism.

i. Plant metabolism. The nature of the residu e in plants (grass) is adequately understood for the purpose of these tolerances. Based on the findings from this metabolism study, the residues of concern in grass are the comb ined residues of aminocyclopyrachlor and aminocyclopyrachlor methyl, expres sed as aminocyclopyrachlor.

ii. Animal metabolism.

The nature of residue of aminocyclopyrachlo r in ruminants is adequately understood for the purpose of this tolerance. In animal commodities, the residues of concern are the combined residues of aminocyclopyrachlor and aminocyclopyrachlor methyl, expressed as aminocyclopyrachlor.

2. Analytical method. Adequate analytical methods for enforcement purposes are

available to monitor residues of aminocyclopyrachlor in gr ass commodities, milk, meat and meat by-products. The analytical methods for both grass commodities and ruminant commodities use an LC/MS/MS system operating with an electrospray interface (ESI) in positive ion mode) with limits of quantitation (LOQ) of 0.01 ppm. Both methods have been successfully inde pendtly validated by out side laboratories. Aminocyclopyrachlor had also been tested through the Food and Drug Administration (FDA), Multi-residue Methodology. EPA offe rs enforcement methodology to anyone interested in pesticide enfo rcement when requested by mail from: Public Response and Program Resources Branch, Field Operati ons Division (7506C), Office of Pesticide Programs, Environmental Protection Agen cy, 401 M St., SW., Washington, DC 20460. Office location CM#2, 1801 South Bell Street, Arlington, VA 22202.

Page 2 of 8E. I. DuPont de Nemours and Company Aminocyclopyrachlor

3. Magnitude of residues

i. Plant residues.

Grass crop group 17 - Geographically representati ve field trials were conducted on grass pastures according to use patterns which s upport the proposed tolerances in or on grass forage and grass hay. The proposed tolerances in grass commodities, and subsequently in milk, meat and meat by-products are adequate to cover the highest residues from the maximum label use of aminocyclopyrachlor in grass pastures.

ii. Animal residues. Of the commodities for which tolerances are being proposed, grass hay and grass forage are possible animal feed items. Therefore, a cattle feeding study was

conducted to establish tolera nces on meat, meat by-products and milk. The proposed tolerances in milk, meat and meat by-products are adequate to cover the highest residues

from the maximum label use of ami nocyclopyrachlor in grass pasture.

B. Toxicological Profile

1. Acute toxicity. Aminocyclopyrachlor has low acute toxicity. Aminocyclopyrachlor is considered toxicology category IV for acute oral toxicity (LD 50 > 5000 mg/kg), acute dermal toxicity (LD 50 > 5000 mg/kg), acute i nhalation toxicity (LD 50 > 5.4 mg/L), and skin irritation. Aminocyclopyrachlor is not a dermal sensitizer. Aminocyclopyrachlor is considered category III for eye irritation.

2. Genotoxicty. Short-term assays for genoto xicity consisting of a bacterial reverse mutation assay (Ames test), an in vitro assay for cytogenetic damage using the Chinese hamster ovary cells, an in vitro chromosomal aberration assa y in human ly mphocytes, and

an in vivo cytogenetic assay in the mouse erythrocytes (micronucleus test) have been conducted with aminocyclopyrachlor. The weight of evidence from these studies indicates that aminocyclo pyrachlor is no n-genotoxic.

