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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Julie Chao, 703 - 308 - 8735 Veto - Pharma SA c/o Arysta LifeScience America 9F7673 EPA has received a pesticide petition ( 9F 7673 ) from Veto

- Pharma SA, care of Ary sta L ifeScience America, 1450 Broadway , 7 th Floor, New York, NY 10018 , 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 180.287 by establishing a tolerance for residues of Am itraz in or on the raw agricultural commodity honey at 1 parts per million (ppm). EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted d ata at this time or whether the data supports granting of the petition. Additional data may be needed befo re EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. 2. Analytical method. There are two adequate methods listed in FDA's Pesticide Analy tical Manual (PAM Vol. II) for purposes of data collection and enforcement of tolerances for residues of amitraz and its metabolites containing the 2,4

- DMA moiety
. Methods I(designed for animal tissues and milk) and II (designed for plant commodities) are both GLC methods with electron capture detection, and convert residues of amitraz to 2,4
- DMA by acid and base hydrolysis, respectively. The detection limits of the methods are 0.01 ppm for milk and 0.05 ppm for plant and other animal commodities. Amitraz and its metabolites containing the 2,4

- DMA moiety have been tested using FDA's Multiresidue Method Protocol D; the metabolite BTS

- 27919 wa s the only compound which could be analyzed by this protocol (MRIDs 00046030, 00051929, 00051930, GS00234013, 40811310, 40811311, 40811312). 3. Magnitude of residues. EPA has data supporting a 1 ppm tolerance in honey following the use of a similar strip that contained three times the amount of amitraz as the product proposed for registration. EPA also has an analytical method for amitraz in honey to enforce the tolerance. B. Toxicological Profile2 1. Acute toxicity. On an acute basis, amitraz has moderate toxicity (Category

I I) by the dermal route, and it is slightly toxic (Category

I II) via the oral and inhalation routes of exposure. Further, it is not a skin or ey e irritant, nor is it a skin sensitizer. 2. Genotoxicty. Results of mutagenic studies indicate that amitraz is not mutagenic. Two metabolites of amitraz [N

- (2,4

- dimethylphen yl )

- N
- methyl formamidine (BTS

- 27271)] and [2,4

- dimethylformanilide (BTS

- 27919)] were also shown to be negative for reverse gene mutation in the Salmonella assay (MRID 00161008). A third metabolite [2,4

- dimethylaniline (BTS

- 24868)] was reported to be positive for forward gene mutation in the mouse ly mphoma assay

with metabolic activation (MRID 00161012). 3
. Reproductive and developmental toxicity. Intwo developmental toxicity studies, Wistar rats were dosed with amitraz at 0, 1, 3, or 12 mg/kg/day , by gavage (assumed route). No treatment related maternal or developmental effects were observed in one study
. In the other study , the maternal and developmental NOELs were 3 mg/kg/day . Both maternal and reproductive LOELs were 12 mg/kg/day , based on decreased weight gain. (MRIDs 00029959; 00029960). In another developmental toxicity study , New Zealand White rabbi ts were dosed with amitraz at 0, 1, 5, or 25 mg/kg/day , from gestation day s 6 through 18. The NOEL for both maternal and developmental effects was 5 mg/kg/day . The LOEL for both maternal effects (reduced bod y weight and increased abortions on gestation day s 17 to 20) and developmental effects (decreased litter size and weight, and reduced implantation and viability indices) was 25 mg/kg/day . (MRID 00029961). In a multi

- generation reproduction study , (MRID 00029962), Boots

- Wistar rats were fed diets contain ing 0, 15, 50, or 200 ppm amitraz. The sy stemic toxicity NOELwas 50 ppm (4.84 mg/kg/day

/ male and 5.22 mg/kg/day /female) and the LOEL was 200 ppm (16.41 mg/kg/day

/male and 20.06 mg/kg/day /female), based on reduced body weight gain and food consumption in F 0 animals. The reproductive toxicity NOEL (15 ppm; 1.47 mg/kg/day

/male and 1.69 mg/kg/day /female) was lower than the s ys temic NOEL. The reproductive toxicity L OEL (50 ppm; 4.84 mg/kg/day /male and 5.22 mg/kg/day

