EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Kevin Sweeney, telephone: 703

- 305

- 5063
McLaughlin Gormley King Company
to be assigned

EPA has received a pesticide petition ( number to be assigned ) from McLaughlin Gormley King Company
, 8810 Tenth Avenue North Minneapolis, MN 55427 request ing, 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

1. by amending a n existing tolerance
MGK is requesting that EPA amend 40 CFR Sec. 180.545 to read:
(a) (1) A tolerance of 1.0 ppm is established for residues of the insecticide prallethrin, including its metabolites and degradates, in or on all raw agricultural commodities and processed food from use of prallethrin in food handling establishments where food and food products are held, processed, prepared and/or served, or as a wide

- area mosquito adulticide. Compliance with the tolerance level specified is to be determined by measuring only prallethrin, (RS)

- 2

- methyl

4

- oxo

- 3

- (2

- propynyl)cyclopent

- 2

- enyl(1RS)

- cis,trans

- chrysanthemate.
A. Residue Chemistry

1. Plant metabolism. Not applicable.

2. Analytical method. An LC/MS/MS analytical method was developed and validated for prallethrin in Grass, Alfalfa, and Leaf Lettuce with an Limit of Quantitation (LOQ) of 10 ppb of and an Limit of Detection (LOD) of 3 ppb. Samples were frozen, homogenized, and extracted with solvent, filtered, and injected onto an LC/MS/MS at the appropriate dilutions to fall within the calibration range of the standards. The me thod is included in Appendix 4 of the report, “Magnitude of the Residue of MULTICIDE® Fogging Concentrate 2798 in Grass, Alfalfa Forage , and Leaf L ettuce Raw Agricultural2

Commodities Following Mosquito Control Aerial Treatment”, submitted concurrently with this petition

. 3. Magnitude of residues. Detailed residue data are found in the report “Magnitude of the Residue of MULTICIDE® Fogging Concentrate 2798 in Grass, Alfalfa, and Leaf Lettuce Raw Agricultural Commodities Following Mosquito Control Aerial Treatment”, submitted concurrently with this petition. The maximum application rate was applied as an adulticide over alfalfa (1x), and no detectable residues were observed. Therefore, ten times the maximum application rate was applied over alfalfa, leaf lettuce, and sudan grass (10x). In these trials, few quantifiable residues above the Limit of Quantitation of 0.010 ppb were found. Analy sis was take n down to the Limit of Detection of 0.003ppb, and still few detectable residues were observed

.
B. Toxicological Profile

1. Acute toxicity. i. The acute oral toxicity of prallethrin gave LD 50 values for male rats of 640 mg/kg and for female rats of 460 mg/kg. (MRID# 413218

- 11)
ii. An acute dermal toxicity study with rats obtained LD 50 values for males and female rats of > 5, 000 mg/kg. (MRID# 413218

- 12)
iii. An acute (4

- hour) inhalation toxicity study of prallethrin in the rat via whole

- body exposure determined that the analytical exposure concentration was 2.1 mg/L (in air) with particle size distribution mass medium aerodynamic diameter of 0.83

– 3.21 μm at 152 mg/m 3 and above. The inhalation LC 50 in rats was: Male 288 mg/m 3 = 0.288 mg/liter 3 Female 333 mg/m 3 = 0.333 mg/liter 3 (MRID# 413218

- 13)
iv. The primary eye irritation study of prallethrin with rabbits showed slight conjunctival redness in all six rabbits, accompanied by slight chemosis in five rabbits one hour after ap plication of 0.1 mL in eyes. Both effects decreased by 24 hours, and were gone by 48 hours. (MRID# 413218

- 14)
v. No skin reactions such as erythema and edema were observed in either abraded or intact sites of any of six rabbits during the observation p eriod of the primary skin irritation study of prallethrin. Prallethrin is non