3. Reproductive and developmental toxicity.

i. Rat developmental study. A developmental study was cond ucted in rats administered technical aminocyclopyrachlor by oral gavage at dose levels of 0, 30 , 100, 300, or 1000 mg/kg/day on gestation days 6 through 20. No tr eatment-related eff ects were noted on maternal or developmental toxi city up to and including the highest dose tested of 1000 mg/kg. The LOAEL for maternal and developmental toxicity could not be determined and the NOAEL is 1000 mg/kg/da y for both maternal and developmental toxicity.

ii. Rabbit developmental study. A devel opmental study was conducted in rabbits administered technical aminocyclopyrachlor by or al gavage at dose levels of 0, 30, 100, 300, or 1000 mg/kg/day on gestatio n days 7 through 28. The NOAEL for maternal toxicity is 500 mg/kg/day) and the LOAEL is 1000 mg/kg/day based on decr eased food consumption and body weights and increased incidences of mortality and abortion. The LOAEL for

Page 3 of 8E. I. DuPont de Nemours and Company Aminocyclopyrachlor

developmental toxicity could no t be established. The NOAEL fo r developmental toxicity is 1000 mg/kg/day (highest dose tested.)

iii. Two-generation rat reproduction study. A two-generation reproduction toxicity study was conducted in rats with aminocyclopyrach lor at dietary con centrations of 0, 500, 1500, 5000 and 17000 ppm. The LOAEL for pare ntal toxicity was 17,000 ppm (1285 / 1454 mg/kg/day for males/females) and the NOAEL was 5000 ppm (363 / 416 mg/kg/day for males/females). The parental LOAEL was based on reduced food efficiency and body weights. Reduced offs pring bodyweights were also observed. The LOAEL for offspring toxicity was 17,000 ppm and the NOAEL wa s 5000 ppm. No

LOAEL was observed for re productive toxicity and the NOAEL was 17,000 ppm.

4. Subchronic toxicity.

i. 90-Day rat feeding study. A 90 day study in rats was conducted at dose levels of 0, 600, 2000, 6000, and 18000 ppm (equivalent to 0/0, 35/45, 114/146, 349/448 and 1045/1425 mg/kg/day for males / females, respectively). Reduced food consumption, food efficiency and body weights/weig ht gains were observed at the highest dose tested. A LOAEL for subchronic toxicity of this test material is 18000 ppm (1045/1425 mg/kg/day for males / females) and a NOAEL is 6000 ppm (349/448 mg/kg/day for males / females).

ii. 90-Day mouse study. A 90 day study in mi ce was conducted at dose levels of 0, 300, 1000, 3000, and 7000 ppm (equivalent to 0/0, 47/61, 154/230/ 459/649 and 1088/1623 mg/kg/day for males / females, respectivel y). No LOAEL was established, and the NOAEL is 7000 ppm (1088/1623 mg/kg/day for males / females).

iii. 90-Day dog study. A 90 day study in dogs was conducted at dose levels of 0, 250, 1250, 5000, and 15000 ppm (equivalent to 0/0, 6.5/7, 33/38, 126/124, and 426/388 mg/kg/day for males / females, respectivel y). No LOAEL was established, and the NOAEL is 15000 ppm (426/388 mg/kg/day for males / females).

iv. 28-day dermal study. A 28 day dermal study wa s conducted in rats at dose levels of 0, 150, 400, and 1000 mg/kg/day. No LOAEL wa s established, and the NOAEL is 1000 mg/kg/day for male and female rats.

5. Chronic toxicity and oncogenicity

i. 18-Month mouse oncogenicity study. An 18-month carcinogenicity study was conducted dose levels of 0, 300, 1000, 3000 and 7000 ppm (equivalent to 0/0, 39/50, 133/171, 393/527, and 876/1190 mg/kg/day in ma les / females, respectively). Aminocyclopyrachlor is not an oncogen in mice. Under the conditions of this study, the NOAEL for aminocyclopyrachlor was 7000 ppm (876/1190 mg/kg/day in males / females).

