1 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PESTICIDES AND TOXIC SUBSTANCES **MEMORANDUM DATE:**  **May 1**  **8 , 2010**  **SUBJECT** : Application for E xperimental

- Use Permit and temporary tolerance exemption for

FAL 1800 (P roh ydrojasmon) **EPA Reg. #: 62097**  **- EUP**  **- R**  **Chemical Class: Biochemical PC Code**  **: 028000**  **CAS Number: 158474**  **- 72**  **- 7**  **MRID 47927801 -**  **43 FROM:**  Miachel Rexrode, Ph.D, Senior Biologist /S/ 0 5 / 1 8 /2010

Biochemical Pesticides Branch Biopesticides & Pollution Prevention Division (7511P) **TO :**  Gina Casciano , Regulatory Action Leader /S/ 0 5 / 1 8 /2010 Biochemical Pesticides Branch Biopestici des & Pollution Prevention Division (7511P) **ACTION REQUESTED** The applicant, Fine Agrochemicals Ltd., h as submitted a EUP application and supporting data for F AL 1800, a plant growth regulator to be used to enhance color formation in apples. The applicant is also requesting a temporary tolerance exemption. **Executive Summary** Prohydrojasmon is not naturally

- occurring but is structurally similar to jasmonic acid (JA). JA is an intermediate in the pathway to plant abscisic acid sy

nthesis and has ABA

- like activity (i.e. growth inhibition, senescence, leaf abscission, as well as a role in wound response and s ys temic resistance). When plants are attacked b y insects there is a release of JA, which inhibits the insect’s ability

to digest protein.2

The toxicolog ical profile of Prohydrojasmon (FAL 1801) shows that this compound is practicall y non - toxic with a Toxicological Category IV for acute oral and acute inhalation and a Toxicology Category III for acute dermal toxicity
. Prohydrojasmon is a slight eye irritant (Toxicity Category IV ) and is not a skin sensitize r or a primary skin irritant (Toxicology Category IV). Assay s for mutagenicity , chromosomal aberration, developmental toxicity , and subchronic oral did not present an y clinical or toxicologically signific ant effects. This compound is relativel y unstable in the environment with an aerobic soil half

- life of 1.6

– 2.3 hours, and upon consumption breaks down under gastric condition with a half

- life of 0.8 day s . All product chemistry , Tier I toxicology , and Ti er I ecotoxicity studies submitted in support of the EUP for FAL 1800 (ai Prohydrojasmon) in support of an exemption from the Requirements of Tolerances are acceptable. There are no data gaps and no additional data are required at this time. No acute, subc hronic, or chronic toxicity endpoints were identified in Guideline studies that were submitted and reviewed. Prohydrojasmon is not a sensitizer, not a mutagen or a developmental toxicant. There are no known endocrine effects via oral, dermal, or inhalation exposure and no significant exposure via drinking water. A temporary Tolerance Exemption is appropriate for this compound. There are no concerns for exposure to non

- target organisms (aquatic and terrestrial species). The Agency

has determined a no effect (NE) for threatened and endangered species when Proh ydrojasmon is used in accordance with EPA

- approved labeling. No efficacy data was submitted, but none were required for this non

- public health use product. **RECOMMENDATIONS AND CONCLUSIONS**
**FATE AND DIST RIBUTION**  **FAL 1801 Prohydrojasmon**  **(PDJ)** The fate and distribution information (Table 5.0) show that PDJ was fairly stable in an aquatic environment (pH 9 and 20 0 C half

- life was 17.7 days ), p hotodegrades in water in about 58 hours, and degrades rapidl y in soil (1.6

– 2.3 hours). Due to rapid metabolism and decomposition of PDJ the adsorption constant could not be calculated (does not bind to soil or sediment). **MRID 47927839: Adsorption/Desorption (OPPTS 835.1230).**  The laboratory study was conducted to dete rmine the adsorption and desorption of prohydrojasmon (PDJ) in four different soils. PDJ was added to the soils at concentrations of 5, 1, 0.2, and 0.04 mg/L , with a test solution/soil ratio of 10 mL/2 grams. The soils were incubated at 25°C. After 16 hour s, PDJ adsorption in the four soils ranged from 78.1 to 99.3%, and desorption ranged from 1.0 to 14.9%. The material balance for the four soils ranged from 13.7 to 71.2%. Due to the rapid metabolism and decomposition of PDJ and the low material balance percentages, **the adsorption constant for PDJ could not be calculated.**  The study is classified as **Ac ceptable.**  **MRID 47927840: Hydrolysis (OPPTS 835.2120).**  A laboratory study was conducted to determine the degradation of proh ydrojasmon (PDJ) in water . Test solutions (2 mg/L) of PDJ3

were buffered to pH 9 and maintained at 20°C for 24 day s or at 40°C for 72 hours. To determine degradation under gastric conditions, a treatment of pH 1.2 and 37°C for 32 hours was also included. The half

- life of PDJ at **pH 9 and 20°C was 17.7 days**  , and at pH 9 and 40°C was 2.0 to 2.1 day s. Based on these results, the Arrhenius equation was used to calculate the half

- life at pH 9 and 25°C as 10.7 day s. Under gastric conditions, the **half -**  **life was 0.8 days** . The major degradation product w as dihydrojasmonic acid. The study is classified as **Ac ceptable.**  **MRID 47927841: Photodegradation in Water**  **(OPPTS 835.2240).** The study author concluded that in this study , the mean half

- life of PDJ under light

- irradiated conditions was 54.0 hours in purifie d water and 57.8 hours in river water. Under light