- irritating. (MRID# 413218

- 14)
vi. In the skin sensitization study (maximization method) no reaction was observed in the skin of male guinea pigs challenged to undiluted prall ethrin. Classified not a sensitizer (MRID# 413218

- 15)
vii. An acute neurotoxicity study on rats was conducted with prallethrin. Functional observation battery (FOB) and motor activity (MA) tests were conducted with the test3

animals two days before oral dosing with S

- 4068SF. Two hours after dosing (the anticipated peak effect time), and on Study Days 7 and 14, these same tests were repeated. Animals were weighed and their food consumption measured during the study, and examined twice daily. The results showed that the NOAEL was 100 mg/kg, and the LOAEL 300 mg/kg. (MRID# 433433

- 01)

2. Genotoxic i ty. i Prallethrin was negative for forward gene mutation in Chinese hamster lung cell assay, with and without activation. (MRID# 413218

- 23)

ii. Prallethrin induced no unscheduled DNA synthesis in rat hepatocytes. (MRID# 420309

- 12) iii. Prallethrin was not mutagenic in Salmonella typhimurium or E. coli reverse gene mutation assays. (MRID# 413218

- 22)

3. Reproductive and developmental toxicity.

i. In a ra t teratology study with female SD rats, various doses of prallethrin were injected subcutaneously on gestation days 7

- 17. No maternal deaths occurred in this study. Exaggerated reflexes, transient tremor, and slight depression of bo dy weight were observe d in the 50 mg/kg/day group. Therefore, the maternal LOEL was established at 50 mg/kg/day, and the maternal N OEL was established at 25 mg/kg/day. The fetuses were removed by cesarean section in late pregnancy in two thirds of each dosage group, and the remainder of the dams’ pups were delivered spontaneously. Among dams allowed to deliver spontaneously, no adverse effects were reported for the dams. Fetuses and delivered pups were evaluated, and the occurrence of lumbar rib variants was signifi cantly higher than the controls in the offspring of the 50 mg/kg/day group , but this result is within the normal range of historical control data from the laboratory

. The developmental and offspring NO ELs are 50 mg/kg/day. (MRID# 413218

- 20)

ii. In a de velopmental toxicity study with SD rats, various doses of prallethrin were administered daily by oral gavage on gestation days 6

- 15. Maternal toxicity was noted as mortality at the highest dose of 300 mg/kg/day, and weight loss and clinical observations of tremors, excess salivation, and chromorrhinorrhea that were noted prior to death, and also in the 100 and 30 mg/kg/day dose groups. Necropsies revealed lesions in the gastric fundus and in the brain in 5/8 of the rabbits that died. There were no
trea tment related effects or toxicity noted in development of the fetuses. The maternal NOEL and LOEL were determined to be 10 and 30 mg/kg/day, respectively. There was no developmental toxicity observed in the fetuses in this study, so the developmental
to xicity NOEL was determined to be >300 mg/kg/day (the highest administered dose). (MRID# 420770

- 05)4

iii. In a two generation reproduction study with Crl:COBS R CD (SD) male and female rats, various doses of prallethrin were fed in the diet to all generation s of the rats. Compound related effects were observed in the 3,000 and 6,000 ppm groups in both sexes and generations: i.e. decreased body weight and body weight gains, significantly increased absolute and relative liver weights; histopathological findi ngs in the liver, kidney, thyroid, and/or pituitary. Therefore, the parental toxicity NOEL was determined to be 600 ppm (approximately 171 mg/kg/day) and the parental toxicity LOEL established at 3,000 ppm (approximately 352 mg/kg/day).
Compound related e ffects were noted in the 3,000 and 6,000 ppm reproductive groups: i.e.. the pups had significantly decreased body weights during the latter half of the lactation period in both generations. Therefore, the reproductive toxicity NOEL was 600 ppm (approxima tely 171 mg/kg/day) and the reproductive toxicity LOEL was 3,000 ppm (approximately 352 mg/kg/day). (MRID# 420770

