Forchlorfenuron Human Health Risk Assessment DP No. D407226

UN ITE D STATES ENVI R ONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

Date: February 6

, 2014 OFFICE OF
CHEM I CAL SA FETY AND
POLLUTION PREVE NTION

SUBJECT: Forchlorfenuron. H uman Health Risk Assessment for Proposed Uses on Almond, Sweet Cherry, Fig, Pear, Pistachio and Plum/Prune.

PC Code: 128819
Decision No.: 470643
Petition No.: NA
Risk Assessment Type: Single Chemical

TXRNo.: NA

MRID No.: NA

FROM: Alexandra LaMay, Biologist

Donna Davis, Chemist DP Barcode: 04072 26 Registration No.: 71049-4 Regulatory Act i on: Section 3
Case No.: NA

CAS No.: 68157-60-8

40 CFR: 180.569

Matt Lloyd

, Industrial Hygieni t

.., Linda T aylor, Toxico l ogist

### ~~**lb-~~..,.** Risk Assessment Branch l

Health Effects Di vis ion (7509 P )

THROUGH: Danett e Drew,**ChemiM-'~­** Michael Metzger, Chief

Risk Assessment Branch VI
Health Effects Division (7509P)

TO: Marcel H owa rd Cynthia Giles-Parker, Chief Fungicide Branch Registration Division (7505P)

Pag e 1 of32F or c hlorfenur o n Hum an H eal th Ri sk Assess m e nt DP No

. 0 40 7 226

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. 0 E xecuti v e Summary

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2.0 HED Recommendations

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2.1 Da t a De fici encies

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2.2 T o l er a nce C onsiderat i ons

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2.2.1 Enforcement A nalytical M ethod

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2.2.2 Recomm e nded T olerances

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2.2.3 Re v ision s to P etitioned-For T oler a nce s

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2.2.4 Int e rn a tional Harmonization

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2

. 3 Label R e commendations

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. 3 .1 Recommend a tions from Res i du e Reviews

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2.3.2 Recommend at ions from Occupatio na l Assessment

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. 3.3 Recommendations from Resid e ntial As s essment.

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3.0 Introduct i on

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. 1 Chemical Iden t ity

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. 2 Phy s icaVChemical Characteristics

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. 3 Pesticide U s e P attern

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3.4 Anticipated E xposure Pathways

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. 5 Consideration of E nvironmental Justice

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4.0 Hazard C h a rac te riz a tion and Dos e -R e sponse Assessment

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4. 1 Summary of T oxicological Effects

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. 2 Safety F a c t or for Infan t s and Children (FQP A Safety F a c t or)

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. 2. 1 Complet e n ess of the Toxicology Database

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4.2.2 E vidence o f Neurotoxicity

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. 2.3 Evidence o f Sensitivity/Susceptibility i n the Developing or Young Animal..

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. 2.4 Residu a l U ncertainty in t he Ex po s ure Database

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. 3 Toxici ty E ndpoint and Point of Depa r ture S elections

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. 0 D i etary E xpo s ure and Risk Ass es sment..

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5 .1 Residue s of C oncern S ummary a nd R a tionale

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. 2 Food Re s idue P rofile

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5.3 Wat e r R es idue Profile

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. 4 Dietary R isk Assessment

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. 4.1 Desc ri ption of R esidue Data Used in Dietary Assessmen t..

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. 4.2 Percent C rop T rea t ed U sed in Dietary A s sessment

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5.4.3 Acut e Diet a ry Risk Assessment

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5.4.4 Chronic Dietary Risk Assessment

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5.4.5 C ancer Dietary Risk Asse s sment..

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5.4.6 Summary Ta ble

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6 .0 Residen t ial (Non-Occupational) E x p osu r e/Ris k Characteriza t ion

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6.1 Residential H and l er E xposure

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6.2 Post

- A p p li ca tion Exposur e

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6.3 Residenti a l By st a nder Post

- applic a tion I nhalation E x posure

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6.4 S pra y Drift

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7 .0 Aggregate Ex po s ure/Risk Characterization

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. 1 Acute A g g reg ate Risk

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7 .2 Short

- Term A ggregate Risk

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7. 3 Intermediate- T erm Aggregate Risk

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P age 2 of32Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 3 of 32 7.4 Chronic Aggregate Risk

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7.5 Cancer Aggregate Risk

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8.0 Cumulative Exposure/Risk Characterization

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9.0 Occupational Exposure/Risk Characterization

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9.1 Short

- /Intermediate

- Term Handler Risk

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9.2 Short

- /Intermediate

- Term Post

- Application Risk

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9.2.1 Dermal Postapplication Risk

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9.2.2 Inhalation Postapplication Risk

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10.0 References

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

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A.1 Toxicology Data Requirements

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A.2 Toxicity Profiles

................................ ................................ ................................ ............ 27 Appendix B. Physical/Chemical P roperties

................................ ................................ ............. 31 Appendix C. Review of Human Research

................................ ................................ ................ 32Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 4 of 32 1.0 Executive Summar y

HED has conducted a human health risk assessment to support requested Section 3 uses for the active ingredient, forchlorfenuron, a plant growth regulator used to increase fruit set and size. The requested action is for a Section 3 Registration and the establishment of a permanent

tolerance for residues of forchlorfenuron in/on almonds, sweet cherries, figs, pears, pistachios and plums/prunes. The use would permit a single application of forchlorfenuron tied to a specific growth stage at a rate of 0.022 lb ai/A.

The toxicological database for forchlorfenuron is considered complete for characterization of potential developmental, reproductive, carcinogenetic, mutagenic, neurotoxic, and immunotoxic effects. Forchlorfenuron is rapidly absorbed following oral exposur e, with the majority of the dose being recovered in the urine within 24 hours. Forchlorfenuron is not acutely toxic via the oral, dermal, and inhalation routes. It produces mild eye irritation, is not a dermal irritant, and is negative for dermal sensitiz ation. Dose

- related effects noted in the dog following subchronic and chronic exposure were generally limited to decreased body weight and body

- weight gain. In the rat, the only organ that appeared to be affected was the kidney, which showed suppurative

i nflammation, suppurative pyelonephritis, non

- suppurative interstitial nephritis, and cortical cysts following chronic exposure. The prenatal developmental studies in rabbits and rats and the

two

- generation reproduction study in rats showed no indication o f increased susceptibility to in

utero and/or postnatal exposure to forchlorfenuron. Developmental toxicity occurred in the rat only at a maternally toxic dose level and was not observed in the rabbit. Reproductive toxicity

was not observed. There is no concern for immunotoxicity or neurotoxicity following exposure to forchlorfenuron. Forchlorfenuron has been classified as not likely to be a human carcinogen, and there is no concern for mutagenicity.