- shielded conditions, the mean half

- life of PDJ was 685 hours in purified water and 247 hours in river water. The study is classified as A **cceptable**
. **MRID 47927842:**  **Aerobic soil metabolism (OPPTS 835 -**  **4100) .**  The study author concluded that under aerobic conditions, the elimination of PDJ was similar in the I baraki and Osaka soils, with a half

- life of **1.6 hours and 2.3 hours** , respectively , and a DT 80 of 3.7 hours and 5.3 hours, respectivel y. The major PDJ meta bolite in both soils was DJA, believed to be the result of de

- n propylation of PDJ, with CO 2 generated as the final product. Under sterile conditions, the half

- life of PDJ in Ibaraki and Osaka soils was extrapolated to be 102 day s and 308 day s, respectivel y. The study is classified as **Acce ptable** 
. **Table 5.0 Fate and Distribution of FAL 1801**  **( PDJ** **) Data Requirement**  **Results MRIDs**  **Study Conclusion** Adsorption/Desorption OPPTS 835.1230 Due to rapid metabolism and decomposition of PDJ and the low material perce ntages, the adsorption constant for PDJ could not be calculated. 47927839 Acceptable

Hydroly sis OPPTS 835.2120 Half

- life of PDJ at pH 9 (20 0 C) was 10.7 days. Under gastric conditions the half

- life was calculated at 0.8 days. 47927840 Acceptable

Photodegradation in Water OPPTS 835.2240 Half

- life in light

irradiated conditions wa s 54.0 hours in purified water 57.8 hours and 57.8 hours in river water. 47927841 Acceptable
Aerobic Soil Metabolism OPPTS 835.4100 Ibaraki and Osaka soils had h alf

- lives of 1.6 and 2.3 hours, respectively. 47927842 Acceptable4

**TOXICOLOGY Test Material**  : **FAL 1800 formulation**  **containing 5.25% PDJ** The toxicological profile of FAL 1800 is s ummarized in Table 6 .0 and shows that this compound is practicall y non - tox ic mammals with a Toxic ity Category IV as noted for acute oral and acute inhalation toxicity studies. The acute dermal toxicity study produced an LD 50 > 2,000 mg/kg bw (Toxicity Category III) and the primary

eye irritation study produced acute sy mptoms af

ter the test material was administered , but were resolved by day 7 ( Toxic ity Category

I II )
. FAL 1800 is not a skin sensitize r or a primary skin irritant.
**1. Acute oral toxicity (OPPTS 870.1100)**  **:** Acute oral toxicity study us ed SD rats. The acute oral LD 50 was > 5000 mg/kg bw in both male and female rats. **2. Acute dermal toxicity (OPPTS 870.1200)**  **:** Acute dermal toxicity study us ed SD rats. The acute dermal LD 50 was > 2 000 mg/kg bw in both male and female rats. **3. Acute inhalation toxicity (OPPTS 870.13**  **00) :**  Acute inhalation toxicity study used rats. The acute inhalation L C 50 was > 5
. 0 mg/ L in both male and female rats. **4. Primary eye irritation (OPPTS 870.2400):**  Primary eye irritation study

used Japanese white rabbits. Acute s ymptoms were observed aft er test material administration, but were resolved by day 7. FAL 1800 produces reversible intense irritation in the eyes. The maximum average score for unwashed eyes was 52.0 one hour after test material instillation. The test material was severel y irri tating. **5. Primary skin irritation (OPPTS 870.2500):**  Primary skin irritation study used Japanese white rabbits. No irritation was noted on the skin. **6. Skin sensitization (OPPTS 870.2600):**  A skin sensitization study (Buehler method) used Hart ley guinea pigs. No skin sensitization was observed. **Table 6.0 Toxicological Data for FAL 1800 (end product)**  **Data Requirement LD**  **50 Toxicity**  **Category MRIDs**  Ac ute Oral Toxicity OPPTS 870.1100 >5000 mg/kg IV 4792781 8 , 47927819 Ac ute Dermal Toxicity OPPTS 870.1200 >2000 mg/kg I II 47927818 , 47927820 Ac ute Inhalation Toxicity OPPTS 870.1300 LC 50 > 5.0 mg/L IV 47927818 , 4792782 15

**Table 6.0 Toxicological Data for FAL 1800 (end product)**  **Data Requirement LD**  **50 Toxicity**  **Category MRIDs**  Primary Eye Irritation OPPTS 870.2400 Ac ute symptoms were observed after test material was administered, but resolved by day 7. FAL 18 00 pro duces reversible intense eye irritation III 47927818 , 4792782 2

Primary Dermal Irritation OPPTS 870.2500 No skin irritation. IV 47927818 , 47927823 Dermal Sensitization OPPTS 870.2600 Not a dermal sensitizer - 47927818 , 47927824 **Test Material** : **FAL 1801 [ prohydrojasmon (PDJ)**  The toxicological profile of FAL 1801 is s ummarized in Table 7 .0 and shows that this compound is practicall y non - toxic mammals with a Toxicological Category IV as noted for acute oral and acute inhalation toxicity

studies. The acute d ermal toxicity study produced an LD 50 > 2,000 mg/kg bw (Toxicity