- 06)

4. Subchronic toxicity.
i. Rats were exposed to prallethrin for 28 consecutive days (four hours per day) in an inhalation aerosol st udy. Decreased spontaneous activity, increased evidence and severity of irregular respiration, and nose discharge were found at the mid and high doses, accompanied by salivation, urinary incontinence and elevated urinary pH. Decreases in body weight gain were observed in high dose males, although there was no change in food or water consumption. The NOAEL was 1.01 mg/m 3 and the LOAEL was 4.39 mg/m 3 . (MRID# 420309

- 07)

ii. In a subchronic 21

- day dermal study, prallethrin was topically applied to the skin of rats. There were no deaths observed during the treatment period. Clinical signs were observed in animals receiving 150 or 750 mg/kg day during the 6 hour treatment period and shortly after removal of the bandages; fixation (prolonged gaze with f ixed posture), increased activity, tremors and pawing. The systemic NOEL was determined to be 30 mg/kg/day; the dermal LOEL was determined to be 30 mg/kg/day. (MRID# 429991

- 01)
iii. Dogs were given prallethrin orally by capsule for 90 days. Tremor, con vulsions, ataxic gait, salivation, tachypnea, tachycardia, high body temperature and sedation, and three of the females died at 30 mg/kg. Slight tremors were noted at 10 mg/kg. Decreases in body weight, food consumption and water intake were observed at 30 mg/kg. One male at 30 mg/kg showed a marked decrease in platelet count, slight prolongation of activated partial thromboplastin time, and marked elevation of GOT, LDH, CPK, GPT and alkaline phosphatase. The NOAEL was determined to be 3 mg/kg/day and the LOAEL determined to be 10 mg/ kg/day. (MRID# 420770

- 01)

iv. A thirteen

- week feeding of male and female Crj:CD (SD) rats with diet containing5

p rallethrin revealed a decrease in body weight gain in the 1,000 ppm and 3,000 ppm groups. Slight transient alopecia was observed on some high dose animals. At the above 1,000 ppm, increased liver weight due to hepatocellular hypertrophy and increased kidney weights were observed. Increased thyroid weight with follicular proliferation was found in the 3,000 p pm group. The NOAEL was adjusted by EPA to 1000 ppm, and the LOAEL to 3000 ppm. (MRID # 420309

- 06)
v. A thirteen week dietary toxicity study in which male and female CD

- 1 mice were fed diet containing prallethrin revealed increased liver weights in both sexes, accompanied by microscopic hepatocyte enlargement, and an increase in serum cholesterol and creatinine levels. Kidney to body weight ratios were increased in both sexes. A decrease in mean body weight and weight gain was observed in males but not females, and alanine and aspartic aminotransferase activities were increased in males. The LOEL was considered to be 6000 ppm (808 mg/.kg/day for males and 890 mg/kg/day for females), and the NOEL was 3000 ppm, equivalent to an intake of 374 or 444 mg/k g/day (males and females, respectively). (MRID # 420770

- 04)

5. Chronic toxicity.

i. In a chronic 52

- week oral feeding study with male and female dogs, the NOEL for systemic toxicity was determined to be 5 mg/kg/day of prallethrin on the basis of
treatm ent

- related histomorphologic changes to the urinary bladder, increases in cholesterol and phospholipid levels and alkaline phosphatase activity, and clinical signs such as trembling, rapid eye blinking, hunched posture, and panting in the dogs receiving 10 or 20 mg/kg/day. Therefore, the LOEL was determined to be 10 mg/kg/day. (MRID# 420770

- 02)
ii. In an 82 week oral feeding study with male and female CD

- 1 mice, the systemic NOEL was determined to be 600 ppm (equivalent to 68 mg/kg/day for males & 78 mg/kg/day for females) on the basis of increased kidney and liver weights in both sexes. Weight gain was depressed in the male mice receiving the higher dose levels, but no effects in weight gains were observed in the female groups. No oncogenic effects w ere observed in any male or female mice. (MRID# 420770

