Document ID: EPA-HQ-OPP-2010-0048-0009
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-05-18T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

 		     WASHINGTON, D.C. 20460

 ADVANCE \d61 			ICE OF PREVENTION,

OFFICE OF PESTICIDES AND TOXIC SUBSTANCES        

MEMORANDUM

DATE:		May 18, 2010

SUBJECT:	Application for Experimental-Use Permit and temporary tolerance
exemption for FAL 1800 (Prohydrojasmon)

				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/       
05/18/2010

Biochemical Pesticides Branch

Biopesticides & Pollution Prevention Division (7511P)

TO:			Gina Casciano, Regulatory Action Leader     /S/         
05/18/2010

Biochemical Pesticides Branch

Biopesticides & Pollution Prevention Division (7511P) 

ACTION REQUESTED

The applicant, Fine Agrochemicals Ltd., has submitted a EUP application
and supporting data for FAL 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 synthesis and has ABA-like activity (i.e. growth
inhibition, senescence, leaf abscission, as well as a role in wound
response and systemic resistance). When plants are attacked by insects
there is a release of JA, which inhibits the insect’s ability to
digest protein.

The toxicological profile of Prohydrojasmon (FAL 1801) shows that this
compound is practically 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 sensitizer or a primary skin irritant
(Toxicology Category IV). Assays for mutagenicity, chromosomal
aberration, developmental toxicity, and subchronic oral did not present
any clinical or toxicologically significant effects. 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 days.

All product chemistry, Tier I toxicology, and Tier 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, subchronic, 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 Prohydrojasmon 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 DISTRIBUTION

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 200C half-life was
17.7 days), photodegrades in water in about 58 hours, and degrades
rapidly 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 determine 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
hours, 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 Acceptable.

MRID 47927840: Hydrolysis (OPPTS 835.2120). A laboratory study was
conducted to determine the degradation of prohydrojasmon (PDJ) in water.
Test solutions (2 mg/L) of PDJ were buffered to pH 9 and maintained at
20°C for 24 days 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 days. Based on these results, the
Arrhenius equation was used to calculate the half-life at pH 9 and 25°C
as 10.7 days. Under gastric conditions, the half-life was 0.8 days. The
major degradation product was dihydrojasmonic acid. The study is
classified as Acceptable.

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 purified 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 Acceptable.

MRID 47927842: Aerobic soil metabolism (OPPTS 835-4100). The study
author concluded that under aerobic conditions, the elimination of PDJ
was similar in the Ibaraki and Osaka soils, with a half-life of 1.6
hours and 2.3 hours, respectively, and a DT80 of 3.7 hours and 5.3
hours, respectively. The major PDJ metabolite in both soils was DJA,
believed to be the result of de-n-propylation of PDJ, with CO2 generated
as the final product. Under sterile conditions, the half-life of PDJ in
Ibaraki and Osaka soils was extrapolated to be 102 days and 308 days,
respectively. The study is classified as Acceptable.

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 percentages, the adsorption constant for PDJ could not be
calculated.	

47927839	

Acceptable

Hydrolysis

OPPTS 835.2120	Half-life of PDJ at pH 9 (200C) 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 was 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 half-lives of 1.6 and 2.3
hours, respectively.	

47927842	

Acceptable

TOXICOLOGY

Test Material: FAL 1800 formulation containing 5.25% PDJ

The toxicological profile of FAL 1800 is summarized in Table 6.0 and
shows that this compound is practically non-toxic mammals with a
Toxicity Category IV as noted for acute oral and acute inhalation
toxicity studies. The acute dermal toxicity study produced an LD50 >
2,000 mg/kg bw  (Toxicity Category III) and the primary eye irritation
study produced acute symptoms after the test material was administered,
but were resolved by day 7 (Toxicity Category III). FAL 1800 is not a
skin sensitizer or a primary skin irritant.  

1.	Acute oral toxicity (OPPTS 870.1100): Acute oral toxicity study used
SD rats.  The acute oral LD50 was > 5000 mg/kg bw in both male and
female rats.

2.	Acute dermal toxicity (OPPTS 870.1200): Acute dermal toxicity study
used SD rats.  The acute dermal LD50 was > 2000 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 LC50 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 symptoms were observed after 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 severely irritating.

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 Hartley guinea pigs.  No skin sensitization was
observed.

