### UN ITED ST A TE S ENV IRO NMENT AL PRO TECT IO N AGENCY

MEMORANDUM



### Date: 

### 19-AUG-2015 WASHINGTO N

, D .C. 2 0 460

OFFIC E O F C ll El\ ll CA L SAFE TY A D POLU IT IO N PllEV E NTIO N



### SUBJECT: Te fluben zuron. 

### Human Health Ri s k Assessment fo r the Propo se d To l e r ances without a U.S. Registration for Re s idues of T eflubenzuro n in / o n th e Co mmoditi es of Orange

, L e mon , App l e , Grape

, T oma t o , Melon

, Brocco li

, Caul i flower

, Su nfl ower, Soybea n , C orn , Coffee B ea n , S u garcane, M a ngo , P apaya , Pi neapple

, and L i ve s tock Commod i ties.

P C C ode : 1290 4 8 DP Barc o de: 0426404
De c i s i o n No.: 486593 R egist rati o n No.: NA
P c lilion No.: 4 E 8230 R eg ulator y Action: Tolerances Wilhout U

. S

. Regi s tTati o n Ri s k A ss es s ment T y pe: Sing l e C h em i cal/Aggre g ate 

### Case No.: NA
TXR No.: N A CASNo.: 83121-18-0
M RID No

. : NA 4 0 CF R: § 1 80.TBD



### FROM: 

### Anwar Y

. Du nbar

, Ph

. D.

, Ph armaco l ogist

# ~ 

# ,,!':_ ·**}J~** George F. Kram e r , Ph

. D

., Senior C hemi st**~ C::::::~~-::::::i~:;...** **----** 

### R i sk Assessment Branch I (RA B I)**~** 

### -

.. 

### Heallh Effects Di v ision (HED; 7509P )**~**



### T HRO UGH: Thurston G. Mort on , Ac tin g Bran c h

# hief**$~** ::;-- 

### RAB I

, 

### HED (7509P )

And

C hri st in e L. 

### Ol in ge r , D esig nat ed Reviewer
PV Sha h

, D esignated Revi ewe r R i sk Assessme nt Review Comm itt ee (RA R C)
HED (7509 P )

TO: Carlyn Patrella, Risk Review Manager Richard Gebken, Risk Ma n age r Registration Divis i o n ( RD ; 7505P )

H

E D of the Office of P est i c id e Programs (O PP ) i s c h arged w ith est im at in g the risk t o human
health from expos ur e t o pestic id es

. RD of OPP h as r e que s ted that H ED evaluate ha zard and

e xposu r e data and conduc t a die t ary exposure assessment as n eeded, to es timat e the ri sk to hum an health that wi ll result from the proposed use o f the new act i ve i n gredie nt

, teflubenzuron

, [ N

- [[(3

, 5-dic hl oro

- 2

, 4 -diflu o r o ph e n y l ) arnino ]ca r bony l ]-2

, 6-difluorobenzamide].

Pa g e I o f 30

### Tetlubenzuron H um a n H ea lth Ri sk Assess m e nt 0426404



### A summary of t he findin gs a nd an ass e ss m e n t of hum a n ri sk r es ultin g fro m the proposed u ses are provi d e d in th is doc um e nt. Th e risk assessme nt a n d hazard c h aracte ri zat i on were provided by Anwar Dunbar (RAB 1 ), an d t h e d i etary risk assessme n t a n d res i due c h emistry rev i ew were provided by George Kramer ( RAB 1 ).

Tab l e o f Contents 1.0 Executive Summary

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

. . ............. ... .. .. ... . .. .. .. .. . ... . ... . ... . . ... .. .. . ..... .. ................................ . .... 5
2.1 Data Deficiencie s

.. .. ..... .. .. . .. .. .. .. ..... ... ... . .. . ... .. .......... . ...................................... .. ......... . ..... 5
2.2 Tolerance Con s ideration s .

.. ................. . .................................... .. ........ .. . .. . ... . .. . .. . .. .. .. ..... 6
2

. 2.1 Enforcement Ana l ytica l Method

......... .. ............. ... ............ .. .. . ..... .. . . .. .. .. .. . .. . .. ..... .. ..... 6
2.2.2 Recommended Tolerance s

.. ...... .. .......... .. .............................. .. ..... .. .... .. ...................... 6 2.2.3 Revi s ion s to Petitioned-For Tolerances

...................................... . ..... . .... .. ..... .. ..... . .... 7
2

. 2.4 International Harmonization

.......... . ......................... .. ..... .. .. .. . .. . ... . .. . .. . .. .. .. .... .. .. . . .. .. . . 7
2

. 3 Label Recommendations

..... .. .. .. ...... .. .. .. .. . .. ... ... . . ... . .. .. ..... .. ..... .. .. . .. . ... .... .. ..... .. .... .. .......... 8 3.0 Introduction

. .. .. ..... . .. .. .. . .. .. .. . ... . .. .. .. ... . .. . ... .. .......... .. ........................................................ . .... 8
3

. 1 Chem i ca l Identity

. .. ..... .. .... . .... ... ..... .. .... . ..... .. ........................................... .. ..... .. . .. . .. . .. . .. .. 8
3

. 2 Ph ys ic a l/Chemical Propertie s

........................... .. ...... .. . ... . .. . .. ..... .. . .. . ... . .. . .. . ... . .. . .. . .. . ... ... . 8
3.3 Use Pattern

. .. ..... .. .. .. . . .. .. .. . ... .. .. .. . .. .. . . . . . . . . ... . ... . ... . .. .. .. .. . .. ... .. . . .. .. .. . . ... . .. . ... . ........................ 8 3.4 Anticipated Expo s ure Pathway s

.................................................................. . ..... . ..... .. ... 9
4.0 Hazard C haracterization and Dose-Re s ponse Asse s sment

.. ..... .. ..... . ......... . . . ............ . .... 9
4

. 1 Toxico l o gy Studies Available for Analy s is

.................. . .... . .......... . ......... . ..... . ..... . ..... .. ... 9
4.2 Ab s orpt i on, Di s tribution, Metabolism

, 

### & Elimination ( ADM E)

. .. ..... . .... .. ..... . ..... . .. 1 0


### 4.2.1 Dermal Ab s orption

............................ . ..... . ... ... .... ... .... .. ..... . ..... . .......... . ..... .. ..... . ......... 

### 11
4

. 3 Toxico l ogical E ffects

... .. ..... .. ... . .. .. .. .. .. .. ...... .. .. .. ...... .. .... .. ... . ..... .. ..... . ...... . ...... . ............... 

### 1 1
4.4 Safety factor for Infants and Children (FQPA Safety Factor)

.. .. ......................... . .. 

### 11
4.4.1 Completeness of the Toxicology Database

.......................................................... ... . 11


### 4.4.2 E vid e nce of N eurotoxicity

................................................ . .................. . ..... .. ..... . ... . . .. 

### 11
4.4

. 3 E vidence of Sensitivity / Su s ceptibility in the Developing or Young Animal..

. .. ... 11 

### 4.4.4 Residual Uncertainty in the Expo s ure Database

.................................................. . 12


### 4.5 Toxicity E ndpoint and Point of Departure S election s

..... .. .... .. ..... .. .... .. .... .. ..... . ........ 1 2


### 4

. 5

. 1 Do s e-Re s ponse As s es s ment

.. . ... .. ...... .. ... . ...... .. ..... . ... .. ..... .. ..... . ...... . ........................ .. . 1 2


### 4.5

. 2 Recommendat i on for Combining Routes of Expo s ure s for Ri s k As s essment

. . . .. 12


### 4

. 5.3 Cancer C l a s sification and Ri s k A ss e ss ment Recommendation

............................ 12


### 4.5

. 4 S ummary of Point s of Departure and Toxicity Endpoints U s ed in Human Ri s k
A ss e ss ment

.... .. .... . ..... .. ..... .. ..... .. ..... .. ... . ...... ... .. . .. . ... ... ... . . . ... .. ..... .. ..... . .... . . .. . .. . . ... .. . .. . ...... . .. . .. .. . .. 1 3


### 5 .0 Dietary Exposure and Risk Assessment

. .. .. .. .. .. ... ..... .. .. . .. . .... . . .. .. .... ... .... .. .. .... ... .... . ......... 13 

### 5.1 Mctabolite/Degradat c Re s idue Profile

.............................................................. . ........ 13


### 5

. 1.1 Summary of Plant and Animal Metabolism Studie s

.. ..... . ...... . ... . . . ... . . . ... .. ..... . ... 1 3 

### 5 .1. 2 Summary of Environmenta l Degradation

. ... . ... . .. .. ..... .. ..... . ..... .. .... .. .. .. . .. .. . . ...... .. 14 

### 5.1.3 Compar i s on of Metabolic Pathwa ys

.............. . ....................... . ............................. 14


### 5.1.4 Re s idue s of Concern Summary and Rationale

... .. ..... .. ... . . . ..... .. .......................... 1 4 

### 5.2 Food Re s idue Profile

......... . ...... . ........... . .......................... . ... . .. . .. . .. . ... .. . .. . .. .. .. . .. . .. . .. .. .. . .. 1 5


### 5.3 Drinking Water Residue Profile

... . ... .. .. ... . .. .. .. .. . . ... ... . ... . .. . .. . ... . .. . .. .. .. . .. . .. .. . .. . .. .. . . ... . .... 16 5.4 Dietary (Food + Drinking Water) R i sk Asse s sment..

