Document ID: EPA-HQ-OPP-2014-0601-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-09-05T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (1/1/2007)

EPA Registration Division contact: [BeWanda Alexander (703) 305 - 7460]

[BASF Corporation on behalf of Whitmire Micro-Gen Research Laboratories, Inc.]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from [BASF Corporation on behalf of Whitmire Micro-Gen Research Laboratories, Inc.], [3568 Tree Court Industrial Blvd., St. Louis, MO 63122-6682] proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. by establishing a tolerance for residues of
[combined residues of alpha-cypermethrin and cypermethrin (including
zeta-cypermethrin)( (S)-α-cyano-3-phenoxybenzyl (1R,3R)-3-(2,2-dichlorovinyl)-2,2-
dimethylcyclopropanecarboxylate and (R)-α-cyano-3-phenoxybenzyl (1S,3S)-3-(2,2-
dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate)] in or on food/feed items (other than those already covered by a higher tolerance as a result of use on growing crops) in food/feed handling establishments where food products are held, processed or prepared is at 0.05 parts per million.    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 is a practical analytical method for detecting and measuring levels of cypermethrin in or on food with a limit of detection that allows monitoring of food with residues at or above the levels set in these tolerances (Gas Chromatography with Electron Capture Detection or GC/ECD, HPLC-UV and LC/MS/MS methods are available).]

	
3. Magnitude of residues. [A residue study was conducted in a simulated food handling establishment using a pressurized liquid aerosol formulation of alpha-cypermethrin 0.05% to make multiple crack and crevice and spot treatments at exaggerated label rates. Testing matrix consisted of perishable, non-perishable and inert food service items. Quantitation of alpha-cypermethrin was performed using GC-ECD and HPLC-UV. Mean recoveries ranged from 75.9% to 108% of expected values. Potential residue-transfer routes were adequately addressed.  Crack and crevice and spot treatments resulted in low residues [less than the limit of quantitation (LOQ)] on non-covered food items, except for one bread sample that returned a residue measurement of 0.01 mg/kg (LOQ). Covered food items (items covered by plastic wrap and items placed in a closet cabinet) did not have measureable amounts of alpha-cypermethrin.]

B. Toxicological Profile

	1. Acute toxicity.  [Alpha-cypermethrin has low acute oral, dermal and inhalation toxicity.  The oral LD50 in rats is 2000 mg/kg bw [F], the dermal LD50 is >2000 mg/kg [M/F], and the inhalation 4-hour LC50 is >2.47 mg/L [M] and >1.07 mg/L [F].  Alpha-cypermethrin is not a skin sensitizer but is moderately irritating to the skin and had no positive effects at 48 hours for the eyes of rabbits.]

	2. Genotoxicty. [Alpha-cypermethrin was negative for inducing mutations in both in vitro Ames and an in vitro CHO/HGPRT locus mammalian cell mutation assays. Alpha-cypermethrin caused no increase in the incidence of chromatid or chromosome aberrations or polyploidy in bone marrow cells following per os in-vivo exposure to Wistar rats. Similarly, alpha-cypermethrin did not increase the frequency of chromatid gaps, chromatid breaks or total chromatid aberrations in rat liver (RL4) cell cultures. Alpha-cypermethrin did not produce any detectable DNA single-strand damage using alkaline elution profiles of
liver DNA.
	
From the all available data on alpha-cypermethrin, it can be concluded that this compound is non-mutagenic in tests with Salmonella typhimurium, Saccharomyces cerevisiae, and in-vivo and in-vitro tests with rat liver cells for the induction of chromosome aberration and production of DNA single-strand damage. Overall, the weight of the evidence demonstrates that alpha-cypermethrin is not genotoxic.]

	3. Reproductive and developmental toxicity. [The reproductive and developmental toxicity of alpha-cypermethrin was investigated in a 2-generation rat reproduction study as well as in rat and rabbit developmental toxicity studies. The test substance in these studies was either alpha-cypermethrin or zeta-cypermethrin  -  the same racemic pyrethroid mixture with similar enantiomeric composition. 

In the rat multi-generation study conducted with zeta-cypermethrin, another related pyrethroid racemic mixture, the test substance was administered via diet at levels of 0, 7.5, 25, 100, 375 or 750 ppm, equivalent to 0, 0.5, 1.8, 7, 27 or 45 mg/kg/day. Clinical signs of neurotoxicity and isolated incidences of mortality were observed in the parental animals at the top dose of 45 mg/kg/day. An increased incidence of pup mortality was also seen at 45 mg/kg/day. At 27 mg/kg/day, decreased body weight gain, especially during lactation, and increased relative brain weights were observed in male and female adult animals. Decreased body weight gain during lactation was also seen among offspring at 27 mg/kg/day. The NOAEL for parental and systemic toxicity was 100 ppm, equivalent to 7 mg/kg body weight per day. Similarly, the NOAEL for offspring toxicity was 100 ppm, equivalent to 7 mg/kg/day.