Based on the toxicity, duration of exposure, and us es of forchlorfenuron, the following toxicity endpoints were selected: Acute dietary (all populations) : No appropriate toxicity endpoint attributable to a single dose (exposure) could be identified from the available toxicology data base. Chronic dietary : cRfD: 0.07 derived from a NOAEL of 7 mg/kg/day in a chronic oral toxicity study in the rat. LOAEL = 93 mg/kg/day based on decreased body weight parameters and kidney toxicity. Dermal and inhalation exposures (short

- term): NOAEL = 100 mg/kg/day from data of the main and range

- finding developmental toxicity studies in the rabbit. LOAEL = 125 mg/kg/day based on body weight loss. Dermal and inhalation exposures (intermediate

- term): NOAEL = 87 mg/kg/day from a chronic oral toxicity in the dog. LOAEL = 195 mg/ kg/day based on decreased body weight /body weight gain/food consumption.

For dermal exposure and risk assessments, 100% absorption was assumed ; inhalation toxicity was assumed to be equivalent to oral toxicity . For the occupational and residential risk assessments the level of concern (LOC) is for MOEs less than 100. The FQPA safety factor has been reduced to 1X since the database is complete, there is no evidence of pre

- or post

- natal sensitivity/susceptibility, there is no evidence of neurotoxicity, a nd exposure estimates are not likely to underestimate risk.Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 5 of 32 The nature of the residue in plants is adequately understood and the residue of concern in plants is forchlorfenuron only for both risk assessment and tolerance setting. The nature of the resid ue in livestock is not adequately understood, but sufficient information is available to evaluate the need for tolerances in livestock commodities. Adequate number and geographic distribution of field trial data have been provided. Further, adequate info rmation has been provided on the potential for residues of forchlorfenuron to concentrate in the processed commodities associated with this petition which include dried plum (prune) and dried fig. The only feed item associated with this petition is almond hulls. HED has classified the proposed uses as 180.6 (a)(3), no reasonable expectation of finite residues with respect to residues in livestock. Tolerances were derived using the Organisation for Economic Co

- operation and Development (OECD) maximum

resi due level (MRL) calculation procedures. Tolerances established for fresh plum and fig are adequate to cover residues likely in dried plum (prune) and dried fig, respectively; therefore tolerances are not required for these processed commodities. Specific tolerance recommendations are discussed in Section 2.2. There are currently no Codex, Canadian, or Mexican MRLs for forchlorfenuron on the crops that are the subject of this petition; therefore, there are no issues with respect to international harmoniz ation associated with this petition. An enforcement analytical method is available to enforce the proposed tolerances and is discussed in

detail in Section 2.2.

The Environmental Fate and Effects Division (EFED) has developed estimated drinking water

co ncentration (EDWC) values for use in human health risk assessment using the PRZM/EXAMS

and PRZM

- GW models for surface and ground water, respectively. For the chronic dietary analysis, the maximum annual mean EDWC value of 7.3 μg/L, derived from the PRZM

- GW

model

, was used as a point estimate to represent chronic drinking water concentration. The EDWC of 7.3 μg/L is a post

- breakthrough mean that occurs after 88 years of annual use. The PRZM/EXAMS (surface water) EDWCs were considerably lower than the PRZM

- GW EDWC (groundwater).

An acute dietary endpoint was not selected since there were no effects seen in the toxicological database that were attributable to a single dose of forchlorfenuron; therefore, quantification of acute dietary exposure and risk ass essment is not required. A highly conservative chronic dietary risk assessment was conducted using tolerance level residues, assuming 100% c rop treated for all commodities, and using default concentration values or actual processing study

information when available for processed commodities. For the U.S. general population and for all subpopulations, risks were <1% of the cPAD, and are, therefore

, not of concern. Since forchlorfenuron has been classified as not likely to be carcinogenic, quantification o f dietary cancer risk assessment is not required.

Quantification of acute aggregate risk assessment is not required since forchlorfenuron does not
pose an acute hazard . Since there are no uses of forchlorfenuron existing or proposed that would result in residential (non

- occupational) exposure to the pesticide, short

- and intermediate

- term aggregate risk assessment are not required. The chronic aggregate risk assessmen t includes only food and drinking water exposure, and is equivalent to the chronic dietary (food and water) risk

assessment . The chronic dietary risk estimates are not of concern for the general population and all population subgroups. Quantification of a ggregate cancer risk assessment is not required.Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 6 of 32 For the purposes of this tolerance action EPA has not assumed that forchlorfenuron has a common mechanism of toxicity with other substances.

HED conducted occupational handler and post

- application exposure and risk assessments for the proposed new uses . Short

- and intermediate

- term MOEs for handlers (mixers/loaders and applicators) were not of concern to HED as they significantly exceeded the target MOE of 100. Total MOEs for the occupational handler asse ssment range from 3,300 to 94,000. The occupational post

- application exposure and risk estimates indicate that short

- and intermediate

term MOEs are not of concern to HED also significantly exceeding the targe MOE of 100. MOEs for the occupational post

- application assessment range from 730 to 10,000.

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

human

- health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions

to Address En vironmental Justice in Minority Populations and Low

- Income Populations. 1 ”

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their exposure. Appendix C provides a dditional information on the review of human research used to complete the risk assessment. There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Resear ch (40 CFR Part 26) have been

satisfied.

2.0 HED Recommendations

HED has no objection to the requested Section 3 registration and permanent tolerances for almonds, sweet cherries, figs, pears, pistachios, and prune plums.

2.1 Data Deficiencies

The toxicity, exposure and residue chemistry data base s are considered complete for the purpose of this petition. No additional data are required to support the requested registrations and tolerances for almonds, sweet cherries, figs, pears, pistachios, and p rune plums.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

HPLC/UV method CCRL

- MTH

- 029, Analytical Method for the Determination of Forchlorfenuron In/On Grapes, Grape Juice and Raisins , (D344334, D. Davis, 2/13/08) is

available for enforcing the proposed tolerances for forchlorfenuron on the proposed plant commodities. For this method, residues are extracted with methanol or acetone, diluted with water, and partitioned against hexane. Residues remaining in the aqueous fraction are then partitioned into dichloromethane (DCM) and if necessary further purified using a silica SPE cartridge. Residues are determined by HPLC/UV using external standards and residues are

1 http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf

.Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 7 of 32 confirmed by LC/MS/MS analysis. This method has been adequately valid ated by the registrant and the Agency. The validated limit of quantitation (LOQ) is 0.01 ppm for forchlorfenuron in fruit and nut crops, and the reported limits of detection (LOD) are 0.002

- 0.003 ppm.

Tolerances are not required for livestock commoditi es; therefore, an enforcement analytical method in livestock commodities is not required.

2.2. 2 Recommended Tolerances

Permanent tolerances are currently established for residues of forchlorfenuron under 40CFR 180.569(a) (1) and temporary tolerances with 12/31/15 expiration are established for residues of forchlorfenuron on almond (0.01 ppm), almond hulls (0.15 ppm), sweet cherry (0.01 ppm), fig (0.01 ppm), pear (0.01 ppm), pistachio (0.01 ppm), and fresh prune plum (0.01 ppm) under 40

CFR 180.569 (a) (2).