...... . ......................................... 16
6.0 Residential (Non-Occupational) Exposure / Ri s k Characterization

................... .. .... .. .. 1 6
7 .0 Aggregate Expo s ure / Ri s k C haracterization

.. .... . . .. .. ... .... .. ... .... . .. ... . .. . ... . . .. .. . ...... .... .. . . .. .. 1 7 8.0 Cumulative Exposure / Risk Characterization

.. .. ...... .. .. ... .... .. ........................................ 17
9.0 Occupationa l Expo s ure/Ri s k C haract e rization

............................................................ 17

Page 2 of3 0Teflubenzuron Human Health Risk Assessment D426404

Page 3 of 30 

### Appendix A. Toxicology Profile and Executive Summaries

................................ .................. 18 A.2 Toxicity Profiles

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

................................ .......................... 24 Appendix B. Metabolism Considerations

................................ ................................ ................ 27 B.1. Metabolism Summary Table

................................ ................................ ....................... 27 B.2 Metabolic Pathways

................................ ................................ ................................ ..... 29 Appendix C. Physical/Chemical Properties

................................ ................................ ............. 30Teflubenzuron Human Health Risk Assessment D426404

Page 4 of 30 

### 1.0 Executive Summary

The new active ingredient ( ai ) teflubenzuron ( N

- [[(3,5

- dichloro

- 2,4

- difluorophenyl)amino] carbonyl]

- 2,6

- difluorobenzamide) is a benzoylurea growth regulator insecticide. It acts by inhibition of chitin synthesis and molting, disrupting chitin deposition in the insect cuticle after ingestion , ultimately resulting in insect mortality at molting. The registrant ( BASF ) submitted a petition for establishment of tolerances for residues of teflubenzuron in/on oranges, lemons, apples, grapes, tomatoes, melons, broccoli, cauliflower, sunflowers, soybean, corn, coffee beans, sugarcane, mangos, papaya, a nd pineapples. There are no domestic uses proposed or established. The proposed tolerances are expressed in terms of the parent only.

Exposure Profile: Based on the proposed uses of teflubenzuron, dietary exposure (food only) is the only anticipated exposure pathway. As there are no domestic agricultural or residential uses registered or proposed for teflubenzuron, there is no potential for drinking water, residential, or occupational exposure.

Hazard Assessment: The effects in the teflubenzuron da tabase are indicative of hepatotoxicity. In all species tested there were adverse effects in the liver; increased enzyme release and numerous microscopic indicators of liver injury (diffuse hypertrophy, disseminated single

- cell necrosis, patchy glycogen s torage, Kupffer cell proliferation, phagocytic foci, lipofuscin accumulation, and patchy fatty change s ). In the mouse

, which is the most sensitive species compared to the rat and the dog, there were liver adenomas following chronic exposure. There is

no evidence of neurotoxicity, immunotoxicity

, or genotoxicity.

There is evidence of increased quantitative offspring susceptibility for teflubenzuron in the rat

two

- generation reproductive study. While there were no parental effects, adverse offspring effec ts were observed and consisted of decreased F 2 

### litter weights and increased incidence of unilateral dilatation of the renal pelvis in F 1 

### offspring. There were no effects in the developmental rat study up to the highest dose tested. In the developmental r abbit study, maternal effects were observed at the limit dose and we re consistent with liver toxicity. No fetal effects were observed.

Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The teflubenzuron risk assessment team recommends that the 10X FQPA SF be reduced to 1X for all exposure scenarios. The toxicity database is complete and dietary exposure analyses are unlikely to underestimate exposure . There is no evidence of neurotoxic ity and the chronic dietary endpoint is protective of the offspring effects in the 2

- generation reproductive study

. Lastly, there are no residual uncertainties in the exposure database.

Dose

- Response Assessment: The chronic reference dose (cRfD) of 0.021 mg/kg/day was determined on the basis of the carcinogenicity study in mice. The lowest

- observed adverse

effect level (LOAEL) of 10.5 mg/kg/day is based on increased microscopic lesions in the liver (diffuse hypertrophy, centrilobular single

- cell nec rosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, and centrilobular fatty change) associated with increased relative liver weights. The no

- observed adverse

- effect level (NOAEL) of 2.1 mg/kg/day is protective of all effects for a ll durations

. This study is appropriate for the duration of exposure and is considered protective of the general U.S. population and all population subgroups. A total uncertainty factor (UF) of 100X (10X for interspecies extrapolation, 10X for intraspeci es variability, and a 1X FQPA SF) was applied to this NOAEL generating a chronic population

-Teflubenzuron Human Health Risk Assessment D426404

Page 5 of 30 

### adjusted dose (cPAD) of 0.021 mg/kg/day. An acute reference dose (aRfD) for the general U.S. population, including infants and children, was not established becaus e no endpoint of concern attributable to a single dose was identified in the toxicological database for teflubenzuron.

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the CARC classified teflubenzuron as “Suggestive Evidence of Carcinogenic Potential” based on the presence of rare liver tumors in male mice only. There was no evidence of carcinogenicity in female mice or in male or female rats. There is also no concern for mutagenicity. Quantification of cancer risk is not required. The CARC recommended using a non

- linear approach (i.e., RfD) that will adequately account for all chronic toxicity, including carcinogenicity, which could result from expos ure to teflubenzuron.

Dietary Risk Estimates (Food Only ): A chronic dietary (food only) exposure and risk assessment was conducted for the general U.S. population and various population subgroups using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16. This software uses 2003

- 2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). The unrefined chronic assessment assumed that teflubenzuron residues are present in all commodities at tolerance levels and that 100% of all crops are treated. DEEM Version 7.81 default processing factors were used to estimate residues in processed commod ities, except for apple and orange juice for which empirical processing factors were used since processing studies showed that residues were greatly reduced when apples and oranges are processed into juice . Drinking water estimates were not incorporated i nto the chronic dietary assessment, as there are no domestic uses proposed or established. Using the DEEM

- FCID software, dietary risk is estimated at 17% of the cPAD for the general U.S. population and 50% of the cPAD for children 1 to 2 years old, the

po pulation subgroup with the highest estimated chronic dietary exposure to teflubenzuron. The chronic dietary risk assessment shows that for all included commodities, the chronic dietary risk estimates are below HED’s level of concern (i.e., <100% cPAD). A n endpoint of concern attributable to a single dose was not identified; therefore, an acute dietary assessment was not performed.

Aggregate Exposure Assessment: Because this action is for tolerance s without U.S. registration and there are no proposed o r existing uses of teflubenzuron that would result in drinking water or residential exposures, the chronic dietary (food only) exposure estimates represent the aggregate exposure assessment

.

2.0 HED Recommendations

HED is also unable to recommend in favor of the tolerance for residues in/on grape and raisins due to the absence of a grape processing study. T here are no data gaps that would preclude establishing the recommended tolerances for residues of teflubenzuron in/on the remainder of the requested crops . The specific tolerance recommendations are discussed in Section 2.2.2.

2.1 Data Deficiencies

With the exception of a processing study for residues of teflubenzuron in/on grape, there are no data deficiencies at this time. HED notes that additional plant metabolism, livestock metabolism, confined rotational crop, and livestock feeding studies may be necessary to support any future use proposed for the U.S.Teflubenzuron Human Health Risk Assessment D426404

Page 6 of 30 

### 2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The petitioner has submitted a high

- performance liquid chromatography method with tandem

mass

- spectrometry detection (LC

- MS/MS) analytical method, BASF Method L0160/01, for analysis of residues of teflubenzuron in/on dry and oily crop co mmodities. The method has been adequately validated by the petitioner as well as by an independent laboratory, and was also adequately radiovalidated using weathered samples obtained from metabolism studies. HED has determined BASF Method L0160/01 is sui table as an enforcement method for plant commodities, as defined in Standard Operating Procedure (SOP) No. ACB

- 019 (9/15/08). In addition, the QuEChERS multiresidue method (MRM) is considered suitable for the analysis of teflubenzuron in fruits and vegeta bles.

2.2.2 Recommended Tolerances

HED has reviewed the available residue data and has determined the appropriate tolerance levels for residues of teflubenzuron (Table 2.2.2.1). The recommended tolerance expression is as follows:

(a) General. (1) Tole rances are established for residues of the insecticide teflubenzuron, including its 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 teflube nzuron ( N

- [[(3,5

- dichloro

- 2,4

- difluorophenyl)amino]carbonyl]

- 2,6

- difluorobenzamide).

