UN IT ED STATES EN VIRONME NTAL PROTECT I ON AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Date: July 8, 2013 OFFICE OF
CHEMICAL SA FETY AND
POLL U T I ON P REV ENTION

SUBJECT: Fenpropid in: Human Health Risk Assessment to Support th e Proposed

To l erance for Imported Banana s

PC Code: 012305

Decision No

. : 459941

Petition No.: 2E7980

Risk Assessment Type: Single Chemica l

TXRNo.: NA

MRID No.: NA

FROM: DP Barcode : 0399597 Regi s tration No.: NA Regulatory Action: Tolerance without a U.S. regis tra tion (Import Tole ra nce)

Case No.: NA
CAS No.: 67306-00-7

40CFR: NA

THROUGH: Pete Savo i a, Chemist 1 " 

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# A.*l/ ;J /) /} 

# J lj 

### 4 And Michael Metzger

,

# Bran**/:~ ef**  1

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Risk A ssess ment Branch V NII

Health E ffects Division (7509P)

TO: Tamue Gibson, Risk Manager R ev iewer Fungicide Branch Registration Division (7505P)

Page I of 54Page 2 of 54

1.0 Executive Summary

................................ ................................ ................................ ............. 4
2.0 HED Recommendations

................................ ................................ ................................ ....... 5
2.1 Data D eficiencies

................................ ................................ ................................ ............. 6
2.2 Tolerance Considerations

................................ ................................ ................................ . 6
2.2.1 Enforcement Analytical Method

................................ ................................ .................. 6
2.2.2 Recommended Tolerances

................................ ................................ ............................ 6
2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ ........ 7
2.2.4 International Harmonization

................................ ................................ ......................... 7
2.3 Label Recommendations

................................ ................................ ................................ .. 7
3.0 Introduction

................................ ................................ ................................ .......................... 7
3.1 Chemical Identity

................................ ................................ ................................ ............. 7
3.2 Physical/Chemical Characteristics

................................ ................................ ................... 7
3.3 Pesticide Use Pattern

................................ ................................ ................................ ........ 8
3.4 Anticipated Exposure Pathways

................................ ................................ ....................... 9
3.5 Consideration of Environmental Justice

................................ ................................ .......... 9
4.0 Hazard Characterization and Dose

- Response Assessment

................................ .................. 9
4.1 Toxicology Studies Available for Analysis

................................ ................................ ..... 9
4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

................................ ... 10
4.2.1 Dermal Absorption

................................ ................................ ................................ ..... 10
4.3 Toxi cological Effects

................................ ................................ ................................ ..... 10
4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

................................ ....... 12
4.4.1 Completeness of the Toxicology Database

................................ ................................ 13
4.4.2 Evidence of Neurotoxicity

................................ ................................ .......................... 13
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

............. 13
4.4.4 Residual Uncertainty in the Exposure Database

................................ ......................... 14
4.5 Toxicity Endpoint and Point of Departure Selections

................................ .................... 14
4.5.1 Dose

- Response Assessment

................................ ................................ ....................... 14
4.5.2 Cancer Classification and Risk Assessment Recommendation

................................ .. 15
4.5.3 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment.

................................ ................................ ................................ ............................... 15
5.0 Dietary Exposure and Risk Assessment

................................ ................................ ............ 17
5.1 Metabolite Residue Profile

................................ ................................ ............................. 17
5.1.1 Summary of Plant Metabolism Studies

................................ ................................ ...... 17
5.1.3 Comparison of Metabolic Pathways

................................ ................................ ........... 18
5.1.4 Residues of Concern Summary and Rationale

................................ ........................... 18
5.2 Food Residue Profile

................................ ................................ ................................ ...... 19
5.4 Dietary Risk Assessment

................................ ................................ ................................ 20
5.4. 1 Description of Residue Data Used in Dietary Assessment

................................ ......... 20
5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .................... 20
5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................. 21
5.4.4 Chronic Dietary Risk Assessment

................................ ................................ .............. 21
5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ................ 21
5.4.6 Summary Table

................................ ................................ ................................ ........... 21
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .... 22 7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ....... 22
8.0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 22Page 3 of 54

9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 22
10.0 References

................................ ................................ ................................ .......................... 22 Appendix A. Toxicology Profile and Executive Summaries

................................ ....................... 24
A.1 Toxicology Data Requirements

................................ ................................ ...................... 24
A.2 Toxicity Profiles

................................ ................................ ................................ ............. 25
A.3 Hazard Identification and Endpoint Selection

................................ ............................... 29
A.4 Executive Summaries

................................ ................................ ................................ ..... 30 Appendix B. Summary of Residues (Metabolism and Field Trial Studies)

................................ . 52 Appendix C. Review of Human Research

................................ ................................ ................... 54Page 4 of 54

1.0 Executive Summar y

This risk assessment was performed to support a request for a tolerance for residues of fenpropidin on imported bananas. Fenpropidin (1

- [3

- [4

- (1,1

- dimethylethyl)phenyl]

- 2

- methylpropyl]piperidine) is an unclassified fungicide which inhibit s ergosterol b iosynthesis in fungi

. There are currently no registered uses and no tolerances for f enpropidin in the U nited
States

. However, because the use on banana includes registrations in countries that are major exporters of bananas to the U .S. , Syngenta Crop Protection has proposed the establishment of a permanent tolerance for residues of fenpropidin on imported bananas.

The only potential source of human exposure to fenpropi din is via consumption of imported
bananas

. Because fenpropidin is not an active ingredient in any pr oduct registered in the U.S., occupational, residential and drinking water exposure are not expected to occur and were not
included in this risk assessment

.

The toxicity database for fenpropidin is complete and is adequ ate for characterizing the hazard associated with the potential exposure route (oral dietary) for the proposed use. The toxicity profile of fenpropidin shows that the nervous system, eye, stomach, esophagus, and skin are the major target organs.

The prin cipal toxic effects following oral exposure to fenpropidin are irritant effects on the esophagus, stomach, and skin, with peripheral parts of the body (tail and ears) affected also.

Clinical signs of neurotoxicity and neuropathology are the other major toxic effects observed following oral exposure in the rat and dog, and the dog is the most sensitive species for the
neurotoxic effects. Neurotoxicity in rats and dogs included demyelin ation of nerves, paresis, and decreased grip strength. Eye catarac ts were also observed in dogs at the high dose. Although an acute neurotoxicity study on fenpropidin is not available, the Hazard and Science Policy Council (HASPOC) determined that the acu te neurotoxicity study in rats is not required (TXR# 0056640, 5/3/13).

Developmental toxicity was observed in the rabbit developmental toxicity study, as evidenced by an increase in fetal (litter) incidence of skeletal malformations in the absence of maternal toxicity. In the rat developmental toxicity stud ies decreased ossification (at same dose as maternal toxicity) or skeletal malformations (at doses with no maternal toxicity) were observed

. Reproductive toxicity was observed, as evidenced by the decrease in spermatids i n the testes and sperm cells. N europathology was observed in the developmental neurotoxicity study in the rat as evidenced by decreased brain weight and decreases in radial thickness of the cortex at le vel 3 and vertical height of the dentate hilus at level 3 in PND 72 females at the same dose level where skin irritation effects (scabbing and hair loss around the mouth and forelimbs) were observed in
the maternal animal

.

There is no concern for mutageni city following exposure to fenpropidin. The carcinogenicity of fenpropidin has been evaluated by the Cancer Assessment Review Committee of OPP, and it classified fenpropidin as “suggestive evidence of carcinogenicity”; quantification of risk using aPage 5 of 54

non

- l inear approach; i.e., RfD, for fenpropidin will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to fenpropidin.

HED recommends that the 10X FQPA Safety Factor (for the protection of infants and chil dren)
be reduced to 1X. Although increased sensitivity of the young animal was observed in several
studies , a n FQPA Safety Factor of 1X is appropriate since clear NOAELs were identified for each endpoint, there are no toxicology datagaps, and the points o f departure selected are protective of the increased susceptibility of the young animal.

The HED Residues of Concern Knowledge

- Based Subcommittee (ROCKS) evaluated fenpropidin. Tolerances are recommended for residues of fenpropidin, including its metab olites and degradates, in or on bananas. Compliance with the tolerance levels is to be determined by measuring only fenpropidin (1

- [3

- [4

- (1,1

- dimethylethyl)phenyl]

- 2

- methylpropyl]piperidine). The residue chemistry data are adequate and support a toleranc e of 1 0 ppm on bananas.

Acute and chronic dietary exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID)
Version 3.16. Residues from food alone were considered, as drinking water exposure is not expected in the U.S. for fenpropidin

. The assessments assumed 100% crop treated and default processing factors and were partially refined with the use of residues from banan a field trails.

The acute dietary ex posure assessments were performed using individual points of departure for
the two population subgroups : all infants and children, and females 13

- 49 years , the only population subgroups with acute toxicological endpoints. Acute dietary risk estimates for food
alone were not of concern.

The chronic dietary risk estimates for the general U.S. population and all population subgroups

were not of concern.

Because there are no registered uses of fenpropidin in the U.S., residential and drinking water

exposu res are not expected. Therefore, aggregate risks are identical to the food

- alone dietary risk
estimates ; t here are no acute or chronic dietary risk estimates of concern.

Potential areas of environmental justice concerns, to the extent possible, were considered in this
human health risk assessment (see Section 3.5).

This risk assessment does not rely on any data from studies in which human subjects were intentionally exposed to a pesticide or other chemical.

2.0 HED Recommendations

Pending submission of a revised Section F (see Section 2. 1) HED recommends establishing a tolerance for residues of fenpropidin on imported bananas. The recommended tolerance is listed
in Table 2.2.2.Page 6 of 54

2.1 Data Deficiencies

A revised Section F should be submitted to reflect the recommended tolerance level and correct commodity definition (see Section 2.2.3). HED also notes that the registrant needs to submit a n analytical reference standard for fenpropidin to the EPA National Pesticide Standards Repository (see Secti on 5.2).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Syngenta has submitted an adequate liquid chromatography with mass spectrometric (LC

MS/MS) detection method (Method No. REM 164.09) for determining residues of fenpropidin in
bananas. Based on the lower limit of method validation (LLMV) t he limit of quantitation (LOQ) in several plant commodities including bananas is 0.01 ppm. This method was used to determine residues in whole fruit, peel and pulp in the submitted banana fie ld trial. The method was adequately validated using fortified control samples of apples, grapes, rape seeds, wheat grain and straw, sugar beets roots, and bananas. A successful independent laboratory validation (ILV)
trail was also conducted for the abov e method. The proposed LC

- MS/MS method (Method No. REM 164.09) is adequate for enforcing the proposed tolerance for fenpropidin i n bananas.

Adequate data have also been submitted evaluating the recovery of fenpropidin from bananas using the FDA multiresi due methods in Pesticide Analytical Manual (PAM) Vol. I. These data indicate that the multiresidue methods (Section 302 E1) are capable of determining residues of fenpropidin in bananas and are suitable for enforcing the tolerance

.

2.2. 2 Recommended Tole rances

Tolerances should be established in 40CFR 180 for residues of fenpropidin, including i ts metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only fenpropidin (1

- [3

- [4

- (1,1

- dimethylethyl)phenyl]

- 2

- methylpropyl]piperidine).

Table 2.2.2 . Tolerance Summary for Fenpropidin Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition )
Banana, unbagged fruit 9 10 Banana Banana, pulp from unbagged fruit 0.4

-- --Page 7 of 54

2.2. 3 Revisions to Petitioned

- For Tolerances

The petitioner

- proposed tolerance for fenpropidin on banana is 9 ppm. EPA is recommending a tolerance of 10 ppm. While both the petitioner and EPA utilized the Organization for Economic Cooperation and Development (OECD) calculation procedure s for estimating
tolerances/Maximum Residue Limits , EPA elected to exclude residue values from one of the
field trials. The stu dy author reported th at samples from that field trial may have been mislabeled as residues were highe r in the control samples; therefore, results from this test were not used in
the tolerance calculations. A tolerance for banana pulp is not required; tole rances are to be
established on the whole banana fruit. The correct commodity definition for the whole fruit is

Banana

. A revised Section F should be submitted to reflect the recommended tolerance level and correct commodity definition.

2.2. 4 International Harmonization

There are currently no established Codex, Canadian, or Mexican maximum residue limits (MRLs) for fenpropidin on bananas so there are no harmonization issues at this time

. Canada is currently reviewing a request for the use of f enpropidin on bananas.

2.3 Label Recommendations

None.

3.0 In troduction

3.1 Chemical Identity

Table 3.1 Fenpropidin Nomenclature. Compound

Common name Fenpropidin Company experimental name CGA 114900

IUPAC name 1

- [( RS )

- 3

- (4

- tert

- butylphenyl)

- 2

- methylpropyl]piperidine

CAS name 1

- [3

- [4

- (1,1

- dimethylethyl)phenyl]

- 2

- methylpropyl]piperidine CAS registry number 67306

- 00

- 7

End

- use product (EP) 750 g/L EC (TERN ® 750 EC; no EPA Reg. No.) Molecular weight 273.46

3.2 Physical/Chemical CharacteristicsPage 8 of 54

Table 3.2 Physicochemical Properties of Fenpropidin.

Parameter Value Reference Melting point

- 64.6 °C Administrative materials for
PP# 8E7347 1 pH 8.6 at 25°C (1% aqueous dispersion) Density 0.913 g/cm 2

Water solubility (mg/L at 20°C) 130000 at pH 6.0 530 at pH 7.0 6.2 at pH 9.0 Solvent solubility (g/L at 20°C) >250 g/L in heptane, xylene, acetone and ethyl acetate Vapor pressure (25°C) 1.7 x 10
- 2 Pa Dissociation constant, pK

a 10.13

Octanol/water partition coefficient, Log(K OW ) 2.6 at pH 7 UV/visible absorption spectrum Not reported

1 Selected data were also obtained from the FOOTPRI NT Pesticide Properties DataBase ( http://www.eu

footprint.org/ppdb.html )

.

3.3 Pesticide Use Pattern

Syngenta is supporting the use of a 750 g/L EC formulation of fenpropidin (TERN ® 750 EC) for repeated broadcast foliar applications to bananas . It is not clear which countries will be usin g fenpropidin on bananas; however, the submitted field trials were performed on bananas grown in
Central and South America . With the current petition for a tolerance on imported bananas, Syngenta has provide d an example label for this end use product

. Th e proposed use directions
are summarized below in Table 3.3.

Table 3.3 Summary of Directions for Use of Fenpropidin.

Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic. Rate Max. No. Applic. per

Season Max. Seasonal

Applic. Rate PHI

(days) Use Directions and Limitations

Banana
Repeated
broadcast foliar applications to
established banana crops; aerial equipment 750 g/L EC

[none] 1 0.45 kg ai/ha

(0.4 lb ai/A) 12 5.4 kg ai/ha (4.8 lb ai/A) 0 Aerial application

recommended at volumes of 20

- 30 L/ha. The minimum RTI is 7 days Can be applied in e ither an oil
and water emulsion or in a

s traight oil mixture.
A maximum of 2 consecutive applications of fenpropidin is
recommended to minimize resistance development.

1 NA = not applicable; no products registered in the U.S.Page 9 of 54

3.4 Anticipated Exposure Pathways

The only potential source of human exposure to fenpropidin in the U.S. is via consumption of imported bananas. There are currently no U.S. tolerances for fenpropidin on any food or feed
commodities. Because fenpropidin is not an active ingredient in any pr oduct registered in the U.S., occupational, residential, drinking water , and aggregate (residential plus dietary) exposure are not expected to occur and were not included in this risk assessment

.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this

h uman health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http:/ /www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subg roups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We E at in America, (NHANES/WWEIA ) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and cat egorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when
conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further

con siderations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among sp ecific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database on fenpropidin is complete. The toxicology studies for fenpropidin are summarized in Table A.1 in Appendix A. The database includes the following studies.

