1

Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations for Prohydrojasmon (PDJ), propyl3-oxo-2-pentylcyclo-pentylacetate

Docket ID Number: EPA-HQ-OPP-2012-0832

Date: August 23, 2013

Section 408(c)(2)(A)(i) of FFDCA allows the U.S. Environmental Protection Agency (EPA or the Agency)

to establish an exemption from the requirement for a tolerance (the legal limit for a pesticide chemical 

residue in or on a food) only if the EPA determines that the exemption is “safe.” Section 408(c)(2)(A)(ii) of 

FFDCA defines “safe” to mean that “there is a reasonable certainty that no harm will result from aggregate 

exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other 

exposures for which there is reliable information.” This includes exposure through drinking water and in 

residential settings but does not include occupational exposure. Pursuant to FFDCA section 408(c)(2)(B), 

in establishing or maintaining in effect an exemption from the requirement of a tolerance, the EPA must 

take into account the factors set forth in FFDCA section 408(b)(2)(C), which require the EPA to give 

special consideration to exposure of infants and children to the pesticide chemical residue in establishing a 

tolerance exemption, and to “ensure that there is a reasonable certainty that no harm will result to infants 

and children from aggregate exposure to the pesticide chemical residue....” Additionally, FFDCA section 

408(b)(2)(D) requires that the EPA consider “available information concerning the cumulative effects of [a 

particular pesticide's] . . . residues and other substances that have a common mechanism of toxicity.”

The EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide 

residues. First, the EPA determines the toxicity of pesticides. Second, the EPA examines exposure to the 

pesticide through food, drinking water, and through other exposures that occur as a result of pesticide use in 

residential settings.

I. Summary of Petitioned-for Tolerance Exemption

In the Federal Register of January 9, 2013, (Vol. 78 FR 1798) (FRL-9374-2), EPA issued a notice pursuant 

to FFDCA section 408(d)(3), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide tolerance petition 

(PP 2F8056) by Fine Agrochemicals Ltd. (the Petitioner), on behalf of SciReg, Inc., 12733 Director’s 

Loop, Woodbridge, VA, 22192. The petition requested that 40 CFR part 180 be amended by establishing 

an exemption from the requirement of a tolerance for residues of prohydrojasmon (PDJ), propyl-3-oxo-2-

pentylcyclo-pentylacetate, in or on red apples and grapes. The notice referenced a summary of the petition 

prepared by the Petitioner, which is available in Docket ID Number EPA-HQ-OPP-2012-0832 via 

http://www.regulations.gov.

II. Toxicological Profile

Consistent with section 408(b)(2)(D) of FFDCA, the EPA reviewed the available scientific data and other 

relevant information on PDJ, and considered its validity, completeness, and reliability, as well as the 

relationship of this information to human risk. The EPA also considered available information concerning 

the variability of the sensitivities of major identifiable subgroups of consumers, including infants and 

children.

A. Overview of PDJ

PDJ is a synthetically made plant growth regulator that is structurally similar and functionally identical to 

jasmonic acid (JA), a naturally occurring plant regulator present in all vascular plants. The jasmonates of 

which JA is a member, is a group of plant hormones involved in multiple stages of plant development and 
2

defense, including the ability to stimulate fruit ripening (Ref. 1). The highest levels of naturally occurring 

JA are found in actively growing plant tissues such as leaves, flowers, and developing fruit (Ref. 1; Ref. 3), 

thus JA has always been a natural component of diets containing plant materials. To date, there have been 

no reported toxic effects associated with the consumption of JA in fruits and vegetables. 

PDJ, a synthetic version of JA, is expected to behave in the same manner and have the same low toxicity

profile as JA because it is structurally similar and functionally identical to naturally occurring JA. Studies 

submitted by the applicant in support of this exemption from the requirement of a tolerance, and reviewed 

by the Agency, indicate that PDJ is not acutely toxic. Specifically, no toxic endpoints were established, and 

no significant toxicological effects were observed in any of the acute toxicity studies. In addition, studies 

submitted indicate that PDJ is not genotoxic, has no subchronic toxic effects, and is not a developmental 

toxicant.

