Document ID: EPA-HQ-OPP-2015-0524-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-09-09T04:00Z

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

EPA Registration Division contact: [PV Shah, Branch Chief Inert Assessment Branch (IAB) 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., "BASF Corporation," with the information specific to your action.

TEMPLATE:

BASF Corporation

[TBD]

	EPA has received a pesticide petition ([TBD]) from [Spring Trading Company, LLC on behalf of BASF Corporation, 100 Campus Drive, Florham Park, NJ 07932, 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 180.910 and 930.

The addition of an exemption from the requirement of a tolerance for Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) as a solvent/co-solvent in or on the raw agricultural commodity [growing crops or in products to treat animals] at [under 40 CFR 180.910, and 930].  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

[The petitioner has provided EPA with sufficient toxicity data to support the issuance of this tolerance exemption for an inert ingredient.   The data submitted will allow EPA to determine the sensitivities of major identifiable subgroups of consumers, including infants and children.]

	
      1. Analytical method. [An analytical method is not required for enforcement purposes since the Agency is establishing an exemption from the requirement of a tolerance without any numerical limitation.]

	2. Magnitude of residues. [BASF Corporation is petitioning the agency to establish an exemption from the requirement of a tolerance for a class of chemistry that is well known and similar to an existing tolerance exemption.  Therefore information regarding the nature and magnitude of chemical residues resulting from the use of this inert ingredient is not required.]

B. Toxicological Profile

      1. Acute toxicity. 
Oral: [Two groups, each of three female HanRcc: WIST (SPF) rats, were treated with Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) by oral gavage administration at a dos of 2000 mg/kg body weight. The test item was diluted in vehicle (purified water) to a concentration of 0.5 g/mL and administered at a dosing volume of 4 mL/kg. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.  Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. No clinical signs were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy. The oral LD50 in the rat was greater than 2000 mg/kg body weight (Toxicity Category III).]

Dermal: Five male and five female HanRcc: WIST (SPF) rats were treated with Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) at 2000 mg/kg by dermal application.  The OECD testing guideline 402. The test item was diluted in vehicle (purified water) at a concentration of 0.5 g/mL and administered at a volume dosage of 4 mL/kg. The application period was 24 hours. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.  Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. No deaths occurred during the study. No clinical signs of systemic toxicity were observed during the course of the study. Local findings were noted at the application site of all animals except one female. These comprised slight erythema, slight scaling and slight to moderate scab formation. At the end of the two-week observation period, local findings were still present in one male and four female animals. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were observed at necropsy. The dermal LD50 was >2000 mg/kg (Toxicity Category III).

Inhalation:  HanRCC:WIST (SPF) (5/sex) were exposed by nose only to Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) at a mean chemically determined concentration of 5.005 mg/L for a period of four hours.  The gravimetrically determined concentration was 5.226 mg/L.  The study was conducted according to OECD test guideline 403 and OPPTS test guideline 870.1300.  The rats were examined at 1, 2, 3 and 4 hours after the start of exposure, approximately 1 and 2.5 hours after exposure on day 1 and at least twice daily during the 14-day observation period. Clinical signs were recorded at approximately 1, 2, 3 and 4 hours after the start of exposure, at approximately 1 hour at the end of exposure and then daily to study termination.  Body weights were recorded on study days 1, 4, 8 and 15.  A complete necropsy was conducted at the end of exposure.  There were no deaths, clinical signs of toxicity or gross necropsy findings.  A body weight loss was noted in some of the rats.  Particle size was determined twice and was 2.52 and 2.32 um with a GSD of 1.93 and 2.15, respectively.  The acute inhalation LC50 was determined to be >5.005 mg/L (Toxicity Category IV).

Eye Irritation:  Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) was tested for eye irritation potential in the eyes of three young adult New Zealand white rabbits according to OECD test guideline 405.  One tenth of an mL of the test substance was to the left eye of one male and two females. The right eye served as the control.  The eyes of each animal were examined 1, 24, 48, and 72 after administering the test material. No corneal opacity or iritis was observed.  Redness (3 rabbit; score = 2) and chemises (2 rabbits; score = 2) of the conjunctiva was observed at 1 hour.  The eyes were clear at 72 hours. No clinical signs of systemic toxicity were observed during the study and no mortality occurred. This product is considered to be "mildly irritating" to the rabbit eye (Toxicity Category III).  The study authors concluded that the test material was "not irritating" to the rabbit eye.

