**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 re place 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 o f the submitted data at this time or whether the data supports granting of the petition. Additional data may b e 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 .]** 2 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 .**  **T herefore**  **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** **- dim** **ethyl -**  **(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 we** **re examined**  **daily during**  **the acclimatizatio**  **n period**  **and mo**  **rtality, 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**  **recorde d**  **at approximately**  **30 minutes,**  **1, 2,**  **3 and**  **5 hours**  **after administration**  **on test**  **day 1**  **(with the**  **clinical signs)**  **and tw** **ice daily**  **during days**  **2 -**  **15. B**  **ody weights**  **were recorded**  **on day**  **1 (prior**  **to administration)**  **and on**  **days 8**  **and 15.**  **All animals**  **were necropsi** **ed and**  **examined ma**  **croscopically. 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**  **ma cro**  **scopic 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 -** **dim ethyl** **- (9CI)**  **a t**  **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 da** **ys 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. B**  **ody weights**  **were recorded**  **on day**  **1 (prior**  **to administration)**  **and on**  **days 8**  **and 15.**  **All animals**  **were necropsied**  **and examined**  **ma croscopically.**  **No deaths**  **occurred during**  **the study.**  **No clinical**  **signs of**  **systemic toxicity**  **were observed**  **during the**  **course of**  **the study.**  **Loca l**  **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**3

**present in**  **one m** **ale and**  **four female**  **animals. The**  **body weight**  **of the**  **animals was**  **within the**  **range commonly**  **recorded for**  **this strain**  **and age.**  **No ma**  **croscopic 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.**  **T he**  **gravimetrically determined**  **concentration was**  **5.226 mg/L.**  **T he**  **st udy**  **was conducted**  **according to**  **OECD test**  **guideline 403**  **and OPPTS**  **test guideline**  **870.1300. T** **he 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.**  **B ody**  **weights were**  **recorded on**  **study days**  **1, 4,**  **8 and**  **15. A**  **complete necropsy**  **was conducted**  **at the**  **end of**  **exposure. T**  **here were**  **no deaths,**  **clinical signs of toxicity or gross necropsy findings. A body weight loss was noted in some**  **of the**  **rats. P** **article size**  **was determined**  **twice and**  **was 2.52**  **and 2.32**  **μm with**  **a GSD**  **of 1.93**  **and 2.15,**  **respectively. T**  **he 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**  **ma terial.**  **No corneal**  **opacity or**  **iritis was**  **observed. R** **edness (3**  **rabbit; score**  **= 2)**  **and chemises**  **(2 rabbits;**  **score =**  **2) of**  **the conjunctiva**  **was observed**  **at 1**  **hour. T**  **he 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). T**  **he 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.**  **T he**  **dressing was**  **wrapped around**  **the abdomen**  **and secured**  **with tape.**  **A nimals**  **were observed**  **for mortality**  **and clinical**  **signs daily**  **during acclimation**  **and t** **hroughout the**  **test. B**  **ody weights**  **were recorded**  **at the**  **start of**  **acclimation, on**  **the day**  **of application**  **and study**  **termination. T**  **he test**  **sites were**  **scored for**  **dermal irritation**  **at 1,**  **24, 48**  **and 72**  **hours after**  **removal of**  **the dressing**  **and gauze**  **patch. N** **o mor** **tality or**  **clinical signs**  **of toxicity**  **occurred. T**  **he only**  **irritation observed**  **occurred in**  **one female**  **rabbit at**  **1 hour**  **after exposure.**  **This animal**  **had erythema**  **with a**  **score of**  **1. I** **t had**  **cleared by**  **24 hours.**  **T he**  **test ma** **terial was considered to be “not irri tating” to rabbit skin (Toxicity Category IV).** 4

**Dermal Sensitization**  **: Propanamide,**  **2 -** **hydroxy -** **N, N** **- dim** **ethyl -**  **(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 μl, was**  **spread over**  **the entire**  **dor sal**  **surface ( ̴**  **8mm) of**  **each ear**  **lobe once**  **daily for**  **three consecutive**  **days. F** **ive days**  **after the**  **first topical**  **application the**  **mice were**  **injected intravenously**  **into a**  **tail vein**  **with radio** **- labelled**  **thymidine (3H** **- methyl**  **thymidine). T**  **he proliferative**  **capaci ty**  **of pooled**  **lymph node**  **cells was determined**  **by the**  **incorporation of**  **3H -** **methyl thymidine**  **measured in**  **a β**  **** **scintillation counter.**  **A p**  **ositive response**  **was considered**  **to be**  **a Stimulation**  **Index of**  **>3. N** **o mo**  **rtality or**  **clinical signs**  **of toxicity**  **was observed.**  **T he**  **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)**  **do es**  **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 studi** **es, 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** **- dim** **ethyl -**  **(9CI) and**  **its effects**  **on the**  **prenatal development**  **in Wistar**  **rats. Propan**  **amide, 2**  **- hydroxy** **- N,**  **N****** **dimethyl -**  **(9CI) was**  **tested for**  **developmental toxicity**  **in Wistar**  **r ats**  **. The**  **test substance**  **was administered**  **as an**  **aqueous solution**  **to groups**  **of 25**  **time -**  **ma ted**  **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 we** **re as follows:**  **Propanamide, 2 -** **hydroxy -** **N, N -** **dim ethyl** **- (9CI)**  **:**  **5 00**  **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 ra ts**   **100 mg/kg/day (HDT) for**  **maternal an d 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. T**  **he 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.**  **B ody**  **w eights**  **and food**  **consumption were**  **recorded weekly.**  **A f**  **unctional observation**  **battery was**  **performed on**  **all animals**  **at the**  **end of**  **the exposure**  **period. Motor**  **activity was** 5