- 03)
iii. The NOEL in a combined oncogenicity and toxicity study with male and female rats was 19 mg/kg/day in diet on the basis of effects on liver weight gain in both sexes of the higher dose treatme nts, and body weight gain in female rats at 103 mg/kg/day. Therefore, the LOEL is 103 mg/kg/day. There was no evidence of an oncogenic response in males or females. (MRID# 420614

- 01)

6. Animal metabolism.
i. After either single or repeated oral doses of either 2 or 100 mg/kg of 14 C labeled (1R,6

trans )

- or (1R, cis )

- isomers of prallethrin were administered to male and female rats, nearly all of the radiocarbon was eliminated in the feces and urine within 4 8 hours. 14 C concentrations in tissues of the organs of excretion; mainly liver and kidneys, were slightly higher than in other tissues. The major metabolic reactions for both isomers appear to be ester cleavage, followed by conjugation. The major route of elimination for the labelled cis isomer was the feces. Approximately half of the labelled trans isomer was excreted in the urine; slightly less than half in the feces. There were a few differences between sexes in the amount of 14 C in excreta, tissue s, or in amounts and identity of metabolites in excreta for the single dose group and a repeated dose group of rats over 14 successive days. (MRID# 420309

- 13)

ii. The metabolism of radiolabelled 14 C cis and trans isomers of prallethrin was studied in male and female rats given either a single oral dose of 2.0 mg/kg or a single subcutaneous dose of 2.0 mg/kg of the labelled isomers. Each isomer was readily absorbed, metabolized and excreted in the urine and feces. Total recovery was made of the doses of b oth isomers administered both ways. The method of dosing resulted in no differences n absorption, distribution, metabolism, or excretion. Excretion of the cis isomer after both routes of administration seven days after dosing was mostly through the feces , rather than the urine. Excretion of the trans isomer by both routes of administration was mostly through the urine, with feces being the minor path. The trans isomer is more readily cleaved, making excretion by urine more abundant, and female rats excr eted greater amounts of radioactivity in their urine than the male rats in all groups. The isomers do not persist in tissues, demonstrated by the low detection of radioactivity in the rat tissues. The major metabolic reactions that produce metabolites are oxidation at different sites of the acid and alcohol moieties, cleavage of the ester linkage, and conjugation with glucuronic and sulfuric acids.

7. Metabolite toxicology

. N/A

8. Endocrine disruption

. i

. Eight pyrethroids, including prallethrin, were tested in a transient reporter gene assay. Bisphenol A, o,p

- DDT, p

- nonylphenol and estradiol show estrogenic activity while 4

- OH

- tamoxifen inhibits estrogenic activity. The pyrethroids showed no greater indu ction of estrogenic activity than did the controls. The four positive controls showed significantly increased induction of estrogenic activity. The pyrethroids, and estradiol, all exhibited negligible inhibition whereas tamoxifen showed significant inhib ition. [ Saito, K., et al (2000). Toxicological Sciences 57, pp. 54

- 60].
ii. Eight pyrethroids, including prallethrin, and the same positive controls that were tested in the preceding assay were evaluated in a yeast two

- hybrid assay, using galactosidase as the reporter and a recombinant yeast to express the coactivator and the7

receptor. The pyrethroi ds produced no significant induction of endocrine function, while significant induction was noted for all the positive controls. The pyrethroids showed little or no inhibition of endocrine function, while significant inhibition occurred with 4

- OH

- tamoxife n. Saito, K. et al (2000). Toxicological Sciences 57, pp. 54

- 60

iii. In both the November 21, 2003 Prallethrin: Human Health Risk Assessment for the Public Health Use of Mosqui to Adulticides Containing Prallethrin (DP Barcode D2893 35) and the June 27, 2003 Prallethrin

- 2 nd Report of the Hazard Identification Assessment Review Committee (TXR No. 0051993) , EPA concludes that there are no uncertainties or concerns for pre

- and postnatal toxicity from the use of prallethrin in wide area mosquito adulticide treatment spray.