The tolerance expression listed in the 40 CFR 180.569 complies with the HED interim tolerance expression policy (S. Knizner, 5/27/09). Permanent tolerances for forchlorfenuron should be established under 180.569(a) for the commodities listed below at th e HED

- recommended

tolerance levels shown in Table 2.2.2.

Table 2.2.2 . Tolerance Summary for Forchlorfenuron

. Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition )

Almond 0.04 0.01 Almond
Almond, hulls (processed commodity) 0.15 0.15 Almond, hulls

Cherry, sweet 0.04 0.01 Cherry, sweet Fig 0.04 0.01 Fig

Pear 0.04 0.01 Pear

Pistachio 0.04 0.01 Pistachio Plum, prune 0.04 0.01 Plum, prune , fresh

Note to RD: Concurrently with establishing the tolerances above under 180.569(a) (1) , the temporary tolerances for the same commodities can be removed from 180.569 (a) (2).

2.2. 3 Revisions to Petitioned

- For Tolerances

The registrant has proposed tolerances for almond, sweet cherry, fig, pear, pistachio, and prune plum at 0.04 ppm, stating that the proposed residue level for each commodity was derived using the OECD MRL calculation procedures. HED does not concur that these are the appropriate outputs from the OECD MRL calculation procedures. All residu e values for all crops (not including processed commodities) are less than the analytical method limit of quantitation (LOQ) of 0.01 ppm. When all inputs for a commodity are less than the LOQ, also known as “censored” values, the OECD calculator recommend s a tolerance level at the method LOQ. Therefore, to be consistent with the OECD MRL calculation procedures, HED is recommending that a tolerance of 0.01 ppm be established for almond, sweet cherry, fig, pear, pistachio, and plum.

No change is recommended to the proposed almond hull tolerance.Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 8 of 32 2.2.4 International Harmonization

There are no Codex, Canadian, or Mexican MRLs established for forchlorfenuron; therefore there are no international harmonization issues associated with this petition.

2.3 Label Recommendations

No revisions to the proposed labels are required.

2.3.1 Recommendations from Residue Reviews

The submitted labels are adequate to allow evaluation of the submitted residue data relative to the proposed uses. The proposed uses are considered adequately supported by the submitted residue chemistry data. No revisions to the proposed labels are required.

2.3.2 Recommendations from Occupational Assessment

N one.

2.3.3 Recommendations f rom Residential Assessment

Not applicable.

3.0 In troduction

3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature

Chemical Structure

Empirical Formula

Common Name Forchlorfenuron
Company experimental name CPPU

IUPAC name 1

- (2

- chloro

- 4

- pyridyl)

- 3

- phenylurea

CAS Name N

- (2

- chloro

- 4

- pyridinyl)

- N’

- phenylurea
CAS Registry Number 68157

- 60

- 8

3.2 Physical/Chemical Characteristics

Forchlorfenuron is a lipophilic compound with a low vapor pressure (not volatile) and has low water solubility. The physicochemical properties for forchlorfenuron are summarized in Table 2.3, below.Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 9 of 32 Table 3.2 Physicochemical Properties of Forchlorfenuron.

Parameter Value Reference Melting point/range 165

- 170°C EPA Fact Sheet, 9/2004 pH Not determined due to low water solubility Density 1.44 g/ml at 21 °C Water solubility 39 ppm Solvent solubility 17g/100 mL in acetone Vapor pressure (25°C) 3.5 x10 - 5 torr Dissociation constant, pK

a Not provided Octanol/water partition coefficient, Log(K OW ) 3.2

UV/visible absorption spectrum Not provided

3.3 Pesticide Use Pattern

CPPUTM Plant Growth Regulator is the end use product for which Section 3 registration has been proposed. CPPUTM Plant Growth Regulator is a soluble concentrate formulation which contains 0.25 grams ai per fluid ounce of product and is packaged such that the entire container contains 8 grams of forchlorfenuron. The proposed use directions for forchlorfenuron on almonds, sweet cherries, figs, pears, pistachios, and plums/prunes are summarized in the table below.

Table 3.3. Summary of Proposed Directions for Use of Forchlorfenuron Application Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

Almond

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 NS Apply during early nut development. Apply in 100

– 200 gallons spray/acre. Sweet Cherry

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 7 Apply in 100

– 200 gallons spray/acre.

Fig

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 NS Apply during early fig development. Apply in

100

– 200 gallons spray/acre.

Pear

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 NS Apply 25

- days post

petal fall. Apply in 100

– 200 gallons spray/acre.

Pistachio

Ground CPPUTM 0.011

– 1 0.022 NS Apply at beginning ofForchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 10 of 32 Table 3.3. Summary of Proposed Directions for Use of Forchlorfenuron Application Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations

application Plant Growth

Regulator [71049

- 4] 0.022 kernel formation. Apply

in 100

– 200 gallons spray/acre.

Plum/Prune

Ground application CPPUTM

Plant Growth Regulator [71049

- 4] 0.011

–

0.022 1 0.022 NS Apply during bloom. Apply in 100

– 200 gallons spray/acre.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed new use of forchlorfenuron on almonds, sweet cherries, figs, pears, pistachios and plums/prunes. Humans may be exposed to forchlorfenuron in food and drinki ng water, since forchlorfenuron may be applied directly to growing crops and application may result in forchlorfenuron reaching surface and ground water sources of drinking water. There are no residential uses of forchlorfenuron, so there is not likely to be exposure in residential or non

occupational settings. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post

application exposure for work ers re

- entering treated fields.

Risk assessments have been previously conducted for forchlorfenuron, but no new toxicity data have been received since the previous risk assessment. A detailed description of the toxicity data

and metabolism information may be found in the risk assessment dated 3/11/08 (D. Davis, D341628). This risk assessment considers all of the aforementioned exposure pathways based on the proposed new uses of forchlorfenuron, but also considers the existing uses as well.

3.5 Consi deration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions

to Address Environmental Jus tice 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 subgroups 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 USDA under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and

are use d in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary expos ure to smaller,Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 11 of 32 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 t oddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that con sider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

No new toxicity and/or rat metabolism data have been received since the last risk assessment, which did not identify any data deficiencies with respect to toxicology. Based on the current 40 CFR Part 158 data requirements, an immunotoxicity study, subchronic dermal and inhalation toxicity studies, and acute and subchronic neu rotoxicity studies are required for forchlorfenuron. However, the Hazard and Science Policy Council (HASPOC) concluded that these studies

should be waived for forchlorfenuron (TXR No. 0056596, dated March 12, 2013 and TXR No.

0056795 , dated September 17 , 2 013) This assessment includes summaries of prior assessments (D. Davis, 3/11/08, D341628).

4.1 Summary of Toxicological Effects

Forchlorfenuron is a plant growth regulator that is absorbed by leaves, stem, cotyledon, and germinated seeds. It promotes cel l division, differentiation, and development; induces budding of callus; controls apical dominance; breaks dormancy of lateral buds; promotes germination; delays the aging process; maintains chlorophyll in excised leaves; regulates the transport of

nutrien ts; and promotes fruit formation.