Table 2.2.2.1 . Tolerance Summary for Teflubenzuron

. Commodity 1 Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition ) Apple 0.5 1.0 Harmonization with the Codex MRL for pome fruit

. Apple, wet pomace 0.8

- Not required as the commodity is not likely to be imported.
Broccoli 0.2 0.20 Significant figures

. Cattle, muscle 0.01

- No expectation of finite residues. Cattle, meat byproducts 0.01

- Cauliflower 0.01 0.01

- Citrus, oil 90 100 Higher value calculated using HED policies for processed commodities. Coffee, bean, green 0.6 0.60 Significant figures Corn, field 0.01 0.01 Corn, field, grain Corn, field, refined oil 0.02 0.02

- Egg 0.01

- No expectation of finite residues. Grape 1

- Tolerances not recommended due to lack of grape processing study. Grape, raisin 3

- Goat, muscle 0.01

- No expectation of finite residues. Goat, meat byproducts 0.01

- Horse, muscle 0.01

- Horse, meat byproducts 0.01

- Lemon 0.9 0.80 Lower value calculated using OECD tolerance calculator

.Teflubenzuron Human Health Risk Assessment D426404

Page 7 of 30 Table 2.2.2.1 . Tolerance Summary for Teflubenzuron

. Commodity 1 Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition ) Mango 1.5 1.5

- Melon 0.3 0.30 Melon, subgroup 9A
Milk 0.01

- No expectation of finite residues. Orange 0.6 0.60 Significant figures

. Papaya 0.4 0.50 Higher value calculated using OECD tolerance calculator. Pineapple 0.8 0.80 Significant figures. Pork, muscle 0.01

- No expectation of finite residues. Pork, meat byproducts 0.01

- Poultry, muscle 0.01

- Poultry, meat byproducts 0.01

-

Sheep, muscle 0.01

- Sheep, meat byproducts 0.01

- Soybean, seed 0.05 0.05

- Soybean, hulls 0.4 0.15 Lower value calculated using HED policies for processed commodities

. Sugarcane, cane 0.01 0.01

- Sunflower, seed 0.3 0.30 Significant figures

. Tomato 1.5 1.5

- Tomato, paste 5

- Not required; concentration of residues is not expected.

1 No U.S. registration as of [publication date of the tolerances]

.



### 2.2.3 Revisions to Petitioned

- For Tolerances

For some commodities, the proposed tolerance levels differ slightly from those being recommended by HED. Although both the petitioner and HED have used the OECD (Organization for Economic Cooperation and Development) calculation procedures to obtain toler ance levels, if a higher residue value was observed at a preharvest interval (PHI) longer than the minimum PHI, then HED used the highest value, resulting in tolerance recommendations that are different from the proposed values. In the case of apple, HED is recommending a higher tolerance in order to harmonize with the established Codex maximum residue limit (MRL). Based on the results of the livestock feeding studies, there is no expectation of finite residues in livestock commodities [§180.6(a)(3)]; the refore, HED is recommending against establishing tolerances for residues in livestock commodities. In addition, HED is recommending a number of changes in the numerical expression of the tolerance values in order to conform to current HED policy on signif

icant figures. HED is also unable to recommend in favor of the tolerance for residues in/o n grape and raisins due to the absence of a grape processing study

.

2.2.4 International Harmonization

There are no established Canadian, Mexican, or Codex MRLs for residues of teflubenzuron, with the exception of a Codex MRL of 1 ppm for residues in pome fruit. As the currently established Codex MRL is higher than the calculated tolerance value of 0.50 ppm for apple, HED is recommending harmonization with the Codex MRL of 1 ppm.Teflubenzuron Human Health Risk Assessment D426404

Page 8 of 30 

### 2.3 Label Recommendations

N one, as no U.S. registrations are requested.

3.0 In troduction

3.1 Chemical Identity

The chemical structure and nomenclature of teflubenzuron is presented in Table 3.1.1.

Table 3.1.1. Teflubenzuron Nomenclature. Compound: ai Chemical Structure

Common name Teflubenzuron Company experimental name BAS 309 I
IUPAC name 1

- (3,5

- dichloro

- 2,4

- difluorophenyl)

- 3

- (2,6

- difluorobenzoyl)urea
CAS name N

- [[(3,5

- dichloro

- 2,4

- difluorophenyl)amino]carbonyl]

- 2,6

- difluorobenzamide
CAS # 83121

- 18

- 0
End

- use product/EP Nomolt ® , Imunit ®



### 3.2 Physical/Chemical Properties

Technical

- grade teflubenzuron is a solid at room temperature and all environmentally relevant temperatures. The compound is not volatile (i.e., vapor pressure is 6.87 x 10

- 9 

### mm Hg at 20° C) ; thus, there is little likelihood for exposure to teflubenzuron in the vapor phase. The technical

grade material has a log K OW 

### of 4.98 at pH 5, indic ating that the compound is fat

- soluble.

3.3 Use Pattern

The petitioner provided copies and English translations of the proposed Nomolt ® 

### and Imunit ®


### labels from several South and Central American countries. Nomolt ® 

### is a SC formulation containing 13.56% teflubenzuron for ground or aerial applications to oranges, lemons, apples, grapes, tomatoes, melons, broccoli, cauliflower, sunflowers, soybean, corn, coffee beans, sugarcane, and papaya. Imunit ® 

### is a SC formulation containing 7.1% teflubenzuron and 7.1% alpha

- cypermethrin for ground or aerial applications to oranges, sunflowers, mango, and pineapples. The proposed critical good agricultural practices (GAP) use directions , as identified by the petitioner, are detail ed in Table 3.3.1.Teflubenzuron Human Health Risk Assessment D426404

Page 9 of 30 Table 3.3.1. Summary of Proposed Critical GAP Use Directions.

Crop Country Product Name Applicatio n R a t e (lb a i/

A) Max. No. Apps. RTI

(days) Applicatio n

R a t e / Season (lb

a i/ A) PHI

(days)

Ora n ges and Lemons Bra z il N o m o lt ® 0

. 1 0 7 2 15 0

. 214 28

Ora n ges Costa Rica,

Hon d uras N o m

o lt ® 0

. 0 3 3 2 15 0

. 0 66 15

B r a z i l I m

un i t ® 0

. 0 3 3 2

1 0 10

3

. 1 1x 30 0

. 0 66 15 Apple Bra z il N o m o lt ® 0

. 0 4 0 4 1 0 0

. 16 0 7 Grap e s Bra z il N o m o lt ® 0

. 0 6 7 3 7 0 .2 01 7

T o mato Argen ti na,

C o l u m b ia, Costa Rica,
Guat e m ala N o m

o lt ® 0.067 2 7 0.134 14

Melon Bra z il N o m o lt ® 0

. 0 6 7 3 7 0 .2 01 7

Broccoli Costa Rica,

Guat e m ala,
Hon d uras N o m

o lt ® 0

. 0 3 3 2 7 0

. 0 66 14

Caulifl o wer Costa Rica,

Guat e m ala,
Hon d uras N o m

o lt ® 0.020 (1st app. 0.023) 3 7 0

. 0 63 21

Soyb e a n Bra z il,

Argen ti n a N o m

o lt ® 0

. 0 3 0 3 10 0

. 0 9 0 21

Sunf l o wer Urugua y ,

Argen ti n a N o m

o lt ® 0

. 0 1 1 2 15 0

. 0 22 7

B raz i l I m

un i t ® 0

. 0 1 1 2 1 5

5

. 3 1x 4 0 0

. 0 22 7
Co r n Bra z il N o m o lt ® 0

. 0 2 0 4 7 0

. 0 8 0 30

C o ffee Bra z il N o m o lt ® 0

. 0 6 7 2 3 0 0.134 30

0

. 0 3 3 2 3 0 0

. 066 15 Sugar c a ne Bra z il N o m o lt ® 0

. 0 2 0 3 3 0 0

. 0 6 0 40
M a ngo B r a z i l I m un i t ® 0

. 2 68 3 7

2

. 5 1x 00 0.804 1 5
Pa pa ya Bra z il N o m o lt ® 0

. 0 6 7 3 7 0.201 7
Pinea p ple B raz i l I m un i t ® 0

. 2 6 8 3 7 0.804 15



### 3.4 Anticipated Exposure Pathways

Based on proposed teflubenzuron application scenarios, dietary exposure (food only) is the only anticipated exposure pathway. As there are no domestic agricultural or residential uses registered or proposed for teflubenzuron, there is no potential for dri nking water, residential, or occupational exposure.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The hazard database for teflubenzuron is adequate for dose

- response and FQPA evaluation. Teflubenzuron was evaluated for the following:

(1) Subchronic and chronic oral toxicity in rats, mice and dogs; (2) Developmental toxicity in rats and rabbits; (3) Reproductive and postnatal toxicity in rats; (4) Carcinogenicity in mice and rats; ( 5) Neurotoxicity in rats;Teflubenzuron Human Health Risk Assessment D426404

Page 10 of 30 

### (6) Immunotoxicity in mice; (7) Genetic toxicology studies ; and (8) Absorption, D istribution, M etabolism, and E xcretion (ADME) studies

.

Appendix A includes a summary of the teflubenzuron toxicological database.

4.2 Absorpti on, Distribution, Metabolism, & Elimination (ADME)

The ADME for teflubenzuron was well characterized in a series of oral gavage studies using low

- and high

- doses (25 and 750 mg/kg bw). Animals were tested using single and repeated dosing regimens. Bilia ry excretion and tissue accumulation experiments were also carried out.

Regarding absorption, following a single oral dose of 25 mg/kg bw, the maximum plasma concentration (C max 

### ) was 0.46 μg/ mL and the time to peak plasma levels (T max 

### ) was 8 hours for

m ales. For females, the C max 

### was 0.25 μg/ mL and the T max 

### ranged from 2 to 8 hours. From 1 to 8 hours post dosing, nearly constant plasma levels were found and started to decline at 24 hours. Plasma concentrations declined to less than 0.01 μg equivalents/mL in both sexes at the end of the experimental period (7 days).

Following single oral dosing at 750 mg/kg bw, the C max 

### was 3.27 μg/ mL and the T max 

### was 24 hours. For females, the C max 

### was 1.43 μg/ mL and the T max 

### was 0.67 hours. The second day after treatment, the plasma levels declined to 1.05 μg/ mL in males while levels were consistent in females. By the end of the 7

- day testing period, plasma levels decreased to 0.06 and 0.08 μ g equivalents/mL in male and female rats, respectively.