Category I II). The primary

eye irritation study

produced slight acute sy mptoms after the test material was administered (Toxic ity Category IV) and FAL 1801 proved to not be skin sensitize r or a primary skin irritant
. **1. Acute oral toxicity (OPPTS 870.1100)**  **:** Acute oral toxicity study us ed SD rats. The acute oral LD 50 was > 5000 mg/kg bw in both male and female rats. **2. Acute dermal toxicity (OPPTS 870.1200)**  **:** Acute dermal toxicity study us ed SD rats. The acute dermal LD 50 was > 2 000 mg/kg bw in both male and female rats. **3. Acute inhalation toxicity (OPPTS 870.1300)**  **:** Acute inhalation toxicity study used rats. The acute inhalation L C 50 was > 2.8 mg/ L in both male and female rats. **4. Primary**  **eye irritation (OPPTS 870.2400):** Primary eye irritation study

used Japanese white rabbits. Slight eye irritation was observed. **5. Primary skin irritation (OPPTS 870.2500):**  Primary skin irritation study used Japanese white rabbits. No irritation was not ed on the skin. **6. Skin sensitization (OPPTS 870.2600):**  A skin sensitization study (Maximization method) used Hart ley

guinea pigs. No skin sensitization was observed. **C omments**  **:** The summary (MRID 47927818) seems to include the study results of PDJ (MRI Ds 47927819 to 47927824) and PDJ Formulation (MRIDs 47927825 to 47927830).6

**Table 7.0 Toxicological Data for P rohydrojasmon (PDJ)**  **FAL 1801 Guideline #**  **Test Results/**  **Toxicity**

**Category MRIDs**  **Study Conclusion** Ac ute Oral Toxicity OPPTS 870.1100 LD 50 > 50 00 mg/kg IV 47927818,

47927825 Acceptable Ac ute Dermal Toxicity OPPTS 870.1200 LD 50 > 2000 mg/kg III 47927818,

47927826 Acceptable Ac ute Inhalation Toxicity OPPTS 870.1300 LC 50 > 5.0 mg/L IV 47927818,

47927827 Acceptable Primary Eye Irritation OPPTS 870.2400 slight eye irritation IV 47927818,

47927828 Acceptable Primary Dermal Irritation OPPTS 870.2500 No skin irritation. IV 47927818,

47927829 Acceptable Dermal Sensitization OPPTS 870.2600 Not a dermal sensitizer 47927818, 47927830 Acceptable 8 70.3100 90 day Oral Toxicity

- Rat NOEL=566
- 587 mg/kg/day 47 927831 Acceptable 870.3700 Prenatal Developmental Toxicity Study

- Rat Maternal NOEL > 500 mg/kg/day Developmental NOEL > 500 mg/kg/day 47 927832 Acceptable

870.5100 Bacterial Reverse Mutation Test There was no evidence of induced mutant colonies over background 47 927833 Acceptable

870.53 75 In Vitro Mammalian Chromosome Aberration Tests There was no evidence of cells with chromosomal abnormalities 47 927834 Acceptable **Classification: Accept able;**  no additional data are required.
**TOXICOLOGY STUDIES**  **FAL 1800 formulation containing 5.25% PDJ M**  **RID 47927819**  **: Acute Oral Toxicity -**  **Rats (OPPTS 870.1100)** The oral LD 50 for males, females, and combined sexes of rats was greater than 5 , 000 mg/kg s uggesting that PDJ Formulation i s a **TOXICITY CATEGORY IV** . This study is classified as Acceptable. **MRID 47927820: Acute Dermal Toxicity**  **- Rats (OPPTS 870.1200)**  The acute dermal LD 50 for males, females, and combined sexes of rats was greater than 2000 mg/k g placing PDJ Formulation in **TOXICITY CATEGORY III** . The study is classified as **Acceptable.**
**MRID 4792782 1**  **: Acute Inhalation Toxicity**  **- Rats (OPPTS 870.1300)**  The inhalation L C 50 for males, females, and combined sexes of rats was > 5.0 mg/L placing DPJ7

For mulation in **TOXICITY CATEGORY IV** . The study is classified as **Acceptable. MRID 47927822:**  **Acute Eye Irritation -**  **Rabbits (OPPTS 870.2400** ) Eye - unwashed group: Corneal opacity was noted on 6/6 rabbits one hour after test material instillation with persistenc e through day 4 with clearance by

day 7. No iritis was noted on any rabbit during the study . Positive conjunctival irritation was noted on 6/6 animals one hour after test material instillation with clearance b y 24 hours. Eye

- washed group: Corneal opacity was noted on 3/3 rabbits at one hour after test material instillation with resolution by day 4. No iritis was noted on an y rabbit during the study. Positive conjunctival irritation was noted on 3/3 animals at one hour after test material instillation w ith resolution by 24 hours The maximum average score for unwashed eyes was 52.0 at one hour after test material instillation. The maximum average score for washed eyes was 40.7 at one and 24 hours after test material instillation. PDJ Formulation was sev erel y irritating and is in **TOXICITY CATEGORY III**
. This study

is classified as **Acceptable. MRID 47927823:**  **Primary Dermal Irritation -**  **Rabbits (OPPTS 870.2500)** Very slight ery

thema was noted on 3/6 rabbits one hour after patch removal with clearance on two rabbits by 24 hours and on one rabbit by 48 hours. The primary