Metabolism studies in rats indicate that forchlorfenuron is rapidly absorbed and metabolized,

with half of the radiolabel excreted via the urine and feces within 16 hours. The majority of the recovered radiolabel was identified as the conjugate, forchlorfenuron sulfate, with the parent compound accounting for only a small component of that excreted. A dermal absorption study is

not avai lable for forchlorfenuron, and 100% dermal absorption is used for risk assessment.

Forchlorfenuron is not acutely toxic via the oral, dermal, and inhalation routes. Dose

- related effects noted in the dog following subchronic and chronic exposure were gene rally limited to decreased body weight and body

- weight gain. In the rat, the only organ that appeared to be affected was the kidney, which showed suppurative inflammation, suppurative pyelonephritis,

non

- suppurative interstitial nephritis, and cortical cys ts following chronic exposure.

Developmental toxicity was not observed in the rabbit but was observed in the rat (decreased fetal body weight) only at a maternally

- toxic dose level (decreased body weight and death). Forchlorfenuron did not induce any s igns of reproductive toxicity or neurotoxic potential. The developmental toxicity studies in rats and rabbits, as well as the reproductive toxicity study in rats, did not demonstrate any pre

- or postnatal sensitivity. There is no evidence of

immunotoxicit y, and the requirement for an immunotoxicity study has been waived.Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 12 of 32 A repeated exposure study via either the dermal or inhalation routes of exposure is not available

for forchlorfenuron ; however, these studies have been waived . It is not a dermal sensitizer or dermal irritant, but it is a mild eye irritant. No neurotoxicity studies are available on forchlorfenuron, but there was no evidence of neurotoxicity in any of the submitted studies and

these studies have been waived.

The database for carcinogenicity is complete, and forchlorfenuron is classified as not likely to be a human carcinogen. The mutagenicity/genetic toxicity database is considered complete, and there is no concern for mutagenicity.

4. 2 Safety F actor for I nfants and Children (FQPA Safety Factor)

The Food Quality Protection Act (FQPA) safety factor for the protection of infants and children has been reduced to 1X. There are no concerns and no residual uncertainties with regard to pre

and/or postnatal toxic ity. An FQPA Safety Factor of 1X is appropriate for the following reasons:

The database for prenatal developmental and reproductive toxicity is considered adequate to assess safety for infants and children. There is no evidence of increased qualitative or quantitative susceptibility in the developmental rat and rabbit studies or in the rat 2

- generation reproduction study. These studies have clearly defined NOAEL/LOAELs. There is a lack of evidence of neurotoxicity in any study on forchlorfenuron.

Exposu re estimates (food and water) are not likely to underestimate risk.

Further details may be found in the following sections.

4.2.1 Completeness of the Toxicology Database

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

- generation reproduction study are available. The
HED’s Hazard and Science Policy Council (HASPOC) determined that the acute and su bchronic neurotoxicity studies and the immunotoxicity study may be waived (HASPOC Memo, TXR No. 0056596, 3/12/13 and TXR No. 0056795 , dated 9/ 17 / 13).

All other required toxicology studies have been submitted and are considered acceptable.

4.2.2 Evidence of Neurotoxicity

There is no concern for neurotoxicity resulting from exposure to forchlorfenuron, based on a lack of evidence of neurotoxicity in any study on forchlorfenuron. There is not a concern for developmental neurotoxicity.

4.2.3 Eviden ce of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased susceptibility [qualitative and quantitative] following in utero exposure to forchlorfenuron in either the rat or rabbit developmental toxicity study, and there isForchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 13 of 32 no evidence of increased susceptibility [qualitative or quantitative] following in utero and/or pre

- /post

- natal exposure in the 2

- generation reproduction study in rats.

Forchlorfenuron has been evaluated for potential developmental effects in the rat and rabbit (gavage administration). Maternal toxicity included death of one dam and significantly decreased body weight in the maternal rat, and maternal toxicity was not observed in the maternal rabbit. Decreased fetal body weight and a slight inc rease in the incidence of delayed ossification were

observed in the rat at the same dose level at which the maternal effects described above were

seen , whereas there were no developmental effects in the rabbit. Retarded growth was observed in the offspring in the 2

- generation reproduction study at a dose level where clinical signs of toxicity and decreased body weight occurred in the parental rats.

4.2.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure dat abase. The dietary exposure estimates are

unrefined and reflect tolerance

- level residue in food, 100% crop treated, and upper

- bound drinking water estimates based on modeling. These assumptions and refinements are detailed in

the Section 5.4.1. There ar e no non

- occupational exposures for forchlorfenuron.

4. 3 Toxicity Endpoint and Point of Departure Selections

There have been no changes to the prior dose

- response assessment, recommendations for combining routes of exposure

, and/or cancer classification.

Refer to Table 4.3.1 for the summary of the toxicological doses and endpoints for

forchlorfenuron.

Table 4. 3 .1 Summary of Toxicol ogical Doses and Endpoints for Forchlorfenuron for Use in Dietary and Occupational Human He alth 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 (All Populations) No appropriate endpoint attributable to a single exposure (dose) was identified from oral toxicity

studies, including the developmental studies; therefore an acute endpoint was not selected and an acute dietary risk assessment is not required.

Chronic Dietary (All Populations) NOAEL =

7 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x chronic RfD =

0.07 mg/kg/day

cPAD = 0.07 mg/kg/day Chronic oral toxicity study

– rat

LOAEL = 93 mg/kg/day, based on decreased body weight/body

- weight gain/food consumption, and kidney toxicity (suppurative inflammation in males; nonsuppurative interstitial nephritis in females)

Dermal Short

Term (1

- 30 days) oral NOAEL

= 100 mg/kg/day

(dermal absorption rate = 100%) UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational
LOC for

MOE = 100 Developmental toxicity study

– rabbit

LOAEL = 125 mg/kg/day, based on body

weight loss during dosing period in the range

finding studyForchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 14 of 32 Table 4. 3 .1 Summary of Toxicol ogical Doses and Endpoints for Forchlorfenuron for Use in Dietary and Occupational Human He alth Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Dermal

Intermediate

Term (1

- 6 months) oral NOAEL

= 87 mg/kg/day

(dermal absorption rate = 100%) UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational

LOC for

MOE = 100 Chronic oral toxicity study

- dog

LOAEL = 195 mg/kg/day based on decreased body weight/body

- weight gain/food consumption

Inhalation

Short

- Term (1

- 30 days) oral

NOAEL=

100 mg/kg/day

(inhalation toxicity

assumed to be equivalent

to oral ) UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational

LOC for

MOE = 100 Developmental toxicity study

– rabbit

LOAEL = 125 mg/kg/day based on body

weight loss during dosing period in the range

finding study

Inhalation

Intermediate

Term (1

- 6 months) oral NOAEL

= 87 mg/kg/day

(inhalation toxicity

assumed to be equivalent

to oral ) UF A = 10x

UF H =10x FQPA SF= 1x Residential

LOC for

MOE = 100 Occupational

LOC for

MOE = 100 Chronic oral toxicity study

- dog

LOAEL = 195 mg/kg/day based on decreased body weight/body

- weight gain/food consumption

Cancer (oral, dermal, inhalation) Classification: not likely to be a human carcinogen, based o n two adequate rodent carcinogenicity

studies.

