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

EPA Registration Division contact: PV Shah, 703-308-1846

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

Nichino America, Inc. 

IN-10541

	EPA has received a pesticide petition (IN-10541) from Nichino America, Inc., 4550 New Linden Hill Road, Suite 501, Wilmington DE 19808 c/o Wagner Regulatory Associates, 7217 Lancaster Pike, Suite A, Hockessin, DE 19707  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 180.1130 for the inert ingredient N-(n-octyl)-2-pyrrolidone to include use in formulations containing pyraflufen ethyl active ingredient.  EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of  FFDCA; 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

Because an exemption from the requirement of a tolerance is requested, no field residue studies are required.

	1. Plant metabolism. "NA-Remove"

	2. Analytical method. "NA-Remove"
 
	3. Magnitude of residues. "NA-Remove"
 
B. Toxicological Profile

	1. Acute toxicity.  
i. Acute oral toxicity --  The acute oral LD50 for N- (n-octyl)-2-pyrrolidone in the Wistar-strain albino rats was determined to be 2050 milligrams per kilogram of bodyweight.

ii. Primary ocular irritation --  N-(n-octyl)-2- pyrrolidone was tested in New Zealand white rabbits where each animal received a single intra-ocular application of 0.1 milliliter of undiluted test substance.  Additional animals received a single application of a 2% aqueous suspension of test substance.  In both assays, the eyes of six animals remained unwashed for 24 hours while the eyes of the remaining three animals were washed 30 seconds after instillation of the test materials. Observations of ocular irritation were recorded 24, 48, and 72 hours following instillation of test materials. Additional readings were made at 4, 7, 14, and 21 days.  The eyes were scored for corneal opacity, iritis, conjunctivitis and other effects. N-(n-octyl)-2- pyrrolidone was found to be extremely irritating however with wash procedures the severity of the observed irritation was reduced. A 2% aqueous suspension was nonirritating both with and without washout procedures. 

iii. Primary dermal irritation -- N-(n-octyl)-2- pyrrolidone was tested on the clipped and abraded skin of six New Zealand white rabbits where each received a single application of 0.5 milliliter of undiluted test substance. In a second assay, an additional six rabbits received single applications of a 2% aqueous suspension of N-(n-octyl)-2- pyrrolidone. In both assays, the wrapping and test substance were removed at 24 hours and the sites scored at 24 and 72 hours for erythema and edema using the Draize scale.  The mean scores at 24 and 72 hours were averaged to yield a primary irritation index of 7.45 for undiluted test substance and 0.50 when tested as a 2% aqueous suspension indicating the undiluted test substance to be extremely irritating to rabbit skin, and minimally irritating as a 2% suspension.  

iv. Acute dermal toxicity --  The acute dermal single dose LD50 for N-(n-octyl)-2-pyrrolidone when tested undiluted in New Zealand white rabbits was determined to be greater than 2000 milligrams per kilogram of bodyweight.  

v. Guinea pig sensitization study --  N-(n- octyl)-2-pyrrolidone was tested for potential dermal sensitization in the albino guinea pig.  In the induction phase twenty animals received intradermal injections of 0.05% v/v N-(n-octyl)-2- pyrrolidone in both water and in Freund's complete adjuvant (FCA) as well as FCA in water alone. One week after the injections, the same interscapular area was covered occlusively for 48 hours with a patch saturated with N-(n-octyl)-2-pyrrolidone 30% v/v in distilled water. During this induction phase, 10 control animals were treated similarly with the exception that the test material was omitted from the injections and topical applications. Two weeks after the induction period, both the test and control animals were challenged topically using a patch saturated in 0.2 mL N-(n-octyl)-2-pyrrolidone, 10% v/v in distilled water applied to an anterior site on the flank and N-(n-octyl)-2- pyrrolidone, 5% v/v in distilled water applied in a similar manner to a posterior site.  The patches were sealed to the flank and covered for 24 hours. The challenge sites were evaluated at 24, 48, and 72 hours after patch removal. In this study there was evidence of delayed contact hypersensitivity in 2 of the 20 test animals.

	2. Genotoxicty. 

i. Ames Salmonella/microsome reverse  mutation assay --  N-(n-octyl)-2-pyrrolidone was tested, in the Ames  assay with Salmonella typhimurium tester strains TA 1535,  TA 1537,  TA 1538,  TA 98, and  TA 100. Tests were conducted in all 5 strains both with and without metabolic activation (induced S - 9 rat liver preparation). The entire assay was performed twice. No mutagenic activity was demonstrated by N-(n-octyl)-2- pyrrolidone when tested in the Ames assay.  

ii. Mouse micronucleus test --  N-(n-octyl)-2- pyrrolidone was found to be non-mutagenic at a dose  level  of 1,720  mg/ kg in this  in vivo  cytogenetic test.  Mice were administered N-(n-octyl)-2- pyrrolidone by intragastric gavage at a dose level of 1,720 mg/kg, based on results of a preliminary toxicity test. Controls were dosed in the same manner. Bone marrow smears were obtained at 24, 48, and  72 hours post-dosing and  examined for the presence of micronuclei in polychromatic and normochromatic erythrocytes. The ratio of polychromatic to normochromatic erythrocytes (P/N ratio) was also assessed. At sampling times mice treated with N-(n- octyl)-2-pyrrolidone showed no significant increase in frequency of micronucleated polychromatic erythrocytes, nor was there a significant decrease in P/N ratio at any of the sampling times.