irritation index was 0.2 suggesting that the PDJ formulation was practically not irritating and is in **TOXICITY CATEGORY IV.**  The study is classified as **Acceptable .**  **MRID 47927824: Skin Sens itization**  **- Guinea Pigs (OPPTS 870.2600)**  After three consecutive weekl y inductions, the test animals, control animals, and controls for positive control animals showed no signs of reactivity at 24 and 48 hours after challenge and the results for the DNCB p ositive control were appropriate. PDJ Formulation **was not a dermal sensitizer**  . The study is classified as **Acceptable.**
**FAL 1801 Prohydrojasmon**  **(PDJ) MRID 47927825: Acute Oral Toxicity**  **- Rats (OPPTS 870.1100**  ) The oral LD 50 for males, females, and combi ned sexes of rats was greater than 5000 mg/kg placing PDJ in **TOXICITY CATEGORY IV** . The study is classified as **Acceptable. MRID**  **47927826: Acute Dermal Toxicity**  **- Rats (OPPTS 870.1200)**  The acute dermal LD 50 for males, females, and combined sexes of rats w as greater than 2000 mg/kg placing PDJ in **TOXICITY CATEGORY III** . The study is classified as **Acceptable**
. **MRID 7927827**  **: Acute Inhalation Toxicity -**  **Rats (OPPTS 870.1300)** The inhalation L C 50 for males, females, and combined sexes of rats was > 2.8 mg/L pla cing DPJ in **TOXICITY CATEGORY IV** . This study is classified as **Acceptable. MRID 47927828: Acute Eye Irritation**  **- Rabbits (OPPTS 870.2400**  ) Eye - unwashed group: Corneal opacity was noted on 2/6 rabbits 24 hours after test material instillation with resolutio n by 48 hours. No iritis or positive conjunctival irritation was noted on8

any rabbit during the study . Eye - washed group: Corneal opacity was noted on 3/3 rabbits at one hour after test material instillation with resolution on two rabbits by 24 hours and on another rabbit by 48 hours. No iritis or positive conjunctival irritation was noted on any rabbit during the study . The maximum average score for unwashed eyes and washed eyes were 5.0 and 11.0, respectivel y, at one hour after test material instillati on. The test material PDJ was minimally irritating and is in **TOXICITY CATEGORY IV** . The study is classified as **Acceptable .**  Note: PDJ Formulation was severel y irritating. **MRID 47927829: Primary Dermal Irritation**  **- Rabbits (OPPTS 870.2500)**  No dermal irrit ation was noted for an y rabbit during the study with a primary irritation index of 0.0. The test material PDJ was not irritating and is in **TOXICITY CATEGORY IV** . The study is classified as **A cceptable**  **. MRID 47927830:**  **Skin Sensitization -**  **Guinea Pigs (OPPT S 870.2600**  ) After intradermal and topical inductions, the test, control, and control for positive control animals showed **no signs of reactivity**  at 24, 48, and 72 hours after challenge. The DNCB positive control animals showed positive reactivity
. **The tes t material PDJ was not a dermal sensitizer**  . The study is classified as A **cceptable .**  **MRID 47927831: Subchronic oral** 

**– rat (**  **OPPTS 870.3100**  **)** No clinically or toxicologicall y significant effects were found in any treatment - group. Therefore, the reviewer estab lishes the NOAEL as the highest dose, 10,000 ppm (566 mg/kg bw/day for males and 587 mg/kg bw/day for females). A LOAEL was not established suggesting that the test animals could have tolerated a higher dose (protocol calls for a high test level of at lea st 1,000 mg/kg). The study is classified as A **cceptable although the LOAEL was not established. The Agency has calculated the possibility of dietary exposure and concludes that in a worst case scenario (no degradation)**  **the PDJ residues consumed by a 70 kg p erson are four orders of magnitude below NOAEL**  **that was calculated for this compound as noted in the risk assessment.**  **MRID 47927832:**  **Prenatal Developmental toxicity** 

**– rat (**  **OPPTS 870.3700)**  **Maternal effects** No treatment
- related effects were found at necrop sy in maternal animals nor were there effects on copra lutei, number of implantations, sex ratio, fetal body weight, or preimplantation embryonic mortality . The reviewer does not consider the transient decrease in body weight or food intake as adverse an d establishes the **NOAEL for the study as 500 mg/kg bw/day**  . A L OAEL was not identified. **Developmental effects** No treatment
- related effects were found on external examination of the fetuses. Visceral examination showed a slight increase in the incidence o f thy mic remnants; however, the increase was within the historical background of the performing laboratory
. Therefore, the Agency does not consider this a treatment

- related effect. There was also a slight increase in the incidence of a 14 th rib but this was not accompanied b y an increased incidence of abnormal embryos either on external, skeletal, or visceral examination. Additonally , no increase in the incidence of litters with this effect was found. This effect is a common variation in this strain of rat and is therefore not considered an adverse effect. Based on the study results, the **NOAEL for the study is the high -**  **dose 500 mg/kg bw/day** but a LOAEL was not identified. The study is classified as A **cceptable although the LOAEL was not established. The A gency** 9

**has calculated the possibility of dietary exposure and concludes that in a worst case scenario (no degradation) the PDJ residues consumed by a 70 kg**  **person are four orders of**  **magnitude below NOAEL that was calculated for this compound as noted in the**  **risk assessment.**  **MRID 4 7927833:**  **S almonella/Escherichia/mammalian activation assay (**  **OPPTS 870.5100 )**  The investigator concluded that **PDJ was not mutagenic** to the tested bacterial strains under the conditions used in this study
. Using doses of the test article up to those that were cy totoxic, both without and with activation, there was no dose that caused at least a 2

- fold increase in the number of revertants compared to the corresponding solvent control. There was also no test condition which caused an y d ose - dependent and reproducible increase in the number of revertants. All positive controls, without and with activation, gave appropriate. This is study is classified as A **cceptable. MRID 47927834**  **: In vitro**  **Mammalian Chromosome Aberration Test (OPPTS**  **870 .5375)**  PDJ was tested up to cy

to toxic dose levels (80 μg/mL , based on reduced mitotic activity) without S9 activation , and up to the limit concentration of 5000 μg/mLwith S9 activation. **None of the test concentrations induced a significant increase in th**  **e incidence of cells with chromosomal abnormalities**  , either in the absence or presence of S9 activation. In both experiments, the fraction of cells with chromosomal aberrations was below 5%, which indicated a negative response. There was also no indication of an y dose