Subchronic: 90

- day oral toxicity (rat, mouse, dog) Developmental toxicity: developmental toxicity (rat and rabbit) Reproduction: 2

- generation reproduction (rat) Chronic: combined oral chronic toxicity/carcin ogenicity (rat), carcinogenicity (mouse), chronic oral toxicity (dog)Page 10 of 54

Neurotoxicity: subchronic neurotoxicity (rat), developmental neurotoxicity (rat) Other: mutagenicity battery, metabolism , immunotoxicity

The studies available for consideration of fenpr opidin toxicity provide a comprehensive database, with routes of administration that are consistent with potential exposure scenarios.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Following oral exposure, fenpropidin is rapidly and nea rly completely absorbed at 0.5 mg/kg by both sexes and almost completely absorbed by males but incompletely absorbed by females at 100 mg/kg. Blood levels reached mean maximum concentrations at 30 minutes post dose in both sexes at 0.5 mg/kg, and at 60 mi nutes (males)/120 minutes (females) post dose at 100 mg/kg. A biphasic elimination was observed in both sexes and the area under the concentration

- time (AUC) curves were similar for the sexes at 0.5 mg/kg. A monophasic elimination was observed at 100 mg/kg , with a calculated half

- life of 750 minutes for males and 670 minutes for females at 100 mg/kg. The decrease to one

- half the maximal concentrations occurred at approximately 800 minutes post dose in both sexes at 100 mg/kg. Also at 100 mg/kg, the AUC was approximately 50% lower in females than in males and did not increase proportionally with dose in females. Fenpropidin is rapidly excreted, with the majority of radioactivity eliminated during the first 24 hours post dose. Fenpropidin is completely metabol ized and excreted mostly in urine. The only major urinary metabolite was 2

- methyl

- 2

- [4

- methyl

- 3

- piperidine

- 1

- yl

- propyl)

- phenyl]

- propionic acid, which accounted for 46%

- 70% of the administered dose. The main metabolite in feces in
females was sulfuric acid mono

- {2

- methyl

- 2

- [4

- (2

- methyl

- 3

- piperidine

- 1

- yl

- propyl)

- phenyl]

- propyl} ester, which accounted for 6%

- 9% of the administered dose at 0.5 mg/kg and 27% of the administered dose at 100 mg/kg, although absorption appeared incomplete at this dose in
females. T his latter compound was the main biliary metabolite in females, accounting for 6% of the administered dose. In males, all identified metabolites in feces were less than 1.7% of the
administered dose. No bioaccumulation occurred.

4.2.1 Dermal Absorption

No dermal absorption studies are available. Quantification of dermal risk is not required at this
time , since exposure may occur only from consumption of imported bananas

.

4.3 Toxicological Effects

The toxicity profile of fenpropidin shows that the nervous system, eye, stomach, esophagus, and skin are the major target organs. The principal toxic effects following oral exposure to fenpropidin are irritant effects on the esophagus, stomach, and skin, w ith peripheral parts of the body (tail and ears) affected also. The skin lesions in the mouse following oral exposure include dry and/or flaky skin on tail, paws, and ears, loss of tail tip; hyperkeratosis of tail, ear, esophagus, subcutis, stomach, dermat itis of ear and tail, and hyperplasia of the nose. Skin lesions in the rat following chronic oral exposure include dry and flaky skin around mouth, tail tip missing, pustules on tail, and damaged or shortened tails. The skin lesions in the dog followingPage 11 of 54

o ral exposure via capsules included indurated and inelastic pads; scale formation on external ear; reddening of skin of thoracic, inguinal, and axillary regions; hardened foot pads; microscopic findings of acanthosis of the epidermis and ear; hyperkeratosis of footpad and ear; and skin inflammation following chronic oral exposure. An acute lethality study shows that fenpropidin is not acutely toxic by the oral route of exposure.

Clinical signs of neurotoxicity and neuropathology are the other major toxic ef fects observed following oral exposure in the rat and dog, and the dog is the most sensitive species for the
neurotoxic effects. In the rat 90

- day neurotoxicity study, hindpaw grip strength was decreased in both sexes and forepaw grip strength was decrease d in males during the functional observational battery (FOB) evaluations. Bilateral hindlimb paralysis/paresis, which correlated with the histopathological finding of demyelination of the spinal cord, cranial and spinal nerve roots, and proximal peripheral nerve, was observed in one female rat at the highest dose tested. In dogs, paresis was observed in one male dog that was sacrificed on week 38, and demyelination of the spinal cord was observed in three of four male dogs at the high dose. Although an ac ute neurotoxicity study on fenpropidin is not available, the Hazard and Science Policy Council (HASPOC) determined that the acute neurotoxicity study in rats is not required (TXR# 0056640

, 5/3/13 ).

Developmental toxicity was observed in the rabbit develo pmental toxicity study, as evidenced by an increase in fetal (litter) incidence of malformations ( persistent truncus arteriosus and severely malaligned sternebrae ) in the absence of maternal toxicity. In one rat developmental toxicity study, decreased ossi fication (increased incidences of half present, poorly ossified, and split or incised neural arches; wave

- like bent rib) was observe d at the same dose level where maternal toxicity was observed (decreased body weight gain and food consumption). In another rat developmental toxicity study, asymmetrically shaped sternebrae #5 occurred at the high dose in the absence of maternal toxicity. In the rat reproductive toxicity study, decreased body weight and delayed sexual maturation were observed in F1 males (2.7 days) and F1 females (9.5 days) at the high dose and in F1 females (4.6 days) at the next lower dose where maternal toxicity was observed (decreased body weight, body weight gain and food consumption). Reproductive toxicity was observed, as evidenced by th e decrease in spermatids in the testes and sperm cells in the cauda epididymides in the P generation males. However, the response was marginal and occurred only at the high dose, and it was not consistent across generations. In the developmental
neurotoxic ity study in the rat, decreased male pup body weight during the preweaning period, increased number of dead pups/cannibalized pups, and decreased brain weight, decreased radial thickness of the cortex (level 3), and decreased vertical height of the dentate hilus (level 3) in PND 72 females were observed at the same dose level where skin irritation effects (scabbing and hair loss around the mouth and forelimbs) were observed in the maternal animal

.

There is no concern for mutagenicity following exposure to fenpropidin. The carcinogenicity of fenpropidin has been evaluated by the Cancer Assessment Review Committee of OPP, and it classified fenpropidin as “suggestive evidence of carcinogenicity”. Although the rat study showed that fenpropidin was associated with an increase in tumors in the pancreas, HED concluded that quantification of risk using a non

- linear approach; i.e., RfD, for fenpropidin will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to f

enpropidin.Page 12 of 54

An immunotoxicity study has been submitted and is currently undergoing review. A preliminary screen of the study indicates that fenpropidin is negative for immunotoxic effects.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

Although there was quantitative and/or qualitative susceptibility observed in the in the rat and rabbit developmental toxicity studies, in the rat developmental neurotoxicity study, and in the rat

2

- generation reproduction study, there is no residual unc ertainty because the effects are well characterized, a clear NOAEL was identified, and the endpoints chosen for risk assessment are protective of potential in utero and developmental effects. Quantitative susceptibility in the rabbit developmental toxicity study was based on the occurrence of malformations and decreased fetal body weight in the absence of maternal toxicity. Quantitative susceptibility in the rat developmental toxicity study was based on asymmetrically shaped sternebrae #5 at the high dose

i n the absence of maternal toxicity. Qualitative susceptibility in the DNT was based on decreased pup body weight during preweaning period, increased number of dead pups/cannilbalized pups, decreased brain weight, decreased radial thickness of the cortex (l evel 3) and decreased vertical height of the dentate gyrus (level 3) in females on PND 72 where skin irritation (scabbing and hair loss around mouth and forelimbs) was observed in the maternal rat. Qualitative susceptibility in the 2

- generation reproductio n study was based on the decrease in pup body weights and delayed onset of sexual maturation observed at the same dose that resulted in decreased maternal body weight and increased incidence/severity of cortical fatty changes in adrenals. The apparent enha nced sensitivity may be due to the limited number of evaluations conducted in dams in these studies rather than a true sensitivity of the young.

Neuropathology was observed (1) in the rat subchronic neurotoxicity study, as evidenced by demyelination of t he spinal cord, cranial and spinal nerve roots, and peripheral nerve in one female displaying bilateral paralysis of the hindlimbs; (2) in the chronic dog study where demyelination was observed in the spinal cord; and (3) in the rat developmental neurotoxi city study, as evidenced by decreases in brain weight, radial thickness of the cortex and vertical height of the dentate hilus at level 3 in PND 72 females. Based on clearly established NOAELs and LOAELs for the populations of concern and the fact that the re are no datagaps, the points of departure are protective of the neuropathology observed.

HED recommends that the 10X FQPA Safety Factor (for the protection of infants and children) be reduced to 1X. An FQPA Safety Factor of 1X is appropriate for the following reasons:

1. The toxicity database for fenpropidin is complete. 2. The level of concern for neurotoxicity is low because there is a developmental neurotoxicity (DNT) study in rats, the effects are well characterized, the dose

- response cur ve for these effects is well characterized, and clear NOAELs have been identified. 3. Although there is evidence of quantitative susceptibility in the rat and rabbit developmental toxicity studies and qualitative susceptibility in the DNT and rat 2

- gen eration reproduction study, the endpoints and doses selected for risk assessment are protective for these effects.

4. There are no residual uncertainties identified in the exposure databases. The dietary food exposure assessments were performed based o n conservative high

- end assumptions in the dietaryPage 13 of 54

exposure assessment, including the use of 100% crop treated assumptions and field trial residues. This is an import tolerance; therefore, there is no drinking water assessment, no residential

assessment, a nd no occupational assessment.

4.4.1 Completeness of the Toxicology Database

The toxicology database for fenpropidin is complete. Acceptable rat and rabbit developmental toxicity studies, a rat 2

- generation reproduction study, a subchronic neurotoxicity study in rats, and a developmental neurotoxicity study in rats are available. An immunotoxicity study is also available and is undergoing review. The HED’s Hazard and Science Policy Council (HASPOC) determined that the acute neurotoxicity study in rats is not required since it will not provide a point of departure lower than those available in the database (TXR# 0056640, 5/3/13 ).

4.4.2 Evidence of Neurotoxicity

There is a concern for and evidence of neurotoxicity resulting from exposure to fenpropidin, based on (1) bilateral paralysis of the hindlimbs (paresis) in one female rat in the subchronic neurotoxicity study, which correlated with neuropathology (demyelination of spinal cord, cranial and spinal nerve roots and peripheral nerve); (2) decreased hin dlimb grip strength (both sexes) and decreased forelimb grip strength (males) during the FOB examination in the subchronic neurotoxicity study, and (3) paresis and demyelination in the spinal cord in males in the chronic dog study; and (4) neuropathology i n the developmental neurotoxicity study in the rat, as evidenced by decreased brain weight and decreases in radial thickness of the cortex at level 3 and vertical height of the dentate hilus at level 3 in PND 72 females.

4.4.3 Evidence of Sensitivity/Susc eptibility in the Developing or Young Animal

There is evidence of increased susceptibility following in utero exposure to fenpropidin in the rabbit developmental toxicity study, in a rat developmental toxicity study, and in the rat developmental neurotoxi city study, and following in utero and/or pre

- /post

- natal exposure in the

2

- generation reproduction study in rats. There is no evidence of increased susceptibility following in utero exposure to fenpropidin in another rat developmental toxicity study.

Fenpropidin has been evaluated for potential developmental effects in the rat and rabbit (gavage administration). Maternal toxicity included decreased body

- weight gain in one rat study, but maternal toxicity was not observed in the other rat study. Develo pmental effects observed in the rat included asymmetrically shaped sternabrae #5 and delayed ossification. Decreased maternal body weight, body weight gain, and food consumption were observed in the rat 2

- generation reproduction study at the same dose leve ls where delayed sexual maturation (females) and decreased pup body weight and pup body

- weight gain were observed in both sexes. In the rabbit, malformations (persistent truncus arteriosus and severely malaligned sternebrae) were observed
in the absence of maternal toxicity. There is evidence of neuropathology in the young in the developmental neurotoxicity study in the rat, as evidenced by decreased brain weight and a
decrease in radial thickness of the cortex at level 3 and a decrease vertical height of t he dentatePage 14 of 54

hilus at level 3 in PND 72 females at the same dose level where skin irritation effects (scabbing and hair loss around the mouth and forelimbs) were observed in the maternal animal

.

4.4.4 Residual Uncertainty in the Exposure Database

The toxic ity and exposure databases are complete

. HED has used conservative high

- end assumptions in the dietary exposure assessment, including the use of 100% crop treated assumptions and field trial residues. HED is confident that the dietary risks in this asses sment are not underestimated.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios is presented in Appendix A.

An acute dietary endpoint for females 13

- 49 years old was selected from the rabbit developmental toxicity study with a NOAEL of 10 mg/kg/day. At the LOAEL of 20 mg/kg/day, malformations ( persistent truncus arteriosus and severely malaligned sternebrae ) were observed in the absence of maternal toxicity. The malformations are considered attributable to a single exposure. Although this study shows increased susceptibility, there is a clear NOAEL for the endpoint of concer n. Additionally, the dose and endpoint are protective of effects observed in prenatal animals (population of concern) in the developmental toxicity, developmental neurotoxicity, and reproduction toxicity studies. The FQPA factor can be reduced to 1X. The

1 00X uncertainty factor was applied to account for inter

- and intra

- species variability resulting in an acute reference dose (aRfD) of 0.10 mg/kg/day. Since the FQPA factor is reduced to 1X, the aRfD is equivalent to the acute population adjusted dose (aPA D).

An acute dietary endpoint for infants and children was selected from the developmental neurotoxicity study in rats with a NOAEL of 7 mg/kg/day. At the LOAEL of 27 mg/kg/day, decreased pup body weight during the preweaning period, increased number of d ead pups/cannibalized pups, decreased brain weight, decreased radial thickness of the cortex at level 3, and d ecreased vertical height of the dentate hilus at level 3 in PND 72 females were observed
at a dose level where skin irritation effects were seen i n the maternal rat. The offspring effects are considered attributable to a single exposure, although it cannot be discerned whether it is due
to pre

- or postnatal exposure. Although this study shows increased susceptibility, there is a clear
NOAEL for the endpoint of concern. Additionally, the dose and endpoint are protective of effects observed in postnatal animals (population of concern) in the developmental neurotoxicity and reproduction toxicity studies. The FQPA factor can be reduced to 1X. The 100X un certainty factor was applied to account for inter

- and intra

- species variability resulting in an acute reference dose (aRfD) of 0.07 mg/kg/day. Since the FQPA factor is reduced to 1X, the aRfD is equivalent to the acute population adjusted dose (aPAD).Page 15 of 54

A n acute dietary endpoint for the general population was not selected. The acute neurotoxicity study was waived by HASPOC who concluded that an acute neurotoxicity study would not provide a point of departure lower than those available in the toxicology dat abase (TXR# 0056640).

The chronic dietary endpoint was selected from the chronic oral toxicity/carcinogenicity study in the rat with a NOAEL of 2.3 mg/kg/day. At the LOAEL of 11.9 mg/kg/day, decreased body weight and body weight gains in females, clinic al signs [pustules on tail, missing tail tip (males
20%/ females 57% vs 2% in control), and dry, flaky skin around mouth], and microscopic liver lesions (centrilobular fat) were observed in females. This study provides the lowest NOAEL. The point of depar ture is protective of the demyelination of the spinal cord and cataracts observed in both the rat (at 90 mkd; NOAEL ≈10 mkd) and dog (at 20 mkd; NOAEL 5 mkd) studies. A 100X uncertainty factor was applied to account for inter

- and intra

- species variability resulting in a chronic reference dose (cRfD) of 0.02 mg/kg/day. Since the FQPA factor is reduced to 1X, the cRfD is equivalent to the chronic population adjusted dose (cPAD).

Because there are no registered or proposed uses of fenpropidin in the U.S., r esidential and drinking water exposures are not expected ; an incidental oral exposure assessment or drinking
water assessment is not required . Similarly, q uantification of dermal and inhalation risk is not required ; the anticipated exposure is from consumption of imported bananas that have been previously treated with fenpropidin.

4.5.2 Cancer Classification and Risk Assessment Recommendation

The Cancer Assessment Review Committee (CARC) classified fenpropidin as “Suggestive Evidence of Carcinoge nicity” based on benign pancreatic cell adenomas seen in high

- dose male rats in the chronic toxicity/carcinogenicity study (TXR No. 0055217, dated June 9, 2009)

. Tumors were not increased in the mouse carcinogenicity study in either sex or in the female ra t. Mutagenicity is not of concern

. Although the rat study showed that fenpropidin was associated with benign pancreatic islet cell adenomas in the male, the EPA has determined that quantification of risk using a non

- linear approach; i.e., RfD, for fenpropi din will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to fenpropidin. That conclusion is based on the following considerations: (1) the tumors found were benign; (2) are common age

- related tumors; (3) occurred in only one sex in one species; (4) fenpropidin is not mutagenic; and (5) no carcinogenic response was seen in either sex in the mouse. A summary of both carcinogenicity studies is presented in Appendix A.3.