Tissue accumulation and distribution was negligible for both sexes treated with radiolabeled test material for 7 consecutive days; being less than 1% of the administered dose at all intervals. The highest detectable levels of the radiolabel were in the li ver (~0.23

- 0.33% for both sexes) which peaked from 1 to 6 hours post dosing and then gradually decreased. All other tissues were less than 0.1%.

The majority of the radiolabel was recovered in the feces (>90%), and was identified as the parent compound. Three metabolites were isolated. Two products were structural isomers formed by hydroxylation of the benzoyl ring at positions 3 and 4, while the remaining metabolite was formed by substitution of one fluorine atom by hydroxide, likely on the aniline rin g. Biliary extracts showed meta

- hydroxylation of the benzoyl ring followed by conjugation was the predominant pathway. Only very small amounts of radioactivity co

- eluted with the hydroxylated

- aniline derivatives of parent teflubenzuron while hydrolytic t reatments of bile indicated that phenyl urea may also be present as a sulfate conjugate.

Regarding excretion, following single low

- dosing, radiolabel detected in the 0

- to 48

- hour interval yielded 45.43

- 46.60% of the administered dose in the feces, 15.28

- 17.04% in the bile, and 1.26

- 1.54% in the urine in both sexes. For this interval and dose, the amount of radiolabel remaining in the tissues and carcass accounted for an average of 23% of the administered dose. Following single high

- dosing, radiolabel de tected in the 0

- to 48

- hour interval, yielded 57.91

- 71.77% of the administered dose in the feces, 1.64

- 2.12% in the bile, and 0.29

- 0.40% in the urine in both sexes. For this interval and dose, the amount of radiolabel remaining in the tissues and carcass accounted for an average of 19% of the administered dose

.Teflubenzuron Human Health Risk Assessment D426404

Page 11 of 30 

### 4.2.1 Dermal Absorption

As only tolerance s without U.S. registration are proposed , there are no dermal absorption or dermal toxicity studies available for teflubenzuron.

4.3 Toxicological Effects

The effects in the teflubenzuron database are indicative of hepatotoxicity. In all species tested there were adverse effects in the liver; increased enzyme release and numerous microscopic indicators of liver injury (diffuse hypertrophy, dissemin ated single

- cell necrosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, lipofuscin accumulation, and patchy fatty change s ). In the mouse

, which is the most sensitive species compared to the rat and the dog, there were liver adenom as following chronic exposure. There is no evidence of neurotoxicity, immunotoxicity

, or genotoxicity.

There is evidence of a quantitative increase in offspring susceptibility for teflubenzuron in the rat

two

- generation reproductive study. While there w ere no parental effects, offspring effects were observed and consisted of decreased F 2 

### litter weights and increased incidence of unilateral dilatation of the renal pelvis in F 1 

### offspring. However, t here were no effects in the developmental rat study up to the highest dose tested. In the developmental rabbit study, no fetal effects were observed, but maternal effects consistent with liver toxicity were observed at the limit dose

.

Teflubenzuron is categorized as having low acute lethality by the oral, dermal or inhalation routes ( Toxicity Categories III and IV). It is not a dermal sensitizer or an eye irritant.

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

The teflubenzuron risk assessment team recommends that the 10X FQPA SF be red uced to 1X for all exposure scenarios. The toxicity database is complete and dietary exposure analyses are unlikely to underestimate exposure

. There is no evidence of neurotoxicity and the selected endpoints are protective of increased offspring susceptibility

. Lastly, there are no residual uncertainties in the exposure database.

4.4 .1 Completeness of the Toxicology Database

The existing toxicology database for teflubenzuron is adequate for FQPA evaluation. Developmental toxicity studies in ra ts and rabbits, a two

- generation reproduction study in rats, and neurotoxicity studies in rats are available for FQPA consideration.

4.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity in the teflubenzuron hazard database

, which includ e s acute and subchronic neurotoxicity studies

.

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

There is no evidence for increased fetal susceptibility. There is an observed increased offspring susceptibility in the two

- gene ration reproductive study

, but the concern is low since ; 1) the effects in pups are well characterized with a clear NOAEL; and 2) the effects are protected for byTeflubenzuron Human Health Risk Assessment D426404

Page 12 of 30 

### the selected chronic dietary endpoint. Therefore, there are no residual uncertainties for pre

- /post

natal toxicity.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The exposure databases are sufficient to determin e the nature/magnitude of the residue in food and dietary analyses are unlikely to underestimate risk of exposure from teflubenzuron. In addition, there are no currently proposed residential uses.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

Acute Dietary Endpoint: An acute p opulation

- a djusted d ose (aPAD) for the general U.S. population, including infants and children, was not established because no endpoint of concern attributable to a single dose was identifi ed in the toxicological database for teflubenzuron

. Therefore, an acute dietary assessment was not performed.

Chronic Dietary Endpoint: The cPAD of 0.021 mg/kg/day was determined on the basis of the carcinogenicity study in mice. The LOAEL of 10.5 mg/kg/day is based on increased microscopic lesions in the liver (diffuse hypertrophy, centrilobular single

- cell necrosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, and centrilobular fatty change s ) associated w ith increased relative liver weights. The NOAEL of 2.1 mg/kg/day is protective of all effects seen following chronic exposure, including the two

- generation reproduction toxicity study. This study is appropriate for the duration of exposure and is conside red protective of the general U.S. population and all population subgroups. This study provides the most protective point of departure in the hazard database with a NOAEL of 2.1 mg/kg/day. A total UF of 100X (10X for interspecies extrapolation, 10X for i ntraspecies variability, and a 1X FQPA SF) was applied to this NOAEL

, generating a cPAD of 0.021 mg/kg/day.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

As there are no domestic agricultural or residential uses registered or proposed for teflubenzuron

, there is no potential for residential /occupational exposure

.

4.5.3 Cancer Classification and Risk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the CARC classified teflubenzuron as “Suggestive Evidence of Carcinogenic Potential” based on the presence of rare liver tumors in male mice only. There was no evidence of carcinogenicity in female mice or in male or female rats. There is also no concern for mutagenicity.

Quantification of teflubenzuron’s carcinogenic potential is not required . The CARC recommended using a non

- linear approach (i.e., RfD) that will adequately account for all chronic toxicity, including carcinogenicity, t hat could result from exposure to teflubenzuron.Teflubenzuron Human Health Risk Assessment D426404

Page 13 of 30 

### 4. 5

. 4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5.4.1

. Summary of Toxicological Doses and Endpoints for teflubenzuron for Use in Dietary and
Non

- Occupational Human Health Risk Assessments

. Exposure/ Scenario Point of

Departure Uncertainty/FQPA

SFs RfD, PAD,

LOC for Risk
Assessment Study and Toxicological Ef fects

Acute Dietary (General Population, including Infants and Children) An endpoint of concern attributable to a single dose was not identified. An acute RfD was not

established.

Chronic Dietary (All Populations) NOAEL =

2.1 mg/kg/day UF A = 10X

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

= 0.021 mg/kg/day

cPAD =
0.021 mg/kg/day Carcinogenicity (mouse)

LOAEL = 10.5 mg/kg bw/day (M), based on increased microscopic lesions in the liver (diffuse hypertrophy, centrilobular single

- cell necrosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, and centrilobular fatty change) associated with increased relative liver weight

.

Cancer (oral, dermal, inhalation) Classification: “Suggestive Evidence of Carcinogenic Poten tial” based on the presence of rare

liver tumors in male mice only. Quantification of teflubenzuron’s carcinogenic potential is not required. The CARC recommended using a non

- linear approach (i.e., RfD ) ) that will adequately account for all chronic toxic ity, including carcinogenicity that could result from exposure to teflubenzuron. Point of departure (POD) = A data point or an estimated point that is 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 animal to human (interspecies). UF H = potent ial variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. LOC = level of concern.



### 5.0 Dietary Exposure and Risk Ass essment

D418271, G. Kramer, 18

- AUG

- 2015 (residue chemistry chapter for the current action) D426403, G. Kramer, 18

- AUG

- 2015 (dietary exposure analysis for the current action)



### 5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The petitioner has provided plant metabolism studies in diverse crops (spinach, cotton, potato, and apple); however, only one study (spinach; MRID 49168727) was determined to be scientifically acceptable. The other studies were determi ned to be tentatively acceptable pending submission of supporting data. However, as the parent teflubenzuron generally accounted for >95% of TRR, submission of these data would be unlikely to change the results. Using a weight

- of

- evidence approach, HED t hus concludes that the translocation and metabolism of teflubenzuron in plants is minimal. Parent teflubenzuron is the only residue of concern for risk assessment and tolerance enforcement. HED notes that this conclusion pertains only to imported commodi ties, and that additional plant metabolism studies (and/or supporting data for the submitted studies) may be necessary to support any future use proposed for the U.S.Teflubenzuron Human Health Risk Assessment D426404

Page 14 of 30 

### The petitioner has provided ruminant and poultry metabolism studies; however, neither st udy was determined to be scientifically acceptable. The potential for actual residues in livestock tissues is minimal (the maximum TRR values extrapolated to a 1X dose are 0.008 ppm in ruminants and 0.0006 ppm in poultry). Minor metabolites resulting fro m hydroxylation (Metabolite 3381 in ruminants) and ring cleavage (3,5

- dichloro

- 2,4

- difluorophenyl urea in poultry) were also seen in rats (see Figure B.2.1 in Appendix B). Metabolite 3381 was monitored in the livestock feeding studies, but residues were f ound to be non

- quantifiable. HED notes that conclusions on the nature of the residue in livestock pertain only to this petition, and that additional livestock metabolism studies may be necessary to support any future uses that result in higher dietary bur dens.