Table 6.0  Toxicological Data for FAL 1800 (end product)

Data Requirement	LD50	Toxicity Category	MRIDs

Acute Oral Toxicity

OPPTS 870.1100	>5000 mg/kg	IV	47927818, 47927819

Acute Dermal Toxicity

OPPTS 870.1200	>2000 mg/kg	III	47927818, 47927820

Acute Inhalation Toxicity

OPPTS 870.1300	LC50 > 5.0 mg/L	IV	47927818, 47927821

Primary Eye Irritation

OPPTS 870.2400	Acute symptoms were observed after test material was
administered, but resolved by day 7. FAL 1800 produces reversible
intense eye irritation	III	47927818, 47927822

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 summarized in Table 7.0 and
shows that this compound is practically non-toxic mammals with a
Toxicological Category IV as noted for acute oral and acute inhalation
toxicity studies. The acute dermal toxicity study produced an LD50 >
2,000 mg/kg bw (Toxicity Category III). The primary eye irritation study
produced slight acute symptoms after the test material was administered
(Toxicity Category IV) and FAL 1801 proved to not be skin sensitizer or
a primary skin irritant.

1.	Acute oral toxicity (OPPTS 870.1100): Acute oral toxicity study used
SD rats.  The acute oral LD50 was > 5000 mg/kg bw in both male and
female rats.

2.	Acute dermal toxicity (OPPTS 870.1200): Acute dermal toxicity study
used SD rats.  The acute dermal LD50 was > 2000 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 LC50 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 noted on the skin.

6.	Skin sensitization (OPPTS 870.2600): A skin sensitization study
(Maximization method) used Hartley guinea pigs.  No skin sensitization
was observed.

Comments:   The summary (MRID 47927818) seems to include the study
results of PDJ (MRIDs 47927819 to 47927824) and PDJ Formulation (MRIDs
47927825 to 47927830).  

Table 7.0  Toxicological Data for Prohydrojasmon (PDJ) FAL 1801

Guideline #

Test	Results/Toxicity Category	MRIDs	Study Conclusion

Acute Oral Toxicity

OPPTS 870.1100	LD50 > 5000 mg/kg

IV	47927818, 47927825	Acceptable

Acute Dermal Toxicity

OPPTS 870.1200	LD50 > 2000 mg/kg

III	47927818, 47927826	Acceptable 

Acute Inhalation Toxicity

OPPTS 870.1300	LC50 > 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 

870.3100

90 day Oral Toxicity-Rat	NOEL=566-587 mg/kg/day	47927831

	Acceptable

870.3700 

Prenatal Developmental Toxicity Study - Rat 	Maternal NOEL > 500
mg/kg/day

Developmental NOEL > 500 mg/kg/day	47927832	Acceptable 

870.5100

Bacterial Reverse Mutation Test	There was no evidence of induced mutant
colonies over background	47927833	Acceptable

 870.5375 

In Vitro Mammalian Chromosome Aberration Tests 	There was no evidence of
cells with chromosomal abnormalities	47927834	Acceptable

Classification:  Acceptable; no additional data are required.  

TOXICOLOGY STUDIES

FAL 1800 formulation containing 5.25% PDJ

MRID 47927819: Acute Oral Toxicity - Rats (OPPTS 870.1100)

The oral LD50 for males, females, and combined sexes of rats was greater
than 5,000 mg/kg suggesting that PDJ Formulation is a TOXICITY CATEGORY
IV.  This study is classified as Acceptable.

MRID 47927820: Acute Dermal Toxicity - Rats (OPPTS 870.1200)

The acute dermal LD50 for males, females, and combined sexes of rats was
greater than 2000 mg/kg placing PDJ Formulation in TOXICITY CATEGORY
III.  The study is classified as Acceptable.

MRID 47927821: Acute Inhalation Toxicity - Rats (OPPTS 870.1300)

The inhalation LC50 for males, females, and combined sexes of rats was >
5.0 mg/L placing DPJ Formulation 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 persistence 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 by 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
any rabbit during the study.  Positive conjunctival irritation was noted
on 3/3 animals at one hour after test material instillation with
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 severely irritating and is in
TOXICITY CATEGORY III.  This study is classified as Acceptable.  