4.5.3 Summary of Points of Departu re and Toxicity Endpoints Used in Human Risk
Assessment.Page 16 of 54

Table 4.5.3 . Summary of Toxicological Doses and Endpoints for Fenpropidin for Use in Dietary Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD/PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary (General Population, excluding Infants and Children) No hazard or appropriate acute endpoint was identified for the general population.

Acute Dietary (Females 13

- 49 years of age) NOAEL = 10

mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1X aRfD = 0. 10

mg/kg

aPAD = 0. 1 0 mg/kg Developmental toxicity study (rabbit)

MRID 48681802 (2011) LOAEL = 20 mg/kg, based on increased fetal (litter) incidence of m alformations ( persiste nt truncus arteriosus

, severely malaligned sternebrae ) and decreased male fetal body weight in the absence of
maternal effects. (does dosed on GD 7

- 28)

Developmental neurotoxicity study (rat ) MRID 48836501 (2011) NOAEL = 7 mg/kg/day

LOAEL = 27 mg/k g /da y , based on decreased brain weight, decreased radial
thickness of the cortex at level 3, and decreased vertical height of the dentate
hilus at level 3 in females on PND 72

.

Acute Dietary (Infants and Children) NOAEL = 7

mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1X aRfD = 0.07

mg/kg

aPAD = 0.07mg/kg Developmental neurotoxicity study (rat)

MRID 48836501 (2011)

LOAEL = 27 mg/k g /da y , based on decreased brain weight, decreased radial

thickness of the cortex at level 3, and decreased vertical height of the dentate

hilus at level 3 in females on PND 72

. Chronic Dietary (All Populations) NOAEL= 2.3

mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1X Chronic RfD =

0.023 mg/kg/day

cPAD = 0.023 mg/kg/day Rat chronic/carcinogenicity.

LOAEL = 11.8 mg/kg/day

, based on decreased body weight and body weight gains in females, clinical signs in males
and females (pustules on tail, missing tail tip, and dry, flaky skin around mouth), and microscopic liver lesions (centrilobular fat)
in females. Cancer (oral ) Classification: "Suggestive evidence of carcinogenic potential" ; quantification of risk using a

non

- linear approach; i.e., RfD, for fenpropidin will adequately account for all chronic toxicity, including carcinogenicity, that could result f rom exposure to fenpropidin. Point of Departure (POD) = A data point or an estimated point derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animals to humans (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. cPAD = chronic population adjusted dose. RfD = reference dose. N/A = not applicable.Page 17 of 54

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite Residue Profile

5.1.1 Summary of Plant Metabolism Studies

Syngenta Crop Protection submitted a n adequate study investigating the metabolism of [N

- 2

- methyl

- propyl

- 3

- 14 C] fenpropidin in greenhouse grown bananas. The [ 14 C] fenpropidin was formulated as a 750 g/L EC and diluted with water and surfactant for application. The formulated [ 14 C]fenpropidin was applied to a banana plant as three foliar applications using a
hand

- held sprayer at a rate of 600 g ai/ha/application for a total of 1800 g ai/ha ( 0.3x proposed

use rate ). The initial application was made just prior to bloom; the second applic ation was made 35 days later during fruit development; and the third application was made 55 days after the 2 nd
application at fruit maturity (90 days after initial application). During each application, the
inflores cence and developing fruit bunch was covered with a plastic bag to protect flowers and fruits from direct application.

Leaf samples were collected immediately prior to the 2 nd and 3 rd applications and one day following the 3 rd application (35, 90 and 91 days after the first application; DAT), a single immature fruit was collected just prior to the 2 nd application (35 DAT), and mature fruits were collected one day after the final application (91 DAT, 1

- day PHI). Fruit samples were separated into peel and pulp fractions for analysis. All samples were stored frozen (

- 18°C) and were extracted and analyzed within 1 month of harvest; therefore, no supporting storage stability data are required for this study.

At 35 days after the first application, t otal ra dioactive residues (TRR) were 159 ppm in/on leaves, 3.63 ppm in/on peel and 1.49 ppm in pulp , for total residues of 3.13 ppm in/on immature fruit. Following the second application, radioactive residues in/on leaves declined to 42.9 ppm just prior to the third application (90 DAT), and then increased to 208 ppm one day following the final applica tion (91 DAT). One day after the final application TRR in/on mature fruits were
3.39 and 5.10 ppm in/on peel and pulp , respectively

.

Samples were extracted with methanol (MeOH):water followed by propanol ( PrOH ) :water.
Post

- extraction solids (PES) accounted for 2.7

- 11.4% of the TRR from leaves, 6.2

- 14.8% of the TRR from peel, and 1.9

- 4.9% of the TRR from pulp. 14 C

- Residues in the MeOH:water fractions
were identified by co

- chromatography with reference standards using two different 2D

- TLC (Two

- Dimensional Thin Layer Chromatography) systems ; the PrOH:water extracts were not further analyzed.

At the first sampling interval (35 DAT), 32.8% of the TRR was identified in leaves and 72.5

- 85.3% of the TRR was identified in immature peel, pulp and whole fruit. Fenpropidin accounted for 27% of the TRR in leaves, 65.9% of the TRR in peel, 83.9% of the TRR in pulp, and 70.1%
of the TRR in whole fruit. The N

- oxide metabolite

, CGA 289263

, was also identified in leaves
and ea ch fruit fraction, accounting for 1.4

- 6.6% of the TRR. Two major unknowns were detected in leaves (I 9 and I 13 ) accounting for 16.5 and 10.9% of the TRR, but fraction I 9 was notPage 18 of 54

detected in fruits and I 13 accounted for ≤2% of the TRR in fruit fractions . A ll other unknowns were present at <10% of the TRR.

In the leaves sampled just prior to the third application (90 DAT), 60.3 % of the TRR was
identified . Fenpropidin accounted for 45.8% of the TRR, CGA 289263 accounted for 7.6% of
the TRR and CGA 289268 ac counted for 6.9% of the TRR. All unknowns accounted for <10%
of the TRR.

In mature fruits sampled one day after the last application (91 DAT), 62.4

- 79.8% of the TRR was identified in peel and pulp. Fenpropidin accounted for 44.2% of the TRR in peel an d 76.5% of the TRR in pulp, or 48.8% of the TRR on a whole fruit basis. CGA 289263 was a major residue in whole fruit, but this metabolite was associated primarily with the peel (16.1% TRR) rather than the pulp (3.3% TRR). Metabolite CGA 289268 was also identified in the peel (2.1% TRR), but was not detected the pulp. No unknowns accounting for ≥10% of the TRR were detected in peel, pulp or whole fruit.

The initial metabolism of fenpropidin in bananas involves either hydroxylation of the tert

- butyl
sid e chain or N

- oxidation of the piperidinyl ring.

5.1.3 Comparison of Metabolic Pathways

The rat metabolism study showed that fenpropidin was rapidly and nearly completely orally absorbed at 0.5 mg/kg, but was incompletely absorbed at 100 mg/kg in females. No
bioaccumulation occurred. The chemical was completely metabolized and excreted mostly in urine. The only major urinary metabolite was 2

- methyl

- 2

- [4

- (2

- methyl

- 3

- piperidine

- 1yl

- propyl)

- phenyl]

- propionic acid, which accounted for 46

- 79% of the dose. The main metabolite found in
feces in females was sulfuric acid mono

- {2

- methyl

- 2

- [4

- (2

- methyl

- 3

- piperidine

- 1

- yl

- propyl)

- phenyl]

- propyl}ester), which accounted for 6

- 9% of the dose at 0.5 mg/kg and 27% at 100 mg/kg. This same compound was the main biliary metabolite in females, accounting for 6% of the dose. In males, all identified metabolites in feces were less than 1.7% of the dose.

Based on the submitted banana metabolism study, the qualitative nature of fenpropidin residues in bananas is adequately understood. Fenpropidin is the major residue identified across all matrices (banana pulp, peel, whole fruit, and leaves). Only one other metabolite was identified as a major metabolite in peel and whole fruit matrices; metabolite CGA 289263 comprises 16 % TRR in banana peel and 14% TRR in banana whole fruit. Since banana peel is not considered an edible commodity and metabolite CGA 289263 represented <5% TRR in the edible part of the banana, banana pulp, this metabolite is not included as a residue of co ncern.

Neither of the rat metabolites were detected in the plant metabolism study; conversely, the major plant metabolite was not detected in the rat metabolism study. See Appendix B for a summary table of the compounds identified from the ba nana and r at m etabolism s tudies.

5.1.4 Residues of Concern Summary and RationalePage 19 of 54

For purposes of the tolerance expression and risk assessment, the HED Residues of Concern Knowledge

- Based Subcommittee (ROCKS) has determined that the residue of concern in/on
bananas i s fenpropidin per se (D362400, 3/09).

The banana metabolism study showed that parent fenpropidin is the major residue identified across all matrices (banana pulp, peel, whole fruit, and leaves). Only one other metabolite, CGA 289263, was identified as a major metabolite in peel and whole fruit matrices. Because of the similar structures of the parent molecule and CGA 289263, as well as the relatively small amounts of the metabolite found in the edible portion of bananas, the hazard and risk resulting

f rom consumption of this metabolite are adequately covered by considering any risks from the parent compound.

Metabolism data for rotational crops, livestock commodities, and drinking water are not required since fenpropidin is proposed for an import tolerance only on bananas.

Table 5.1.4 Summary of Metabolites and Degradates to be included in th e Risk
Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Fenpropidin Fenpropidin

Rotational Crop NA NA

Livestock Ruminant NA NA

Poultry NA NA

Drinking Water NA NA

NA= Not applicable. Fenpropidin is proposed for an import tolerance only on bananas. No livestock, rotational crop or drinking water data are required.

5 .2 Food Residue Profile

Fenpropidin may be used on bananas for up to 12 repeated broadcast foliar applications throughout plant development at a rate of 0.45 kg ai/ha/applicat i on (0.4 lb ai/A) with a minimum

RTI of 7 days (maximum yearly rate of 5.4 kg ai/ha )

.

There are currently no tolerances for f enpropidin in the U.S. H owever, because the proposed use on banana includes registrations in countries that are major exporters of bananas to the U .S. (Columbia, Ecuador, Guatemala, Honduras, and Costa Rica), Syngenta is proposing the establishment of a permanent U.S. tolerance f or residues of fenpropidin on banana

.

Adequate residue data are available to support the establishment of a fenpropidin tolerance on bananas and for risk assessment purposes. Thirteen b anana field trials were conducted in Colombia, Ecuador, Guatemala, Hon duras, and Costa Rica, which t ogether account for > 90% of the bananas imported into the U.S. The available residue data support up to 12 foliarPage 20 of 54

applications of fenpropidin (EC) to banana plants during flowering through fruit development at ~0.45 kg ai/ha/ application with a minimum retreatment interval ( RTI ) of 7 days, for a maximum rate of 5.4 kg ai/ha/year

. Fenpropidin residues were quantifiable at levels of 0.03

- 7.0 ppm in/on samples of unbagged bananas and <0.01

- 1.0 ppm in/on samples of bagged bananas from the field
trials . Recommended tolerances are based on residues on unbagged fruit.

In four of the field t rails , banana s were also separated into peel and pulp fractions for additional analysis ; residues were primarily on the peel: residues of fenpropidin were up to 3.3 ppm on unbagged banana peels, and up to 0.19 ppm in unbagged banana pulp. There are no residue
decline data.

Adequate storage stability data were submitted indicating that residues of fenpropidin are stable in banana pulp and peel stored at ≤

- 18°C for up to 24 months.

Residue chemistry deficiencies include the following : a r evised Section F is required amendin g the proposed tolerance on bananas and a n analytical reference standard for fenpropidin must be provided to the EPA National Pesticide Standards Repository (see D410080, 6/11/ 13, Fenpropidin, Petition for the Establishment of a Tolerance on Imported Bananas. Summary of Analytical Chemistry and Residue Data ).

See Appendix B for a summary table of the residues measured in the banana field trials.

5.4 Dietary Risk Assessment

5.4.1 Description o f Residue Data Used in Dietary Assessment

Acute and chronic dietary (food only) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16. This softw are uses 2003

- 2008 food consumption data from the
USDA’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). Food alone residues were considered, as drinking water exposure is not expected because the proposed fenprop idin use is for imported bananas only.

T he highest and average field trial values of 0.19 ppm and 0.08 ppm for banana pulp

, the edible portion of the banana, were used for acute and chronic dietary assessments, respectively. Agricultural practices fo r bananas may involve treating bananas in bags or unbagged and residue data are available for both bagged and unbagged fruit. The data f rom the unbagged banana s was used in the dietary assessment since it showed higher residues than those treated in the b ag s. DEEM 7.81 default processing factors (PFs) we re also incorporated for dried bananas and plantains

.

5.4.2 Percent Crop Treated Used in Dietary AssessmentPage 21 of 54

The acute and chronic dietary assessments were performed under the assumption that 100% of
bananas are treated with fenpropidin.

5.4.3 Acute Dietary Risk Assessment

Partially refined acute dietary exposure assessments were performed using individual points of departure (PODs) for the two population subgroups all infants and children, and females 13

- 49

years old . The analyses were conducted with the highest field trial residue (banana pulp) , 100% crop treated (%CT) and default processing factors (PFs). The analysis resulted in acu te dietary
risk estimates for food alone that are below the HED’s level of concern

. The highest risk
estimate at the 95 th percentile was 3.0 % of the acute population

- adjusted dose (aPAD) for all infants (<1 year old). For females 13

- 49 years, the risk es timate was <1% of the aPAD at the
95 th percentile of exposure.

5.4.4 Chronic Dietary Risk Assessment

A partially refined chronic dietary exposure assessment was performed for fenpropidin using average field trial residue (banana pulp) , 100 % CT and default PFs. The analysis resulted in
chronic dietary risk estimates for food alone that are below the HED’s level of concern. The risk estimates for the general U.S. population and all population subgroups were <1% of the chronic population

- adj usted dose (cPAD).

5.4.5 Cancer Dietary Risk Assessment

Fenpropidin was considered with "Suggestive evidence of carcinogenic potential". However

, quantification of risk using a non

- linear approach ( i.e., RfD) adequately accounts for all chronic
toxici ty, including carcinogenicity, that could result from exposure to fenpropidin. A separate cancer assessment was not performed.

5.4.6 Summary Table

Table 2 . Summary of Dietary (Food Only) Exposure and Risk for Fenpropidin.

Population Subgroup Acute Dietary ( 95 Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD*

General U.S. Population NA NA 0.000030 <1
All Infants (<1 year old) 0.002090 3.0 0.000154 <1

Children 1

- 2 years old 0.001943 2.8 0.000171 <1

Children 3

- 5 years old 0.001310 1. 9 0.000083 <1

Children 6

- 12 years old 0.000638 <1 0.000032 <1

Youth 13

- 19 years old NA NA 0.000013 <1Page 22 of 54

Table 2 . Summary of Dietary (Food Only) Exposure and Risk for Fenpropidin.

Population Subgroup Acute Dietary ( 95 Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD*

Adults 20

- 49 years old NA NA 0.000017 <1

Adults 50

- 99 years old NA NA 0.000028 <1

Females 13

- 49 years old 0.00033 <1 0.000018 <1

*The subpopulation(s) with the highest risk estimates is highlighted in bold. For acute dietary exposure separate endpoints were used for all infants and children, and for females 13

- 49 years old. N/A

– not applicable, no endpoint was concluded for this population subgroup.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no residential uses of fenpropidin.

7.0 Aggregate Exposure/Risk Characterization

Because there are no registered uses of fenpropidin in the U.S., residential and drinking water

exposures are not expected. Therefore, aggregate risks are identical to food

- alone dietary risk
estimates

. There are no acute or chronic dietary risk estimates of concern. See section 5. 4 above.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxici ty finding as to fenpropidin and any other substances and fenpropidin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,
EPA has not assumed that fenpropidin has a common mechanism of toxicity with other substances. For information regarding EPA’s eff orts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedur es for cumulating effects from substances found to have
a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

There is no occupational exposure associated with fenpropidin in the U.S. because fenpropidin is not applied in this country.

10.0 ReferencesPage 23 of 54

D.Drew, 6/11 / 13, D410080, Fenpropidin. Petition for the Establishme nt of a Tolerance on Imported Bananas. Summary of Analytical Chemistry and Residue Data.

I. Encarnacion, 6/4/13, D410081 , Fenpropidin. Revised Acute and Chronic Dietary (Food Only) Exposure and Risk Assessments for the Proposed New Tolerance on Imported Bananas.

A. Dunbar, 5/3/13, TXR #0056640, Fenpropidin: Summary of Hazard and Science Policy Council (HASPOC) Meetings of April 11, 2013: Recommendations on the Requirement of the Acute Neurotoxicity Study.