iii. Mouse lymphoma mutagenesis assay. The results of this  assay  indicate that  N-(n-octyl)-2-pyrrolidone produced a negative response in cultures treated in either the absence of exogenous activation or the presence of Aroclor- induced rat liver  S - 9 mix.  In this  assay, N-(n-octyl)-2-pyrrolidone was tested for its potential to induce mutations at the thymidine Kinase locus of L5128Y TK+/-mouse lymphoma cells  both  in the presence and  absence of exogenous metabolic activation. Based on the results of a range finding test the test article was tested in the assay at doses ranging 0.005 to 100 uL/mL which produced varying degrees of reduction in cell growth.

	3. Reproductive and developmental toxicity. 

N-(n-octyl)-2-pyrrolidone was administered orally by gavage,  once daily, to pregnant female Wistar rats from day 6 through day 15 post  coitum, at dosages of 50, 200, or 800 mg/kg  bwt/ day in order to assess the effects  on embryonic and  fetal development. At 800 mg/kg/day, 1 dam died after the 7th and 1 after the 10th test article administration. The females of this group had marked clinical signs of reaction to treatment, reduced food consumption, slight body weight loss during the first day of dosing and reduced corrected body weight gain. The mean fetal body weight was reduced at this dosage, combined with a delay of skeletal ossification. At 50 mg/kg/day, no effects of treatment with the test article on maternal or fetal parameters were evident. Based on the results of this study, the no observed adverse effect level (NOAEL) for the maternal and fetal parameters was considered to be 50 mg/kg  bwt/day and the lowest observed adverse affect level (LOAEL) for developmental effects considered to be 800 mg/kg bwt/day.  

	4. Subchronic toxicity. 

i. 28 - Day oral toxicity --  In a 28 - day oral toxicity study in rats, the no-effect level of N-(n-octyl)-2-pyrrolidone was determined to be 55 mg/kg/day. At 320 mg/kg/day specific changes in general health, body weight gain, hematological and biochemical parameters were recorded. N-(n-octyl)-2-pyrrolidone, formulated as a solution in corn  oil, was administered to rats (5 males, 5 females per dosage level)  by intragastric intubation at dosage levels of 5, 55, or 320 mg/kg/day. Treatment was carried out once daily for 28 consecutive days. Similarly, control animals received corn oil (5 mL/kg/day). Statistically significant observations noted at the high dose level of 320 mg/kg day included: Lower body weight gains in females (week 3); lower packed cell volume (PCV) and red blood cell counts in males, corpuscular hemoglobin concentration (MCHC) in males; and higher glutamic-pyruvic transaminase levels in females. In all other respects including food consumption, organ weights, macroscopic and microscopic pathology, no changes were noted that were considered to be treatment-related.

ii. 90 - Day oral toxicity in dogs.  In a 90 - day oral toxicity study in dogs, a dose level of 30 mg/kg/day was determined to be the NOAEL. N-(n- octyl)-2-pyrrolidone was administered orally via capsule at dosage levels of 30, 90, and 240 mg/kg/day. All animals were observed daily for clinical signs of toxicity. After treatment, all surviving animals were subjected to complete necropsy with histological examination. Dose related neurological signs and body weight loss were observed at 90 and 240 mg/kg/day levels. Also at 90 and 240 mg/kg/day, changes in clinical pathological parameters were observed and were dose-related. In addition, dose-related increases in both absolute and relative liver weights were observed in all groups but was significant in only 90 and 240 mg/kg/day groups. One female death occurred on day 42 in the 240 mg/kg/day group.

iii. 90 - Day dietary toxicity in rats.
Based on the results of a 90 - day feeding study in rats, 600 parts per million (ppm) was considered a NOAEL following dietary administration of N-(n-octyl)-2-pyrrolidone for 90 days.  N- (n-octyl)-2-pyrrolidone was administered orally via diet to rats at dosage levels of 60, 600, and 10,000 ppm. All animals were observed daily for clinical signs of toxicity. After treatment, all surviving animals were subjected to complete necropsy with histological examination. Reduced weight gain, increased absolute and relative liver weights and mild hepatocyte hypertrophy were observed at 10,000 ppm. No treatment-related effects were observed at 60 and 600 ppm.


	5. Chronic toxicity. 

An oncogenicity study on N-methyl pyrrolidone, a structurally related compound, was judged negative by reviewers in the EPA Office of Pollution Prevention and Toxics as noted in the Federal Register Volume 59, Number 119, Wednesday, June 22, 1994.


	6. Animal metabolism. [No data is available]


	7. Metabolite toxicology. [No data is available]

	8. Endocrine disruption. N-(n-octyl)-2-pyrrolidone is not included in the EPA initial list of chemicals to be screened for potential effects on the endocrine system (Tier I testing).