- response effect either without or with activation. All of the negative, solvent and positive controls gave appropriate responses. This study

is classified as **A cceptable**  **. ECOTOXICITY STUDIES**  **FAL 1801 Prohydrojasmon**  **(PDJ)** Ecotoxicity

studies (Table 8.0) show that proh ydrojasmon (PDJ) is moderately toxic to fish and aquatic invertebrates (L C 50 and EC 50 = 3.3 and 9.54 mg/L, respectivel y) and practicall y non - toxic to avian species (LD 50 >2 , 000 mg/kg ; LC 50 >5 , 000 ppm)
. This compound is relatively unstable in the environment with an aerobic soil half

- life of 1.6

– 2.3 hours, and upon consumption breaks down under gastric condition with a half

- life of 0.8 day s . **Table 8.0. Ecotoxicity Data for Prohydrojasmon (PDJ )** 

**Guideline # Test**  **Results/Toxicology Category**  **MRID Study**  **Conclusion Aquatic Species Testing**  850.1010 Ac ute Toxicity Test, Daphnids EC 50 = 9.54 mg/L. Moderately toxic 47927838 Acceptable 850.1075 Ac ute Toxicity Freshwater Fish Cyprinus carpio 96 hr LC 50 = 3.3 mg/L. Moderately toxic 47927 837 Acceptable **Avian Species Testing** 850.2100 Avian Acute Oral Toxicity Bobwhite ( Colinus virginianus ) LD 50 >2000 mg/kg Practically non

- toxic 47927835 Acceptable10

**Table 8.0. Ecotoxicity Data for Prohydrojasmon (PDJ )** 

**Guideline # Test**  **Results/Toxicology Category**  **MRID Study**  **Conclusion** 850.2200 Avian Dietary Toxicity Japanese quail ( Colinus virginianus ) LC 50 >5000 ppm Prac tically non

- toxic 47927836 Acceptable

**FAL 1801 Prohydrojasmon**  **(PDJ) MRID**  **47927835: Avian Acute Oral Toxicity (OPPTS 850.2100)** The acute Northern Bobwhite ( Colinus virginianus ) oral nominal **LD 50**  **was >2,000 mg a.i./kg.** The no

- mortality concentration and the no

- observed

- effect concentration were 2,000 mg a.i./kg. This study is classified as **Acceptable. MRID**  **47927836: Avian Dietary Toxicity (OPPTS 850.2200)**  Ina five

- day dietary toxicity test, a group of 10

- day

- old Japanese quail was administered prepared diet containing a nominal dose 5000 ppm PDJ (a.i., 98.08% n

- prop yldihydrojasmonate), followed b y three days of untreated basal diet. A control group was fed untreated basal diet only . There were no treatment

- related mortalities, and all birds appeared norm al during the test. Mean body weight, body weight gain, feed intake, and feed conversion were comparable between the control and test material groups. The measured concentration of the test material in the prepared diet was 4721 ± 255.1 ppm, 94.4% of the n ominal concentration. The 5
- day dietary study produced an **L C**  **50 >**  **5 ,**  **000 ppm** and the NOEC of 5,000 ppm. This study is classified as **Acceptable**
. **MRID 47927837**  : **Fish Acute Toxicity Testing (OPPTS 850.1075)** Based on the mean measured concentrations, the 96

- hour L C 50 for PDJ Technical in common carp ( Cyprinus carpio ) was **3.3 m**  **g a.i./L** with the LOEC of 2.76 mg a.i./L , and the NOEC of 1.42 mg a.i./L. This study is classified as **Acceptable**
. **M RID**  **47927838: Aquatic Invertebrate Acute Toxicity Testing (OPPTS 850.1010 ).**  Based on the mean measured concentrations, the 24

- hour **EC 50**  **was 9.54 mg/L** (95% a .i., 7.62

- 12.0 mg/L), and the 48

- hour EC 50 was 2.13 mg/L(95% a .i., 1.64

- 2.70 mg/L). The study is classified as **Acce ptable** 
.11



### Risk **Assessment**
**HUMAN HEALTH Chron**  **ic Exposure and Oncogenicity** : None of the results of the submitted studies triggered the need for chronic exposure or oncogenicity testing. No morphologic effects ( e.g. hy perplasia or metaplasia) in any organ that could potentially

lead to neoplastic chan ge. Assays for mutagenicity, chromosomal aberration, developmental toxicity, and subchronic oral did not present any clinical or toxicologically significant effects. **Effects on the Endocrine System:** No data are available regarding the effects of Prohydro jasmon on endocrine sy stems via oral, dermal, or inhalation exposure. No significant treatment

- related effects were observed for prenatal d evelopmental or maternal testing. **Dose Response Assessment:** No toxicological endpoints were identified; therefore a dose response assessment was not required. **Dietary Exposure:** The most likely dietary route of exposure of humans to Prohydrojasmon is via exposure to treated fruit or foliage (e.g. apples). Table 9 .0 shows possible Prohydrojasmon residues on various matrices after one maximum application of 0.009 lbs ai/A ( 200 ppm ai/A )
. The dietary

- based estimated environmental concentrations range from 0.77 to 0.06 ppm on the day of application and decline to 0.0 by

Day 2. **This compound is relatively unstable in the e nvironment with an**  **aerobic soil half**

**- life of 1.6** 

**– 2.3 hours, and upon consumption breaks down under gastric**  **condition with a half**

**- life of 0.8 days.**  The Agency **has calculated the possibility of**  **risk to humans through dietary exposure**  **by using a worst cas**  **e scenario of maximum application and**  **no degradation. These calculations (Appendix**  **A ) show that the**  **Prohydrojasmon r esidues consumed by a 70 kg person are**  **about seven orders of magnitude below Developmental Toxicity**  **NOAEL >**  **500 mg/kg and about eight**  **order s of magnitude below the Acute O**  **ral toxicity value (LD**  **50 > 5,000 mg/kg)**  **, suggesting no dietary or sublethal risk** 12