E. Scollon. 3/09 , D362400, Fenpropidin: Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS )Page 24 of 54

A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for the food use for fenpropidin (import tolerance) are in
Tab le 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical
Required Satisfied
870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

no a

no a

no a

no a

no a yes

--

--

--

--

-- 870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

no a

no a

no a yes

yes

--

--

-- 870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... yes

no

yes

yes yes

yes

yes

yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5395 Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes yes

yes

yes 870.6100a Acute Delayed Neurotox. (hen)

................................ ..... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Developmental Neurotoxicity

................................ ........ no b

no b

no c

yes
CR --

--

--
yes

yes

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no b

yes yes

--
yes Special Studies for Ocular Effects no

--

a Not required to support tolerance s on imported food.

b Not required for fenpropidin (not an organophosphate)

c An acute neurotoxicity study is not required for fenpropidin (HASPOC TXR# 0056640, dated 5/3/13); demyelination, which occurred in the subchronic neurotoxicity study, is not expected to occur after a single dose; irritant properties of the compound limit the dose that could be given in a gavage study.Page 25 of 54

A.2 Toxicity Profile s

Acute Toxicity Profile

– Fenpropidin

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [species] 47317310 LD 50 = 2.17♂/♀1.45 g/kg III

870.1200 Acute dermal N/A and not required for import tolerance

870.1300 Acute inhalation N/A and not required for import tolerance

870.2400 Acute eye irritation N/A and not required for import tolerance

870.2500 Acute dermal irritation N/A and not required for import tolerance

870.2600 Skin sensitization N/A and not required for import tolerancePage 26 of 54 Fenpropidin Toxicity Profile

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 28

- Day oral

toxicity ( Sprague

Dawley rat) 47317312 (1994)

Acceptable/ non

- g uideline 50, 200, 1000, 2000 ppm M: 5, 20, 105, 200 F: 0, 6, 20, 103, 212 mg/kg/day NOAEL = 5 mg/kg/day LOAEL = 20 mg/kg/day, based on hyperkeratosis of the epithelium of the esophagus in males. At 103 mg/kg/day, decreased B W gain and histopath lesions of irritation [esophagus: hyperkeratosis of the epithelium; lung: alveolar macrophages (foam cells)]. More severe effects at HDT (non

- glandular stomach: hyperkeratosis of the epithelium and acanthosis; urinary bladder: hyperpl asia of the epithelium, inflammatory cell infiltration of submucosa; esophagus: hyperkeratosis of the epithelium and acanthosis; lungs: alveolar macrophages.

870.3100 90

- Day oral

toxicity ( albino rat

, feeding ) 47317314 (1981)

Unacceptable /Guideline Dietary concentrations not provided MF: 0, 20, 60, 120 mg/kg/d ay NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on decreased BW/BWG At 120 mg/kg/day, shaggy fur, rhagades of mouth, feet, tail and/or hairless areas; incipient necrosis of tail; hunched post ure; narrow palpebral fissures; scaliness of feet, tail, dorsum of nose, and/or hairless areas/skin
lesions

870.3100 90

- Day oral

toxicity ( albino

SPF mouse) 47317315 (1981)

Acceptable/Guideline 0, 625, 1250, 2500, 5000 ppm (0/0, 58/87, 155/179, 359/361, 547/566 mg/kg/day NOAEL < 87 mg/kg/day LOAEL = 87 mg/kg/day based on decreased BW at 155 mkd: ↓BW, decreased feed efficiency at 359 mkd: mortality (weeks 2

- 4, 13), ↓BW, ↑liver enzymes, hunched posture, decreased activity, skin lesions (hyperkeratosis and inflammation); ring

- like tail lesions with/without necrosis of the tip; peeling of skin on paws and nose; inflammation of the ears All mice died at 5000 ppm (females 4 wk; males 7 wk)

870.3150 28

- Day oral

toxicity ( Beagle dog , capsule ) 47317316 (1993)

Acceptable/Non

- guideline 0, 5, 15, 25 mg/kg/day NOAEL = 5 mg/kg/day LOAEL = 15 mg/kg/day based on signs (vomiting and salivation), decreased BW gains At 25 mg/kg/day, vomiting, salivation, and body weight loss were observed.

870.3150 26

- Week oral

toxicity ( Beagle dog , capsule) 47317317 (1981)

Acceptable/Non

- guideline 0, 2, 5,12 mg/kg/day NOAEL = 2 mg/kg/day LOAEL = 5 mg/kg/day based on vomiting and
decreased BW G at 12 mkd: 1 male died (week 16, 5 minutes after dosing)

870.3200 21/28

- Day dermal

toxicity N/A This study not required for import tolerance.

870.3465 90

- Day inhalation

toxicity N/A This study not required for import tolerance.

870.3700a Prenatal

developmental ( Fűllinsdorf albino rat) 47317320 (1981)

Acceptable/ Nonguideline 0, 20, 48, or 88 mg/kg/day
GD 7

- 16 Maternal NOAEL = 48 mg/kg/day LOAEL = 88 mg/kg/day based on decreased BW gain
and FC Developmental NOAEL = 48 mg/kg/day LOAEL = 88 mg/kg/day based on decreased ossification (increased incidences of half prese nt, poorly ossified, and split or incised neural arches;

wave

- like bent rib)Page 27 of 54 Fenpropidin Toxicity Profile

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3700a Prenatal

developmental ( Sprague

- Dawley rat) 47317318 (1994)

Acceptable/Guideline 0, 10, 60, or 90 mg/kg/day
GD 6

- 15 Maternal NOAEL = 90 mg/kg/day

LOAEL > 90 mg/kg/day Developmental NO AEL = 60 mg/kg/day LOAEL = 90 mg/kg/day based on asymmetrically shaped sternebrae #5.

870.3700b Prenatal

developmental (rabbit) 47317319 (1981)

Unacceptable /Guideline 0, 5, 12, 30 mg/kg/day Materna l NOAEL = 12 mg/kg/day

LOAEL = 30 mg/kg/day based on decreased BW gain. Developmenta l NOAEL = 30 mg/kg/day

LOAEL > 30 mg/kg/day , highest dose test.

870.3700b Prenatal

developmental ( New Zealand
White Hra:NZW)SPF rabbit) 48681802 (2011) main

48681801 (2011) pilot Acceptable/Guideline 0, 5, 10, 20 mg/kg/day

GD 7

- 28 Materna l NOAEL = 20 mg/kg/day
LOAEL = not identified. Developmenta l NOAEL = 10 mg/kg/day LOAEL = 20 mg/kg/day, based on an increase in fetal (litter) incidence of malformations ( persistent truncus arteriosus and severely malaligned sternebrae ) and decreased male fetal body weight in the absence of maternal toxicity.

870.3800 Reproduction and

fertility effects ( Wistar rat) 47317321 (2003)

Acceptable/Guideline 0, 25, 100, 500, 1000 ppm (0/0, 2.5/2.5, 9.0/9.5, 50.0/50.5, and 103/101 mg/kg/day M/F Parental/Systemic NOAEL = 9 mg/kg/day LOAEL = 50 mg/kg/day based on ↓ BW, FC ↑incidence/severity of cortical fatty change in adrenals

in P and F1females and at 101 mkd Reproductive NOAEL = 50 mg/kg/day

LOAEL = 101 mg/kg/day based on reduction in testes spermatids and cauda epididymides sperm cells Offspring NOAEL = 9 mg/kg/day LOAEL = 50 mg/kg/day based on decreased BW and delayed sexual maturation in females (4.6 days)

. At HDT, ↓BW, delayed sexual maturation in males (2.7 days); females (9.5 days).

870.3800 Reproduction and

fertility effects ( Sprague

- Dawley rat) 47317322 (1987)

Acceptable/Nonguideline 0, 6.25, 25, 100 ppm 0/0, 0.4/0.5, 1.8/2.0, 7.2/8.2 mg/kg/day M/F Parental
, Reproductive

, Offspring

NOAEL = 8.2 mg/kg/day

LOAEL > 8.2 mg /kg/day, highest dose tested. No toxicity occurred in this study.

870.4100b Chronic toxicity

( Beagle dog

, capsule )

– 52
weeks 47317323 (1995)

Acceptable/Guideline 0, 2, 5, 20 mg/kg/day NOAEL = 5 mg/kg/day LOAEL = 20 mg/kg/day based on mortality, altered

EKG

, demyelination of spinal cord (cervical, thoracic, lumbar)

, paresis of hind limbs, vomiting, decr eased BW, cataracts (bilateral) , skin lesions (indurated and inelastic pads; scale formation on external ear; reddening of skin of thoracic, inguinal, and axillary regions; hardened foot pads; microscopic findings of acanthosis of the epidermis and ear, hyperkeratosis of footpad and ear, inflammation of skin

. Dog that died on day 261 showed reduced motor activity, slight to moderate ataxic gait, severe paresis of
hindlimbs.Page 28 of 54 Fenpropidin Toxicity Profile

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.4200 Carcinogenicity

( CD

- 1 mouse) 47317325 (1983)

Acceptable/Guideline 0, 30, 100, 300, 1000 ppm 0, 4.5, 15, 45, 150 mg/kg NOAEL = 15 mg/kg/day
LOAEL = 45 mg/kg/day , based on hyperkeratosis in the esophagus of both sexes and in stomach in females. At 150 mg/kg/day, mortality, decreased BW, skin lesions (dry and/or flaky skin on tail, paws, and ears, loss of tail tip; hyperkera tosis of tail, ear, esophagus, subcutis, stomach; dermatitis of ear and tail; hyperplasia of mandibular lymph nose.

N o evidence of carcinogenicity

870.4300 Combined chronic

toxicity/carcinogen icity ( Sprague

Dawley rat) 47317324 (1989)

0, 2, 10, 50, 250 ppm 0, 0.07/0.09, 0.34/0.45,
1.68/2.27 and 8.53/11.83 mg/kg/day M/F NOAEL = 1.7/ 2.27 mg/kg/day (M/F)
LOAEL = 8.5/ 11.8 mg/kg/da y (M/F) based on
decreased BW and body weight gains in females

, clinical signs in males and females (pustules on tail, missing ta il, and dry, flaky skin around the mouth) and microscopic lesions in females (centrilobular fat in the liver). Benign pancreatic islet cell adenomas increased in
males

Gene
Mutation

870

. 5100 Bacterial reverse

mutation test 47317326 (1993) Negative

Cytogenetics
870.5300 In vitro

mammalian cell gene mutation test 47317327 (1988) Negative

Other Effects
870.5395 Mammalian

erythrocyte
micronucleus test 47317328 (1993) Negative

870.6200a Acute

neurotoxicity screening battery N/A This study not required for fenpropidin. Demyelination

, which occurred in the subchronic neurotoxicity study

, is not expected to occur after a single dose. Furthermore, the irritant effects of fenpropidin limit the dose which could be given in a gavage study. HASPOC waiver of ACN (TXR#0056640, dated May 3, 2013), since no appropriate endpoint would be determined.

870.6200b Subchronic

neurotoxicity screening battery ( Tif: RAIf (SPF), hybrid of RII/1 x RII/2 (SD derived rat) 47317313 (1995)

A cceptable/ G uideline 20, 150, or 1500 ppm
M: 1.14 , 9.84, 89.9 F: 1.24, 10.1, 97. 3 mg/kg/day NOAEL = 9.84 mg/kg/day LOAEL = 89.9 mg/kg/day based on decr eased BW,

cataracts (bilateral opaque eyes on Day 56 in 1♀), paresis, demyelination of spinal cord, cranial and spinal

ner ve roots and peripheral nerve , and decreased hindlimb grip strength. (bilateral paralysis of hindlimbs in one female) Microscopic findings indicative of irritation were observed in the esophagus, non

- glandular stomach, and urinary bladder ( skin effects were not reported ).Page 29 of 54 Fenpropidin Toxicity Profile

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.6300 Developmental

neurotoxicity [Wistar Han Crl:WI(HAN) rat] 48836501 (2011)

Acceptable/Guideline 40, 100, or 400 ppm Gestation: 3, 7, or 27 mg/kg/day Lactation: 7, 17, 67 mg/kg/day Maternal NOAEL = 7 mg/kg/day Maternal LOAEL = 27 mg/kg/day, based on skin irritation effects (scabbing and hair loss around the mouth and forelimbs)

. Offspring NOAEL = 7 mg/kg/day Offspring LOAEL = 2 7 mg/kg/day, based on decreased pup body weight during the preweaning period,
increase number of dead pups/cannibalized pups, decreased brain weight, decreased radial thickness of
the cortex at level 3, and decreased vertical height of
the dentate hilus at level 3 in females on PND 72

. 870.7485 Metabolism and

pharmacokinetics ( Sprague

- Dawley rat) 47317330 (1994)

47317331 (1996) 47317332 (1994) Rapidly and nearly completely orally absorbed at 0.5 mg/kg, completely absorbed in males and incompletely absorbed at 100 mg/kg. Completely metabolized and excreted mostly in urine (1 maj or metabolite = 46%

- 70% AD), also in bile in females (1 major metabolite = 6% AD). No bioaccumulation occurred.

870.7600 Dermal penetration N/A This study not required for import tolerance.

870.7800 Immunotoxicity 48681803 (2011) Currently u ndergoing review.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

– Females 13+

Study Selected: developmental toxicity study

- rabbit

MRID No. : 48681802 Executive Summary : See Appendix A, Guideline § 870.3 7 00 b
Dose and Endpoint for Risk Assessment: NOAEL = 1 0 mg/kg/day based on increased fetal (litter) incidence of malformations ( persistent truncus arteriosus and severely malaligned
sternebrae ) and decreased male fetal body weight in the absence of maternal toxicity at L OAEL

= 2 0 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factors: T he endpoint is appropriate for an

acute oral assessment for females 13+, since the malformations can be attributed to a single

exposure

. The developmental neurotoxicity study is co

- cr itical; the NOAEL is 7 mg/kg/day, and the LOAEL is 27 mg/kg/day, based on decreased brain weight, decreased radial thickness of the cortex (level 3), and decreased vertical height of the dentate hilus (level 3) in females on PND

72 , which may be attributed to a single exposure

. Since it could not be discerned whether these adverse effects on the brain are the result of pre

- or post

- natal exposure, they were included to be
conservative. There are clearly established NOAELs and LOAELs for populations of concern, no data gaps in the database, and the PODs are protective of susceptibility. Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability), FQPA
SF 1X.

A.3.2 Acute Reference Dose (aRfD)

– Infants and ChildrenPage 30 of 5 4

Study Selected: developmental neuro toxicity study

- rat

MRID No. : 48836501 Executive Summary : See Appendix A, Guideline § 870. 63 00 Dose and Endpoint for Risk Assessment: NOAEL = 7 mg/kg/day based on decreased brain weight, decreased radial thickness of the c ortex (level 3), and decreased vertical height of the dentate hilus (level 3) in females on PND 72 at LOAEL = 27 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factors: T he endpoint is appropriate for an

acute oral assessment for infants and children , since the findings in the brain can be attributed to a single exposure and it cannot be determined whether the findings are due to pre

- or postnatal

exposure

. There are clearly established NOAELs and LOAELs for populations of concern, no data gaps in the database, and the dose and endpoint are protective of the susceptibility observed in the rat developmental toxicity study, the rabbit developmental toxicity study, and rat 2

- generation reproduction study at higher exposure levels. Uncertainty Factor: 100 X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.3 Chronic Reference Dose (cRfD ) Study Selected: Chronic oral toxicity /carcinogenicity study

- rat

MRID No. : 4 7 3 1 7 32 4 Executive Summary : Se e Appendix A, Guideline [§ 870.4 100 a ] Dose and Endpoint for Risk Assessment: NOAEL = 2.3 mg/kg/day based on decreased body weight and body weight gains in females, clinical signs [pustules on tail, missing tail tip (males
20%/ females 57% vs 2% in control), and dry, flaky skin around mouth], a nd microscopic liver lesions (centrilobular fat) in females at LOAEL = 11.8 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint provides the most sensitive NOAEL available from a study of appropriate duration and exposure ( oral). The dose and endpoint are protective of the demyelination of the spinal cord and cataracts observed in both the rat and dog at higher exposure levels. Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.4 Exec utive Summaries

A.4.1 Subchronic Toxicity

870.3100 In a subchronic oral toxicity study (MRID 47317314 ), Ro 12

- 3049/000 (Fenpropidin; 94.7 % a.i.;

Lot No. N

- 3 ) was administered in the diet to albino rats ( 16 /sex/dose) for 13 weeks. Dietary concentrations were not reported, however, the study report stated that doses were 0, 20, 60, or 120 mg/kg/day. Six rats/sex from the 120 mg/kg/day were maintained for a 14 day recovery period after the treatment period of 13 weeks.