5.1.2 Summary of Environmental Degradation

As there are no domestic agricultural or residential uses registered or proposed for teflubenzuron, environmental degradation is not relevant for this petition.

5.1.3 Comparison of Metabolic Pathways

Translocation and metabolism of teflubenzuron in plants is minimal. No metabolites were identified. The absorption of teflubenzuron in livestock is minimal. Minor metabolites resulting from hydroxylation (Metabolite 3381 in ruminants) and ring cleavage (3,5

- dichloro

- 2,4

- difluorophenyl urea in poultry) were also seen in rats (see Figure B.2.1)

.

5.1.4 Residues of Concern Summary and Rationale

Upon examination of the available data, the HED Residues of Concern Knowledgebase Subcommittee (ROCKS) determin ed that the parent compound, teflubenzuron, is a suitable residue definition for purposes of both tolerance enforcement and risk assessment in plants and livestock commodities (Memo

, E. Holman, 22

- M A Y

- 2015, D426402).

Table 5.1.4.1. Summary of Metabolites and Degradates to be Included in the Risk Assessment

and Tolerance Expression.

Matrix Residues Included in Risk
Assessment Residues Included in Tolerance Expression

Plants Primary Crop Teflubenzuron Teflubenzuron

Rotational Crop Not Applicable Not Applicable

Livestock Ruminant Teflubenzuron Teflubenzuron

Poultry



### Primary Plants. The petitioner has provided plant metabolism studies in diverse crops (spinach, cotton, potato, and apple); however, only one study (spinach) was determined to be scientifically acceptable. The other studies were determined to be tentatively acceptable pending submission of supporting data. However, as the parent teflubenzuron generally accounted for >95% of the TRR, submission of these data would be unlikely to change the results. Using a weight

- of

evidence approach, HED concludes that the translocati on and metabolism of teflubenzuron in plants is minimal. No metabolites were identified. Parent teflubenzuron is thus adequate as the only residue of concern for risk assessment and tolerance enforcement. HED notes that this conclusion pertains only to imported commodities, and that additional plant metabolism studies may be necessary to support any future use proposed for the U.S.Teflubenzuron Human Health Risk Assessment D426404

Page 15 of 30 

### Livestock. The petitioner has provided ruminant and poultry metabolism studies; however, neither study was determined to b e scientifically acceptable. The potential for actual residues in livestock tissues is minimal (the maximum TRR values extrapolated to a 1X dose are 0.008 ppm in ruminants and 0.0006 ppm in poultry) and imported livestock commodities are not likely to be significant contributors to chronic dietary exposure (an aRfD was not established.). Using a weight

- of

- evidence approach, HED concludes that the absorption of teflubenzuron in livestock is minimal. Minor metabolites resulting from hydroxylation (Metaboli te 3381 in ruminants) and ring cleavage (3,5

- dichloro

- 2,4

- difluorophenyl urea in poultry) were also seen in rats (see Appendix B). Metabolite 3381 was determined in the livestock feeding studies, but residues were found to be non

- quantifiable. Parent tef lubenzuron is thus adequate as the only residue of concern for risk assessment and tolerance enforcement. HED notes that this conclusion pertains only to the current action, and that additional livestock metabolism studies may be necessary to support any future uses that result in higher dietary burdens.

5.2 Food Residue Profile

The residue chemistry database includes submissions addressing analytical methods; metabolism in target crops, rotational crops, and livestock; storage stability; residues from f ield trials; residues from ruminant and poultry feeding studies; and residues in processed commodities. During the 90

- day screen of the data, the lack of a processing study for residues of teflubenzuron in/on grape was identified as a data gap (Memo, A. D unbar et al. , 30

- APR

- 2014; D419593 ). ChemSAC determined that raisin

- processing data are required (Minutes of 18

- JUN

- 2014 ChemSAC meeting). As HED would be unable to recommend in favor of a tolerance for residues in/on grape in the absence of the requisit e processing study, the grape field trial data have not been reviewed at this time.

With the exception of a processing study for residues of teflubenzuron in/on grape, the submitted residue data are adequate to fulfill data requirements. Based on the N orth American Free Trade Agreement (NAFTA) guidance (NAFTA Guidance Document on Data Requirements for Tolerances on Imported Commodities in the United States and Canada, 12/05), an adequate number of trials were performed for each crop in the countries whe re use is proposed or which represent the critical GAP. Teflubenzuron residues were limited to the surface of crops and dissipated slowly under field conditions. The recommended tolerance levels for residues of teflubenzuron in/on imported oranges, lemon s, apples, tomatoes, melons, broccoli, sunflowers, soybean, coffee beans, mangos, papaya, and pineapples were obtained using the OECD tolerance

- calculation procedures. As all residues in sugarcane, cauliflower, and field corn grain were below the LOQ, HED recommended the method LOQ (0.01 ppm) as the tolerance level for these commodities. Based on the results of the livestock feeding studies, there is no expectation of finite residues in livestock commodities [§180.6(a)(3)].

The submitted processing data are adequate to fulfill data requirements. Significant concentration of teflubenzuron residues was seen in the following commodities: apple, wet pomace and dry pomace; citrus, oil; corn, aspirated grain fractions (AGF) and r efined oil; pineapple, process residue; soybean, AGF and hulls; and tomato, wet pomace and peel. Tolerances for residues in apple, dry pomace; and tomato, wet pomace and peel are not required as the Agency does not generally establish tolerances for resid ues in these commodities. Tolerances for residues in apple, wet pomace; AGFs; and pineapple, process residue are not required as these commodities are not likely to be imported. Significant reduction of teflubenzuron residues was seen in the following co mmodities: applesauce, apple juice, orange juice, roasted coffee beans, instant coffee, corn grits, corn meal, corn starch, soybean meal,Teflubenzuron Human Health Risk Assessment D426404

Page 16 of 30 

### soybean oil, molasses, refined sugar, sunflower meal, sunflower oil, tomato purée, and tomato juice. The appropriate tolerance levels for citrus, oil; corn, refined oil; and soybean, hulls are shown in Table 2.2.2.1.

5.3 Drinking Water Residue Profile

As there are no domestic agricultural or residential uses registered or proposed for teflubenzuron, a drinking water as sessment is not relevant for this petition.

5.4 Dietary (Food + Drinking Water) Risk Assessment

A chronic (food only) analysis was performed using DEEM

- FCID, ver. 3.16, which incorporates consumption data from the USDA NHANES/WWEIA; 2003

- 2008, to estim ate the dietary exposure of the U.S. population and various population subgroups. The unrefined chronic assessment assumed that teflubenzuron residues are present in all commodities at tolerance levels and that 100% of all crops are treated. DEEM Version 7.81 default processing factors were used to estimate residues in processed commodities, except for apple and orange juice for which empirical processing factors of 0.08 and 0.04, respectively, were used. Drinking water estimates were not incorporated in to the chronic dietary assessment, as there are no domestic uses proposed or established. The results are summarized in Table 5.4.1. The resulting chronic food estimates are not of concern to HED (<100% cPAD) for U.S. general population and all populatio n subgroups (≤50% cPAD); the most highly exposed population subgroup is children 1

- 2 years old. The chronic dietary exposure and risk estimates are highly conservative since they assume that all subject crops consumed in this country have been treated (bu t use is not registered not in the U.S.) and that residues are present at tolerance levels. Dietary exposure estimates could be refined using anticipated residues and percent crop imported data. However, since estimated exposures and risks using conserva tive assumptions are below HED’s level of concern, such refinement is not warranted.

Table 5.4.1. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Teflubenzuron.*

Population Subgroup Acute Dietary Chronic Dietary Cancer Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population

N/A N/A 0.003505 17

N/A N/A All Infants (<1 year old) 0.004994 24
Children 1

- 2 years old 0.010548 50
Children 3

- 5 years old 0.009182 44
Children 6

- 12 years old 0.005347 26
Youth 13

- 19 years old 0.003075 15
Adults 20

- 49 years old 0.002822 13
Adults 50

- 99 years old 0.002525 12
Females 13

- 49 years old 0.002709 13 *Population subgroup with the highest exposure and risk is in bold type.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

As there are no domestic agricultural or residential uses registered or proposed for teflubenzuron

, a residential exposure assessment was not performed.Teflubenzuron Human Health Risk Assessment D426404

Page 17 of 30 

### 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, H ED considers both the route and duration of exposure. Because this action is for tolerance s without a U.S. registration and there are no proposed or existing uses of teflubenzuron which would result in drinking water or residential exposures

, the dietary (food only) exposure estimates provided in Table 5.4.1 represent the aggregate exposure assessment

.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of tox icity, EPA has not made a common mechanism of toxicity finding as

to teflubenzuron and any other substances and teflubenzuron does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,
EP A has not assumed that teflubenzuron has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemi cals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticid es/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Since the proposed use is for a tolerance without an U.S. registration, an occupational exposure assessment is unnecessary.

