Document ID: EPA-HQ-OPP-2010-0051-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-03-24T04:00Z

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 (9F7673) from Veto-Pharma SA, care of Arysta LifeScience 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

	Amitraz 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 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.

	2. Analytical method. There are two adequate methods listed in FDA's Pesticide
Analytical 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 was 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 Profile

	1. Acute toxicity. On an acute basis, amitraz has moderate toxicity (Category II) by the dermal route, and it is slightly toxic (Category III) via the oral and inhalation routes of exposure. Further, it is not a skin or eye 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-dimethylphenyl)-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 lymphoma assay with metabolic activation (MRID 00161012).  

	3. Reproductive and developmental toxicity. In two 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 rabbits were dosed with
amitraz at 0, 1, 5, or 25 mg/kg/day, from gestation days 6 through 18. The NOEL for both
maternal and developmental effects was 5 mg/kg/day. The LOEL for both maternal effects (reduced body weight and increased abortions on gestation days 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 containing 0, 15, 50, or 200 ppm amitraz. The systemic toxicity NOEL was
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 F0 animals. The reproductive toxicity NOEL (15 ppm;
1.47 mg/kg/day/male and 1.69 mg/kg/day/female) was lower than the systemic NOEL. The reproductive toxicity LOEL (50 ppm; 4.84 mg/kg/day/male and 5.22 mg/kg/day/female) was also lower than the systemic LOEL and was based on reduced litter size and pup survival in all 3 generations (F1, F2, and F3), and a slight reduction in pup weights in the F1 and F2 generations. Further reproductive toxicity was observed at the high dose (most of the F1 generation rats died, and there were not enough animals left for subsequent matings). 

	4. Subchronic toxicity. In a subchronic oral toxicity study, mice were administered amitraz by gavage, at levels of 0, 3, 12, 50, or 200 mg/kg/day for 90 days. The systemic NOEL was 3 mg/kg/day. Higher doses produced reduced body weight gain and liver toxicity (increased serum glutamic pyruvate transaminase activity, increased liver weight, hepatocyte enlargement, bile duct proliferation, and focal necrosis). The systemic LOEL 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 days. The systemic NOEL was
0.25 mg/kg/day. At the LOEL (1.0 mg/kg/day) there were slight enlargement of the central and midzonal hepatocytes of the liver and slight hyperplasia of the zona glomerulosa of the adrenals. Both the LOEL and the high dose (4 mg/kg/day) produced transient CNS (central nervous system) depression, decrease in pulse rate, glucosuria, neutrophilia of the bone marrow and recurrent hypothermia 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 conjunctivitis. (MRIDs 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/carcinogenicity study.  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 systemic NOEL was 15 ppm. The systemic 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
lymphoreticular tumors in females at 400 ppm, the highest level studied. Tumors were not evident at the mid dose level of 100 ppm. The systemic NOEL was 25 ppm, due to a
reduction in body weight gain at higher doses (MRID 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 systemic 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 hyperkeratosis, spleen hematopoiesis, and liver changes (nodules, and telangietactic and basophilic foci). Hyperactive or aggressive behavior, reduced weight gain, and a reduced myeloid/erythroid ratio in bone marrow were observed at the 100 and 400 ppm levels (MRID 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 hydrolysis 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 compound 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 days in the liver, bile, kidney, adrenal glands, and pigmented areas of the eye. (MRID 00160964) 

	7. Metabolite toxicology. NA-Remove

	8. Endocrine disruption. As required by FFDCA Section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substance may have an effect produced by 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 be 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 was undertaken for purpose of determining the incremental exposure that would 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 States.  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 on single dose studies in humans.

Acute 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 Water Assessment for Tolerance Reassessment Eligibility Decision, dated February, 11 2004 and Revised Amitraz Drinking Water Assessment 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 result in residues in drinking water.  Since the only 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 result in drinking water exposure, and a drinking water assessment is not needed. 

	2. Non-dietary exposure. For a discussion of residential and post-application residential exposure see "Revisions for "Amendment to Amitraz: Revised Residential Exposure Assessment for the Reregistration Eligibility Decisions", dated July 27, 2006 and Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk 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 toxicity with other compounds and a cumulative risk assessment is not necessary.

E. Safety Determination

	1. U.S. population. The Agency has previously evaluated the human health risks associated with all registered uses of amitraz and has determined that there is reasonable certainty 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 safety standards. 

	2. Infants and children. The Agency has concluded that sufficient toxicity data are available to assess human health risks and potential susceptibility to children.  The EPA has retained the 10X FQPA safety 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