No treatment

- related effects were observed on mortality, ophthalmoscopic examinations, hematology, urinalysis, organ weights, or macroscopic or microscopic pathology. Body weights
were decreased in mid

- and high

- dose animals throughout the study. At te rmination, the 60 mg/kg/day males and females weighed 15% and 9% less than controls, respectively. The 120Page 31 of 54

mg/kg/day, males and females weighed 31% and 13% less than controls, respectively. Total food consumption was decreased in 60 mg/kg/day males by 7% compared to controls and in 120 mg/kg/day males by 18% compared to controls.

In the 120 mg/kg/day group, increased incidences in the following signs were observed (compared to 0/16 controls): (i) shaggy fur in 16/16 male and female; (ii) rhagades (m outh, feet, tail, and/or hairless areas) in 11 males and 6 females; (iii) incipient necrosis of the tail in 8 males and 11 females; (iv) hunched posture in 7 males and 6 females; (v) narrowed palpebral fissures in 6/16 females; (vi) scaliness (feet, tai l, dorsum of the nose, and/or hairless areas) in 16/16
males and females.

Several microscopic changes were noted in high

- dose animals but were of uncertain toxicological significance. An increased incidence of alveolar cells in the alveolar spaces of the lung was noted (number affected/16 at 120 mg/kg/day vs controls) in males (8 vs 0) and females (9 vs 2). The severity was petty to minimal, except in 2 treated females (in which moderate severity was observed). The following findings were also observ ed: (i) interstitial pneumonia in males (3 vs 0); (ii) nephrocalcinosis (4 vs 0); (iii) urinary bladder cystitis (4 vs 0); (iv) thyroid inflammation in males (5 vs 1, with 1 moderate severity in treated) and females (6 vs 2); and (v)
adrenal cortical zone inflammation in females (5 vs 1).

The LOAEL is 60 mg/kg/day , based on decreased body weights and body weight gains in

both sexes. The NOAEL is 20 mg/kg/day

.

This study is classified una cceptable/guideline and does not satisfy the guideline requirement s (OPPTS 870.3100; OECD 408) for a subchronic oral toxicity study in the rat. Dietary concentrations were not reported.

28

- Day Oral Toxicity

– Rat

In a repeated dose oral toxicity study (MRID 47317312), CGA114900 (Fenpropidin, 97 % a.i.,
Batch # P.110094002) was administered in the diet to 5 Sprague

- Dawley rats/sex/dose group at dietary concentrations of 0, 50, 200, 1000, or 2000 ppm (equivalent to 0/0, 5.4/5.6, 20.1/19.9, 104.6/103.4, and 200.1/212.2 mg/kg/day [M/F], respectively) for 4 weeks.

No t reatment

- related effects on mortality, clinical signs , hematology, clinical chemistry, organ weights, or gross pathology findings were observed at any dose.

At 1000 ppm, minor decreases in body weights were noted in the males and females during
Weeks 2

- 4, attaining statistical significance in the males at Week 3 ( ↓ 8%; p<0.05). Overall body weight gains were decreased by 20

- 25% in both sexes at this dose. Increased incidence (# affected/5 treated vs. 0/5 controls, unless otherwise noted) of the foll owing histopathological
effects were noted at 1000 ppm : esophagus ; minimal (4 females) or m oderate (5 males) hyperkeratosis of the epithelium , and lungs; minimal alveolar macrophages (foam cells) in 4 females (vs. 1 control).Page 32 of 54

At 2000 ppm, body weights we re decreased by 15

- 28% in the males and by 10

- 14% in the females during Weeks 2

- 4 (p<0.05), and overall body weight gains were decreased by 42

- 54% in both sexes. These decreases in the males corresponded to decreases (p<0.05) in food consumption (decr 23

- 28%) in this group during these weeks , and mean overall (Weeks 1

- 4) food consumption was decreased by 23% compared to controls in the males. Increased incidence (# affected/5 treated vs. 0/5 controls; unless otherwise noted) of the following histopathologi cal
effects were noted at 2000 ppm : (i) non

- glandular stomach; minimal (2 females) or m oderate (5 males) hyperkeratosis of the epithelium , and minimal acanthosis in all males ; (ii) esophagus ;

m oderate hyperkeratosis of the epithelium in all males and femal es, and minimal acanthosis in all males; (iii) urinary bladder; minimal hyper plasia of the epithelium in 4 animals of each sex, and minimal inflammatory cell infiltration in the submucosa in 4 males; and (iv) lungs; minimal to moderate alveolar macrophages (foam cells) in the males (4 treated vs. 1 control) and in the females (4 treated vs. 1 control).

Effects in the 200 ppm males were limited to decreased overall body weight gain and food consumption (both not dose

- dependent), and minimal hyperkeratosis o f the epithelium of the esophagus in 3/5 males vs. 0/5 controls. No effects of treatment were observed in the 50 or 200 ppm females or in the 50 ppm males.

T he LOAEL is 200 ppm ( 20 mg /kg/day) , based on hyperkeratosis of the epithelium of the esophagus in males. The NOAEL is 50 ppm (5 mg/kg/day).

This range

- finding study is classified acceptable/ non
- guideline

. It was not designed to satisfy a guideline requirement.

870.3100 90

- Day Oral Toxicity

- Mouse In a subchronic oral toxicity study (MRID 47317315), Ro 12

- 3049/000 (Fenpropidin, >99 % a.i., Lot # 6) was administered to 16 albino

- SPF mice/sex/dose in the diet at dose levels of 0, 625, 1250, 2500, or 5000 ppm (equivalent to 0/0, 58/87, 155/179, 359/361, and 547/566 mg/kg/day [M/F]) for up to 13 weeks.

All animals in the 5000 ppm group died or were sacrificed in extremis within the first 4 weeks (females) or 7 weeks (males) of the study, and no data from the 5000 ppm group were statistically analyzed. A low

- dose group (625 ppm) was started 7 weeks after the beginning of the initial study, and the animals in this group we re administered the test material in the diet for 13 weeks. Because of the mortality in the 5000 ppm group, the 2500 ppm group (Group IV) was referred to as the high

- dose group throughout the study report.

No treatment

- related effects were noted on ophth almoscopic examinations, hematology, urinalysis, organ weights, or gross pathology at any dose in either sex.

At 2500 ppm, one male was found dead during Week 13 after being in poor condition for 3 weeks. Five females were found dead during Weeks 2

- 4, and symptoms preceding death in these females generally included hunched back, reduced activity, skin lesions (hyperkeratosis and inflammation), and emaciation. In addition to the clinical signs of toxicity mentioned above, the following clinical signs (% affected) were observed at this dose: (i) ring

- like tail lesions with orPage 33 of 54

without necrosis of tip in the males (19

- 56%; Weeks 3

- 13) and females (7

- 91%; Weeks 2

- 13); (ii) peeling of the skin on paws and occasionally the nose in the males (6

- 13%; Weeks 5, 6 , and

9

- 12) and females (13

- 46%; Weeks 2

- 6); and (iii) inflammation of the ears in males (19

- 81%;
Weeks 4

- 13) and females (7

- 82%; Weeks 3

- 13). Histopathological effects of the skin were limited to hyperkeratosis in the males (6/15 treated vs. 0/15 control s). The Sponsor stated that

Ro 12

- 3049/000 is known to cause skin irritation, and the most probable cause of the local skin irritation observed at this dose was contact with the feed admixture. Additionally, the Sponsor
concluded that the localization of irritation on paws, tail, and nose, that is areas of the skin which are not protected by a dense fur, supports this interpretation, and inflammation of the ears was also explained by local skin irritation of the test material. Another reported local effe ct of the compound was roughening of the fur, especially around the head and forepart of the body being in contact most frequently with the feed admixture. It was stated that this finding was clearly dose and time dependent, being observed at 1250 (Week 5 in males and Week 2 in females) and 2500 ppm (Week 2 in both sexes). However, no tabular data for this finding were provided. At 2500 ppm, m ean body weights were decreased by 8

- 17% (p<0.05) in the males at Weeks 4

- 13 and by 9

- 18% (p<0.01) in the female s throughout the study. Overall body weight gain was decreased by 37% in the males and by 25% in the females. Food consumption was increased compared to controls throughout the study in both sexes at this dose (incr 4

- 97% in males and
incr 3

- 109% in fema les). Likewise, overall (Weeks 0

- 13) food consumption was increased by 9% in the females and by 49% in the males. As body weight gains were decreased despite these increases in food consumption, a less efficient utilization of the feed by dosed animals w as probable.

At 2500 ppm, a slight to moderate hepatotoxic effect was observed at this dose, as indicated by the following clinical chemistry and histopathological effects (# affected/# treated vs. 0 controls, unless otherwise stated): (i) a spartate am inotransferase levels were increased (p<0.05) by 85

- 100% in both sexes; (ii) alkaline phosphatase activity was slightly increased (↑46%, not statistically significant) in the males; (iii) intensively eosinophilic hepatocellular cytoplasm (4/15
males and 7/ 11 treated females); and (iv) appearance of PAS (Periodic Acid Schiff’s reaction) positive granules in the hepatocytes (15/15 treated males vs. 0/15 controls and 9/11 treated females vs. 4/16 controls).

At 1250 ppm, body weights were decreased (p<0.05) by 5

- 11% in the females throughout the study and overall (Weeks 0

- 13) body weight gain was decreased by 19% in both sexes. Food consumption was generally increased (no statistical analysis) compared to controls throughout the study in both sexes at this dos e (↑45

- 59% in males and ↑3

- 115% in females), and overall (Weeks 0

- 13) food consumption was increased by 28% in the males and by 8% in the females at this dose. Again, these decreases in body weight gain despite the increased food consumption,
indicate red uced food efficiency.

In the 625 ppm females, treatment

- related effects were limited to decreases in body weights ( ↓ 5

- 11%, p<0.05) during Weeks 3 and 5

- 13, and overall (Weeks 0

- 13) body weight gain ( ↓ 38%). The decreases in body weight gains were not dose

- dependent and no other evidence of toxicity was observed at this dose; however, significant decreases in body weight gains were seen in all female dose groups, and the magnitude of decrease was at least 19% at each dose level.Page 34 of 54

T he LOAEL is 625 ppm ( 87 mg/kg/day ) based on decreased body weight and gains in
females. The NOAEL was not determined.

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3100a; OECD 408) for a subchronic oral toxicity study in the mouse.

870.3150 90

- Day Oral Toxicity

- Dog

I n a range

- finding oral toxicity study (MRID 47317316), CGA114900 (Fenpropidin, 97 % a.i.,
Batch # P.110094002) was administered to 2 Beagle dogs/sex/dose via gelatin capsule at dose levels of 0, 5, 15, or 25 mg/kg/day for 28

- 29 days.

No effects of treatment were observed on mortality, ophthalmological examinations, hematology, clinical chemistry, ur inalysis, or gross or microscopic pathology. At 15 and 25 mg/kg/day, clinical signs of toxicity observed included vomiting (Week 1, at 15 mg/kg/day one female, and at 25 mg/kg/day one male and both females) and salivation (Week 2, at 15 mg/kg/day both fema les, and at 25 mg/kg/day both dogs of each sex). Mean overall (Week

1

- 4) body weight gains (calculated by reviewers) were decreased by 44% in the 25 mg/kg/day males, and the 15 mg/kg/day males did not gain any weight during the study. The 15 and 25 mg/kg /day females lost weight during the first two weeks of treatment, which resulted in overall body weight losses (

- 0.2 to

- 0.4 kg treated vs. 0.35 kg controls). These decreases corresponded to decreases in food consumption observed in the females during Wee ks 1 (decr 55

- 62%) and 2 (decr 23

- 40%). The feeding period was increased from 3 hours to 24 hours in the 15 and 25 mg/kg/day female groups during Days 11

- 14 and 11

- 21, respectively. During these intervals, food consumption returned to normal; however, du ring the final week of treatment (when the feeding period was returned to 3 hours) food consumption was decreased by 32% in the 25 mg/kg/day group. No treatment

- related effects were observed at 5 mg/kg/day in either sex.

The LOAEL is 15 mg/kg/day, based on clinical signs of toxicity (vomiting and salivation) and decreased body weight gains and food consumption. The NOAEL is 5 mg/kg/day.

This study is classified acceptable/non

- guideline.

In a non

- guideline subchronic oral toxicity study (MRID 47317317), Ro 12

- 3049/000 (Fenpropidin, 94.7 % a.i., Lot # N

- 3) was administered to 4 Beagle dogs/sex/dose via gavage (gelatin capsule) at dose levels of 0, 2, 5, or 12 mg/kg/day for 26 weeks. After 26 weeks of treatment, 2 dogs/sex/dose were sacrificed im mediately and tissues were collected for microscopic examination. The remaining 2 dogs/sex in each group were held for an additional 4 weeks without treatment (recovery period) before sacrifice and collection of tissues for microscopic examination.

No eff ects of treatment were observed on body weights, ophthalmological examinations, hematology, clinical chemistry, urinalysis, organ weights, or gross or microscopic pathology.

At 5 mg/kg/day, vomiting up to 2 hours post

- dosing was observed sporadically in b oth sexes throughout the study. Pooled (males and females combined) body weights were initially decreased (p<0.05) by 12

- 13% compared to controls at Weeks 0 and 1, and remained slightly decreased (not statistically significant) throughout the remainder of the treatment period. In thePage 35 of 54

females, mean overall (Weeks 0

- 25) body weight gains were decreased by 20% compared to
controls.

At 12 mg/kg/day, the frequency of vomiting in both sexes was higher than in the 5 mg/kg/day group. Additionally, females at th is dose showed salivation following administration of the compound, and during the first week of treatment, dogs of both sexes appeared excited at about 1 hour post

- dosing. Pooled body weights were initially decreased (p<0.05) by 13

- 15% at Weeks 1, 2, and 5, and remained slightly decreased (not statistically significant) throughout the remainder of the treatment period. In the females, mean overall (Weeks 0

- 25) body weight gains were decreased by 80%. Additionally at 12 mg/kg/day, one male (No. 641) was f ound dead during
Week 16 , five minutes after dosing

. No adverse treatment

- related effects were observed at 2 mg/kg/day in either sex. Vomiting was only observed on 1 or 2 occasions and there were no other findings indicative of toxicity.

The LOAEL is 5 mg/kg/day, based on clinical signs of toxicity (vomiting) and decreased body weight gains in females. The NOAEL is 2 mg/kg/day.

This study is classified a cceptable/non

- guideline

.

870.3200 21/28

- Day Dermal Toxicity

– Rat

A dermal toxicity is not ava ilable. Not required for an import tolerance.

870.3465 90

- Day Inhalation

– Rat

An inhalation study is not available. Not required for an import tolerance.

A.3.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

- Rat

In a developmental toxicity study (MRID 47317320 ), Ro 12

- 3049/000 (Fenpropidin; purity, batch no., and dietary concentrations not reported) was administered daily in the diet from gestation day (GD) 7

- 16 to 40 time

- mated F ü llinsdorf albino rats/dose group. Target doses were 0, 20, 50, or 125 mg/kg/day, and achieved doses were 0, 20, 48, or 88 mg/kg/day. On GD 21, half of the dams were euthanized; each dam’s uterus was removed via cesarean section and its

conte nts examined. Fetuses were examined for external, visceral, and skeletal malformations
and variations.

The remaining dams were allowed to deliver their young. On lactation day (LD) 23, the dams were killed, subjected to necropsy, and the uteri examin ed for implantation sites. The offspring were weighed on LD 1, 4, 12, and 23, and the young from 8 litters were killed and necropsied. The weights of the hearts, livers, and kidneys from these weanlings were measured.

No treatment

- related effects were observed on clinical signs or gross pathology. In the high

- dose group, one dam died on GD 19 and one dam died at GD 21; both dams died of unknown causes. Decreased body weight gains were noted in the mid

- (decr 34%) and high

- dose groups (decrPage 36 of 54

151%, body weight loss). Decreased total food consumption was noted during the treatment interval (GD 7

- 17) in the mid

- (decr 9%) and high

- dose group (decr 36%). In the high

- dose group, the decrease in food consumption was only 22% during GD 7

- 9 but the decrease gr ew as treatment continued to 58% during GD 15

- 17.

The maternal LOAEL is 88 mg/kg/day, based on decreased body weight gains and decreased food consumption. The maternal NOAEL is 48 mg/kg/day.