Based on the data submitted in support of this petition (summarized in Unit II. B., below) and the 

comprehensive risk assessment conducted by the Agency (Ref. 2, below), EPA concludes that there is a 

reasonable certainty of no harm from aggregate exposures to PDJ, including the consumption of food 

treated with this active ingredient in accordance with label directions and good agricultural practices. EPA 

has made this determination for the following reasons: (1) available toxicology data indicate that the active 

ingredient is of low acute toxicity and is not a developmental toxicant, a mutagen, or toxic via repeat oral 

exposure, and (2) available information from the scientific literature indicates that humans are already

exposed to the structurally similar and functionally identical naturally occurring compound, jasmonic acid 

(JA), a compound present in all vascular plants. 

B. Biochemical Pesticide Toxicology Data Requirements

All applicable mammalian toxicology data requirements supporting the request for an exemption from the 

requirement of a tolerance for residues of PDJ in or on apple and grape have been fulfilled with data 

submitted by the petitioner. The following is a summary of EPA’s review of the toxicity profile of this 

biochemical:

 

Acute Toxicity: Acute toxicity studies on the technical grade active ingredient (TGAI) for PDJ, containing 

97.98% PDJ, confirm a low toxicity profile. The acute toxicity data show virtual nontoxicity for all routes 

of exposure. Therefore, it can be concluded that any dietary risks associated with this plant regulator would 

be negligible. 

1. The acute oral median lethal dose (LD50) in rats was greater than 5,000 milligrams per kilogram 

(mg/kg) bodyweight. There were no observed toxicological effects on the test subjects in the acute oral 

study submitted (MRID No. 47927825). PDJ is classified as Toxicity Category IV for acute oral 

toxicity. 

2. The acute dermal LD50 in rats was greater than 2,000 mg/kg body weight (MRID 47927826). PDJ is 

classified as Toxicity Category III for acute dermal toxicity.

3. The acute inhalation median lethal concentration (LC50) was greater than 2.8 milligrams per liter 

(mg/L) in rats and showed no significant inhalation toxicity (MRID 47927827). PDJ is classified as 

Toxicity Category IV for acute inhalation toxicity. 

4. A primary eye irritation study on rabbits indicates that PDJ is minimally irritating to the eye (MRID 

47927828). PDJ is classified as Toxicity Category IV for primary eye irritation. 
3

5. A skin irritation study on rabbits indicates that PDJ is not irritating to the skin (MRID 47927829). PDJ 

is classified as Toxicity Category IV for primary skin irritation. 

6. Data indicate that PDJ is not a dermal sensitizer (MRID 47927830). 

Mutagenicity: Two mutagenicity studies, using the TGAI of PDJ (97.98% PDJ) as the test substance, were 

performed. These studies are sufficient to confirm that there are no expected dietary or non-occupational 

risks of mutagenicity with regard to food use of PDJ.

1. A Bacterial Reverse Gene Mutation Test (MRID No. 47927833) investigating doses of test substance up 

to those that were cytotoxic, both with and without metabolic S9 activation, found no incidences of a 2-fold 

or greater increase in the number of revertants compared to the corresponding solvent control. Therefore, 

PDJ is considered to be non-mutagenic under the conditions of this assay.

2. An in vitro Mammalian Cell Chromosome Aberration Test (MRID No. 47927834) tested PDJ 

genotoxicity on Chinese hamster lung cells (CHL/IU) up to the cytotoxic dose level (80 micrograms per 

milliliter [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 substance 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%, indicating a negative response of the test substance. There was also no indication of a doseresponse effect either with or without metabolic activation. All of the negative, solvent, and positive 

controls gave appropriate responses. Therefore, under the conditions of this assay, PDJ is considered to be 

non-mutagenic and does not cause chromosome aberrations. 