Appendix A. Toxicology Profile and Executive Summaries Appendix B. Metabolism Considerations Appendix C. Physical/Chemical Properties of Teflubenzuron

RDI: RAB1 ( 17

- JUN

- 201 5 ) Anwar Dunbar:S10952:Potomac Yard 1:703

- 603

- 0611:7509P:RAB1Teflubenzuron Human Health Risk Assessment D426404

Page 18 of 30 

### A ppendix A

. Toxicology Profile and Executive Summaries

The requirements (40 CFR 158.340) for an import tolerance for teflubenzuron are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study 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

................................ ..................... Y es Y es Y es Y es Y es Y es Y es

Y es Y es Y es Y es Y es 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 1

No 1

No 1 Yes

Yes

-

-

- 870.3700a Developmental Toxicity (rodent)

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

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

................................ ................................ . Yes
Yes
Yes No

Yes
No 870.4100a Chronic Toxicity (rodent)

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

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

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

................................ ................... 870.4300 Chronic/Oncogenicity

................................ ................... Yes
Yes

- Yes
Yes Yes

Yes

- Yes
Yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

............... 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... Yes
Yes
Yes
Yes Yes

Yes
Yes
Yes 870.6100a Acute Delayed Neurotoxicity (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Develop. Neurotoxicity

................................ ................. No
No
Yes
Yes
No -

- Yes
Yes

- 870.7485 General Metabolism

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

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

................................ ............................. Yes
No
Yes Yes

- Yes
1

- Not required for tolerances without U.S. registration.



### A.2 Toxicity Profiles

Table A.2.1

. Acute Toxicity Profile

- Test Substance

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

870.1100 Acute oral [rat] 42727305 LD 50 ≥ 5000 mg/kg IV

870.1100 Acute oral [mouse] 42727306 LD 50 ≥ 5000 mg/kg IV

870.1200 Acute dermal [rat] 42727307 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation [inhalation] 42727308 LC 50 = 5.038 mg/L IV

870.2400 Acute eye irritation [rabbit] 42727309 Teflubenzuron is minimally irritating. IVTeflubenzuron Human Health Risk Assessment D426404

Page 19 of 30 Table A.2.1

. Acute Toxicity Profile

- Test Substance

. Guideline No. Study Type MRID(s) Results Toxicity Category
870.2500 Acute dermal irritation [rabbit] 42727310,
42727311 Non

- irritating to

rabbits under these study
conditions IV

870.2600 Skin sensitization [guinea pig] 42727312 No evidence of
irritation Negative

Table A.2.2

. Subchronic, Chronic , and Other Toxicity Profile

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

870.3100 28

- Day oral

toxicity (rat) 49168793 (1986)

Acceptable/Non

- guideline 0, 500, 1000, 2000, 4000, 8000, 16,000, or 32,000

ppm (0, 39, 77, 154, 305, 624, 1259, and 2160 mg/kg bw/day [M]) (0, 38, 78, 158, 320, 607, 1313, and 2544 mg/kg bw/day [F]) The NOAEL for male and female rats treated with teflubenzuron for 28 days was 32,000 ppm (equivalent to 2520 mg/kg bw/day for males and 2544 mg/kg bw/day for females). A LOAEL was not established. The data also indicated that test material absorption became saturated at dietary concentrations of 1000 and 2000 ppm in male and female rats, respectively.

870.3100 28

- Day oral

toxicity (rat) 49168791, 49168792

(1983 and 1989) Acceptable/Non

- guideline 0, 100, 1000, or 10,000

ppm (0, 12.8/11.7, 134/114, and 1254/1219 mg/kg bw/day [M/F]) NOAEL = 10,000 ppm (1254/1219 mg/kg bw/day [M/F])

. A LOAEL was not established

.

870.3100 90

- Day oral

toxicity (mouse) 49168795 (1979)

Acceptable/guideline 0, 100, 1000, or 10,000 ppm (0, 11.85/13.7, 115.3/143.1, and 1,213/1,450 mg/kg bw/day [M/F]) NOAEL = 100 ppm (11.9/13.7 mg/kg bw/day [M/F])

. LOAEL = 1,000 ppm (115/143.1 mg/kg bw /day [M/F]) based upon increased liver enzyme release, and changes in liver histopathology (hepatocellular swelling/fatty changes).

870.3100 90

- Day oral

toxicity (rat) 49168794, 49168796

(1983,1984) Acceptable/guideline 0, 100, 1000, or 10,000 ppm (0, 8/9, 82/94, and 809/942 mg/kg bw/day [M/F]) NOAEL = 10,000 ppm (809/942 mg/kg bw/day [M/F])

. A LOAEL was not identified

.

870.3150 90

- Day oral

toxicity (dog) 49168798 (1985)

Acceptable/guideline 0, 30, or 100 ppm (0, 1.0, and 3.6 mg/kg bw/day [M] 0, 1.2, and 4.1 mg/kg bw/day [F]) NOAEL was 100 ppm (3.6/4.1 mg/kg bw/day [M/F])

. A LOAEL was not identified

.Teflubenzuron Human Health Risk Assessment D426404

Page 20 of 30 Table A.2.2

. Subchronic, Chronic , and Other Toxicity Profile

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

870.3150 90

- Day oral

toxicity (dog) 49168797 (1985)

Acceptable/guideline 0, 100, 1000, and 10,000

ppm (0, 2.7, 29.0, and 251.8 mg/kg bw/day [M] 0, 3.1, 36.7, and 327.0 mg/kg bw/day [F]) NOAEL = 1000 ppm (29.0/36.7 mg/kg bw/day [M/F])

. LOAEL = 10,000 ppm (251.8/327.0 mg/kg bw/day [M/F]) based on (1) macroscopically apparent nodular foci accompanied by foll icular hyperplasia in the stomachs and (2) liver damage described as hepatopathy that morphologically resembles chronic active hepatitis accompanied by elevated activities for several hepatic enzymes (AST, ALT, ALP, GGT, and OCT) seen after 4 and/or 8 (but not 13) weeks of continuous treatment.
870.3200 21 / 28

- Day dermal

toxicity (species) NA NA

870.3465 90

- Day inhalation

toxicity (species) NA NA

870.3700a Prenatal

developmental in (rat) 49168806, 49168805

(1987, 1984) Acceptable/non

- guideline 0, 100, 300, or 1000 mg/kg bw/day Maternal NOAEL = 1000 mg/kg/day

. The maternal LOAEL was not established

. Developmental NOAEL = 1000 mg/kg/day

. The developmental LOAEL was not established

. 870.3700b Prenatal

developmental in (rabbit) 49168807, 49168808

(1984, 1985) Acceptable/guideline 0, 10, 50, or 250 mg/kg bw/day Maternal NOAEL = 250 mg/kg/day

. The maternal LOAEL was not established

. Developmental NOAEL = 250 mg/kg/day
The developmental LOAEL was not established

. 870.3700b Prenatal

developmental in (rabbit) 49168809

(1987) Acceptable/non

- guideline 0, 1000 mg/kg bw/day Materna l NOAEL is 0 mg/kg/day

. LOAEL is 1000 mg/kg bw/day on increased incidence of gross liver findings (granulated cut surface)

. Developmenta l NOAEL is 1000 mg/kg/day

. LOAEL was not established

. 870.3800 Reproduction and

fertility effects (rat) 49168810 (1989)

Acceptable/non

- guideline 0, 20, 100, or 500 ppm (0, 1.5

- 1.9, 7.4

- 9.6, and 39.6

- 48.2 mg/kg bw/day [M] 0, 2.2

- 2.5, 10.8

- 12.4, and 54.9

- 61.5 mg/kg bw/day [F]) Parental/Systemic NOAEL = 39.6/54.9 mg/kg/day (M/F)

. A LOAEL was not established

. Reproductive NOAEL = 39.6/54.9 mg/kg/day (M/F)

. A LOAEL was not established

. Offspring NOAEL = 12.4 mg/kg/day

. LOAEL = 61.5 mg/kg/day based on decreased
F 2 litter weights and increased incidence of unilateral dilatation of the renal pelvis in F 1 offspring

. 870.4100b Chronic toxicity

(dog) 49168801 (1986)

Acceptable /guideline 0, 30, 100, or 500 ppm. (0, 0.98, 3.15, and 17.30 mg/kg bw/day [M] 0, 1.16, 4.02, and 17.98 mg/kg bw/day for males [F]) NOAEL = 500 ppm (17.30/17.98 mg/kg bw/day [M/F])

. A LOAEL was not identified

.Teflubenzuron Human Health Risk Assessment D426404

Page 21 of 30 Table A.2.2

. Subchronic, Chronic , and Other Toxicity Profile

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

870.4200 Carcinogenicity

(rat) 49168811, 49168812

(1987, 1989) Acceptable /guideline 0, 20, 100, 500, 2500,
10000 0, 1.0, 4.8, 24.8, 122.5, and 487.3 mg/kg bw/day [M] 0, 1.2, 5.9, 29.9, 154.0, and 615.2 mg/kg bw/day [F] NOAEL = 2500 ppm ( 25.6/30.5 mg/kg bw/day [M/F])

. LOAEL = 10000 ppm ( 122.5/154.0 mg/kg/day [M/F]) based on microscopic effects in the liver (fatty ch ange and basophilic and mixed cell foci)

.

No evidence of carcinogenicity

.