**Table 9**  **.0 Estimated Prohydrojasmon Residues on Terrestrial Matrices Using the Terrestrial**  **Exposure Model (T -**  **REX ; USEPA ) Terrestrial Ma**  **trix Dietary**  **- based Estimated Environmental Concentrations**  **(ppm) 0 days after application**  **2 days after first application**  Short Grass **0.77 0.0**  Tall Grass **0.32 0.0**  Broadleaf Plant Foliage **0.41 0.0**  Fruits, Pods, and Seeds **0.06 0.0**  **Drinking W ater**  **E xposu**  **re and Risk Characterization:** No significant exposure via drinking water is expected when Prohydrojasmon is used in accordance with EPA

- approved product labeling. The end product is not to be applied directly to water or to areas where surface water is present . In the unlikely event that exposure via drinking water did occur, the health risk would be expected to be minimal, based on low acute oral and dermal toxicity

of Prohydrojasmon. The Agency

e stimated environmental concentrations (EECs) to an aquat ic site from Prohydrojasmon runoff (spray to apple trees) using the GENeric Estimated Environmental Concentration model (GENEEC; EPA, 2001). The model assumed 2 maximum applications of end product at 0.009lbs ai/A (4g ai/A) at 7 day intervals, a 10.7 day

a quatic half

- life, a 57.8 hours photodegradation half

- life in water, and a 1.6

– 2.3 hour half

- life in aerobic soil. The peak aquatic EEC was calculated at about 0.00048 ppm w ith a decline to 0.000024 ppm after 21 days (Table 10 .0). No acute or subacute end points were identified through mammalian testing and the expected concentrations in surface water are well below (6 to 7 orders of magnitude) the maximum doses used in laboratory testing (e.g. Acute Oral Toxicity LD 50 > 5,000 mg/kg; Developmental Toxicity NOAEL > 500 mg/kg). **Table 10**  **.0 Generic Estimated Environmental Concentratio ns (EECs) of Prohydrojasmon in A**  **quatic Sites using the GENEEC**  **Model, ver 2.0 (EPA, 2001) in Parts P er**  **M illion (ppm**  **) Peak EEC**  **Max 4 Day**

**Avg EEC Max 21 Day** 

**Avg EEC Max 60 day** 

**Avg EE C**  **Max 90 Day**

**Avg EEC** 0.000 48 0.00013 0.0000 24 0.00000 8 0.000006 **Occupational Exposure:** Occup ational exposure to Prohydrojasmon is mitigated as long as the end

- use product is used in accordance with EPA

- approved labeling. Occupational exposures are not included under the Federal Food, Drug, and Cosmetic Act (FFDCA) in the assessment of aggregated exposures for the purpose of establishing tolerances and exemptions from tolerance. **Residential, school and Day Care Exposure and Risk Characterization:** Sign ificant human exposure to Prohydrojasmon is highl y unlikely in residential, school and day13

care areas when the end use product is used in accordance with EPA

- approved labeling. The product is only

intended for commercial use as a plant growth regulator on apples. **Aggregated Exposure from Multiple Routes Including Dermal, Oral and Inhalation:** There is reasonable certainty that no harm to the U
. S
. population will result from aggregate exposure to residues of Prohydrojasmon. This included all exposures for which there is reliable information. The Agency arrived at this conclusion based on the low toxicity and rapid break

down of the compound. The risk from aggregate exposure via oral, dermal, and inhalation are a compilation of three low

- risk exposure scenari os (oral, dermal, and inhalation) and are negligible. Since there are no threshold effects of concern for this compound, and no known toxic endpoints, the provision requiring an additional margin of safety does not appl y. **Cumulative Effects** : R esidues of Prohydrojasmon will not reach levels th at are of toxicological concern if the compound is used as proposed. Because of its low toxicity and low level of exposure, cumulative effects with other substances that share a common mechanism of toxicity are not expected. **Human Risk Characterization** : The Agency

considered human exposure to Prohydrojasmon in light of relevant safety factors in FQPA and FIFRA. A determination has been made that no unreasonable adverse effects to the U.S. population in general, and t o infants and children in particular, will result from the use of Prohydrojasmon when used in accordance with EPA

- approved labeling. 

### Ecological **Assessment ECOTOXICITY RISK**  **Terrestrial** Prohydrojasmon is not naturally

- occurring but is structurally similar to jasmonic acid (JA). JA is an intermediate in the pathway to plant abscisic acid sy

nthesis and has ABA

- like activity (i.e. growth inhibition, senescence, leaf abscission, as well as a role in wound response and s ys temic resistance). When plants are atta cked b y insects there is a release of JA, which inhibits the insect’s ability

to digest protein. In order to evaluate risk of Prohydrojasmon exposure to terrestrial species, the Agency has estimated RQ values using the Terrestrial Residue Exposure Model ( T
- REX) Version 1.4.1. A terrestrial risk assessment includes calculated expected residues, as well as, numerous calculations of dietary exposure for multiple weight class animals (Appendix B). Expected residues were calculated for avian and mammalian food items along with dissipation rate of a chemical applied to foliar surfaces (single or multiple applications) in order to estimate worst case acute RQs relative to weight class for various sized birds and mammals. These calculations showed upper bound Keneg a values and that exposure to Prohydrojasmon (0.0 09 lbs ai/A) has a low potential for14