Subchronic Toxicity: In a subchronic oral toxicity study using the TGAI of PDJ (97.98% PDJ) as the test 

substance, no clinically or toxicologically significant effects were found in any treatment group (MRID 

47927831). Therefore, the no observed adverse effect level (NOAEL) for PDJ has been established as the 

highest test substance dose, 10,000 parts per million (ppm) (equivalent to 566 mg/kg bw/day for male test 

animals and 587 mg/kg bw/day for female test animals). A lowest observed adverse effect level (LOAEL) 

was not established, suggesting that the test animals could have tolerated a higher dose. In sum, the data 

submitted to the Agency indicate that PDJ has no subchronic toxicological effect.

Developmental Toxicity: In a developmental toxicity study, using the TGAI of PDJ (97.98% PDJ) as the 

test substance (MRID 47927832), there were no treatment-related effects 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 Agency does not consider the temporary decrease in body

weight or food intake observed in the 500 mg/kg bw/day test group to be an adverse effect, as this is likely

due to the palatability of the food containing this high dose of test substance. Therefore, the Agency 

establishes the NOAEL for this study as 500 mg/kg bw/day. A LOAEL was not identified for maternal 

effects, suggesting that the test animals could have tolerated a higher dose. No treatment-related 

developmental 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 range of the 

performing laboratories historical control data. Therefore, the Agency does not consider this a treatmentrelated effect. There was also a slight increase in the incidence of a 14th rib, which is a common variation in 

this strain of rat and is therefore not considered an adverse effect. This variation was not accompanied by

an increased incidence of abnormal embryos, either on external, skeletal, or visceral examination, and did 

not appear at a higher than normal rate. Based on the study results, the developmental effects NOAEL for 
4

the study is the highest dose tested 500 mg/kg bw/day. A LOAEL was not identified for developmental 

effects, suggesting that the test animals could have tolerated a higher dose. In sum, the data submitted to the 

Agency indicate that PDJ is not a developmental toxicant.

III. Aggregate Exposure

In examining aggregate exposure, FFDCA section 408 directs the EPA to consider available information

concerning exposures from the pesticide residue in food and all other non-occupational exposures, 

including drinking water from ground water or surface water and exposure through pesticide use in 

gardens, lawns, or buildings (residential and other indoor uses).

Food Exposure: Dietary exposure to residues of PDJ is expected to be insignificant, even in the event of 

exposure. In a worst case scenario, such as no degradation of the applied compound, PDJ residues 

consumed by a 70 kg person are four orders of magnitude below the No Observed Adverse Effect Level 

(NOAEL ) that was calculated for this compound (Ref. 2). Furthermore, dietary exposure to residues of 

PDJ via exposure to treated fruit or foliage is not expected to exist above background levels of naturally

occurring JA (Ref. 2).

Drinking Water Exposure: Exposure of humans to PDJ in drinking water is unlikely since products are 

labeled for application directly to terrestrial plants and because data demonstrate a soil half-life for this 

chemical from 1.6-2.3 hours, as well as rapid degradation in water (Ref. 2). Furthermore, the expected 

concentrations in surface water are well below (6 to 7 orders of magnitude) the maximum doses used in 

laboratory testing, where no toxic effects were seen (i.e., Acute Oral Toxicity LD50 > 5,000 mg/kg; 

Developmental Toxicity NOAEL > 500 mg/kg) (Ref. 2).

Other Non-occupational Exposure: 

Non-occupational exposure is not expected because PDJ is not approved for residential uses. The active 

ingredient is applied directly to commodities and degrades rapidly.

IV. Cumulative Effects from Substances with a Common Mechanism of Toxicity

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke 

a tolerance, the EPA consider “available information concerning the cumulative effects of [a particular 

pesticide’s] . . . residues and other substances that have a common mechanism of toxicity.”