C. Aggregate Exposure 

In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, EPA considers both the route and duration of exposure.  For aggregate exposure this petition uses the conservative assumption that crop residue levels for pyraflufen ethyl can be used as a surrogate for N-(n-octyl)-2-pyrrolidone residue levels when this inert ingredient is used in a mixture with pyraflufen ethyl.  For pyraflufen-ethyl, potential exposures from food, drinking water, and residential scenarios were aggregated by EPA in 2011 and are now applied to N-(n-octyl)-2-pyrrolidone based on the surrogate assumption previously noted.

Short-term aggregate risk is based on residential handler exposure, children's incidental oral exposure (from residential post-application treatment) and dietary exposure (food and drinking water).  The anticipated exposure level for pyraflufen ethyl and by default for N-(n-octyl)-2-pyrrolidone compared to the N-(n-octyl)-2-pyrrolidone developmental NOAEL of 50 mg/kg/day indicates that the MOE for children 1-2 years old (the highest exposed population subgroup) is below EPA's level of concern.

The EPA estimated aggregate (food + water + residential) exposure to adults and children from pyraflufen-ethyl residues and by default to N-(n-octyl)-2-pyrrolidone compared to N-(n-octyl)-2-pyrrolidone developmental NOAEL of 50 mg/kg/day indicates that the MOE for children 1-2 years old (the highest exposed population subgroup) is below EPA's level of concern.

	1. Dietary exposure. 

The dietary exposure estimate uses the conservative assumption that crop residue levels for pyraflufen ethyl can be used as a surrogate for N-(n-octyl)-2-pyrrolidone residue levels when this inert ingredient is used in a mixture with pyraflufen ethyl.  For purposes of this petition the EPA's 2011 dietary exposure calculations for pyraflufen ethyl are used as a surrogate for determining the dietary exposure for N-(n-octyl)-2-pyrrolidone.

	i. Food. 

Using the DEEM-FCID software, EPA estimates the dietary exposure for pyraflufen ethyl at 0.000081 mg/kg/day for the general U.S. population and 0.000228 mg/kg/day for children one - two years old, the population subgroup with the highest estimated chronic dietary exposure to pyraflufen ethyl.  It is assumed that these exposure estimates can conservatively represent exposures to N-(n-octyl)-2-pyrrolidone when it is used in a mixture with pyraflufen ethyl.

      ii. Drinking water.   The estimated drinking water exposure to pyraflufen ethyl and by default to N-(n-octyl)-2-pyrrolidone has been considered in combination with food and residential exposures.

	2. Non-dietary exposure. 

(a) Residential Handler Exposure and Risk

Using the EPA estimated exposures for pyraflufen ethyl as a surrogate for N-(n-octyl)-2-pyrrolidone exposures, and using the developmental toxicity NOAEL for N-(n-octyl)-2-pyrrolidone of 50 mg/kg/day, the resulting MOE is greater than 35 million and is below the EPA level of concern.


(b) Non-Occupational (Post-Application) Exposure from Treated Lawns

Using the EPA estimated exposures for pyraflufen ethyl as a surrogate for N-(n-octyl)-2-pyrrolidone exposures, and using the developmental toxicity NOAEL for N-(n-octyl)-2-pyrrolidone of 50 mg/kg/day, the calculated MOE for combined short-term exposure is greater than 270,000 and is below the EPA level of concern.

D. Cumulative Effects

No information is available to indicate that N-(n-octyl)-2-pyrrolidone shares a common mechanism of toxicity with any other substance or that it produces a toxic metabolite produced by other substances.  For the purposes of this tolerance action, it is assumed that N-(n-octyl)-2-pyrrolidone does not have a common mechanism of toxicity with other substances.



E. Safety Determination

The EPA has previously determined in its assessment for N-(n-octyl)-2-pyrrolidone that based on available information, there is no concern for increased sensitivity to infants and children when this ingredient is used in pesticide formulations. For the same reason, a safety factor analysis has not been used to assess risk and, therefore, the additional tenfold safety factor for the protection of infants and children is deemed as unnecessary.

	1. U.S. population. 

Based on a 2011 EPA estimate of the dietary exposures of pyraflufen ethyl and using pyraflufen ethyl as a surrogate for N-(n-octyl)-2-pyrrolidone, the dietary exposure and risk for N-(n-octyl)-2-pyrrolidone is estimated to be <1% of the cPAD (chronic population adjusted dose) for N-(n-octyl)-2-pyrrolidone for the general U.S. population and is therefore below the EPA's level of concern. 

	2. Infants and children. 

Based on a 2011 EPA estimate of the dietary exposures of pyraflufen ethyl and using pyraflufen ethyl as a surrogate for N-(n-octyl)-2-pyrrolidone, the dietary exposure and risk for N-(n-octyl)-2-pyrrolidone is estimated to be <1% of the cPAD (chronic population adjusted dose) for N-(n-octyl)-2-pyrrolidone for children 1-2 years old and is therefore below the EPA's level of concern.


F. International Tolerances

No international tolerances have been established for N-(n-octyl)-2-pyrrolidone.