/female) was also lower than the s ys temic L OE L and was based on reduced litter size and pup survival in all 3 generations (F 1 , F 2 , and F 3 ), and a slight reduction in pup weights in the F 1 and F 2 generations. Further reproductive toxicity was observed at the high dose (most of the F 1 generation rats d ied, and there were not enough animals left for subsequent matings). 4. Subchronic toxicity. Ina subchronic oral toxicity stud y, mice were administered amitraz by

gavage, at levels of 0, 3, 12, 50, or 200 mg/kg/day for 90 day s. The sy stemic NOEL was 3 mg/kg/day . Higher doses produced reduced bod y weight gain and liver toxicity (increased serum glutamic p yruvate transaminase activity , increased liver weight, hepatocy te enlargement, bile duct proliferation, and focal necrosis). The s ys temic L OEL was 12 mg/kg/day

(MRID 00028715). In another subchronic oral toxicity study , Beagle dogs were administered amitraz, by capsules, at levels of 0, 0.25, 1.0, or 4.0 mg/kg/day for 90 day s. The s ys temic NOEL was3

0.25 mg/kg/day . At the LOEL(1.0 mg/kg/day) there were sl ight enlargement of the central and midzonal hepatocy tes of the liver and slight hy perplasia of the zona glomerulosa of the adrenals. Both the LOEL and the high dose (4 mg/kg/day) produced transient CNS (central nervous sy stem) depression, decrease in puls e rate, glucosuria, neutrophilia of the bone marrow and recurrent h ypothermia of short

- lasting duration that appeared within three hours after dosing and only lasted a few hours. The high dose additionally

produced ataxia, emesis, and catarrhal conjunctivi tis. (MRI Ds 00040345, 00028716). In a 21
- day

dermal toxicity

study in rabbits, doses of 50 or 200 mg/kg/day were applied to the skin of rabbits (6 hours/day for a total of 15 times over the 21

- day period). 5. Chronic toxicity. Carcinogenic effects were not observed in a combined chronic/carcinogenicit y s tudy . Wistar rats were fed levels of 0, 15, 50, or 200 ppm (0, 0.77, 2.5 or 10.18 mg/kg/day for males and 0, 0.97, 3.13 or 12.59 mg/kg/day for females) for two years. The s ys temic NOEL was 15 ppm. T he sy stemic LOEL was 50 ppm, based upon findings of aggressive or excitable behavior, clinical signs, and reduced weight gain at this level and at 200 ppm. (MRID 00044585). In a carcinogenicity

feeding study , CFLP mice were fed diets containing 0, 25, 100, or 400 ppm amitraz (0, 3.75, 15, or 60 mg/kg/day) for 80 weeks. Amitraz produced ly mphoreticular tumors in females at 400 ppm, the highest level studied. Tumors were not evident at the mid dose level of 100 ppm. The sy stemic NOEL was 25 ppm, due to a redu ction in body

weight gain at higher doses (MRI D 00111886). In another carcinogenicity feeding study , B6C3F1 mice were fed diets containing 0, 25, 100, or 400 ppm amitraz for 104 weeks. Amitraz produced liver adenomas and carcinomas as well as lung adenomas at the highest dose level studied, 400 ppm (50.1 mg/kg/day

for females and 44.7 mg/kg/day for males). Tumors were not evident at the next dose level (100 ppm; 15 mg/kg/day). The sy stemic NOEL was less than the lowest level tested. The systemic LOEL was 25 ppm (the lowest level tested; 2.6 mg/kg/day

for females and 2.3 mg/kg/day for males), based upon stomach hy perkeratosis, spleen hematopoiesis, and liver changes (nodules, and telangietactic and basophilic foci). Hy

peractive or aggressive behavior, reduced weight gain, and a reduced my eloid/ery

throid ratio in bone marrow were observed at the 100 and 400 ppm levels (MRI D 00013952).

. 6. Animal metabolism. Extensive metabolism studies have been conducted with amitraz in several species, including humans, baboons, dogs, rats, and mice. In all species, amitraz was rapidly metabolized in the stomach, following oral administration, to form at least six metabolites, among which are the three cited above. Metabolites BTS

27271 and BTS

- 27919 (which are formed via hy droly sis at the C

- N [N
methylmethanimidamide] bond) are the primary metabolites of amitraz. Excretion of metabolites occurred mainly in the urine over 48 hours (62%

- 82% in all species) and to a lesser extent in feces (9%

- 39%), with no unchanged parent c ompound observed in urine. The proportion of various metabolites recovered in the urine of all species was also similar. The highest levels of 14C tissue residues in animals were found over 3 to 4 day s in the liver, bile, kidney , adrenal glands, and pigmented areas of the ey e. (MRI D 00160964)4