Dermal Irritation:  Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) was tested for dermal irritation according to OECD test guideline 404.   The test material (0.5 mL0 was applied to a gauze patch and placed on the clipped intact skin of the left flank of one male and two female New Zealand white rabbits.  The patch was covered with a semi-occlusive dressing.  The dressing was wrapped around the abdomen and secured with tape.  Animals were observed for mortality and clinical signs daily during acclimation and throughout the test.  Body weights were recorded at the start of acclimation, on the day of application and study termination.  The test sites were scored for dermal irritation at 1, 24, 48 and 72 hours after removal of the dressing and gauze patch.  No mortality or clinical signs of toxicity occurred.  The only irritation observed occurred in one female rabbit at 1 hour after exposure.  This animal had erythema with a score of 1.  It had cleared by 24 hours.  The test material was considered to be "not irritating" to rabbit skin (Toxicity Category IV).

Dermal Sensitization:  Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) was tested for possible skin sensitization potential using the local lymph node assay in mice. Three groups of four females CBA/CaOlaHd mice were treated daily with the test item at concentrations of 25, 50, and 100% (w/v) for three consecutive days, and a separate control group of four female mice were treated with the vehicle only. The application volume, 25 ul, was spread over the entire dorsal surface ( ̴ 8mm) of each ear lobe once daily for three consecutive days.  Five days after the first topical application the mice were injected intravenously into a tail vein with radio-labelled thymidine (3H-methyl thymidine).  The proliferative capacity of pooled lymph node cells was determined by the incorporation of 3H-methyl thymidine measured in a β-scintillation counter.  A positive response was considered to be a Stimulation Index of >3.  No mortality or clinical signs of toxicity was observed. The Stimulation Indices were 1.6, 1.8 and 2.4 at concentrations of 25, 50 and 100%, respectively. This product was found not to be a skin sensitizer under the conditions of this study.

	2. Genotoxicty. [Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) does not react with DNA or protein, and bacterial mutagenicity studies do not indicate a concern for mutagenicity. Based on the lack of genotoxicity and lack of specific organ toxicity in the repeated dose studies, carcinogenic effects are unknown. Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) shows no evidence of mutagenicity, (AMES).] 

	3. Reproductive and developmental toxicity. Several developmental toxicity studies were located on Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) and its effects on the prenatal development in Wistar rats. Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) was tested for developmental toxicity in Wistar rats. The test substance was administered as an aqueous solution to groups of 25 time-mated female Wistar rats by gavage at doses of 100, 200, and 500 mg/kg body weight/day (mg/kg bw/d) on gestation days (GD) 6 through 19. A standard dose volume of 10 mL/kg body weight was used for each test group. 

The NOAELs for maternal and developmental toxicity were as follows:
   * Propanamide, 2-hydroxy-N, N-dimethyl- (9CI):  
   * 500 mg/kg/day (highest dose tested; HDT) for maternal and developmental toxicity in female rats
   * 200 mg/kg/day (HDT) for maternal and developmental toxicity in female rats
   * 100 mg/kg/day (HDT) for maternal and developmental toxicity in female rats

	4. Subchronic toxicity. [Wistar rats (10/sex/group) were administered Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) by gavage at dose levels of 0, 100, 200, 500 and 1000 mg/kg/day for 90 days. The study was conducted according to OECD test guideline 408.  The animals were observed for mortality twice daily and for clinical signs of toxicity daily and within 2 to 5 hours of dose administration.  Detailed clinical examinations were conducted weekly.  Body weights and food consumption were recorded weekly.  A functional observation battery was performed on all animals at the end of the exposure period. Motor activity was measured the same day as the FOB was conducted.  Ophthalmology was performed prior to dose administration and on study day 91 for males and study day 89 for females.  Vaginal smears were taken daily for three weeks to determine estrus cycling.  Blood was taken from fasted animals for hematology and clinical chemistry evaluations.  Urinalysis parameters were examined at study termination.  The following sperm parameters were evaluated:  sperm motility, sperm morphology and sperm head count (cauda epididymis and testis.  A complete necropsy was performed and a full set of organs were weighed and examined microscopically.