C. Aggregate Exposure

1. Dietary exposure.

E PA has already conducted a Human Health Risk Assessment for the Public Health Use of Mosquito Adulticides Containing Prallethrin (DP Barcode : D289355 ) in a report dated November 21, 20 03 . Any residues on crops from mosquito adulticide treatments will be negligible; indeed in the magnitude of the residues trials, aerial adu lticide application of Multicide Fogging Concentrate 2798 at ten times the maximum application rate over alfalfa, leaf lettuce, and sudan grass (10x) produced few quantifiable residues above the Limit of Quantitation of 0.010 ppb. Analysis was taken down to the Limit of Detection of 0.003ppb, and still few detectable residues were observed , There will be no increased residues of prallethrin in any dietary food allowed in the existing tolerance, so there is no need to increase the current allowed residues of 1.0 ppm of prallethrin

. The labels for the two end use products being registered for this use call for low application rates, and establish maximum applications of active ingredient per acre and per year.

i. Food.
In the risk assessment noted above, dietary exposures were estimated from the registered food handling use, that were provided in the Human Health Risk Assessment for the Use of Prallethrin in Food Handling Establishments, ( P. Hurley, D239112, 03/08/2000). Dietary exposure was estimated to be greatest for children ages 1

- 6 years old. Acute exposure was estimated to be 0.044305 mg/kg/day, or 89% of the acute population

– adjusted dose. Chronic exposure was estimated to be 0.002152 m g/kg/day, or 4.3% chroni c population

- adjusted dose.

ii. Drinking water

.8

In the risk assessment noted above, EPA calculated drinking water levels of comparison (DWLOC) using conservative assumptions , and compared them to modeled estimates of a pesticide concentration in water (EEC)

. At this time, EPA concluded that the DWLOC are more than the modeled EECs, so there should not be unacceptable levels of aggregate human health risk with the mosquito control use

. 2. Non

- dietary exposure

.
Non

- dietary e xposure to prallethrin is unlikely to occur from this use because of the very low to non

- detected residues that result from the mosquito adulticiding use.
D. Cumulative Effects
Prallethrin is a Type I pyrethroid

. EPA completed the Pyrethrins/Pyrethroid Cumulative Risk Assessment on October 4, 2011 (DP Barcode D394576; Decision # 455436)

. This screening

- level cumulative risk assessment is highly conservative, overestimating actual risk. That is, the assessment assumes that people are exposed to the highest levels of residues in food, water, and in their homes, all on the same day. Even with these conservative and protective assumptions, the assessment shows that cumulative risks for both children and adults are not of concern for the currently registered uses of pyrethrins/pyreth roid pesticides. Further, the assessment shows that there is sufficient room in the pyrethroid cumulative risk cup to support consideration of additional individual pyrethroid pesticide uses.
E. Safety Determination

1. U.S. population. As noted in EPA’s 2011 EPA ’s Pyrethrins/Pyrethroid Cumulative Risk Assessment , the cumulative risks for both children and adults are not of concern for the currently registered uses of pyrethrins/pyrethroid pesticides. Further, the assessment shows that there is sufficient room in the pyrethroid cumulative risk cup to support consideration of additional individual pyrethroid pesticide uses.

2. Infants and children

. As noted in EPA’s 2011 EPA’s Pyrethrins/Pyrethroid Cumulative Risk Assessment, the cumulative risks for both children and adults are not of concern for the currently registered uses of pyrethrins/pyrethroid pesticides. Further, the assessment shows that there is sufficient room in th e pyrethroid cumulative risk cup to support consideration of additional individual pyrethroid pesticide uses.

F. International Tolerances
There are no international tolerances for prallethrin

.