Developmental toxicity studies, via gavage exposures, were conducted in rats and rabbits with alpha-cypermethrin. In these studies, there was no evidence of teratogenicity in animals treated during the phase of organogenesis.

In rabbits (0, 3, 15 or 30 mg/kg/day via gavage in corn oil vehicle), reduced maternal food consumption and body weights were observed at 30 mg/kg/day; no treatment related effects on fetal weights were observed. The NOAEL for maternal toxicity and embryotoxicity was 15 mg/kg/day and 30 mg/kg/day, respectively. There were no indications for teratogenicity.

Administration of alpha-cypermthrin via gavage at 0, 3, 9, or 18 mg/kg/day to pregnant rats during fetal organogenesis (gestational days 6-15) elicited maternal toxicity at the two top doses, characterized by changes in clinical conditions and reduction in food consumption and body weight gain. Due to marked clinical signs of toxicity the dose level of 18 mg/kg/ day was lowered to 15 mg/kg/day on day 10 of gestation. Females at 18 or 15 mg/kg/day showed unsteady gait, piloerection, and other signs of maternal toxicity. Slight body weight reductions were also seen in the females at 9 mg/kg/day. A slight reduction in fetal weights was observed at these dose levels (9, 15/18 mg/kg/day) in concert with maternal toxicity. There was no indication for teratogenicity. The NOAEL for maternal and fetal toxicity was 9 mg/kg/day.

In the rat developmental toxicity study, the maternal and developmental NOAEL was 9 mg/kg/day.  For rabbits, the NOAEL for systemic toxicity was 15 mg/kg/day, and the NOAEL for developmental toxicity was mg/kg/day, the highest dose tested.]

	4. Subchronic toxicity. [A similar toxicity profile was observed across rats, mice and dogs following subchronic exposure to alpha-cypermethrin. These profiles are mostly related to the mode of action of alpha-cypermethrin and include effects on the neuromuscular system. Typical indicator effects for this mode of action were observed and included tremors, gait abnormalities, decreased motor activity and increased salivation. Surviving animals recovered within 3 -7 days. The short term and reversible nature of these neurotoxic effects is in line with studies showing that type II pyrethroids such as alpha-cypermethrin can cause exaggerated pharmacological effects at high dose levels that do not result in histopathologic lesions on nervous system tissues.

In rats, clinical signs characteristic for pyrethroid neurotoxicity were observed in short-term toxicity studies (4-6 weeks) at >=800 ppm. Clinical signs were more pronounced in males and included high stepping, splayed gait, abasia and hypersensitivity. Further observed effects comprised decreased food intake and body weights, and some hematological findings at >=400 ppm. The NOEL was 200 ppm, equivalent to 10 mg/kg/day. After dietary administration at 540 ppm for 90 days, abnormal gait with splayed hind limbs in male rats and decreased food intake and body weights were observed. No other treatment-related effects occurred during the course of this study. The NOEL was 60 ppm, equivalent to 3 mg/kg/day.

In mice, clinical signs of toxicity including abnormal gait were also observed after dietary administration of alpha-cypermethrin at >=800 ppm for 4 weeks. The death of two animals and neurological signs of toxicity were associated with administration of alpha-cypermethrin at 1200 or 1600 ppm. The NOEL was 400 ppm, equivalent to 57 mg/kg/day. In a 90-day dietary exposure toxicity study in mice, un-groomed coat, hair loss and encrustations on the dorsal surface, reduced body weights, and increased aspartate aminotransferase activity were observed at 250 ppm. The NOEL was <50 ppm, equivalent to <7.1 mg/kg/day, based on hair loss seen at the lowest dose tested.

In dogs, clinical signs including body tremors, head nodding, ataxia, agitation, lip licking, subdued behavior and high stepping gait were observed at the top dose level (270 ppm) of a 90-day dietary toxicity study. No other treatment-related effects were observed after administration of alpha-cypermethrin to dogs. The NOEL was 90 ppm, equivalent to 2.25 mg/kg/day.]