There were no deaths during the study.  Food consumption, FOB observations, motor activity, urinalysis parameters, ophthalmology, sperm parameters and estrous cyclicity were unaffected by treatment. Body weight gain was statistically decreased in males at 1000 mg/kg/day. Platelet counts and relative eosinophil counts were statistically decreased at the high dose in females.  Cholesterol levels were statistically increased in males and females at the high dose and in males at 500 mg/kg/day.  Creatinine levels were statistically decreased in both sexes at 500 and 1000 mg/kg/day.  Triglyceride levels were statistically increased in males at 500 and 1000 mg/kg/day.  Absolute and relative liver weights were statistically increased in males at 500 and 1000 mg/kg/day and relative liver weights in females at 1000 mg/kg/day which were accompanied with an increase in centrilobular hypertrophy.  Relative liver weights were also, but statistically increased at 200 mg/kg/day. Absolute kidney weights were statistically increased in females at 200, 500 and 1000 mg/kg/day and relative kidney weights at 1000 mg/kg/day.  Relative kidney weights were statistically increased in males at 500 and 1000 mg/kg/day.  Grade 3 eosinophilic droplets were observed in the kidneys of the males at 500 and 1000 mg/kg/day.  The kidney effects in males were considered to be related to alpha-2u-globulin and were therefore considered treatment related but not adverse.  The effect on kidney weight in females was not considered adverse because it was not accompanied with any histopathological findings.  The liver effects observed at 100 and 200 mg/kg/day were considered to be adaptive. The NOAEL was therefore considered to be 200 mg/kg/day and the LOAEL 500 mg/kg/day.

	5. Endocrine disruption. [There is no available evidence that Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) is an endocrine disruptor.  The literature was searched for any information on the endocrine disruption of the solvent/ co-solvent. No information was located indicating any potential for endocrine disruption nor was any evidence observed in the studies supporting this petition.]

C. Aggregate Exposure

	1. Dietary exposure. [In examining aggregate exposure, section 408 of the FFDCA directs EPA to consider available information concerning exposures from the pesticide residue in food and all other non-occupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor uses).

EPA establishes exemptions from the requirement of a tolerance only in those cases where it can be demonstrated that the risks from aggregate exposure to pesticide chemical residues under reasonably foreseeable circumstances will pose no appreciable risks to human health. In order to determine the risks from aggregate exposure to pesticide inert ingredients, the Agency considers the toxicity of the inert in conjunction with possible exposure to residues of the inert ingredient through food, drinking water, and through other exposures that occur as a result of pesticide use in residential settings. If EPA is able to determine that a finite tolerance is not necessary to ensure that there is a reasonable certainty that no harm will result from aggregate exposure to the inert ingredient, an exemption from the requirement of a tolerance may be established.

Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) as a food ingredient that is consumed and result in intermediate-term residential exposure and BASF has determined that it is appropriate to aggregate chronic exposure through food and water with intermediate-term residential exposures to this solvent/ co-solvent.

D. Cumulative Effects

	[Cumulative effects from substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity.  BASF Corporation has not found that Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) share a common mechanism of toxicity with any other substances, and Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, BASF Corporation has assumed that Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) does not have a common mechanism of toxicity with other substances.]

E. Safety Determination

	1. U.S. population. [Based on these risk assessments, BASF concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to residues of Propanamide, 2-hydroxy-N, N-dimethyl- (9CI).]

	2. Infants and children. [Based on these risk assessments, BASF concludes that there is a reasonable certainty that no harm will result to the general population or to infants and children from aggregate exposure to residues of the lower weight of Propanamide, 2-hydroxy-N, N-dimethyl- (9CI).]

F. International Tolerances

	[BASF Corporation is not aware of any country requiring a tolerance for the Propanamide, 2-hydroxy-N, N-dimethyl- (9CI) nor have any CODEX Maximum Residue Levels been established for any food crops at this time.