Page 4 of 8E. I. DuPont de Nemours and Company Aminocyclopyrachlor

ii. 1-Year chronic dog study. A 1-year feeding study was conducted with dogs fed dosages of 0, 1250, 5000, 15 000 and 30000 ppm (equ ivalent to 0, 38/47, 178/175, 465/542 and 1077/1073 mg/kg/ day in males /females, re spectively). Unde r the conditions of this study, the (NOAEL) for aminocyclopyr achlor was considered to be 30000 ppm, (1077 and 1073 mg/kg/day in males and females, respectively.

iii. Two-year combined rat chronic toxicity/oncogenicity study. A combined chronic toxicity/oncogenicity 2-year feeding study was conducted in rats fed dosages of 0, 600, 2000, 6000, or 18000 ppm (equivalent to 0/0, 27/29, 97/100, 279/309, and 892/957 mg/kg/day for males / females, respectively). Aminocyclopyrachlor is not an oncogen in

rats. Under the conditions of this stud y, the NOAEL for aminocyclopyrachlor was 6000 ppm, equivalent to 279 /309 mg/kg/day in males/females, respectively. Under the conditions of this study, The NOAEL is based on adverse test article related effects on body weights in rats fed 18000 ppm (892/957 mg/kg/day for males / females).

6. Acute and subchronic neurotoxicity

i. Acute neurotoxicity - An acute neurotoxicity study was co nducted in rats administered a single oral (gavage) dose of 0, 200, 1000 or 2000 mg/kg aminocyclopyrachlor. Under the conditions of this assay, aminocyclopyr achlor was not neurot oxic. The NOAEL was 2000 mg/kg. There was no LOAEL for acu te neurotoxicity established.

ii. Subchronic neurotoxicity – A combined 90 day systemic toxicity and neurotoxicity study in rats was conducted at dose le vels of 0, 600, 2000, 6000, 18000 ppm (equivalent to 0/0, 35/45, 114/146, 349/448 and 1045/1425 mg /kg/day for males / females, respectively). A NOAEL for neurotoxicity is 18000 ppm (1045/1425 mg/kg/day for males / females). There was no LOAEL fo r subchronic neurotoxicity established.

7. Immunotoxicity

i. 28-Day immunotoxicity study in rats. A 28-day immunotoxicity study was conducted

in male rats fed diets that containe d 0, 600, 6000 or 18000 ppm aminocyclopyrachlor. This was equivalent to 0, 42, 407, a nd 1277 mg/kg/day. There was no LOAEL established for immunotoxicity or system ic toxicity. The NOAEL was 18000 ppm (1277 mg/kg/day).

ii. 28-Day immunotoxicity study in mice. 28- Day immunotoxicity study in mice. A 28- day immunotoxicity study was conducted in male mice fed diets th at contained 0, 300, 3000 or 7000 ppm aminocyclopyrachlor. This was equivalent to 0, 45, 425 and 1056 mg/kg/day. There was no LOAEL established for immunotoxicity or systemic toxicity. The NOAEL was 7000 ppm (1056 mg/kg/day).

8. Rat metabolism

The metabolism of aminocyclopyrachlor has been evaluated in rats. The results demonstrated rapid absorption and clearance, wi th an average of 82 to 93% excreted in

Page 5 of 8E. I. DuPont de Nemours and Company Aminocyclopyrachlor

urine and feces during the first 24 hours following administration. By 72 hours postadministration 95 to 98% of the administered dose was eliminated in urine and feces, with a mean percent dose in urine ranging from 40 to 56.5% a nd that in the feces ranging from 40 to 54.8%. By 72 hours following si ngle or multiple-dose administration the body burden was very low ranging from 0.03 to 0.22%. There were no sex differences or impact of single or multiple exposures evident for the excretion rates. Based on analyses of data from single and multiple exposures and tissue:plasma concentration ratio data,

there was no evidence for accumulation of am inocyclopyrachlor in tissues. Chemical analyses of urine, feces and bile demons trated that aminocyclopyrachlor was not

metabolized in the rat.

9. Metabolite toxicology

There is no evidence that the metabolites of aminocyclopyrachlor iden tified in either the grass residue study or feeding study are of toxicologi cal significance.

10. Endocrine disruption

In the available toxicity studies on aminocyc lopyrachlor, there was no estrogen, androgen, and/or thyroid mediated toxicity.