7. Metabolite toxicology
. NA - Remove 8. Endocrine disruption
. As required b y FFDCA Section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substance may

have an effect produced b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” Amitraz was not among the 58 pesticide active ingredients on the initial list to b e screened under the EDSP. EPA anticipates issuing future EDSP orders for registered pesticides. C. Aggregate Exposure 1. Dietary exposure. Tolerances exist for meat and milk and are proposed here for honey. There is no liklihood of residues in drinking water. Uses have been cancelled for pears and cotton and tolerances on eggs and animal parts have been identified for revocation. An assessment of the dietary exposure of the remaining uses, including honey will likely not exceed the aPAD. i
. Food. ] A dietary exposure w as undertaken for purpose of determining the incremental exposure that w ould be associated with the establishment of a tolerance for amitraz of 1.0 ppm in honey. The individual consumption of honey is small in the United Stat es. Only 14.5% of the population reported consuming honey on at least one day of the three day sampling period (see USDA, 1997, Food Commonly Eaten in the United States, attached). The USDA Continuing Survey of Food Intakes by Individuals, 1989
- 1991 found that honey consumption averaged approximately 1 gram per day in all individuals age 2 or older. A tolerance of 1.0 ppm of amitraz and a daily consumption rate of 1.0 gram of honey for a 60 kg individual results in a daily dietary intake of 1 microgram /person, or 0.000017 mg/kg bw/day. This is much less than the Acute RfD of 0.0125 mg/kg bw/day or Acute PAD of 0.00125 mg/kg bw/day that was established based upon human studies. The chronic RfD is the same as the Acute RfD because both RfD are based o n single dose studies in humans. Ac ute dietary exposures and risks were determined using CARES software. The acute Margins of Exposure (MOEs) were all large. The MOE at the 99.9% percentile was 181 compared with the target MOE of 10 for amitraz (as identified in the “Report of the Food Quality Protection Act (FQPA) Tolerance and Reassessment Progress and Risk Management Decision (TRED) for Amitraz”, D. Edwards, July 2006.

ii. Drinking water
. EPA initially calculated estimated environmental concentrations (EECs) for amitraz based on the swine use (see Amitraz: Drinking W ater Assessment for Tolerance Reassessment Eligibility Decision, dated February , 11 2004 and Revised Amitraz Drinking W ater As sessment for Tolerance Reassessment Eligibility Decision (TRED) , dated May 1, 2004). However, EPA has since determined that cattle and swine are seldom treated outdoors. Use of amitraz in impregnated strips that are inserted into bee hives is unlikely to r esult in residues in drinking water. Since the onl y other use of amitraz is in impregnated dog collars, amitraz is not expected to enter water

bodies through currently

registered uses. As a result, the Agency has determined that use of amitraz will not re sult in drinking water exposure, and a drinking water assessment is not needed. 2. Non

- dietary exposure
. For a discussion of residential and post

- application5

residential exposure see “ Revisions for “Amendment to Amitraz: Revised Residential Exposure A ssessment for the Reregistration Eligibility Deci si ons ”, dated July

27, 2006 and Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and R isk Management (TRED) for Amitrax, July 2006 )
. D. Cumulative Effects FQPA requires that the Agency consider “available information” concerning the cumulative effects of a particular pesticides residues and “other substances that have a common mechanism of toxicity .” Amitraz is not known to share a common mechanism of toxici ty with other compounds and a cumulative risk assessment is not necessary
. E. Safety Determination 1. U.S. population. The Agency has previousl y evaluated the human health risks associated with all registered uses of amitraz and has determined that there is reasonable certaint y that no harm to any population subgroup will result from aggregate non

occupational exposure to amitraz (see Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management (TRED) for Amitraz , July 2006 ). Dietary

exposure from the proposed tolerance of 1.0 ppm on honey and all other current tolerances meets the FQPA safet y standards. 2. Infants and children
. The Agency has concluded that sufficient toxicity data are available to a ssess human health risks and potential susceptibility to children. The EPA has retained the 10X FQPA safet y factor to account for database uncertainties (see Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk Management (TRED) for Amitraz , July 2006

). F. International Tolerances The European Union has established a MRL of 0.2 ppm for residues of amitraz in honey and New Zealand has established a provisional MRL of 0.2 ppm for residues of amitraz in honey