toxic impact to birds (RQ = 0.00) and mammals (RQ= 0.00) that may be feeding in the area of appl ication as noted in Appendix B
. The unique characteristics of th is product, Prohydrojasmon , and the non - toxic mode of action, biodegradability and low potential for exposure will result in **no risk to all non -**  **target terrestrial**  **organisms .**  **Aquatic** Prohydrojasmon exposure to aquatic species should result in no toxicity effects. Est imated environmental concentrations (EECs) in aquatic sites from Prohydrojasmon runoff after appl ication to terrestrial crops were estimated using the GENeric Estimated Environmental Concentration model (GENEEC; EPA, 2001). The model assumed 2 maximum appl ications of end product at 0.009lbs ai/A (4g ai/A) at 7 day intervals, a 10.7 day

aquatic half

- life, a 57.8 hours photodegradation half

- life in water, and a 1.6

– 2.3 hour half

- life in aerobic soil. The peak aquatic EEC was calculated at a peak of about 0. 00048 ppm which declined to 0.000024 ppm after 21 day s (Table 10.0). Since the L C 50 values for fish and aquatic invertebrates is 3.3 mg/L and 9.54 mg/L this would result in Risk Quotient s (RQ s ) of 0.0001 and 0.00 005 , respectivel y, which are about three an d four order s of magnitude below the Agency ’s levels of concern (LOCs = 0.1 ) , suggesting **no risk concerns for aquatic**  **species**
. **Endangered Species** The Agency ’s Individual Effects Chance Model Version 1.1 was used to estimate to the chance of risk to endangered/threatened avian and aquatic species from exposure to Prohydrojasmon . These values (avian risk at 1 in 294,000 and aquatic risk at 1 in 418,000,000) suggest that Prohydrojasmon should not cause toxic risk to endangered/threatened species. Inevaluat ing risk to aquatic endangered species the calculated RQs are about two and three orders of magnitude below the aquatic endangered species LOC = 0.05 resulting in **no effect (NE) to aquatic endangered species** 
. The calculated RQ values for terrestrial specie s are 0.00 resulting in a **no effect (NE) to endangered/threatened**  **terrestrial organisms**
.15

**Appendix A**  **Human Toxicity Calculations** Poly hydrojasmon (PDJ) is to be sprayed on red apples in order to promote fruit color change. The product is t o be applied to tree canopies with 1

- 2 applications of 100

- 200 ppm at 7
- 14 day intervals , 7
- 28 day s prior to anticipated harvest. The active ingredient (PDJ) amounts to 50 grams per liter of end product (FAL 1800). The maximum amount of FAL 1800 that can b e applied per acre is 52 oz. or 2.73 oz. ai (5.25% ai in product). Given: 50 g ai/Lor 50 g ai/33.8oz; 52oz of formulation/A or 2.73oz ai/A (5.25 % ai in FAL 1800); **X 2.73 oz**  **= 4g ai/A**  **or 0.009 lbs. ai/A to be sprayed**  **at each application. 50g 33.8 oz**  **Information on apple production:** 300

– 400 trees/A (Minnesota) can produce about 300

– 500 bushels of apples /A 1 ; One bushel = 4 2 lbs of apples 1

. Weight of 10 apples is 3.5 lbs., 3.5 lbs. ÷ 10 apples = .35 lbs./apple 1

. Human consumption is about 42 lbs. of apples/year or about 120 apples 1

. Therefore if we project a worst case scenario (no degradation and maximum application) this will result in 4g ai/A (0.009 lbs ai/A) and 0.013g ai/bushel x 2 applications = 0.026 g ai/ b ushel of apples (no degradation)
. **Risk Scenario** In order to evaluate toxic risk to humans the Agency calculated acute and sublethal chronic effects in combination with an extrapolated possible exposure scenario . The a cute oral toxicity was calculated at > 5 , 000 mg/kg (MRID 4792 7825) while a sublethal NOAEL> 500 mg/kg/day (MRID 47927832). The worst case scenario of maximum application and no degradation was used as an exposure component that amounted to 26 m g ai/4 2lbs apples or about 0.07 mg ai/ apple
. The refore, if the average 70kg human consumes about 120apples/year 1 the annual body burden of ai would amount to 8.4mg (120 x 0.07mg = 8.4mg). A 70kg human would have to consume > 35,000mg ai/ day in order to approach the sublethal NOAEL > 500 mg/kg/day or 350 ,000mg ai to approach the acute oral dietary of 5,000mg/kg.

1 **http://www.rma.usda.gov/handbooks/25000/2001/0**16

**Appendix B. TREX Output for Terrestrial Exposure and Risk from**  **Prohydrojasmon Application**  **to Apples**

**Av ia**  **n Bo**  **dy In**  **gesti on**  **( Fd**  **ry )**  **In ge**  **sti on**  **( Fw** **et) % b**  **od y**  **wg t**  **FI Cl**  **ass Wei**  **gh t**  **(g )**  **(g b**  **w/ day)**  **(g /d**  **ay) co**  **ns um**  **ed (kg**  **-d ie**  **t/ da**  **y) Smal**  **l 20**  **5 23**  **11 4**  **2. 28E-02**  **Mid 100**  **13 65**  **65 6.** **49E-02 La**  **rg e**  **1000 58**  **291 29**  **2. 91E-01** 
**Av ia**  **n Bo**  **dy Adj**  **us ted**  **L D5**  **0 We**  **ig ht** **( g)**  **(mg /k**  **g- bw**  **) 20**  **1038. 45**  **100 1322.**  **00 1000**  **1867. 37** 
**smal l**  **mi d**  **la rg**  **e 20**  **g 100**  **g 1000**  **g Sho**  **rt Gr**  **ass 2.** **46 1.**  **40 0.**  **63 Ta**  **ll G**  **ra ss**  **1. 13**  **0. 64**  **0. 29**  **Br oa**  **dl eaf**  **pl an**  **ts/**