	5. Chronic toxicity. [The results of long-term oral exposure studies indicate that alpha-cypermethrin is not carcinogenic in mice or rats. At high doses in long term oral exposure studies with rats, mice and dogs, observations demonstrate evidence of slight neurologic signs and decreased body weight gains. This is consistent with the mechanism of action of alpha-cypermethrin on the peripheral and central nervous system, through interactions with sodium channels. The NOAEL in the mouse oncogenicity study was 30 ppm, equivalent to 3 mg/kg body weight/day in males and 3.5 mg/kg body weight/day in females. In the rat chronic/oncogenicity study, the NOAEL was 100 ppm, equivalent to 5 mg/kg body weight/day in males and females. In a chronic (1-year) dog study, the NOAEL was 60 ppm, equivalent to 2 mg/kg/day in males and 2.2 mg/kg/day in females.]

	6. Animal metabolism. [The metabolism of cypermethrin in animals is adequately understood. Cypermethrin is rapidly absorbed, distributed, and excreted in rats when administered orally. Biotransformation is principally governed by hydrolytic and oxidation reactions.]

	7. Metabolite toxicology. [No metabolites of toxicological concern were identified with alpha-cypermethrin.]

	
8. Endocrine disruption. [No specific tests have been conducted with alpha-cypermethrin to determine whether the chemical may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen or other endocrine effects. However, there were no significant findings in other relevant toxicity studies (e.g., sub-chronic and chronic toxicity, developmental toxicity and multi-generation reproductive studies) which would suggest that alpha-cypermethrin produces any endocrine disruption.]

C. Aggregate Exposure

	1. Dietary exposure. [The acute and chronic dietary exposure assessment for alpha-cypermethrin was determined with the Dietary Exposure Evaluation Model software with Food Commodity Intake Database (DEEM-FCID(TM)), version 2.16, from Exponent, Inc.  The analysis included established tolerances for alpha-cypermethrin and the proposed food/feed handling establishments tolerances. Both the acute and chronic exposure estimates are within the EPA's level of concern; therefore, the aggregate acute and chronic dietary exposure of alpha-cypermethrin, including the contribution of drinking water, meets the standard of reasonable certainty of no harm. ]

      i. Food. [The aPAD for cypermethrin is based on a
NOAEL of 10 mg/kg bw/day with a 100x uncertainty factor and a 1x FQPA SF to give a aPAD of 0.1 mg/kg bw/day. The aPAD for alpha-cypermethrin is based on a NOAEL of 4 mg/kg bw/day with a 100x uncertainty factor and a 1x FQPA SF to
give a aPAD of 0.04 mg/kg bw/day. The results of dietary expousre analysis show that the estimated food exposures are well below the Agency's level of concern (< 100% aPAD).]

	ii. Drinking water. [Alpha-cypermethrin registration cites all the environmental fate studies done for the registration of zeta-cypermethrin and cypermethrin. Therefore, the drinking water assessment conducted for the zeta-cypermethrin assessment is used for this alpha-cypermethrin exposure assessment. The results of drinking water analysis show that the estimated exposures are well below the Agency's level of concern. 

	2. Non-dietary exposure. [There are no levels of concern which are exceeded from the residential uses.]

D. Cumulative Effects

	[Alpha-cypermethrin is a member of the pyrethroid class of pesticides. Although all pyrethroids alter nerve function by modifying the normal biochemistry and physiology of nerve membrane sodium channels, EPA is not currently following a cumulative risk approach based on a common mechanism of toxicity for the
pyrethroids.

E. Safety Determination

	1. U.S. population. [BASF concludes that there is a reasonable certainty that no harm will result to the general population from the aggregate exposure to alpha-cypermethrin from the proposed uses.]

	2. Infants and children. [BASF concludes that there is a reasonable certainty that no harm will result to infants or children from the aggregate exposure to Alpha-cypermethrin from the proposed uses.]

F. International Tolerances

	[There are CODEX maximum residue levels established for cypermethrin
residues in many different crop and crop groups. JMPR considered the residue
trials for alpha-cypermethrin, zeta-cypermethrin and cypermethrin collectively.
Codex maximum residue levels have been established in the following crops:

Leafy vegetables
  0.7
 Edible offal, mammalian
    0.05
Pome fruits
  0.7
 Meat, from mammals
    2.0
Stone fruits
  2.0
 Poultry meat
    0.05
Roots and tubers
  0.01
 Eggs
    0.01
Fruiting vegetables, cucurbits
  0.07
 Milks
    0.05
Legume vegetables
  0.7
 Milk fats
    0.5
Pulses
  0.05

Dry bean
  0.05

Brassica
  1.0

Leafy vegetables
  0.7

Citrus fruits
  2.0

Cereal grains
  0.3

Corn, sweet
  0.05

Oilseed
  0.1

Eggplant
  0.03

Okra
  0.5

Onion bulb
  0.01

Bell pepper
  0.1

Non-bell pepper
  2.0

Pimentos
  0.1

Sugar beet
  0.1

Sugar cane
  0.2

Tomato
  0.2]