MRID 47927823: Primary Dermal Irritation - Rabbits (OPPTS 870.2500)

Very slight erythema 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 Sensitization - Guinea Pigs (OPPTS 870.2600)

After three consecutive weekly 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 positive 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 LD50 for males, females, and combined 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 LD50 for males, females, and combined sexes of rats was
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 LC50 for males, females, and combined sexes of rats was >
2.8 mg/L placing 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 resolution by 48 hours.  No iritis
or positive conjunctival irritation was noted on 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, respectively, at one hour after test material instillation.  The
test material PDJ was minimally irritating and is in TOXICITY CATEGORY
IV.  The study is classified as Acceptable.  Note: PDJ Formulation was
severely irritating.

MRID 47927829: Primary Dermal Irritation - Rabbits (OPPTS 870.2500)

No dermal irritation was noted for any 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
Acceptable.

MRID 47927830: Skin Sensitization - Guinea Pigs (OPPTS 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 test material PDJ was not a dermal sensitizer.
The study is classified as Acceptable.

MRID 47927831: Subchronic oral – rat (OPPTS 870.3100) No clinically or
toxicologically significant effects were found in any treatment-group. 
Therefore, the reviewer establishes 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 least 1,000 mg/kg). The study is classified as Acceptable 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 person 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 necropsy 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 and establishes the
NOAEL for the study as 500 mg/kg bw/day.  A LOAEL 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 of thymic 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 14th rib but this was not accompanied by 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 Acceptable
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 person
are four orders of magnitude below NOAEL that was calculated for this
compound as noted in the risk assessment. 

MRID 47927833: Salmonella/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 cytotoxic, 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 any
dose-dependent and reproducible increase in the number of revertants.
All positive controls, without and with activation, gave appropriate. 
This is study is classified as Acceptable. 

MRID 47927834: In vitro Mammalian Chromosome Aberration Test
(OPPTS 870.5375) 

PDJ was tested up to cytotoxic dose levels (80 µg/mL, based on reduced
mitotic activity) without S9 activation, and up to the limit
concentration of 5000 µg/mL with S9 activation. None of the test
concentrations induced a significant increase in the 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 any dose-response effect either without or with
activation. All of the negative, solvent and positive controls gave
appropriate responses.

This study is classified as Acceptable.

ECOTOXICITY STUDIES

FAL 1801 Prohydrojasmon (PDJ)

Ecotoxicity studies (Table 8.0) show that prohydrojasmon (PDJ) is
moderately toxic to fish and aquatic invertebrates (LC50 and EC50 = 3.3
and 9.54 mg/L, respectively) and practically non-toxic to avian species
(LD50 >2,000 mg/kg; LC50 >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 days.

Table 8.0. Ecotoxicity Data for Prohydrojasmon (PDJ)

Guideline #

Test	Results/Toxicology Category	MRID	Study Conclusion

Aquatic Species Testing

850.1010

Acute Toxicity Test, Daphnids 	EC50 = 9.54 mg/L.

Moderately toxic	47927838	Acceptable

850.1075 

Acute Toxicity Freshwater Fish

Cyprinus carpio	96 hr LC50 = 3.3 mg/L.

Moderately toxic	47927837	Acceptable

Avian Species Testing

850.2100

Avian Acute Oral Toxicity 

Bobwhite (Colinus virginianus) 	LD50 >2000 mg/kg

Practically non-toxic	47927835	Acceptable

850.2200

Avian Dietary Toxicity 

Japanese quail (Colinus virginianus)	LC50 >5000 ppm

Practically 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 LD50 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) In a 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-propyl dihydrojasmonate), followed by 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 normal
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 nominal concentration. The
5-day dietary study produced an LC50 > 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 LC50 for PDJ Technical in
common carp (Cyprinus carpio) was 3.3 mg 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.

MRID 47927838: Aquatic Invertebrate Acute Toxicity Testing (OPPTS
850.1010).

Based on the mean measured concentrations, the 24-hour EC50 was 9.54
mg/L (95% a.i., 7.62-12.0 mg/L), and the 48-hour EC50 was 2.13 mg/L (95%
a.i., 1.64-2.70 mg/L). The study is classified as Acceptable.

Risk Assessment

HUMAN HEALTH

Chronic 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.
hyperplasia or metaplasia) in any organ that could potentially lead to
neoplastic change. 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 Prohydrojasmon on
endocrine systems via oral, dermal, or inhalation exposure. No
significant treatment-related effects were observed for prenatal
developmental 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 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 days. 