There were no abortions, premature deliveries, or dead fetu ses, and no adverse effects of treatment were noted on the numbers of litters, live fetuses, complete litter resorptions, or early or late resorptions. Similarly, the sex ratio of the treated groups was comparable to controls, and
post

- implantation loss w as not adversely affected. No treatment

- related effects were observed on litter size or viability. No adverse effect was noted on mean pup weights, and all weanling organ weights that were evaluated in the high dose group and the controls were of similar values. Evidence of delayed skeletal ossification was present. Increased incidences of half present, poorly ossified, and split or incised neural arches, as well as wave

- like bent rib were noted in the high

- dose group. The developmental LOAEL is 88 mg /kg/day
, based on delayed ossification. The developmental NOAEL is 48 mg/kg/day.

This study is classified acceptable/non

- guideline. The requirement for a developmental toxicity study in rats (OPPTS 870.3700; OECD 414) is satisfied when this study is considered with another developmental toxicity study in rats, MRID 47 317318.

870.3700a Prenatal Developmental Toxicity Study

- Rat

In a developmental toxicity study (MRID 47317318 ), CGA 114900 Technical (Fenpropidin;
97% a.i. ; Batch No. 110094002) in 0.5% (w/w) aqueous solution of sodium carboxymethylcellulose was administered via daily oral gavage in a dose volume of 10 mL/kg to
24 time

- mated Sprague

- Dawley rats/dose group at doses of 0, 10, 60, or 90 mg/kg/day from gestation days (GD) 6

- 15 . On GD 21 , all dams were euthanized; each dam’s uterus was removed via cesarean section and its contents examined. Fetuses were examined for external, visceral,
and skeletal malformations and variations.

No adverse, treatment

- related effect was noted on mortali ty, clinical signs, body weights, body weight gains, food consumption, or macroscopic pathology.

The maternal LOAEL was not established. The maternal NOAEL is 90 mg/kg/day.

There were no abortions, premature deliveries, complete litter resorptions, lat e resorptions, or dead fetuses and no effects of treatment on the numbers of litters, or early resorptions. Similarly, sex ratio, and post

- implantation losses of the treated groups were comparable to controls.

There were no effects of treatment on grow th or development of the fetuses, and no treatment

related effects noted on external or visceral examinations. The only skeletal variation was an increase in asymmetrically shaped sternebrae 5 (21.7% litter incidence vs 9.1% in controls). Although not st atistically significant, the litter incidence was slightly outside the historicalPage 37 of 54

control range.

The developmental LOAEL is 90 mg/kg/day based on asymmetrically shaped sternebrae 5. The developmental NOAEL is 60 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rats.

870.3700b Prenatal Developmental Toxicity Study

- Rabbit

In a prenatal developmental toxicity study ( MRID 48681802), Fe npropidin (96.9% a.i.;
Lot/Batch # SMO4E034 ) in 0.5% (w/v) aqueous carboxymethylcellulose (CMC) was administered orally by gavage to groups of 25 time

- mated female New Zealand White [Hra:(NZW)SPF] rabbits at doses of 0, 5, 10, or 20 mg/kg/day from gestatio n day (GD) 7 to GD 28. The doses were based on the results of a ranging

- finding study (MRID 48681801). Controls were dosed with CMC. Test substance and vehicle were administered in a dosing volume of 10 mL/kg. The does were sacrificed on GD 29 for eval uation of maternal and developmental parameters. Fetuses were weighed, sexed, and examined for external abnormalities. Visceral examination was performed using a modified Stuckhardt and Poppe fresh dissection technique that included the heart and major b lood vessels, and the heads of all fetuses were examined by
mid

- coronal slice. All fetuses were eviscerated, fixed in alcohol, cleared in potassium hydroxide, and stained with Alizarin Red S and Alcian Blue for skeletal examination.

There were no treatment

- related maternal deaths. One doe in the control group, two in the 10

- mg/kg/day group, and one in the 20

- mg/kg/day group died during the study, and one doe in the
20

- mg/kg/day group aborted; none of the deaths or abortion was considered treatment related. Absolute body weight was not significantly affected in any group and GD 29 body weight corrected for uterine weight was similar in treated and control groups. Body w eight gain initially (GD 7

- 8) was decreased at all dose levels (

- 2 grams,

- 4 gra ms, + 2 grams with increasing dose) compared to the control (+18 grams). During the first week (GD 7

- 13), reduced body weight gain was seen at 10 mg/kg/day (↓37%) and 20 mg/kg/day (↓20%) compared to the control. Body

w eight gain in the 20

- mg/kg/day group w as s ignificantly reduced during the GD 13

- 21 interval (↓62%) , and loss of body weight occurred during the GD 21

- 29 interval in the 10 and 20 mg/kg/day groups (

- 28 g and

- 60 g , respectively, vs +25 g for controls). Overall (GD 7

- 29), body weight gain was si gnificantly reduced at 20 mg/kg/day (↓64%) compared to the control and at 10 mg/kg/day (↓30%), although statistical significance was not attained. Food consumption in the

20

- mg/kg/day group was decreased by 17% to 18% during the latter phase of the study ( GD 13

- 29) and by 11% overall (GD 7

- 29). The only treatment

- related clinical sign observed was
decreased defecation in the 20

- mg/kg/day group starting on GD 16 and continuing to study termination. This observation is likely related to the reduction in food consumption observed during the same time period.

The lowest

- observed

- adverse

- effect level (LOAEL) for maternal toxicity for Fenpropidin administered orally to pregnant rabbits was not attained. The maternal no

- observed

adverse

- effect level ( NOAEL ) is 20 mg/kg/day.Page 38 of 54

No treatment

- related effects were observed on cesarean section parameters, fetal deaths, or growth at any dose level. Gravid uterine weight, number of corpora lutea, pre

- and post

implantation losses, total resorptions, early and late re sorptions, number of abortions, number of premature deliveries, number of litters produced, number of dead and viable fetuses, male and/or female fetal weight, and sex ratio were comparable among the groups.

A total of 222 (23), 224 (24), 197 (20), and 204 (23) fetuses (litters) in the control, 5

- , 10

- , and
20

- mg/kg/day groups, respectively, were examined externally, viscerally, and skeletally. The fetal (litter) incidence of malformations was significantly (p < 0.05) increased in the 20

- mg/kg/day group compared with that of controls. Malformations were observed in a total of 1 (1), 3 (3), 3 (2), and 7 (7) fetuses (litters) in the 0, 5

- , 10

- and 20

- mg/kg/day groups, respectively. The mean percent (malformations per litter) was 3.6±5.73 at 20 mg/kg/day, 0.4±1.90 in the concurrent controls, and 2.0±1.25 in historical controls. The overall increase in the incidence of malformations was due to persistent truncus arteriosus (visceral malformation) observed in 3 (3) fetuses (litters) and severely malaligned sternebrae observed in 3 (3) fetuses (litters). The incidence of the latter malformation (1.6±4.15) exceeded that of historical controls (0.1±0.24).

No treatment

- related external malformations or external, visceral, or skeletal variations were
observed i n this study. The most common variations observed at high incidences in all groups
included 13 th full rib, 5 th and/or 6 th unossified sternebrae, 13 th rudimentary rib, and 27 presacral
vertebrae.

The LOAEL for developmental toxicity for Fenpropidin admin istered orally to maternal rabbits is 20 mg/kg/day, based on the increase in the fetal (litter) incidence of malformations ( persistent truncus arteriosus and severely malaligned sternebrae) and decreased male fetal body weight

. The developmental toxicity NOAEL is 10 mg/kg/day.

The developmental toxicity study in the ra bbit is classified Acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study ( OCSPP 870.3700 b ; OECD 414) in
the ra bbit. There were no deficiencies in t his study that would affect the interpretation of the
results.

A.3.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

- Rat

In a two

- generation reproduction toxicity study (MRID 47317321), Fenpropidin (CGA 114900; 97%, Batch # P.110094002 ) was administered in the diet to 30 Wistar rats/sex/dose group at dietary levels of 0, 25, 100, 500, or 1000 ppm (equivalent to 0/0, 2.5/2.5, 9.0/9.5, 50.0/50.5, and 103/101 mg/kg/day in males/females, resp ectively) for two successive generations with one litter per generation. The P generation animals were fed the test diets for 10 weeks prior to mating to produce the F1 litters. After weaning of the last F1 litter, selected F1 offspring (30/sex/dose

group ) were fed the same test diet concentration as their dam for 10 weeks prior to mating to produce the F2 litters.

All P and F1 generation males and females survived until scheduled termination. Piloerection was noted in 1000 ppm F1 males early in the st udy. There were no other treatment

- related effects on clinical signs, gross pathology, or organ weights in the parents.Page 39 of 54

At 500 and 1000 ppm, body weights were decreased in the P and F1 males throughout the pre

mating period and remained decreased in thes e animals for the remainder of the study. Body weights were decreased in the P and F1 females at these doses throughout pre

- mating and gestation and in the P generation throughout lactation. On day 68, body weights were decreased in comparison to control s of both generations in 500 ppm males ( ↓ 10% and ↓ 12%), 500 ppm females ( ↓ 6% and ↓ 5%), in 1000 ppm males ( ↓ 12% for P generation and ↓ 30% for F1), 1000 ppm females ( ↓9% for P generation and ↓ 17% for F1 generation).

Body weight gains were decreased during the pre

- mating period in the P males and females at 500 ppm and 1000 ppm. Body weight gains were decreased in the 500 ppm P females during
GD 7

- 14. Additionally at 1000 ppm, body weight gains were decreased throughout gestation in both generations. Bod y weight gains were decreased in the P dams at 500 and 1000 ppm during
lactation. Food consumption was decreased in the 500 and 1000 ppm P males throughout much of the study.

Microscopic changes included an increased incidence and severity of cortical fatty change in the adrenals at 500 and 1000 ppm in the P and F1 females.

The LOAEL for parental toxicity is 500 ppm (50.0 mg/kg/day) based on decreased body weights, body weight gains, and food consumption in both sexes in both generations and
increase d incidence/severity of cortical fatty change in the adrenals of P and F1 females. The NOAEL is 100 ppm (9.0 mg/kg/day).

In the F2 litters at 1000 ppm, the mean numbers of implantations were decreased, resulting in decreased number of pups delivered and litter size. After culling, the litter sizes in the treated groups were comparable to controls throughout the remainder of the study, resulting in comparable lactation indices.

In the F1 and F2 litters, pup body weights were decreased at 500 ppm on PND 14 and 21 and at 1000 ppm throughout the post

- natal period. Pup body weights in the F1 litter on postnatal day 21 were decreased compared to controls at 500 ppm (

- 15%) and at 1000 ppm (

- 33%). F2 pup body weights on day 21 were decreased at 500 ppm (

- 11% ) and at 1000 ppm (

- 32%).

Delayed sexual maturation was noted in the 1000 ppm F1 males (2.7 days; day 28.0 compared to day 25.3 in controls). Sexual maturation was delayed in 500 ppm F1 females (4.6 days; day 37.1 vs day 32.5) and was markedly delayed in 1000 ppm F1 females (9.5 days; day 42.0 vs day 32.5).

The LOAEL for offspring toxicity is 500 ppm (50mg/kg/day) based on decreased body weights and gains in males and females and delayed sexual maturation in females. The NOAEL is 100 ppm (equivalent to 9 mg/kg/day).

There were no effects of treatment on the precoital interval, gestation duration, or on the mating, fertility, delivery, gestation, or parturition indices in either generation. There was a marginal decrease in spermatids and s perm cells at the high dose in the P generation males only. EstrousPage 40 of 54

cycle duration was increased in 1000 ppm F1 females (4.4 days vs 4.1 days in controls) but is not considered adverse and was within the normal range.

The LOAEL for reproductive toxicity is 1000 ppm (10 3 mg/kg/day) based on decreased spermatids and sperm cells in the P generation males. The NOAEL is 500 ppm (50 mg/kg/day).

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.3800; OECD 416) for a two

- generation reproduction study in the rat.

In a two

- generation reproduction toxicity study (MRID 47317322), Fenpropidin (RO 12

- 3049/000; 91%, Lot #5) was administered in the die t to 30 Sprague

- Dawley rats/sex/dose group at dietary levels of 0, 6.25, 25, or 100 ppm (equivalent to 0/0, 0.4/0.5, 1.8/2.0, and 7.2/8.2 mg/kg/day in males/females, respectively) for two successive generations with two litters per generation. The P gener ation animals were fed the test diets for 13 weeks prior to mating to produce the F1a litters. After weaning of the first litter, the P animals were rested for 10 days and mated again to produce the F1b litters. Selected F1b offspring (30/sex/dose group) were fed the same test diet concentration as their dam for 14 weeks prior to mating to produce the F2a and F2b litters as in the previous generation. All P and F1 parents and 10 rats/sex/dose group from the F2b weanlings were subjected to a gross necrops y, and selected tissues were examined microscopically.

In the parental animals, there were no treatment

- related mortalities or clinical signs of toxicity in either generation. There were no treatment

- related effects on parental body weights, body weight gains, food consumption, food efficiency, or water consumption in the P or F1 rats during

pre

- mating and no effects on body weights or body weight gains during gestation or lactation.
There were no treatment

- related gross or microscopic findings in the P or F1 males or females.

The LOAEL for parental toxicity was not observed. The NOAEL is 100 ppm (8.2 mg/kg/day).

In both litters from both generations, the number born in the treated groups was comparable to controls, and the live birth index was unaf fected by treatment. The mean litter size in the treated groups was comparable to controls throughout the post

- natal period, resulting in viability and lactation indices that were unaffected by treatment. There were no treatment

- related effects on

sex ra tio. No clinical signs of toxicity were noted. No gross lesions were attributed to treatment in the F1a, F2a, or F1b offspring not selected to be parents. There were no treatment

- related effects on organ weights, gross pathology, or histopathology in th e selected F2b offspring.

The only finding possibly related to treatment was an increase (p<0.05) in the mean number of days until completion of pinna unfolding in the F2b offspring at 100 ppm (3.6 days) compared to controls (2.9 days). However, the number of days until onset of pinna unfolding in this group was comparable to controls, and other developmental landmarks (hair growth, tooth eruption, and eye opening) were unaffected by treatment. Therefore, this finding is considered equivocal.Page 41 of 54

The LO AEL for offspring toxicity was not observed. The NOAEL is 100 ppm (8.2 mg/kg/day).

There were no effects of treatment on: estrous cycle duration or periodicity; the mating, conception, or fertility indices; gestation duration; or on the precoital inter vals for either generation.

The LOAEL for reproductive toxicity was not observed. The NOAEL is 100 ppm (8.2 mg/kg/day).

This study is classified acceptable/non

- guideline and does not satisfy the guideline requirements (OPPTS 870.3800; OECD 416) for a two

- generation reproduction study in rats. Although no toxicity was observed, this study does provide information about treatment with Fenpropidin at lower doses. Another more recent 2

- generation reproduction study with Fenpropidin (MRID 47317321), which tested at higher doses, is available.

A.3.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat In a combined chronic toxicity/carcinogenicity study (MRID 47317324), 50 Sprague

- Dawley rats/sex/dose were exposed to Ro 12

- 3049/000 (Fenpropidin; 91 % a.i. ; Lot No.: 5) for up to 2

years. Animals were treated at 5, 25, 125, and 625 ppm for Weeks 1

- 7, and subsequently were treated at 2, 10, 50, and 250 ppm, respectively , due to toxicity observed at 625 ppm

. However,

t he 125/50 and 625/250 ppm group were untreated during Weeks 8

- 11 to allow recovery

. Intake
for Weeks 8

- 104 for the 2 and 10 ppm group was 0.07/0.09 and 0.34/0.45 mg/kg/day in males/females. The average intake for Weeks 12

- 104 for the 50 and 250 ppm grou p was 1.68/2.27 and 8.53/11.83 mg/kg/day in males/females. Additionally, 10 rats/sex/dose were treated similarly for up to 52 weeks and then sacrificed. An additional 10 rats/sex/dose (except 20 rats/sex at the high dose) were treated similarly for up to 2 years and were intended for blood sampling, in addition to the other evaluations of this study.

The dose administered to each treatment group was reduced after 7 weeks due to toxicity observed primarily at 625 ppm. At 625 ppm, t he most widespread si gns were dry and flaky skin around the mouth and on the forepaws, hind feet, and tail; sore skin around the mouth was also in the majority of the animals. In both sexes, decreased body weights were observed at Week 7, and body weight gains were decreased during the interval of Weeks 0

- 7. In both sexes, decreases in food consumption were observed, and de creased food efficiency was noted . Body weights were also decreased by 7% in the 125 ppm males during the interval Weeks 0

- 7.