**measured the**  **same day**  **as the**  **FOB was**  **conducted. O** **phthalmology was**  **performed prior**  **to dos**  **e administration**  **and on**  **study day**  **91 for**  **males and**  **study day**  **89 for**  **females. V** **aginal smears**  **were taken**  **daily for**  **three weeks**  **to determine**  **estrus cycling. Blood was taken from fasted animals for hematology and clinical chemistry**  **evaluations. U** **rinalysis p**  **arameters were**  **examined at**  **study termination.**  **T he**  **following sperm**  **parameters were**  **evaluated: s** **perm motility,**  **sperm mo**  **rphology and**  **sperm head**  **count (cauda**  **epididymis and**  **testis. A** **c om** **plete necropsy**  **was performed and a full set of organs were weighed and**  **examined microscopically. There**  **were no**  **deaths during**  **the study.**  **F ood**  **consumption, FOB**  **observations, mo**  **tor activity,**  **urinalysis parameters,**  **ophthalmology, sperm**  **parameters and**  **estrous cyclicity**  **were unaffected**  **by treatment.**  **Body weight**  **gain was**  **statistic ally**  **decreased in**  **males at**  **1000 mg/kg/day. Platelet counts and relative eosinophil counts were**  **statistically decreased**  **at the**  **high dose**  **in females.**  **C holesterol**  **levels were**  **statistically increased**  **in males**  **and females**  **at the**  **high dose**  **and in**  **males at**  **500 m** **g/kg/day. C**  **reatinine levels**  **were statistically**  **decreased in**  **both sexes**  **at 500**  **and 1000**  **mg/kg/day. T**  **riglyceride levels**  **were statistically**  **increased in**  **ma les**  **at 500**  **and 1000**  **mg/kg/day. A** **bsolute and**  **relative liver**  **weights were**  **statistically increased**  **in ma** **les at**  **500 and**  **1000 mg/kg/day**  **and relative**  **liver weights**  **in fe** **males 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**  **wei ghts**  **were statistically**  **increased in**  **females at**  **200, 500**  **and 1000**  **mg/kg/day and**  **relative kidney**  **weights at**  **1000 mg/kg/day.**  **R elative**  **kidney weights**  **were statistically**  **increased in**  **males at**  **500 and**  **1000 mg/kg/day.**  **G rade**  **3 eosinophilic**  **droplets were**  **observe d**  **in the**  **kidneys of**  **the males**  **at 500**  **and 1000**  **mg/kg/day. T**  **he kidney**  **effects in**  **males were**  **considered to**  **be related**  **to alpha** **- 2u** **** **globulin and**  **were therefore**  **considered treatment**  **related but**  **not adverse.**  **T he**  **effect on**  **kidney weight**  **in females**  **was not**  **consid ered**  **adverse because**  **it was**  **not accompanied**  **with any**  **histopathological findings.**  **T he**  **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

. E ndocrine disruption

. **[ There**  **is no**  **available evidence**  **that Propanamide,**  **2 -**  **hydroxy -** **N, N** **- dim** **ethyl -**  **(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**6

**where it**  **can be**  **demonstrated that**  **the risks**  **from aggregate**  **exposure to**  **pesticide chemical**  **residues under**  **reasonably fore** **seeable 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**  **o f**  **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**  **cert ainty**  **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 -** **dim ethyl** **- (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. B** **ASF Corporation**  **has not**  **found that**  **Propanamide, 2**  **- hydroxy** **- N,**  **N -** **dimethyl -**  **(9CI) share**  **a common**  **mechanism of**  **toxicity with**  **any other**  **substances, and**  **Propa namide,**  **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**  **gener al**  **population or**  **to infants**  **and children**  **from aggregate**  **exposure to**  **residues of**  **the lower**  **weight of**  **Propanamide, 2 -** **hydroxy -** **N, N -** **dim ethyl** **- (9CI)**  **. ]**  F. International Tolerances7 **[ 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.**