870.4300 Carcinogenicity

(mouse) 49168813 (1987)

Acceptable/non

- guideline 0, 15, 75, or 375 ppm (0, 2.1, 10.5, and 53.6 mg/kg bw/day [M] 0, 3.1, 15.4, and 71.7 mg/kg bw/day [F]) NOAEL = 15 ppm (2.1 mg/kg bw/day [M]) and 75 ppm (15.4 mg/kg bw/day [F])

. LOAEL = 75 ppm (10.5 mg/kg bw/day [M]), based on increased microscopic lesions in the liver (diffuse hypertrophy, centrilobular single

cell necrosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, and centrilobular fatty change) associated with increased relative liver weight

. LOAEL = 375 ppm (71.7 mg/kg bw/day[F]), based on increased microscopic lesions in the liver (diffuse hypertrophy, disseminated sin gle

cell necrosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, lipofuscin accumulation, and patchy fatty change) with associated increased absolute and relative liver weights and increased alanine aminotransferase and lactate dehy drogenase activities

. There was a treatment

- related increase in tumor incidence of hepatocellular adenomas in males
of the 375

- ppm (10.5 mg/kg/day) group when compared to controls. The incidence of hepatocellular adenomas was 6/50, 5/50, 11/50, and 16/50 at 0, 15, 75, and 375 ppm, respectively. Evidence of carcinogenicity (an increa sed occurrence of liver adenomas and carcinomas at 75 and 375 ppm).
870.5100 Bacterial Mutation

Assay In S. typhimurium And E .coli 49168814 (1982)

Acceptable /guideline
Non

- activated conditions: 0, 125, 250, 500, 1250, 2500 and 5000 μg/plate Activated conditions: 0, 125, 250, 500, 1250, 2500 and 5000 μg/plate There was no evidence of induced mutant colonies over background.Teflubenzuron Human Health Risk Assessment D426404

Page 22 of 30 Table A.2.2

. Subchronic, Chronic , and Other Toxicity Profile

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

870.5100 Bacterial Mutation

Assay In S. typhimurium And E .coli 49168815 (1982)

Acceptable /guideline
Non

- activated conditions: 0, 25, 50, 125, 250, 500 and 1000 μg/plate Activated conditions: 0, 25, 50, 125, 250, 500 Third test: 0, 25, 50, 75, 100, 125, 150, 200, 250, 300, 350, 400, 450 and 500 μg/plate There was no evidence of induced mutant colonies over background.

870.5100 In vitro Bacterial

Gene Mutation In Salmonella typhimurium and
E. coli 49168817 (2003)

Acceptable /guideline 0, 5, 17, 50, 167, 500 and 1667 μg/plate ± S9 There was no evidence of induced mutant colonies over background.

870.5300 In Vitro

Mammalian Cell Gene Mutation
Test 49168816 (1986)

Acceptable /guideline 0, 5, 10, 25 and 50 μg/mL ± S9 Either without or with S9 activation, the test article did not induce a mutagenic response in Chinese hamster V79 cells at any concentration level. There was no evidence of induced mutant colonies over background.
870.5735 In Vitro

Cytogenetics 49168817 (1985)

Acceptable /guideline 0 and 50 μg/mL (7

- hour preparation time) 0, 4, 25 and 50 μg/mL (18

- hour preparation time) 0 and 50 μg/mL (28

- hour preparation time) Without or with S9 activation, there was no increase in the percent of aberrant cells, including or excluding gaps, or in the percent of cells with exchanges, among the cells that were treated with the test article using a 7, 18

,
or 28

- hour preparation interval. All of the positive controls gave appropriate responses. There was no evidence of chromosome aberrations induced over background.
870.5395 In vivo

Mammalian Cytogenetics

- Erythrocyte
Micronucleus

assay 49168818 (1983)

Acceptable /guideline 5000 mg/kg bw (M/F) There was not a significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment condition in either sex.

870.5550 Unscheduled

DNA Synthesis in Primary Rat Hepatocytes/Mam malian Cell Culture 49168818 (1986)

Acceptable /guideline 0, 0.4, 1.0, 4.0, 10.0, 40.0 and 100.0 μg/mL for 3 h (preliminary cytotoxicity assay) 0, 1.0, 3.3, 10.0, 33.0 and 100.0 μg/mL, for 3 hours (main assay) There was no evidence that unscheduled DNA synthesis, as determined by unscheduled incorporation of ( 3 H)

- Tdr into hepatocyte DNA [( 3 H)

- Tdr dpm/ μ g DNA ], was induced.

870.6200a Acute

neurotoxicity screening battery 49168820 (2010)

Acceptable /guideline 0, 125, 500, or 2000 mg/kg Systemic NOAEL = 2000 mg/kg/day

. Systemic LOAEL was not established

. Neurotoxicity NOAEL = 2000 mg/kg/day

. Neurotoxicity LOAEL was not established

. 870.6200b Subchronic

neurotoxicity screening battery 49168821 (2011)

Acceptable /guideline 0, 100, 300 or 1000 mg/kg bw/day Systemic NOAEL = 1000 mg/kg/day

. Systemic LOAEL was not established

. Neurotoxicity NOAEL = 1000 mg/kg/day

. Neurotoxicity LOAEL was not established

. 870.7485 Metabolism and

pharmacokinetics (rats) 46198823, 49168824,

49168825, 49168826 (1984, 1986, 1985 and Regarding absorption, following a single oral dose of 25 mg/kg bw, the C max was 0.46 μg/ mL and the T max was 8 hours for males. ForTeflubenzuron Human Health Risk Assessment D426404

Page 23 of 30 Table A.2.2

. Subchronic, Chronic , and Other Toxicity Profile

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

1987) Acceptable /guideline 25 (single and repeated) and 750 mg/kg bw (single) females, the C max was 0.25 μg/ mL and the T max ranged from 2 to 8 hours. From the 1 to the 8 hours post dosing, nearly const ant plasma levels were found and started to decline at twenty

- four hours. Plasma concentrations declined to less than 0.01 μg equivalents/mL in both sexes at the end of the experimental period (7 days). Following single oral dosing at 750 mg/kg bw,
the C max was 3.27 μg/ mL and the T max was 24 hours. For females, the C max was 1.43 μg/ mL and the T max was 0.67 hours. The second day after treatment, the plasma levels declined to 0.06 and 0.08 μg equivalents/mL in male and female rats by the end of the 7 day s, respectively. Individual average biliary excretion values for the single low

- dose for males and females were 17.04 ± 0.04 % and 15.28 ± 5.18 % of the total absorbed dose. For the high

- dose of 750 mg/kg bw, the values for males and females were 1.64

± 0.94 % and 2.12 ± 0.21 % respectively suggesting saturation of absorption from the GI

tract. Tissue accumulation and distribution was negligible for both sexes treated with radiolabeled test material for 7 consecutive days

, being less than 1% of the admin istered dose at all intervals. The highest detectable levels of the radiolabel were in the liver (~0

. 23

- 0.33% for both sexes) which peaked from 1 to 6 hours and then gradually decreased. All other tissues were less than 0.1%. The majority of the radiolab el was recovered in the feces (>90%), and was identified as the parent compound. Three metabolites were isolated. Two products were structural isomers formed by hydroxylation of the benzoyl ring at positions 3 and 4, while the remaining metabolite was fo rmed by substitution of one fluorine atom by hydroxide, likely on the aniline ring. Biliary extracts showed meta

hydroxylation of the benzoyl ring followed by conjugation was the predominant pathway. Only very small amounts of radioactivity co

eluted wit h the hydroxylated

- aniline derivatives
of teflubenzuron while hydrolytic treatments of bile indicated that phenyl urea may also be present as a sulfate conjugate. Regarding excretion, following single low dosing of bile

- duct cannulated rats, for both

sexes radioactivity excreted in the 0

- to 48

- hour interval yielded 45.43

- 46.60% excretion of the administered dose in the feces, 15.28

- 17.04% in the bile, and 1.26

- 1.54% in the urine. Following a single high dosing of bile duct

cannulated rats, radiolabel exc reted in the 0

- toTeflubenzuron Human Health Risk Assessment D426404

Page 24 of 30 Table A.2.2

. Subchronic, Chronic , and Other Toxicity Profile

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

48

- hour interval, in both sexes, feces accounted for 57.91

- 71.77% of the administered dose,
1.64

- 2.12% in the bile, and 0.29

- 0.40% in the urine.
870.7800 Immunotoxicity

(mouse) 49168822 (2011)

Acceptable /guideline 0, 200, 1000, or 5000 ppm (0, 44, 218, or 1059 mg/kg bw/day [M]) Systemic NOAEL was ≥ 5000 ppm (equivalent to 1059 mg/kg bw/day)

. The systemic LOAEL for dietary
administration not identified

. Immunotoxicity NOAEL was ≥ 5000 ppm (equivalent to 1059 mg/kg bw/day)

. The immunotoxicity LOAEL was not
identified

.



### A.3 Hazard Identification and Endpoint Selection

A.3.1 Chronic Reference Dose (cRfD) `

Study Selected: Carcinogenicity

- mice, feeding

MRID No.: 49168813

Executive Summary : In a carcinogenicity study (MRID 49168813 ), teflubenzuron (92.4±0.9% ai , batch no. DW 44/83) was administered to 60 NMRI mice/sex/dose in the diet at dose levels of 0, 15, 75, or 375 ppm (equivalent to 0, 2.1, 10.5, and 53.6 mg/kg bw/day for males and 0, 3.1, 15.4, and 71.7 mg/kg bw/day for females) for 78 weeks. Ten mice/sex/dose were sacrificed at 52 weeks for interim evaluations. Evaluated parameters included mortality, clinical signs, body weight, body weight gain, food consumption, ophthalmoscopic examination, hematology, clinical chemistry, organ weights, and gross and histopathological examination.

In all three dose groups, no treatment

- related effects were observed on the following parameters: mortality, clinical signs, body weight, body wei ght gain, food consumption, ophthalmoscopic examination, and hematology parameters.