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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key

dat a (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Ass essment

5.1 Residues of Concern Summary and RationaleForchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 15 of 32 The qualitative nature of the residue in plants is understood, based on acceptable apple and kiwifruit metabolism studies and supportive grape metabolism data. The residue of concern for

both tolera nce expression and risk assessment is parent forchlorfenuron.

The nature of the residue in livestock cannot be delineated at this time. There are significant deficiencies in the submitted goat metabolism study that preclude a clear understanding of the

n ature of the residue in ruminants

, and a poultry metabolism study is not available.

The nature of the residue in rotational crops has not been delineated as a confined rotational crop study has not been submitted to the Agency.

HED has determined that th e residue of concern in drinking water is parent forchlorfenuron only.

Table 5.1. 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 Forchlorfenuron Forchlorfenuron

Rotational Crop Not Determined Not Determined

Livestock Ruminant Not Determined Not Determined

Poultry Not Determined Not Determined

Drinking Water Forchlorfenuron Not Applicable

5 .2 Food Residue Profile

Available metabolism data shows that forchlorfenuron does not significantly translocate, therefore residues from foliar application are likely to be surface residues. However, forchlorfenuron is used at relatively low application rates, and the submitted field trial studies demonstrate that when applied at early nut/fruit formation stages, quantifiable residues are not likely in human food items and quantifiable residues are not seen in sweet cherries treated up to

7

- days before harvest. Further, quantifi able residues were not seen in processed commodities resulting from the drying of fresh plums and figs. Quantifiable residues were only seen in almond hulls and occurred at low levels in the only animal feedstuff associated with this action.

5.3 Water Residue Profile

For the chronic dietary analysis, the maximum annual mean chronic estimated drinking water concentration (EDWC) value (7.3 μg/L) derived from the PRZM

- GW model was used as a point estimate to represent chronic drinking water concentration. The EDWC of 7.3 μg/L is a post

breakthrough mean that occurs after 88 years of annual use. This maximum post

- breakthrough average value was from the WI corn modeled scenario. The PRZM/EXAMS (surface water) EDWCs were considerably lower than the PRZM

- GW EDWC (groundwater).Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 16 of 32 Table 5.3 Summary of Estimated Surface Water and Groundwater Concentrations

for Forchlorfenuron

.
Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 0.6 8.8

Chronic (non

- cancer) 0.21 7.3

a From the Tier II PRZM

- EXAMS

- Index Reservoir model; 34% PCA

b From the Tier I PRZM

- GW model.
Source: G. Orrick, D 407227, 3/11/13

.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Tolerances are established for residues of forchlorfenuron in/on grapes at 0.03 ppm, raisins at 0.06 ppm, kiwifruit at 0.04 ppm, and the bushberry subgroup 13

- 07B at 0.01 ppm [40 CFR §180.569(a)]. There are no forchlorfenuron tolerances established for animal commodities.

HED has det ermined that the residues of concern in plants include only the parent compound for purposes of both the tolerance expression and risk assessment. No animal commodity tolerances are required to support the existing or newly proposed uses for forchlorfenur on.

Tolerance level residues and 100% crop treated was assumed for all existing and new uses. The recommended tolerances of 0.01 ppm were used for the new uses on almonds, sweet cherries, figs, pears, plums and pistachios under the proposed use (D414083, D. Davis, 9/12/13 ). HED notes that the temporary tolerances in/on olive and apple have expired; thus, these commodities were not included in the assessment. DEEM (Version 7.81) default processing factors were used for dried pears, prune juice, cranberry juice and grape juice. A processing factor was not used for raisins because a separate tolerance has been established for that commodity. In addition, a processing factor was not used for prunes (dried plums) because data show that residues of forchlorfenuron in prunes are not likely to exceed 0.01 ppm, the tolerance established for fresh plums. A processing factor was also not used for dried figs because data show that residues of forchlorfenuron in dried figs are not likely to exceed the tol erance for fresh figs ( D414083, D. Davis, 9/12/13 ). Lastly, the maximum annual mean groundwater concentration from the PRZM

GW model was incorporated into the assessment.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated (%CT) da ta were not applied to the chronic assessment; 100% CT was

assumed for all commodities.

5.4.3 Acute Dietary Risk Assessment

An acute dietary endpoint was not selected since there were no effects seen in the toxicological

database that were attributable to a single dose of forchlorfenuron; therefore, quantification of acute dietary exposure and risk assessment is not required.Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 17 of 32 5.4.4 Chronic Dietary Risk Assessment

HED conducted a Tier 1, screening level chronic dietary (food and drinking water) risk

assessment. The assessment assumed that all commodities will contain residues of forchlorfenuron at the tolerance level. When available, data from processing studies w ere used to estimate residue in processed commodities; however, in the absence of data, DEEM default processing factors were incorporated into the assessment. Lastly, the highest modeled estimate of the exposure to drinking water concentrations was used i n this assessment. Based on the conservative inputs into the analysis, it is unlikely that the assessment will underestimate chronic dietary risks from the proposed and existing uses of forchlorfenuron.

HED is concerned when dietary risk exceeds 100% of the PAD. The dietary analysi s estimates the dietary exposure of the U.S. population and various population subgroups. The results are reported for the general U.S. Population, all infants (<1 year old), children 1

- 2, children 3

- 5,
children 6

- 12, youth 1 3

- 19, females 13

- 49, adults 20

- 49, and adults 50

- 99 years.

For forchlorfenuron, the U.S. population and all population subgroups had dietary risk (food and drinking water) estimates that were below 1% of the cPAD. The general population had an

exposure of 0.000175 mg/kg/day . The most highly exposed subpopulation, all infants, had an

exposure of 0.000447 mg/kg/day . The results of the chronic dietary exposure analysis for all subpopulations are summarized in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

Forchlorfenuron has been classified as not likely to be carcinogenic; therefore quantification of cancer dietary exposure and risk assessment is not required.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk
for Forchlorfenuron.

Population Subgroup Chronic Dietary Dietary Exposure (mg/kg/day) % cPAD*

General U.S. Population 0.000175 <1
All Infants (<1 year old)* 0.000447 <1

Children 1

- 2 years old 0.000346 <1

Children 3

- 5 years old 0.000261 <1

Children 6

- 12 years old 0.000165 <1

Youth 13

- 19 years old 0.000122 <1

Adults 20

- 49 years old 0.000167 <1

Adults 50

- 99 years old 0.000168 <1

Females 13

- 49 years old 0.000167 <1 *The subpopulation(s) with the highest risk estimates.Forchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 18 of 32 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

6.1 Residential Handler Exposure

There are no registered or proposed non

- occupational uses for forchlorfenuron; therefore a residential handler exposure and risk assessment is not required.