The Agency has calculated the possibility of risk to humans through
dietary exposure by using a worst case scenario of maximum application
and no degradation. These calculations (Appendix A) show that the
Prohydrojasmon residues consumed by a 70 kg person are about seven
orders of magnitude below Developmental Toxicity NOAEL  > 500 mg/kg and
about eight orders of magnitude below the Acute Oral toxicity value
(LD50 > 5,000 mg/kg), suggesting no dietary or sublethal risk

Table 9.0 Estimated Prohydrojasmon Residues on Terrestrial Matrices
Using the Terrestrial Exposure Model (T-REX ; USEPA )

Terrestrial Matrix	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 Water Exposure 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 estimated environmental concentrations (EECs) to an aquatic
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 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 about 0.00048 ppm
with a decline to 0.000024 ppm after 21 days (Table 10.0). No acute or
subacute endpoints 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 LD50 > 5,000 mg/kg; Developmental Toxicity NOAEL > 500
mg/kg).

Table 10.0 Generic Estimated Environmental Concentrations (EECs) of
Prohydrojasmon in Aquatic Sites using the GENEEC Model, ver 2.0 (EPA,
2001) in Parts Per Million (ppm)

Peak EEC	Max 4 Day

Avg EEC	Max 21 Day

Avg EEC	Max 60 day

Avg EEC	Max 90 Day

Avg EEC

0.00048	0.00013	0.000024	0.000008	0.000006

 

Occupational Exposure:

Occupational 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:

Significant human exposure to Prohydrojasmon is highly unlikely in
residential, school and day 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
scenarios (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 apply.

Cumulative Effects:

Residues of Prohydrojasmon will not reach levels that 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 to 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 synthesis and has ABA-like activity (i.e. growth
inhibition, senescence, leaf abscission, as well as a role in wound
response and systemic resistance). When plants are attacked by 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 Kenega values and that
exposure to Prohydrojasmon (0.009lbs ai/A) has a low potential for toxic
impact to birds (RQ = 0.00) and mammals (RQ= 0.00) that may be feeding
in the area of application as noted in Appendix B. The unique
characteristics of this 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. Estimated environmental concentrations (EECs) in aquatic sites
from Prohydrojasmon runoff after application to terrestrial crops were
estimated 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
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 days (Table 10.0). Since the LC50 values for fish and aquatic
invertebrates is 3.3 mg/L and 9.54 mg/L this would result in Risk
Quotients (RQs) of  0.0001 and 0.00005, respectively, which are about
three and four orders 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. In evaluating 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 species are
0.00 resulting in a no effect (NE) to endangered/threatened terrestrial
organisms. 

Appendix A Human Toxicity Calculations

Polyhydrojasmon (PDJ) is to be sprayed on red apples in order to promote
fruit color change. The product is to be applied to tree canopies with
1-2 applications of 100-200 ppm at 7-14 day intervals, 7-28 days 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 be applied per acre is 52 oz. or 2.73 oz. ai (5.25% ai in product). 

Given: 50 g ai/L or 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/A1; One bushel = 42 lbs of apples1. Weight of 10 apples is 3.5
lbs., 3.5 lbs. ÷ 10 apples = .35 lbs./apple1. Human consumption is
about 42 lbs. of apples/year or about 120 apples1. 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 = 0.026g ai/bushel 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 acute oral toxicity was calculated at >
5,000 mg/kg (MRID 47927825) 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 26mg
ai/42lbs apples or about 0.07 mg ai/apple. Therefore, if the average
70kg human consumes about 120apples/year1 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. 

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

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

References

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 Symposium on Water Quality Modeling;
American Society of Agricultural Engineers, pp. 485-490; Orlando,
Florida.

U.S. EPA.  1998.  Guidance for Ecological Risk Assessment.  Risk
Assessment Forum.  EPA/630/R-95/002F, April 1998.

U.S.EPA  2008. Terrestrial Residue Exposure Model (T-REX) Version 1.4.1.
EFED/OPP/USEPA.

U.S.EPA  2004. Individual Effects Chance Model Version 1.1.
EFED/OPP/USEPA.

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 Pesticide Programs.  Washington, D.C. 
January 23, 2004.

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