At 75 ppm, the incidences of centrilobular cell necrosis and Kupffer cell proliferation were significantly increased (80% and 50% vs. 0% in the controls) at 52 weeks. A t the terminal sacrifice, the incidences of diffuse hypertrophy (44% vs. 0% in the control), centrilobular single

cell necrosis (52% vs. 16% in the control), patchy glycogen storage (34% vs. 2% in the control), Kupffer cell proliferation (50% vs. 4% in the control) and phagocytic foci (70% vs. 26% in the control) were significantly increased in the males. A trend for increasing incidence of phagocytic foci was also observed in females (50 vs. 40% in the control).

At 375 ppm, statistically significant inc reases were observed in the activities of aspartate aminotransferase (↑130

- 168%), alanine aminotransferase (329

- 583%), and ornithine carbamyl transferase (↑398

- 549%) in males at 52 and 78 weeks. Alkaline phosphatase activity was increased 100% and lactate dehydrogenase was increased 125% in males at 52 weeks. In females, alanine aminotransferase activity was significantly increased 124

- 196% at 52 and 78 weeks and lactate dehydrogenase activity was significantly increased 66% at 78 weeks. At the interim s acrifice at 52 weeks, absolute and relative (to body and brain weights) liver weightsTeflubenzuron Human Health Risk Assessment D426404

Page 25 of 30 

### were increased 30

- 40% in both sexes, compared to controls. By the terminal sacrifice at 78 weeks, absolute and relative (to body and brain weights) liver weights in male s were increased
65

- 70% and 27

- 28% in females.

At 52 weeks, several liver lesions were found including diffuse hypertrophy (60% vs. 10% in the control), single

- cell necrosis (80% vs. 0% in the control), patchy glycogen storage (70% vs. 0% in the control ), Kupffer cell necrosis (80% vs. 0% in the control), and phagocytic foci. There was a trend for increasing incidence of phagocytic foci (80% vs. 40% in the control). In females sacrificed at 52 weeks, a significantly increased incidence of patchy fatty changed was observed (90% vs. 0% in the control). A trend for increasing incidence of phagocytic foci was also observed for females in the mid

- and/or high

- dose groups (80% vs. 40% in the control). At the terminal sacrifice, the incidences of diffuse hyp ertrophy (84% vs. 0% in the control), centrilobular single

- cell necrosis (80% vs. 16% in the control), patchy glycogen storage (76% vs. 2% in the control), Kupffer cell proliferation (70% vs. 4% in the control) and phagocytic foci (92% vs. 26% in the contr ol) were significantly increased in the males. Furthermore in males, the incidences of nodular hyperplasia (20% vs. 6% in the control), disseminated single

- cell necrosis (40% vs. 8% in the control), lipofuscin accumulation (50% vs. 16% in the control) and bile duct proliferation (20% vs. 0% in the control) were also significantly increased. In females, there was a significant increase in the incidences and severity of diffuse hypertrophy (30% vs. 2% in the control), disseminated single

- cell necrosis (48% vs. 4% in the control), patchy glycogen storage (10% vs. 0% in the control), Kupffer cell proliferation (24% vs. 4% in the control), phagocytic foci (64% vs. 32% in the control), lipofuscin accumulation (20% vs. 0% in the control), and patchy fatty change (42% vs. 2% in the control).

At the doses tested, there was a treatment

- related increase in tumor incidence of hepatocellular adenomas in males of the high

- dose group when compared to controls. The incidence of hepatocellular adenomas was 6/50, 5/50, 11/50, and 16/50 at 0, 15, 75, and 375 ppm, respectively. There was no treatment

- related effect on the time to appearance of liver tumors. Dosing was considered adequate based on microscopic liver lesions in both sexes. Lastly the

concurrent cont rol was consistent with the historical control.

The LOAEL in male mice is 75 ppm (10.5 mg/kg bw/day), based on increased microscopic lesions in the liver (diffuse hypertrophy, centrilobular single

- cell necrosis, patchy glycogen storage, Kupffer cell proli feration, phagocytic foci, and centrilobular fatty change) associated with increased relative liver weight. The NOAEL is 15 ppm (2.1 mg/kg bw/day). The LOAEL in female mice is 375 ppm (71.7 mg/kg bw/day), based on increased microscopic lesions in the liv er (diffuse hypertrophy, disseminated single

- cell necrosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, lipofuscin accumulation, and patchy fatty change) with associated increased absolute and relative liver weights and increased alanine aminotransferase and lactate dehydrogenase activities. The NOAEL is 75 ppm (15.4 mg/kg bw/day).

Dose and Endpoint for Risk Assessment: NOAEL = 2.1 mg/kg/day based on increased microscopic lesions in the liver (diffuse hypertrophy, centrilobular single

- cell necrosis, patchy glycogen storage, Kupffer cell proliferation, phagocytic foci, and centrilobular fatty change) associated with increased relative liver weight at the LOAEL = 10.5 mg/kg/day.

Comments about Study/Endpoint/UF s : This study prov ides the most protective point of departure in the hazard database with a NOAEL of 2.1 mg/kg/day. A total UF of 100X (10X for interspecies extrapolation, 10X for intraspecies variability, and a 1X FQPA SF) was applied toTeflubenzuron Human Health Risk Assessment D426404

Page 26 of 30 

### this NOAEL generating a cPAD of 0. 021 mg/kg/day. This study is appropriate for the duration of exposure. It protects for the offspring effects in the two

- generation reproductive study and it is protective of the general U.S. population.Teflubenzuron Human Health Risk Assessment D426404

Page 27 of 30 

### Appendix B. Metabolism Considerations

B.1. Metabolism Summary Table

Table B.1.1. Tabular Summary of Metabolites and Degradates.

Chemical Name (Other Names in Parenthesis) and Structure Matrix Percent TRR (ppm)
Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR)
Teflubenzuron Spinach 77

- 99 (0.083

- 13.5) Apple Fruit: 97.3 (1.23)

Leaves: 99.9 (81.5)
Potato Tops: 99.2 (6.07)
Cotton Leaves: 96 (24.1) Rotational Crops Identified in soil
Ruminant Milk: 4.2 (<0.001) Poultry Egg Yolk: 80.1 (0.684)

Liver: 26.8 (0.090) Fat: 94.0 (1.025) Kidney: 27.1 (0.047)
Rat Feces: 60

- 90% AD
Water N/A N/A

Metabolite 3381 Ruminant Liver: 0.5 (0.002)
Poultry
Rat Trace amounts in the urine
Water N/A N/A

Metabolite E15 3,5

- dichloro

- 2,4

- difluorophenyl urea Rotational Crops Identified in soil

Ruminant Poultry Kidney: 11.5 (0.020)
Rat Trace amounts in the feces
Water N/A N/A

3,5

- dichloro

- 2,4

- difluoroaniline Rotational Crops Identified in soil

Ruminant Poultry
Rat
Water N/A N/A

Ruminant Poultry
Rat Trace amounts in the urine
Water

RuminantTeflubenzuron Human Health Risk Assessment D426404

Page 28 of 30 Table B.1.1. Tabular Summary of Metabolites and Degradates.

Chemical Name (Other Names in Parenthesis) and Structure Matrix Percent TRR (ppm)
Matrices

- Major Residue (>10% TRR) Matrices

- Minor Residue (<10% TRR) Poultry
Rat Trace amounts in the urine
Water

Spinach; 49168727; 0.0892 lb ai/A; 1.4X the proposed rate for broccoli; immature & mature leaves; 18

- hour, 15

- day, and
30

- day PHI. Apple; 42727332; 0.0019 lb ai/gal/application; fruit & leaves; 30

- day PHI. Potato; 42727333; 0.324 lb ai/A; tubers & leaves; 25

- day PHI. Cotton; 42727334; 0.24 lb ai/A; lint, seeds, & leaves; 14

- day PHI. Goats; 42727336 & MRID 42727337; 25 ppm; 64X MTDB; 8 days. Laying Hen; 42727338 & MRID 42727339; 25 ppm; 1800X MTDB; 8 days. Rotational Crops; 49168780 & 49168781; 2.2X, applied to bare soil; lettuce, carrot, and wheat; 28/30, 120/121, and 365/374 days PBI. Rat Metabolism; 49168823

- 26; 25 mg/kg bw/day; Chbb:THOM, 24

- 192 hr. depuration.Teflubenzuron Human Health Risk Assessment D426404

Page 29 of 30 

### B.2 Metabolic Pathways

Figure B.2.1. Proposed Metabolic Pathway for Animals (copied from Section D of the Tolerance Petition).Teflubenzuron Human Health Risk Assessment D426404

Page 30 of 30 

### Appendix C

. Physical/Chemical Properties

Table C. Physicochemical Properties of the Teflubenzuron TGAI.
Parameter Value Reference Molecular weight (g/mole) 381.1 EFSA Scientific Report (2008) 184, 50

- 51 Conclusion on the peer review of teflubenzuron Melting point/range (°C) 225

- 229°C Water solubility (mg/L 20°C) <0.01 (pH 5) <0.01 (pH 7) 0.11 (pH 9) Solvent solubility (g/L at 20°C) n

- Heptane: 0.01 Toluene: 0.74 1,2

- Dichloromethane: 1.51 Methanol: 1.06
Acetone: 8.85 Ethyl acetate: 6.28 Vapor pressure at 20°C 6.87 x 10

- 9 mm Hg Dissociation constant (pK a ) 9.7 Octanol/water partition coefficient at 20°C Log(K OW ) 4.98 (pH 5)