6.2 Post

- Application Exposure

There are no registered or proposed uses for forchlorfenuron which would result in residential (non

- occ upational) post application exposures; therefore a post application exposure and risk assessment is not required.

6.3 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inha lation exposure assessment was not performed for forchlorfenuron at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 3.5 x 10

- 5 torr (25°C) ) , and low proposed use rate (0.025 lb ai/acre)

. However, volatilization of pesticides may be a source of
post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal

Insect icide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/sap/meeti ngs/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into t he Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment

for forchlorfenuron.

6.4 Spray Drift

Spray drift is a potential source of expos ure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for forchlorfenuron

. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data

Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide re gulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information). 2 The Agency is also taking means to qualitatively and qualitatively address spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during

the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmForchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 19 of 32 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, d rinking 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, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

An acute endpoint was not selected; therefore quantification of acute aggregate risk is not required.

7.2 Short

- Term Aggregate Risk

Since there are no uses for forchlorfenuron that would result in residential (non

- occupational)

exposure , a short

- term aggregate risk assessment is not required.

7.3 Intermediate

- Term Aggregate Risk

Since there are no uses for forchlorfenuron that wou ld result in residential (non

- occupational)

exposure, an intermediate

- term aggregate risk assessment is not required.

7.4 Chronic Aggregate Risk

The chronic aggregate risk assessment includes only food and water exposure only

. The chronic food plus dr inking water risk estimates are not of concern to HED for the general population and all population subgroups. Refer to section 5.4.4 for a detailed discussion of the chronic dietary

risk assessment.

7.5 Cancer Aggregate Risk

Since forchlorfenuron has been classified as not likely to be carcinogenic, quantification of aggregate cancer risk is not required.

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 toxicity finding as to forchlorfenuron and any other substances and forchlorfenuron does not appea r to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that forchlorfenuron has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts t o determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see theForchlorfenuro n Human Health Risk Assessment DP No. D407226

Page 20 of 32 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/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- /Intermediate

- Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED has determined that there are potential exposures to handlers during application of forchlorfenuron. Scenarios assessed include mixing/loading dry flowable formulations for groun dboom and airblast applications and applying sprays with groundboom and airblast equipment. Although the product associated with the new use is a liquid product, the assessment completed for mixing/loading dry flowable is protective of the use as a liquid ; exposure for mixing/loading dry flowable is greater than exposure for mixing/loading liquids 3

. No chemical

- specific data for assessing human exposures during pesticide handling activities were submitted to the Agency in support of this Section 3 applica tion; therefore, handler exposure was assessed using the Pesticide Handlers Exposure Database version 1.1 (PHED V.1.1). The forchlorfenuron product labels direct mixers, loaders, applicators and other handlers to wear baseline PPE plus chemical

- resistant gloves. The occupational handler exposure and risk

estimates indicate that short

- and intermediate

- term MOEs are not of concern to HED (i.e.,

MOEs > 100) with label

- specified PPE. Total MOEs for the occupational handler assessment range from 3

, 300 to 94,000. While the assessment has been completed for both the short

- and

intermediate

- term exposure durations, the 1 application per season make the short

- term exposure duration risk estimates more probable from a risk management perspective.

3 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( [March 2012] );Forchlorfenuron Human Health Risk Assessment DP No. D407226

Page 21 of 32 Table 9 .1.1. Occupational Handler Short

- Term Non

- Cancer Exposure and Risk Estimates for Forchlorfenuron

.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation Total

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

DF

- Airblast applications Orchard 51.6

– SL/G 8.96 0. 0 3 40 0.000897 110000 0.000157 640000 94000

DF

- Groundboom applications Field Crops 51.6

– SL/G 8.96 0. 0 3 80 0.0018 56000 0.000312 320000 48000

Applicator

Liquid

- Airblast applications Orchard 1770

– SL/no G 4.71

– no

- R 0. 0 3 40 0.0307 3300 0.0000819 1200000 3300

Liquid

- Groundboom applications Field Crops 78.6

– SL/no

- G 0.34

– no

- R 0. 0 3 80 0.00274 36000 0.0000118 8500000 36000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( [March 2012] ); Level of mitigation: Baseline, PPE, Eng. Controls.

2 Based on registered or proposed label (Reg. No. 71049

- 2).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (%) ÷ BW (kg).

5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg /kg/day).

8 Total MOE = NOAEL (mg/kg/day) ÷ Dermal Dose + Inhalation Dose OR Total MOE = 1 ÷ (1/Dermal MOE + 1/Inhalation MOE).Forchlorfenuron Human Health Risk Assessment DP No. D407226

Page 22 of 32 Table 9 .1.2. Occupational Handler Intermediate

- Term Non

- Cancer Exposure and Risk Estimates for Forchlorfenuron

.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation Total

Mitigation Level Mitigation Level Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

DF

- Airblast applications Orchard 51.6

– SL/G 8.96 0.3 40 0.000774 110000 0.000135 640000 94000

DF

- Groundboom applications Field Crops 51.6

– SL/G 8.96 0.3 80 0.00155 56000 0.000269 320000 48000

Applicator

Liquid

- Airblast applications Orchard 1770

– SL/no G 4.71

– no

- R 0.3 40 0.0265 3300 0.0000706 1200000 3300

Liquid

- Groundboom applications Field Crops 78.6

– SL/no

- G 0.34

– no

- R 0.3 80 0.00236 37000 0.0000102 8500000 37000

1 Based o n the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( [March 2012] ); Level of mitigation: Baseline, PPE, Eng. Controls.

2 Based on registered or proposed label (Reg. No. 71049

- 2).

3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (%) ÷ BW (kg).

5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (mg/kg/day) ÷ Dermal Dose + Inhalation Dose OR Total MOE = 1 ÷ (1/Dermal MOE + 1/Inhalation MOE).Forchlorfenuron Human Health Risk Assessment DP No . D407226

Page 23 of 32 9.2 Short

- /Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Postapplication Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry ex posure). HED has determined that there are potential exposures to persons entering treated sites (e.g., harvesters) after application of forchlorfenuron is complete. Since no postapplication data were submitted in support of this registration action, der mal exposures during postapplication activities were estimated using dermal transfer coefficients from the Science Advisory Council for Exposure Standard Operating Procedure (SOP) Number 3.1: Agricultural Transfer Coefficients, August 2000 and using dislod geable foliar residue values estimated using the standard assumption that 25 percent of the application rate is initially available to dislodge from foliar surfaces and the residues dissipate at a rate of 10 percent per day. The results of the postapplic ation occupational exposure and risk assessment indicate that risk estimates are not a concern on the day of application (12 hours following the end of the application). HED concurs with a 12

- hour REI for all proposed crops.

The table below summarizes th e occupational post

- application risk estimates for the proposed applications of forchlorfenuron. The occupational post

- application exposure and risk estimates

indicate that short

- and intermediate

- term MOEs are not of concern to HED (i.e., MOEs > 100).

MO Es for the occupational post

- application assessment range from 730 to 10 ,000.