C. Aggregate Exposure

1. Dietary exposure

–

i. Food and Water.

Chronic dietary exposure assessment. Chr onic dietary exposure resulting from the currently approved uses and proposed uses of aminocyclopyrachlo r is well within acceptable limits for all sectors of the popul ation. The chronic module of the Dietary Exposure Evaluation Model with Food Co mmodity Intake Database (DEEM-FCID TM

, version 2.16, Exponent, Inc.) was used to conduct the assessment with the chronic reference dose (cRfD) of 2.80 mg/kg/ day. This model incorporates nationwide food consumption data as reported by respondents in the U.S. Department of Agriculture (USDA) 1994-1996, 1998 Continuing Surveys of Food Intake by Individuals (CSFII). The analysis used tolerance values in place of residue values for meat and milk. The chronic dietary exposure of the US populati on to aminocyclopyrachlo r utilizes <1% of the cRfD for the overall U.S. population. No population subgroup had an exposure that

utilized more than 1% of the cRfD. There are large margins of safety for each population subgroup and very low probability of effects resulting from chronic exposure to aminocyclopyrachlor.

Acute Dietary Exposure. Acut e dietary risk assessments are performed for a food-use pesticide if a toxicological st udy indicates the possibility of an effect of concern as a result of a one day or a single exposure. No acu te dietary endpoint attributable to a single

Page 6 of 8E. I. DuPont de Nemours and Company Aminocyclopyrachlor

dose was identified for aminocyclopyrachlor. Therefore the quan tification of acute dietary risk is not considered necessary. Ther e is reasonable certainty that no acute effects would result from dietary exposure to aminocyclopyrachlor.

ii. Drinking water. Based on the FIRST Ti er 1 surface water and SCI GROW Tier 1 groundwater models under worst-case conditions the chronic estimated environmental concentrations (EECs) of aminocyclopyr achlor are 16.965 ug/L for surface water and 40.2 ug/L for ground water.

When the higher surface water concentration was included in the chronic dietary risk assessment, the predicted exposure for the ge neral population was <1% of the cRfD. No population subgroup had an exposure that utilized more than 1% of the cRfD. Thus, the chronic dietary exposure of aminocyclopyrac hlor including the cont ribution of drinking water clearly meets the standard of reasonable certainty of no harm.

2. Non-dietary exposure. Assessment of hypothetical post-applicati on consumer exposure from use on turf results in margins of expos ure greater than 100 for inhalation, hand to mouth oral, and soil ingestion exposures. Thus these are not of concern. Quantification of dermal exposures is not required because no toxicity was observed in a dermal study

conducted at limit dose.

D. Cumulative Effects

EPA has not made a common mechanism of t oxicity finding as to aminocyclopyrachlor and any other substances and has not assu med that aminocyclopyrachlor has a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population. Based on the completeness and reliability of the toxicity data and the conservative exposure assessments, there is a r easonable certainty that no harm will result from the establishment of the proposed tolera nces as evidenced by the assessment of the aggregate exposure of residues of aminocycl opyrachlor including all anticipated dietary exposure and all other non- occupational exposures.

2. Based on the completeness and reliability of th e toxicity data, the lack of toxicological endpoints of special concern, the lack of any indication that children are more sensitive than adults to aminocyclopyrachlor, and the c onservative exposure assessment, there is a reasonable certainty that no harm will result to infants and children from the aggregate exposure of residues of aminocyclopyrachlor, including all anticipated dietary exposure and all other non-occupational exposures. Acco rdingly, there is no need to apply an additional safety factor for infants and children.

Page 7 of 8E. I. DuPont de Nemours and Company Aminocyclopyrachlor

Page 8 of 8 F. International Tolerances

There is neither a Codex proposal, nor an esta blished Canadian or Mexican tolerance for grass and/or ruminant commodities.