The EPA has not found PDJ to share a common mechanism of toxicity with any other substances, and PDJ

does not appear to produce a toxic metabolite produced by other substances. For the purposes of this 

tolerance action, therefore, the EPA has assumed that PDJ does not have a common mechanism of toxicity

with other substances. Following from this, the EPA concludes that there are no cumulative effects 

associated with PDJ that need to be considered. For information regarding the EPA’s efforts to determine 

chemicals that have a common mechanism of toxicity and to evaluate the cumulative effects of such 

chemicals, see the EPA’s website at http://www.epa.gov/pesticides/cumulative.

V. Determination of Safety for the United States Population, Infants and Children

FFDCA section 408(b)(2)(C) provides that, in considering the establishment of a tolerance or tolerance 

exemption for a pesticide chemical residue, the EPA shall assess the available information about 

consumption patterns among infants and children, special susceptibility of infants and children to pesticide 

chemical residues, and the cumulative effects on infants and children of the residues and other substances 
5

with a common mechanism of toxicity. In addition, FFDCA section 408(b)(2)(C) provides that the EPA 

shall apply an additional tenfold (10X) margin of safety for infants and children in the case of threshold 

effects to account for prenatal and postnatal toxicity and the completeness of the database on toxicity and 

exposure, unless the EPA determines that a different margin of safety will be safe for infants and children. 

This additional margin of safety is commonly referred to as the Food Quality Protection Act Safety Factor. 

In applying this provision, the EPA either retains the default value of 10X, or uses a different additional or 

no safety factor when reliable data are available to support a different additional or no safety factor. 

Because there are no threshold effects associated with this biochemical, an additional margin of safety for 

infants and children is not necessary. 

EPA has determined that there are no foreseeable dietary risks to the U.S. population, including infants and 

children, from the use of PDJ as a pesticide (plant growth regulator) on apple and grape, when label 

instructions and good agricultural practices are followed. The available data and information indicate that 

the chemical (1) is of low toxicity and not a developmental toxicant, and (2) is structurally similar and 

functionally identical to jasmonic acid (JA), a compound naturally occurring in the human diet. When 

compared to the amount of JA that is likely already consumed in the human diet, dietary exposure from 

pesticidal use of PDJ is not anticipated to significantly increase overall dietary exposure of infants and 

children. 

Therefore, EPA concludes that there is a reasonable certainty that no harm will result to the U.S. 

population, including infants and children, from aggregate exposure to the residues of PDJ when it is used 

as labeled and in accordance with good agricultural practices. Such exposure includes all anticipated 

dietary exposures and all other exposures for which there is reliable information. EPA has arrived at this 

conclusion because the data and information available on PDJ do not demonstrate significant toxic 

potential to mammals, including infants and children.

VI. Conclusions

EPA concludes that there is a reasonable certainty that no harm will result to the U.S. population, including 

infants and children, from aggregate exposure to residues of PDJ. Therefore, an exemption is established 

for residues of the biochemical pesticide PDJ in or on apple and grape when used as a plant growth 

regulator pre-harvest and in accordance with label directions and good agricultural practices.

VII. References

1. Creelman, R.A. and J.E. Mullet (1995) Jasmonic acid distribution and action in 

plants: Regulation during development and response to biotic and abiotic stress. Proceedings of the 

National Academies of Science, 92: 4114-4119.

2. EPA (2013) Environmental Protection Agency (EPA) Risk Assessment: 

Request for new registration for prohydrojasmon technical and product registration Section 3 for 

BLUSH 5.25% ai with tolerance exemption. May 12, 2013. 

3. Mason, H.S., DeWald, D.B., Creelman, R.A., Mullet J.E. (1992) Coregulation of

Soybean and Vegetative Storage Protein Gene Expression by Methyl Jasmonate and Soluble 

Sugars. Plant Physiology, 98: 859-867.