Table 9.2.1. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for forchlorfenuron.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

Short

- term

Sweet cherry/plum/pear/fig Hand harvesting 1400 0.841 0.137 730

Sweet cherry/plum/pear/fig Hand pruning 580 0.841 0.057 1800

fig transplanting 230 0.841 0.02 4500

Almond/pistachio harvesting 190 0.841 0.02 5400

Almond/pistachio Orchard maintenance 100 0.841 0.009 10000

Intermediate

- term

Sweet cherry/plum/pear/fig Hand harvesting 1400 0.841 0.12 730

Sweet cherry/plum/pear/fig Hand pruning 580 0.841 0.057 1800

fig transplanting 230 0.841 0.02 4500

Almond/pistachio harvesting 190 0.841 0.02 5400

Almond/pistachio Orchard maintenance 100 0.841 0.008 10000

1 DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (kg).

3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm 2 ) × TC × 0.001 mg/μg × 8 hrs/day × dermal absorption factor (%)] BW (kg).Forchlorfenuron Human Health Risk Assessment DP No . D407226

Page 24 of 32 Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of forchlorfenuron. Forchlorfenuron is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is not a ski n sensitizer. Short

- and intermediate

- term post

application risk estimates were not a concern on day 0 (12 hours following application) for all
post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), active ingredient’s classified as

Acute III o r IV for acute dermal, eye i rritation and primary skin irrit ation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to forchlorfenuron.

9.2.2 Inhalation Postapplication Risk

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for forchlorfenuron at this time primarily because of the low acute

inhal ation toxicity (Toxicity Category IV), low vapor pressure ( 3.5 x 10

- 5 torr (25°C) ), and the low proposed use rate (0.025 lb ai/A). However, there are multiple potential sources of post

application inhalation exposure to individuals performing post

- applica tion activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agenc y is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequ ently, the way to incorporate occupational
post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational
post

- application inha lati on exposure assessment for forchlorfenuron

.

Although a quantitative occupational postapplication inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resu lting from application of pesticides outdoors is likely to result in higher exposure than postapplication exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational postapplication

inhalat ion exposure scenarios.

10.0 References

Davis, D. 3/11/08. D341628. Forchlorfenuron: Human Health Risk Assessment for Proposed Uses on the Bushberry Subgroup 13 B and to Support a Requested Experimental Use Permit on Almonds, Sweet Cherries, Figs, Pears, Pistachios and Plums/Prunes. PC Code: 128819, Petition No: 7E7228, DP Barcode: D341628.Forchlorfenuron Human Health Risk Assessment DP No . D407226

Page 25 of 32 Davis, D. 9/12 /13. D414083. Forchlorfenuron (CPPU). Petition for the Establishment of Permanent Tolerances and Registration for Use on Almond, Cherry (Sweet), Fig, Pear, Pistachio, Plum/Prune. Summary of Analyt ical Chemistry and Residue Data.

Orrick, G. 3/11/13. D407227. Forchlorfenuron: Drinking Water Exposure Assessment for Proposed New Uses on Almonds, Sweet Cherries, Figs, Pears, Pistachios, and Plums Including

Prunes

Lloyd, M. 1/23/13. D407548. For chlorfenuron (CCPU)

- Occupational/Residential Exposure/Risk Assessment for the Use of Forchlorfenuron on Figs, Plums, Pears, Sweet Cherries, Almonds and Pistachios.

LaMay, A. 2/6/14

. D414331. Forchlorfenuron

- Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Almonds, Sweet Cherries, Figs, Pears, Pistachios and Plums/PrunesForchlorfenuron Human Health Risk Assessment DP No . D407226

Page 26 of 32 A ppendix A

. Toxicology Profile and Exec utive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for forchlorfenuron 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

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

................................ .................. 870.3200 21/28

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

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

yes

yes

no CR yes

yes

--- A

---

--- A

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)

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

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

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

......................... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

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

— Other Genotoxic Effects

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

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

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

- Day Neurotoxicity (hen)

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

................................ . 870.6200b 90 Day Neurotox. Screening Battery (rat)

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

................................ ........................... no

no

yes

yes

CR ---

---

--- A

--- A

---

870.7485 General Metabolism

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

................................ ................................ . 870.7800 Immunotoxicity...................................................... yes CR

yes yes

---

--- B

Non guideline Thyroid MOA Investigation Study no

---

A Waived by HASPOC (TXR# 0056596 )

B Waived by HASPOC (TXR# 0056795 )Forchlorfenuron Human Health Risk Assessment DP No . D407226

Page 27 of 32 A.2 Toxicity Profile s

Table A.2.1 Acute Toxicity Profile

- Forchlorfenuron

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

870.1100 Acute oral [ rat ] 44394609 LD 50 (mg/kg) = M = 4904

F = 4899 III

870.1200 Acute dermal [ rabbit ] 44394611 LD 50 (mg/kg) = >2000 III

870.1300 Acute inhalation [ rat ] 44394608 LC 50 (mg/L) = >3.0 IV

870.2400 Acute eye irritation [ rabbit ] 44394607 Mild eye irritant III

870.2500 Acute dermal irritation [ rabbit ] 44394610 Non

- irritant IV

870.2600 Skin sensitization [ guinea pig ] 44394606 Non

- sensitizer

-

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Forchlorfenuron

Guideline

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

870.3100 90

- Day oral

toxicity ( F i s ch e r 34 4 r a ts ) 44394614 (1987)

Acceptable/Guideline

0, 200, 1000, 5000 ppm M: 0, 16, 79, 400mg/kg/day F: 0, 17, 84, 428 mg/kg/day NOAEL = 400 (male)

LOAEL = no adverse effe c ts observed (male) NOAEL = 84 mg/kg/day (female) LOAEL = 428 mg/kg/day (female), based on decrease BW, BW gain & food efficiency

870.3150 Sub c hroni c or a l

tox i c i t y (Beagle dog) 44394615 (1987/1993)

Acceptable/Guideline

0, 50, 500, 5000 ppm M: 0, 1.8, 16.8, 162.4 mg/kg/day F: 0, 1.8, 19.1, 188.7 mg/kg/day NOAEL = 16.8/19.1 mg/kg/day (male/female)

LOAEL = 162.4/188.7 mg/kg/day (male/female), based on decreases ( 10%) in BW gain, FC & food efficiency

870.3700a Developmental

toxicity
(Sprague Dawley

Crl:CD ®BR rat)

(GD 6

- 15) 44394612 (1986)

45840123 (2002) Acceptable/Guideline

0, 100, 200, 400 mg/kg/day

45840113 (2002) analytical information Maternal NOAEL = 200 mg/kg/day

Maternal LOAEL = 400 mg/kg/day, based on death of one dam, increased incidence of alopecia; significantly decreased in BW & BW gains Developmental NOAEL = 200 mg/kg/day Developmental LOAEL = 400 mg/kg/day, based on decreased mean fetal BW, a slight increase in the incidence of delayed ossification

of the sternebraeForchlorfenuron Human Health Risk Assessment DP No . D407226

Page 28 of 32 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Forchlorfenuron

Guideline

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

870.3700b Prenatal

developmental in (New Zealand White rabbit)

GD 6

- 18 44394613 (1986)

45840122 (2002) Acceptable/Guideline

0, 25, 50, 100 mg/kg/day

44359526 (1985)

- range finding 0, 125, 250, 500, 1000 mg/kg/day 45840113 (2002) analytical information Maternal NOAEL = ≥100 mg / k g /day

M a t e rn a l L O A EL = not determined.