**sm In**  **se cts**  **1. 38**  **0. 79**  **0. 35**  **Fr ui** **ts/ po**  **ds /s**  **eed s/**  **lg i**  **nsects 0.**  **15 0.**  **09 0.**  **04**

**20 g**  **100 g 1000 g**  **Sho rt** **Gr ass**  **0. 00**  **0. 00**  **0. 00**  **Ta ll**  **G ra**  **ss 0.**  **00 0.**  **00 0.**  **00 Br**  **oa dl**  **eaf pl**  **an ts/** 

**sm in**  **se cts**  **0. 00**  **0. 00**  **0. 00**  **Fr ui** **ts/ po**  **ds /s**  **eed s/**  **lg i**  **nsects 0.**  **00 0.**  **00 0.**  **00**

**Ac ut**  **e Ch**  **ro ni**  **c Sho**  **rt Gr**  **ass 0.**  **00 #D**  **IV /0!**  **Ta ll**  **G ra**  **ss 0.**  **00 #D**  **IV /0!**  **Br oa**  **dl eaf**  **pl an**  **ts/**

**sm In**  **se cts**  **0. 00**  **#D IV**  **/0! Fr**  **ui ts/**  **po ds**  **/s eed**  **s/ lg**  **i nsects**  **0. 00**  **#D IV**  **/0! RQ**  **s Di**  **et ary-based**  **RQ s**  **(D ie**  **ta ry-**  **ba sed**  **EE C/**  **LC50 or NO**  **AE C)**  **Av ian**  **A cu**  **te R**  **Qs Dose-**  **based RQs**  **(D os**  **e- ba**  **se d**  **EE C/**  **ad**

**ju st**  **ed L**  **D5 0)**  **Av ia**  **n Cl**  **asses an**  **d Bo** **dy W**  **ei gh**  **ts Do**  **se-based E**  **EC s**  **(mg /k**  **g- bw** **)**17 **Mammalian Body**  **Ingestion (Fdry) Ingestion (Fwet)**  **% body wgt FI**  **Class Weight**  **(g bwt/day) (g/day)**  **consumed (kg-diet/day)**  **15 3**  **14 95**  **1.43E-02 Herbivores/**  **35 5**  **23 66**  **2.31E-02 insectivores**  **1000 31**  **153 15**  **1.53E-01 15**  **3 3**  **21 3.18E-03**  **Grainvores 35**  **5 5**  **15 5.13E-03**  **1000 31**  **34 3**  **3.40E-02 Mammalian**  **Body Ad**  **justed Adjusted**  **Class Weight**  **LD50 NOA**  **EL 15**  **10989.15 1098.92**  **Herbivores/ 35**  **8891.40 889.14**  **insectivores 1000**  **3845.80 384.58**  **15 10989.15**  **1098.92 Grainvores**  **35 8891.40**  **889.14 1000**  **3845.80 384.58** 

**15 g 35 g**  **1000 g 15 g**  **35 g 1000 g**  **Short Grass 2.06**  **1.42 0.33**  **Tall Grass 0.94**  **0.65 0.15**  **Broadleaf plants/sm Insects 1.16**  **0.80 0.19**  **Fruits/pods/seeds/lg insects 0.13**  **0.09 0.02**  **0.03 0.02**  **0.00**

**Acute Chronic**  **Acute Chronic**  **Acute Chronic**  **Short Grass 0.00**  **0.00 0.00**  **0.00 0.00**  **0.00 Tall Grass**  **0.00 0.00**  **0.00 0.00**  **0.00 0.00**  **Broadleaf plants/sm insects 0.00**  **0.00 0.00**  **0.00 0.00**  **0.00 Fruits/pods/lg insects**  **0.00 0.00**  **0.00 0.00**  **0.00 0.00**  **Seeds (granivore) 0.00**  **0.00 0.00**  **0.00 0.00**  **0.00**

**Acute Chronic**  **Short Grass 0.00**  **0.00 Tall Grass**  **0.00 0.00**  **Broadleaf plants/sm insects 0.00**  **0.00 Fruits/pods/seeds/lg insects**  **0.00 0.00**  **Dose-Based EECs (mg/kg-bw)**  **Herbivores/ insectivores Granivores**  **Mammalian Classes and Body weight**

**15 g mammal 35 g mammal**  **1000 g mammal Dose-based RQs**  **(Dose-based EEC/LD50 or NOA EL)** 
**Dietary-based RQs (Dietary-based EEC/LC50 or**  **NOAEC) Mammal RQs** 18

**References** 1. Parker, R.D., R.D. Jones and H.P. Nelson., 1995. GENEEC: A Screening Model for Pesticide Environmental Exposure Assessment., in Proceedings of the International Exposure Sy

mposium on Water Quality Modeling; American Society of Agricul tural Engineers, pp. 485

- 490; Orlando, Florida. 2. U.S. EPA. 1998. Guidance for Ecological Risk Assessment. Risk Assessment Forum. EPA/630/R

- 95/002F, April 1998. 3. U .S.EPA 2008. Terrestrial Residue Exposure Model (T

- REX) Version 1.4.1. EFED/OPP/USEPA. 4. U .S.EPA 2004. Individual Effects Chance Model Version 1.1. EFED/OPP/USEPA. 5. U.S. EPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs. Office of Prevention, Pesticides, and Toxic Substances. Office of Pestic ide Programs. Washington, D.C. January 23, 2004.