The following discussion considers primarily the treatment of the animals from Weeks 11

- 104. No adverse, treatment

- related effects were observed on mortality, food consumption, food conversion, water consumption, ophthalmoscopic examination, hematology, c linical chemistry, urinalysis, or organ weights. There was increased survival in high

- dose males (48% vs 30% in controls).Page 42 of 54

There was an increase in the incidence of centrilobular fat in the liver of females at 250 ppm. At 250 ppm, dry and flaky skin a round the mouth was noted at later stages of the study at a very low incidence among males and at a higher incidence in females. At 250 ppm, an increased incidence in the tail tip missing was noted in the females at the interim sacrifice (5/10 treated vs 0 /10 controls); no tail lesions were observed in males. At the terminal sacrifice (including the satellite groups)

, increased incidences of pustule(s) were found on the tail of males (56% treated vs 32% controls) and females (39% treated vs 22% controls), and the tail tip was missing, damaged or shortened in males (20% treated vs 2% controls) and females (57% treated vs 2% controls). At the terminal sacrifice (including the satellite groups), the incidences of pustules on the tail observed microscopically were increased in the males (44% treated vs 22% controls) and females (31% treated vs 20% controls), which corroborated gross observations. In a concurrently submitted chronic toxicity study in mice (MRID 47317325), the tip of the tail was missing in many of the high dose animals, and evidence of dermatitis was observed.

After Week 11, body weights in the 250 ppm group were decreased 8% to 9% in males through Week 52 and by 7% to 9% in females. Body weight gain (Weeks 11

- 80) was increased by 7% in
male s, but was decreased (p<=0.05) in females by 14%. At 250 ppm, overall (Weeks 0

- 104) bodyweight gain was increased in the males by 11% and decreased in the females by 2%. As a definite decrease in body weight gain was noted in the majority of the lifespan of the 250 ppm females, and body weights were decreased in this group throughout treatment, this finding was
considered adverse.

The LOAEL is 250 ppm (8.5/11.8 mg/kg/day), based on decreased body weights and body weight gains in females and clinical sig ns in males and females (pustules on tail, missing tail, and dry, flaky skin around the mouth) and microscopic lesions in females (centrilobular fat in the liver)

. The NOAEL is 50 ppm (1.7/2.3 mg/kg/day).

Benign pancreatic islet cell adenomas were increased in high

- dose male rats compared to controls (26% vs 10% in controls; the pancreas was not examined in all mid

- dose animals).

This study is classified acceptable/guideline and satisfies the guideline r equirements (OPPTS 870.4300; OECD 453) for a combined chronic toxicity/carcinogenicity study in rats.

870.4100b Chronic Toxicity

- Dog In a chronic oral toxicity study (MRID 47317323), CGA 114900 (fenpropidin; 97% a.i.; Batch # P. 110094002) was administ ered to four beagle dogs/sex/dose group daily by capsule at doses of 0, 2, 5, or 20 mg/kg/day for at least 12 months.

Systemic toxicity was observed at 20 mg/kg/day. One male (#16) was killed and necropsied on Day 261, following clinical signs of paresis , reduced food intake, and body weight loss. This dog was observed with reduced locomotor activity, slightly to markedly ataxic gait, and severe paresis of the hindlimbs prior to termination. In the females, a higher incidence of vomiting was
observed du ring Weeks 1

- 6; body weights were decreased (p<0.05, except Week 14) by 9

- 15% from Week 2 through 15; food consumption was decreased (p<0.05) by 14

- 68% during Weeks 1 through 4; and food utilization was decreased during Weeks 1

- 3. These decreases caused a 62% decrease in body weight gains for Weeks 1

- 13. Electrocardiography revealed that the relativePage 43 of 54

QT

- interval (QTc) was prolonged in the males at Week 52. Platelets were increased by 41

- 54% in the males and by 17

- 27% in the females on Weeks 13, 26, and 5 2.

The nervous system was a target organ at 20 mg/kg/day. In addition to the male described above with paresis, demyelination was observed in the following areas of the spinal cord in the males (# affected/# of dogs): cervical (minimal; 1/4), thoracic ( minimal to marked; 3/4), and lumbar (moderate; 1/4).

The liver was a target organ at 20 mg/kg/day. In the males, albumin was decreased at all time points, and globulins were increased at all time points, resulting in a decreased albumin/globulins
ratio a t all time points, and alkaline phosphatase was slightly increased on Weeks 26 and 52. In the females, albumin was decreased and globulins were increased at Week 52, resulting in a decreased albumin/globulins ratio at this week, and alkaline phosphatase w as slightly increased in the females at all time points. Absolute and relative liver weights were increased by 26

- 31% in the males. The following microscopic findings were observed compared to 0 controls, except as noted: (i) minimal to marked hepatocel lular hypertrophy in 4/4 males and females; (ii) minimal hepatocellular pigmentation in 2/4 females; (iii) moderate hepatocellular inclusion bodies in 1/4 females; (iv) minimal to marked pigmentation of the Kupffer cells of the liver in 4/4 females compare d to 1/4 controls; (v) minimal inflammatory cell infiltration in the liver of 3/4 females compared to 2/4 controls; and (vi) minimal to moderate lymphohistiocytic infiltration in the liver of 4/4 females compared to 2/4 controls.

The eye was a target organ at 20 mg/kg/day. Clinically, an opacity of the lens, first noted at Week 22 and progressing to complete bilateral opacity by Week 39 in all animals, was observed. This finding correlated with a gross finding of whitish lens of the eye (bilateral) in all males and females at necropsy, and a microscopic finding of moderate to marked cataract of the lens of the eyes in all males and females.

The skin was a target organ at 20 mg/kg/day. Clinically, all males and females presented with
ind urated and inelastic pads; all males and 3/4 females had scale formation on the external ear; and 1/4 females showed reddening of the skin of the thoracic, inguinal, and axillary regions. Grossly, scale formation in the ears of 4/4 males and 1/4 females, reddish forelimb in 2/4 males and 3/4 females, reddish hindlimb in 2/4 males and 3/4 females, and foot pads hardened in 4/4 males and females were noted, correlating with microscopic findings of minimal to moderate acanthosis of the epidermis in 3/4 males and 4/4 females, minimal to marked hyperkeratosis of the footpad in 4/4 males and females, minimal to moderate acanthosis of the ear in 2/4 females, minimal to moderate hyperkeratosis of the ear in 4/4 males and 3/4 females, minimal to moderate
chronic inf

lammation of the inguinal skin in 2/4 males and 3/4 females, and minimal to moderate chronic inflammation of the axillary dermis in 2/4 males and 3/4 females.

Additionally at 20 mg/kg/day, absolute and relative kidney weights were increased by 13

- 26% in

t he females. Grossly, enlarged popliteal lymph node was noted in 2/4 males and 3/4 females and mottled parenchyma of the lung was observed in 2/4 males, all compared to 0 controls. Microscopically, the following findings were noted: (i) minimal to modera te cholesterol granuloma in the lung in 4/4 males and 1/4 females; (ii) minimal to marked pigmentation of the renal tubules in 4/4 females compared to 1/4 controls; (iii) minimal to moderate inclusion bodiesPage 44 of 54

in the urinary bladder epithelium in 4/4 males a nd 2/4 females; and (iv) minimal to moderate hyperplasia of the urinary bladder epithelium in 2/4 males.

The LOAEL is 20 mg/kg/day, based on mortality, altered electrocardiograms, nervous system toxicity, vomiting, decreased body weights and food utilizat ion, liver toxicity, cataracts, and skin lesions in both sexes. The NOAEL is 5 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirements (OPPTS 870.4100b; OECD 452) for a chronic oral toxicity study in dogs.

A.3.5 Carcinogenicity

870.4200a Carcinogenicity Study

- rat

See executive summary for MRID 47317324 in chronic toxicity section , above.

870.4200b Carcinogenicity (feeding)

- Mouse

In a carcinogenicity study (MRID 47317325 ), Fenpropidin (purity not reported; Lot No. 3 ) was
administered in the diet to CD1 mice (5 1 /sex/dose group ) for up to 80 weeks in males and 90
weeks in females at doses of 0 , 30, 100, 300, or 1000 ppm (approximately equivalent to 0, 4.5, 15, 45, and 150 m g/kg bw/day, based on 1 ppm being equivalent to 0.150 mg/kg/day). Additionally, 12 mice/sex/dose group were treated similarly for up to 52 weeks.

No treatment

- related effects were observed on hematology, clinical chemistry, urinalysis, or organ weights.

At 1000 ppm, the survival probability after 80 weeks was decreased (p<0.05) in the males (0.51) compared to the control group (0.72), and a dose

- related trend (p<0.01) was noted between increasing mortality and dose. The incidence of dry and/or flaky skin on tail, paws, and ears was increased in both sexes, and loss of the tail tip was also associated with this condition. The incidence was greatest at Week 12 in both sexes.

With the exception of Week 4 in the 1000 ppm males, decrea sed weights were observed throughout treatment in the 300 ppm males, and the 1000 ppm males and females. Decreased overall (Weeks 0

- 80 in males and 0

- 88 in females) body weight gains were observed in the 300 ppm males and the 1000 ppm males and females. Although food efficiency was not calculated, the decreases in body weights while food consumption remained unaffected suggest that food efficiency was decreased in the 300 and 1000 ppm males; however, the effect at 300 ppm was
considered minor.

At both s acrifices, the tail was clearly adversely affected grossly at 1000 ppm. At the interim and terminal sacrifices, increased incidences of the tip missing, and dry and flaky tail were noted in both sexes. Other findings were also occasionally noted on the t ail, such as kinked, swollen, thickened, sore, necrotic, or dark red.Page 45 of 54

At the interim sacrifice, increased incidences of the following findings were noted at 1000 ppm: (i) acanthosis in the tail in both sexes; (ii) hyperkeratosis in the esophagus in both sexes; and (iii) hyperkeratosis in the forestomach in females. Additionally, increased incidences of hyperkeratosis in the esophagus were noted in the 300 ppm group.

At the terminal sacrifice, increased incidences and severity of the following findings were noted at 1000 ppm in both sexes (except as noted): (i) tail lesions; (ii) dermatitis in the tail; (iii) hyperkeratosis in the tail; (iv) dermatitis in the ear; (v) hyperkeratosis in the ear in males; (vi) hyperkeratosis in the esophagus; (vii) subcutis hyperkeratosis in males; (viii) dermatitis in females; (ix) hyperkeratosis in the stomach; and (x) hyperplasia in the mandibular lymph node in
females.

Additionally at 300 ppm (u nless noted otherwise) at the terminal sacrifice, increased incidences hyperkeratosis were noted in the following organs: (i) the tail in females; (ii) the stomach in females; and (iii) the esophagus in 100 and 300 ppm males and the 300 ppm females.

Sig ns of localized irritation on the skin, paws, ears, and particularly the tail, as well as the esophagus and stomach were apparent. These effects likely contributed to the decreased body weight gain in both sexes and decreased food consumption in females. However, it is not clear if localized irritation adequately explains the decreased food efficiency and increased mortality that were observed in the 1000 ppm males.

The LOAEL i s 300 ppm ( 45 mg/kg/day), based on hyperkeratosis in the esophagus of both

se xes and in stomach in females. The NOAEL is 100 ppm (15 mg/kg/day)

.

At the doses tested, there was no treatment

- related increase in tumor incidence when compared
to controls. Dosing was considered adequate based on decreased body weight and body weight gain in both sexes and increased mortality in males.

This study is classified acceptable/guidelin e and satisfies the guideline requirement for a carcinogenicity study [OPPTS 870.4 3 00; OECD 45 3 ] in mice.

A.3.6 Mutagenicity

Gene Mutation

870.5100, Bacterial reverse mutation test 47317326 Acceptable/guideline No evidence of induced mutant colonies over background.

870.5300, Gene mutation, HGPRT locus 47317327 Acceptable/guideline No evidence of induced mutant colonies over background in the presence or absence of S9

- activation. 870.5395, Mammalian erythrocyte micronucleus test 47317328 Acceptable/guideline No significant increase in frequency of micronucleated polychromatic erythrocytes in bone marrow at any time point

.

A.3.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening BatteryPage 46 of 54

An acute neurotoxicity study is not available. HASPOC (TXR# 0056640) concluded that an acute neurotoxicity study in the rat can be waived since the doses needed to elicit neurotoxic effects following an acute exposure would not provide a POD lower than those available for an

acute assessment. Although demyelination was observed in the rat subchronic neurotoxici ty study and in the chronic dog study, i t is highly unlikely that a neuropathological process such as demyelination could occur after one exposure to fenpropidin.

870.6200 Subchronic Neurotoxicity Screening Battery In a subchronic toxicity/neurotoxicit y study (MRID 47317313), CGA114900 tech. (Fenpropidin; 97%; Batch No.: P.110094002) was administered in the diet to groups of 15 rats/sex/dose group at concentrations of 0, 20, 150, or 1500 ppm (equivalent to 0/0, 1.14/1.24, 9.84/10.1, and 89.9/97.3 mg/kg bw/day in males/females) for 13 weeks. Additionally, groups of ten rats/sex/dose group were treated as above with diets containing either 0 or 1500 ppm for 13 weeks, then fed control diet only for a 4

- week recovery period. FOB, motor activity, and
exami nation of perfused nervous system tissue were made. Positive control data for the laboratory have been previously reviewed and found acceptable.

There were no adverse, treatment

- related effects observed on mortality, food utilization, water consumptio n, motor activity, urinalysis, hematology, clinical chemistry, or gross pathology.

Treatment

- related effects were observed in the 1500 ppm group. Male body weights were decreased by 9

- 17% from Week 2 throughout treatment, and food consumption was decrease d by

6

- 14% during Weeks 1

- 13 . Body weights were still decreased

- 18% in males and

- 8% in
females at the end of the 4

- week recovery period.

One female in the 1500 ppm group had bilateral opaque eyes (from Day 56 onwards) and bilateral paralysis of the hindlimbs (from Day 76 onwards). Upon neurological examination, this finding was described as paresis, and correlated with histopathologically diagnosed demyelination of the spinal cord, cranial and spinal nerve roots, and proximal peripheral nerve.

In the FOB exam, hindpaw grip strength was decreased in males (

- 16% on weeks 4, 9, and 13) and in females (

- 10% on week 9 and

- 18% on week 13). Forepaw grip strength was decreased at week 4 in males (

- 12%).

Additionally at 1500 ppm, alveolar foam cells of the lungs were observed with increasing severity (minimal to marked) compared to controls (minimal to moderate) in both sexes. The following microscopic findings in the 1500 ppm group are attributed to irritation by the test
material or metabolites: h yperkeratosis, dilatation, and acanthosis of the esophagus; hyperkeratosis, inflammatory cell infiltration, ulceration, and acanthosis of the nonglandular stomach; diffuse hyperplasia and inflammatory cell infiltration of the urinary bladder. At 150

ppm, minimal hyperkeratosis of the esophagus (both sexes) and non

- glandular stomach epithelium (males) were observed.

There was a partial reversibility of the lesions in the esophagus, nonglandular stomach and urinary bladder. Severity of foam cells was still increased after the recovery period in males, but
not in females.Page 47 of 54

The LOAEL is 1500 ppm (89.9 mg/kg/day), based on decreased body weights, bilateral cataracts, paresis, demyelination in the nervous system, and decreased hindpaw grip strength . The NOAEL is 150 ppm (equivalent to 9.84 mg/kg/day).

This study is classified acceptable/guideline and satisfies requirements for a subchronic neurotoxicity study (870.6200) and for a subchronic toxicity study (OPPTS 870.3100).

870.6300 Developmental Neurotoxicity Study In a developmental neurotoxicity study (MRID 48836501), fenpropidin tech (96.9% a.i., batch SMO4E034) was administered to groups of 30 mated female Wistar Han Crl:WI(HAN) rats in the diet from gestation day (GD) 6 through lactation day (LD) 21 at dietary mix levels of 0, 40, 100, and 400 ppm [equivalent to 0, 3, 7, and 27 mg/kg/day, respectively, during gestation, and 0, 7, 17, and 67 mg/kg/day, respectively, during lactation]. Dams were euthanized on LD 21, at
which time the F 1 offspri ng were weaned onto the basal diet and maintained on the study up to postnatal day (PND) 72. Evaluated maternal parameters included the following: c linical observations, body weights, weight gains, and food consumption, detailed clinical observations

outs ide of the home cage on GDs 10 and GD 17 and LDs 2 and LD 9; and limited neuropathological evaluation, which did not include brain samples. Evaluated offspring parameters included the following: clinical observations; survival; body weights, weight gains, and food consumption; detailed clinical observations (PNDs 4, 11, 21, 35, 45, and 60); auditory startle response (PNDs 20 and 60); locomotor activity (PNDs 13, 17, 21, and 61); evaluation of learning and memory via Biel maze swimming trials (PNDs 22 and 6 2); evaluation for sexual development (balanopreputial separation and vaginal patency); brain weight and measurement (PNDs 21 and 72); neuropathological evaluations (PNDs 21 and 72); and brain morphometric evaluations (PNDs 21 and 72).