D e ve l op m en t a l N O A

EL = ≥100 m g/kg/d a y Develo p mental LOAEL = not determined.

870.3800 Reproduction and

fertility effects (Sprague Dawley

Crl:CD ®BR rat) 44394616 (1997)

Acceptable/Guideline

0, 150, 2000, 7500 ppm

F 0 M: 0, 11, 144, 544 mg/kg/day

F 0 F: 0, 13, 169, 701 mg/kg/day

F 1 M: 0, 13, 168, 829 mg/kg/day

F 1 F: 0, 15, 202, 926 mg/kg/day Parental NOAEL = 11 mg/kg/day. Parental LOAEL = 144 mg/kg/day, based on

decreased food consumption (F 0 & F 1 males), clinical signs of toxicity, and lower BW in F 1 males and females

At HDT, decreased BW and kidney lesions (suppurative inflammation in F 0 rats; suppurative pyelonephritis in F 1 rats)

Reproductive N OAEL = 7500 ppm (544/701 mg/kg/day (HDT). Reproductive LOAEL not determined.

Offspring NOAEL = 11 mg/kg/day Offspring LOAEL = 144 mg/kg/day based growth retardation in F 1 & F 2 pups.

At the highest dose tested, increased pup mortality (F 1a , F 1b & F 2a ), growth retardation in

F 1b , and decrease in F 2 pups/litter

870.4100b Chronic toxicity

(dog) 45840105 (1998)

Acceptable/Guideline

0, 150, 3000, 7500 ppm M: 0, 5, 87, 195 mg/kg/day F: 0, 5, 91, 246 mg/kg/day NOAEL = 87/91 mg/kg/day (male/female)

LOAEL = 195/246 mg/kg/day (male/female), based on decreases in BW, BW gains & FC

870.4200 Carcinogenicity

(Crl:CD

- 1®(ICR) BR mouse) 45840106 (2002)

Acceptable/Guideline

M: 0, 10, 991.4 mg/kg/day F: 0, 9.9, 1001.8 mg/kg/day NOAEL = 10.0/9.9 mg/kg/day (male/female)

LOAEL = 991.4/1001.8 mg/kg/day (male/female), based on decreases in BW & BW gains (both sexes)

no evidence of carcinogenicityForchlorfenuron Human Health Risk Assessment DP No . D407226

Page 29 of 32 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Forchlorfenuron

Guideline

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

870.4300 Combined

Chronic Toxicity/ Carcinogenicity

(Crl:CD®BR rats) 44394617 (1996)

Acceptable/Guideline

0, 150, 2000, 7500 ppm M: 0, 7, 93, 352 mg/kg/day F: 0, 9, 122, 518 mg/kg/day NOAEL= 7/9 mg/kg/day (male/female) LOAEL= 93/122 mg/kg/day (male/female), based on reduced BW & BW gain & FC; kidney toxicity (suppurative inflammation in males; non

- suppurative interstitial nephritis in females) no evidence of carcinogenicity

870.5265 Salmonella /

mammalian activation gene mutation assay 44394621 (1985)

Acceptable/Guideline

10

- 1000 g/plate +S9

2

- 200 g/plate

- S9 Evidence of induced mutant colonies over background in tester strain TA1535 in absence of S9 (repeat of MRID 44394620).

There is no evidence of reproductive effects (no decrease in fertility; no increase in dead implants/fetuses) to suggest a genetic
component

870.5265 Salmonella /

mammalian activation gene mutation assay 44394620 (1985)

Acceptable/Guideline

10

- 1000 g/plate +S9

2

- 200 g/plate

- S9 Evidence of a positive response in tester strain TA1535 in absence of S9 at 50, 100, and 200 g/plate; negative ± S9 at all other doses and strains (see above)

870.5375 in vitro

mammalian cytogenetics assay

in Chinese

Hamster CHO

- KI
cells 44394618 (1985)

Acceptable/Guideline

10, 20, 40, and 80 g/mL ±
S9 activation No increase in chromosomal aberrations over background ± S9

870.5550 Unscheduled DNA

synthesis in primary rat hepatocytes/mam

malian cell

cultures 44394619 (1985)

Acceptable/Guideline

0.1 to 60 g/mL Negative for induction of unscheduled DNA synthesisForchlorfenuron Human Health Risk Assessment DP No . D407226

Page 30 of 32 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Forchlorfenuron

Guideline

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

870.7485 Metabolism and

pharmacokinetics (Sprague Dawley rat) MRID 45840107 (2002)

Acceptable/Guideline

100 mg/kg (acute) Recovery of 97% (M & F) by 168 hours.

Absorbed dose 72

- 84%. Urine 62

- 74%. Feces

16

- 28%. Biliary excretion, 20

- 23% in bile.

Urine & feces, elimination half

- life 13.1

- 16.2 hours. Analyses identified parent and 6

metabolites in excreta. Parent not in urine and

1

- 2% in feces. Major metabolite forchlorfenuron sulfate in urine of males (84%) and females (57%). Hydroxy forchlorfenuron ( 2 isomers) <4% in urine; predominant metabolite in feces (11% males and 18% females). Other metabolites include hydroxy

forchlorfenuron

- sulfate, methoxy forchlorf

enuron

- sulfate, forchlorfenuron glucuronide and dihydroxy forchlorfenuron (each<%5).

Metabo lism of forchlorfenuron in rats: conjugation with sulfate at phenyl ring before (major pathway), conjugation with glucuronide at phenyl ring, methylation of hydroxy group of hydroxy forchlorfenuron

- sulfate and hydroxylation of both chloropyridinyl and phe nyl rings.Forchlorfenuron Human Health Risk Assessment DP No . D407226

Page 31 of 32 Appendix B

. Physical/Chemical Properties

Table C1. Physico

- Chemical Properties

Parameter Value Reference Melting point/range 165

- 170°C

EPA Fact Sheet, 9/2004 pH Not determined due to low water solubility Density 1.44 g/ml at 21 °C

Water solubility 39 ppm

Solvent solubility 17g/100 mL in acetone

Vapor pressure (25°C) 3.5 x10 - 5 torr
Dissociation constant, pK

a Not provided

Octanol/water partition coefficient, Log(K OW ) 3.2

UV/visible absorption spectrum Not providedForchlorfenuron Human Health Risk Assessment DP No . D407226

Page 32 of 32 Appendix C

. Review of Human Research

Human Studies Review This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from

PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; and the ARTF database; are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency

website 4

.

4 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html