There were no trea tment

- related effects on maternal survival. Treatment

- related clinical findings consisted of an increased incidence of scabbing and hair loss around the mouth and forelimbs in the 400 ppm group. F 0 body weights, body weight gains, and food consumption were not adversely affected during gestation or lactation at any exposure level. There were no treatment

related effects on detailed clinical observations, mean gestation length, the process of parturition, or the numbers of former implantation or unaccounted

- for sites. There were no treatment

- related macroscopic findings or microscopic neuropathology of spinal cord, peripheral nerves, or eyes of
the dams.

The maternal LOAEL is 400 ppm (27 mg/kg/day), based on skin irritation effects (scabbing
and hair loss a round the mouth and forelimbs) . The maternal NOAEL is 100 ppm (7 mg/kg/day).

The mean number of pups born, viable litter size on PND 0, and the percentage of males at birth were not affected by maternal test substance exposure. There were no treatmen t

- related effects

on F 1 postnatal survival, as based on mean percent of litter surviving at various intervals during the postnatal period. However, based on the total number of pups found dead or missing (5, 5, 4, and 17 for the 0, 40, 100, and 400 ppm gro ups, respectively), the higher number of dead/missing pups in the 400 ppm group compared with the control is considered a treatment

- related effect.Page 48 of 54

There were no treatment

- related effects on F 1 postnatal clinical observations or necropsy findings
at any exposure level.

Pup body weights were decreased during the pre

- weaning period at 400 ppm (males ↓8%/ females ↓6%) from PND 7

- PND 21. Pup body weight gains were decreased at 400 ppm in both sexes, with the largest decrease observed during PND 4

- 7 (males ↓16%/females ↓12%); overall (PND 4

- 21) body weight gain at 400 ppm was decreased also (males ↓8%/females ↓8%). Post

weaning offspring body weights and body weight gains in the 40, 100, and 400 ppm groups were unaffected by treatment.

Detailed clinical obs ervations (FOB), attainment of sexual developmental landmarks (balanopreputial separation and vaginal patency), and startle responsiveness were unaffected by maternal test substance exposure. No significant treatment

- related effects were found in

measures of locomotor activity (sexes pooled), although slight increases in total activity were observed on PND 13 (↑15% and ↑24%, respectively) and PND 17 (↑10% and ↑23%, respectively) at 100 ppm and 400 ppm. Habituation was more rapid in the control group

compare d to the treated groups on PND 17. On PND 61, a ll treated groups displayed decreased ambulatory motor activity compared to the control, although there was no dose

- response. Performance in the Biel water maze showed swimming ability to be unaffected by trea tment for either the PND 22 or PND 62 offspring, and learning and memory performance were comparable among the groups.

There were no histopathological alterations related to test substance exposure in PND 21 or PND 72 brains or in PND 72 spinal cord or peripheral nervous system tissues. Spinal cord and peripheral nervous system tissues were not included in the histopathological evaluations of the PND 21 offspring. Treatment

- related effects on morphometric measurements included statistically significant lower mean values for height of the cerebellum (level 5) in the 400 ppm females at PND 21 (↓4.6%), decreased radial thickness of the cortex at level 3 in 40, 100, and 400 ppm females at PND 72 (↓10%, ↓9%, and ↓5%, respectively), and decreased vertical hei ght of the dentate hilus (level 3) in the 400 ppm females at PND 72 (↓6%). On PND 21, there were no significant treatment

- related effects on mean absolute brain weight, mean brain weight relative to final body weight, or mean brain length and width of F 1 male and female offspring. On PND 72, no treatment

- related effects on mean brain weight (males), mean brain weight relative to final body weight (both sexes) or mean brain length and brain width (both sexes) were observed. However, mean brain weight for t he 400 ppm group females was statistically significantly lower than the control group (↓3.1%), and this difference is considered treatment

related due to the correlated morphometric differences in the brains from the 400 ppm females at this same time point

.

The lowest

- observed

- adverse

- effect level (LOAEL) of dietary fenpropidin in F 1 offspring was 400 ppm (27 mg/kg/day) based on decreased pup body weight during the preweaning period, increase number of dead pups/ cannibalized pups, decreased brain weight, decreased radial thickness of the cortex (level 3), and decreased vertical height of the dentate hilus (level 3) in females on PND 72. The offspring no

- observed

- adverse

- effect level (NOAEL) for fenpropidin was 100 ppm (7 mg/kg/day).Page 49 of 54

This study is classified as A cceptable/Guideline, and it satisfies the guideline requirement for a developmental neurotoxicity study in rats [OCSPP 870.6300 (§83

- 6); OECD 426 (draft)].

A.3.8 Metabolism

870.7485 Metabolism

- Rat
In a series of metabolism studies (MRIDs 47317330, 47317331, and 47317332), [3

- 14 C]

- propyl CGA114900 (Fenpropidin; Batch # ILS

- 21.1G; radiochemical purity ≥96.2%) was administered to groups of Sprague Dawley rats. Mass balance studies were conducted on five rats/sex with the following dose groups: (i) a single 0.5 mg/kg intravenous dose; (ii) a single 0.5 mg/kg oral gavage dose; (iii) 14 non

- radioactive daily 0.5 mg/kg oral gavage doses followed a single radioactive 0.5 mg/kg oral gavage dose on Day 15; (iv) or a si ngle 100 mg/kg oral gavage dose. Blood pharmacokinetic studies were conducted on three rats/sex given single 0.5 or 100 mg/kg oral gavage doses. Tissue distribution and depletion studies were performed on twelve rats/sex/dose group given single 0.5 or 10 0 mg/kg oral gavage doses, with three rats/sex/dose group being terminated at the time of maximum concentration (t Cmax ), the time of half

- maximum concentration (t Cmax1⁄2 ), and either 2.5 h and 6 h post

- dosing for the low dose groups, or 24 h and 48 h post

- do sing for the high dose groups. Biliary excretion studies were conducted on four female rats using a single 0.5 mg/kg oral gavage dose. The concentration time

- courses of radioactivity in blood and plasma were plotted, the concentration and recovery of rad ioactivity in tissues and excreta were determined, and metabolites were identified and quantified in the urine, feces, and bile.

A 0.5 mg/kg dose of the test substance was extensively absorbed by males and females and the bile duct cannulated females, as estimated by radioactivity present in the urine and tissues. In contrast, a 100 mg/kg dose was almost completely absorbed by the males, but appeared to be incompletely absorbed by the females. In animals given a 0.5 mg/kg dose, blood levels of radioacti vity reached mean maximum concentrations at 30 minutes post

- dosing. A biphasic elimination was observed, with no
differences noted between sexes. The areas under the concentration

- time curve (AUC) were
similar for males and females.

In animals given a 100 mg/kg dose, sex differences were observed. Blood levels of radioactivity reached a mean maximum concentration at 60 minutes post

- dosing in males, while females attained a mean maximum concentration at 120 minutes post

- dosing. A monophasic elimination was observed, with a calculated half

- life of 750 minutes for males and 670 minutes for females.
The decrease to one

- half the maximal concentrations occurred at approximately 800 minutes
post

- dosing in both sexes. The AUC were approximately 50% lower in females than in males, and did not increase proportionally with dose in females. The lower maximum blood concentration and decreased AUC were also suggestive of incomplete absorption of this dose
level in female rats.

Total recoveries ranged from 84.7

- 10 4.9% of administered dose [AD] across all groups and in both sexes. The test compound was rapidly excreted, with the majority of radioactivity eliminated during the first 24 h post

- dosing. Urine was the predominant route of excretion. Across all groups, males eliminated the majority of radioactivity in the urine, with most of thePage 50 of 54

remainder excreted in the feces.

The 0.5 mg/kg females eliminated radioactivity in a similar fashion, with a greater proportion excreted in the feces. However, the 100 mg/kg females excreted approximately one

- half of the radioactive dose in the urine and approximately one

- third of the dose in the feces, further suggesting incomplete absorption by these females.

In females, the majority of radioactivity in feces at 0.5 mg/k g appeared to represent absorbed compound because bile accounted for 12.0% AD in the bile

- duct cannulated females, which was similar to the per cent fecal excretion in orally dosed females (17.90%) and to the per cent fecal
excretion in i.v. dosed females (13.50%). Negligible amounts of radioactivity were recovered in the cage wash and expired air. Administration of repeated daily doses had no effect on the route of excretion or the extent of recovery.

At 168 h post

- dosing, tissue residues were very low in rats dosed at 0.5 mg/kg. Only the liver, spleen, and uterus of female rats had residual concentrations of radioactivity above 0.01 ppm. Rats treated with repeated daily doses had slightly lower tissue concentrations than rats that were
treated with a single oral dose.

For rats treated with 100 mg/kg, tissue concentrations 168 h post

- dosing were highest in liver and fat in both males (approximately 1.0 ppm each) and females (approximately 2.6 ppm each).
Tissue concentrations in all other tissues wer e <0.9 ppm in both sexes. In all groups, tissue concentrations were generally higher in females than in males.

In the 0.5 mg/kg dose group, the liver and kidney consistently had concentrations above blood and plasma. Assuming first order excretion kin etics, half

- lives of 3

- 6 h were calculated for tissues, with the exception of longer half

- lives in the liver in males, and the liver, ovaries, and muscle in females. Spleen, testis, and fat in males, and brain in both sexes did not show depletion at 6 h p ost

- dosing, but the residue levels were low. Radioactivity in the carcass was similar to blood at all time points.

In the 100 mg/kg rats, the liver and kidney consistently had concentrations above blood and plasma. For the males, assuming first order excretion kinetics, half

- lives of 9

- 13 h were calculated, with the exception of the liver. In the females, a biphasic decrease in tissue residues was observed, with an initial rapid decrease during the period between t Cmax and t Cmax1⁄2 , followed by a slower second phase. In the first phase, half

- lives of 4

- 9 h were calculated, with the exception of carcass (12 h) and fat (not possible to determine). During the second phase, half

lives of 14

- 29 h were calculated, with the exception of longer half

- lives in th e liver, ovaries, and bone. In the carcass, radioactivity levels were similar to blood at t Cmax and t Cmax1⁄2 , and depletion
was observed at 48 h.

Parent compound was not found in the excreta. Comparison of the metabolite profiles in the different excreta revealed that there were no extra metabolites in bile and fecal extracts compared to urine. A total of 10 urinary metabolites were identified. O ne urinary metabolite, 2

- methyl

- 2

- [4

- (2

- methyl

- 3

- piperidine

- 1yl

- propyl)

- phenyl]

- propionic acid, predominated (46

- 79% AD). All other urinary metabolites (identified or unidentified) were present at ≤2.5% AD.Page 51 of 54

In fecal extracts of female rats, the sulfate conjugate of the propyl alcohol (sulfuric acid mono

- {2

- methyl

- 2

- [4

- (2

- methyl

- 3

- piperidine

- 1

- yl

- propyl)

- phenyl]

- propyl}ester) was the predominant metabolite (5.7

- 9.0% AD at 0.5 mg/kg and at 26.6% AD at 100 mg/kg). In males, no metabolite (identified or un identified) was present in the fecal extracts at >1.7% AD. In bile, the sulfate conjugate of the propyl alcohol was identified as the predominant biliary metabolite (6.2% AD). All other metabolites (identified or unidentified) were present at ≤2.1% AD.

Two major initial metabolic processes occurred. The first involved oxidation of the tert

- butyl moiety to the propyl alcohol (Met. 4U). Subsequent oxidation of the alcohol yielded the propionic acid (Met. 1U), the primary metabolite. Minor metabolites we re generated from the alcohol by sulfate conjugation (Met. 2U), or from the propionic acid by oxidation of a second methyl group of the tert

- butyl moiety (Met. 8U). The second initial metabolic step was the oxidation and cleavage of the piperdine ring, yi elding the methyl

- propyl

- amino pentanoic acid derivative (Met. 5U). Subsequent oxidation reactions resulted first in the formation of the respective methyl

- propyl

- amino propionic acid (Met. 3U), the hydroxylated methyl

- propyl

amine (Met. 7U), and ultimate ly, the benzoic acid derivative (Met. 11U). The methyl

- propyl

amino pentanoic acid and hydroxylated methyl

- propyl

- amine undergo further oxidation at the

tert

- butyl moiety to produce the respective propionic acid derivatives (Met. 10U and 9U). These ring

- opened metabolites were almost exclusively excreted in the urine, with only marginal amounts secreted in the bile, and detected in the feces.

These metabolism studies are collectively classified acceptable/guideline and when reviewed together satisfy the guideline requirement for a Tier 1 metabolism study [OPPTS 870.7485, OECD 417] in rats.

870.7600 Dermal Absorption

- Rat Not available. Dermal assessment not required for an import tolerance.

870.7800 Immunotoxicity An immunotoxicity study has been su bmitted (MRID 48681803) and is undergoing review.Page 52 of 54

Appendix B. Summary of Residues (Metabolism and Field Trial Studies)

TABLE B.1 Identification of Compounds from Banana and Rat Metabolism Studies.

Common name /
Chemical Codes Chemical name Chemical structure Matrices (% TRR) 1

Banana Metabolism

Fenpropidin
CGA 114900 1

- [3

- [4

- (1,1

-

dimethylethyl)phenyl]

- 2

- methylpropyl]piperidine Whole fruit (48.8%) Peel (44.2%) Pulp (76.5%) Leaves (45.8%)

CGA 289263 1

- [3

- [4

- (1,1

-

dimethylethyl)phenyl]2

- methylpropyl]piperidine

1

- oxide Whole fruit (14.3%) Peel (16.1%) Pulp (3.3%) Leaves (7.6%)

CGA 289268 2

- methyl

- 2

- [4

- (2

- methyl

3

- piperidin

- 1

- yl

- propyl)

- phenyl]propan

- 1

- ol Whole fruit (1.8%) Peel (2.1%) Leaves (6.9%)

Rat Metabolism

IU (UC

- 32)
CGA 289267 2

- Methyl;

- 2

- [4

- (2

-

methyl

- 3

- piperidine

- 1

- yl

propyl)

- phenyl]

- propionic
acid Urine (46

- 70%) for females only

2U (UC

- Z6) Sulfuric acid mono

- [2

-

methyl

- 2

- [4

- 2(

- methyl

- 3

- piperidine

- 1

- yl

- propyl)

- phenyl]

- propyl]ester Bile (6%) for females only

1 The %TRR in each matrix at maturity: prior to the final application for leaves, and 1 day after the final application for who le fruit, peel and pulp. TRR values were 43 ppm for leaves, 3.39 ppm for peel, 5.10 ppm for pulp, an d 3.63 ppm for whole fruit. Metabolism study conducted at 1x single rate, 0.3x seasonal rate.Page 53 of 54

Table B.2 Summary of Residue Data from Banana Field Trials with Fenpropidin.

Crop matrix Total

Applic. Rate (kg ai/ha) 2 PHI

(days) Residue Levels (ppm) 1

n Min. Max. HAFT 3 Median Mean Std.

Dev.
Banana (proposed use = 5.4 kg ai/ha total application rate, 0

- day PHI)

Whole fruit, unbagged 5.39

- 5.72 0 24 0.03 7.00 6.00 0.51 1.41 1.96

Whole fruit, bagged 24 <0.01 1.00 0.59 0.04 0.14 0.22

Pulp, unbagged 5.39

- 5.72 0 8 0.02 0.19 0.12 0.06 0.08 0.06

Pulp, bagged 8 <0.01 0.04 0.03 0.02 0.02 0.01

Peel, unbagged 5.39

- 5.72 0 8 0.13 3.30 2.03 0.65 1.08 1.11

Peel, bagged 8 0.04 1.60 0.85 0.09 0.27 0.54

1 Based on the LLMV the LOQ is 0.01 ppm in/on whole banana and pulp. For residue values < LOQ, the LOQ was used for calculating medians, means and standard deviations. N = # of samples.

2 Total application rate is equivalent to 4.8

- 5.1 lb ai/A

. 3 HAFT = Highest average field trial result.Page 54 of 54

Appendix C

. Review of Human Research

This risk asse ssment does not rely on any data from studies in which human subjects were intentionally exposed to a pesticide or other chemical.