Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations for Ethyl-2E,4Z-decadienoate (Pear Ester) 

                    Docket ID Number: EPA-HQ-OPP-2011-1018
                              Date: July 9, 2013
                                       
Section 408(c)(2)(A)(i) of FFDCA allows the EPA 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 March 14, 2012, (77 FR 15012), the 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 1F9701) by Wagner Regulatory Associates, Inc., on behalf of Bedoukian Research, Inc., 21 Finance Drive, Danbury, CT, 06810.  The petition requested that 40 CFR part 180 be amended by establishing an exemption from the requirement of a tolerance for residues of ethyl-2E,4Z-decadienoate (pear ester). The notice referenced a summary of the petition prepared by the petitioner, Wagner Regulatory Associates, Inc. (on behalf of Bedoukian Research, Inc.), which is available in Docket ID Number EPA-HQ-OPP-2011-1018 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 ethyl-2E,4Z-decadienoate (pear ester), 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 Ethyl-2E,4Z-decadienoate (pear ester)	

Ethyl-2E,4Z-decadienoate (pear ester) is a naturally occurring biochemical substance, as defined in 40 CFR § 158.2000(a)(1), with a history of unremarkable human exposure. Pear ester is emitted naturally from mature, ripening fruit, and also functions as a mating disruptor for the codling moth (CM), Cydia pomonella, a key pest of apples and other pome fruits worldwide (Ref. 1). Mating disruption occurs because applicant applied pear ester masks natural pear ester signals, confusing the moth and making them unable to find a mate. Mating disruption is enhanced when pear ester is combined with other CM pheromones (Ref. 1). Based upon this information, EPA considers the mode of action of pear ester to be non-toxic (Ref. 1).

Synthesized pear ester is structurally identical to naturally occurring pear ester. Therefore, as with straight chain lepidopteran pheromones, the Agency does not distinguish between the synthesized kairomone and its naturally occurring form with regards to product chemistry or toxicology. In addition, the petitioner has demonstrated, in accordance with 40 CFR 158.340, that no impurities of toxic concern are produced during their manufacturing process (MRID 48538901). 

Pear ester is an approved additive listed by the U.S. Food and Drug Administration (FDA) on the Everything Added to Food in the United States (EAFUS) list (Ref. 2). The average daily intake of pear ester reported by the Joint Food and Agriculture Organization of the United States/World Health Organization Expert Committee on Food Additives is 34ug in Europe and 3ug in the United States. JECFA has determined that current intake of pear ester poses no safety concerns (Ref. 1). 
 
Foliar sprays of pear ester that reach the fruit are expected to degrade over the course of the season prior to harvest because this biochemical is a volatile kairomone (Henry's Law Constant estimated 7 x 10[-4] atm m[3]/mol) that dissipates rapidly in the environment and undergoes degradation in the presence of air and light (Ref. 1).  However, assuming a foliar spray worst case scenario (no volatilization or degradation), the potential dietary exposure of pear ester has been calculated as 6.4ug in unwashed fruit. When the product is to be released over time (volatilization) from a polymeric dispenser attached to the tree branch, a worst case scenario indicates 0.16 ug pear ester in unwashed fruit (Ref. 3). Therefore, consumption of pear ester as a result of pesticidal exposure is not expected to exceed the current exposure to pear ester as a flavoring agent. 

Based on information submitted in support of this petition (summarized in Unit II. B., below) and the comprehensive risk assessment conducted by the Agency, EPA concludes that there is a reasonable certainty of no harm from aggregate exposures to pear ester, 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 and information indicate that the active ingredient is of low acute toxicity and is not a likely developmental toxicant, mutagen, or toxic via repeat oral exposure (2) available information from the scientific literature indicates that humans are already exposed to pear ester in their diet from foods that naturally contain the chemical and from foods to which the chemical has been added as higher levels.

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 pear ester in or on all food commodities have been fulfilled with data or information submitted by the petitioner or data waiver requests that have been granted by the EPA. The following is a summary of EPA's review of the toxicity profile of this biochemical:
  
1. Acute Toxicity (OCSPP Guideline Nos. 870.1100, 870.1200, 870.1300, 870.2400, 870.2500, and 870.2600; Master Record Identification (MRID) Nos. 48538708, 48538906, 48975101): 

The petitioner submitted data on two pear ester analogs, ethyl-2,4,7-decatrienoate and methyl-2-nonenoate, in order to fulfill the biochemical pesticide date requirements for Acute Toxicity. These two compounds are structural and functional analogs of pear ester, according to the Research Institute for Fragrance Materials (RIFM), and are expected to have biochemical pathways comparable to pear ester (Ref. 4). RIFM categorizes pear ester and the two analogs as "Ester/Simple C1-C4 Alcohol Straight Chain Ester/Unsatured/α, β-Unsaturated (Ref. 4)." Based upon data on ethyl-2, 4, 7-decatrienoate and methyl-2-nonenoate, pear ester is estimated to have an Acute Oral Toxicity (rat) of LD50 > 4,027 mg/kg (Ref. 4). Researchers have found a nearly 100% concordance between results of oral and dermal routes for over 1,600 substances where the oral LD50 > 2,000 mg/kg (Ref. 4). Therefore, the Agency predicts the Acute Dermal Toxicity (rat) of pear ester to be LD50 > 2,000 mg/kg. 

The petitioner provided scientific rationale to fulfill the data requirement of Acute Inhalation Toxicity: Pear ester has a low vapor pressure (0.173 mm Hg) and is 137 times less volatile than water at 25°C (Pear ester volatility = 23.8 mm Hg at 25[o]C. Maximum manufacturing operating temperatures are 110 °C and 50 °C, which is much lower than its boiling point (258.4 °C). This information suggests that airborne concentrations of Pear ester will be minimal and unlikely to pose potential risk from inhalation exposure in the work place. In addition, Bedoukian, Inc., has produced pear ester for more than 30 years for non-pesticide uses with no reported worker related adverse effects (Ref. 4).  

Acute toxicity data on pear ester submitted by the petitioner indicate Primary Eye Irritation (rabbit): moderately irritating; Primary Dermal Irritation (rabbit): non-irritant; and Dermal Sensitization (guinea pig): not a dermal sensitizer (Ref. 4). 
      
2. Subchronic Toxicity, Developmental Toxicity, and Mutagenicity Testing (Tier I) (OCSPP Guideline Nos. 870.3100, 870.3250, 870.3465; 870.3700, 870.5100, 870.5300, 870.5375; MRID Nos. 48975101, 48975102): 

The petitioner submitted scientific rationale, or waiver requests, to fulfill Subchronic, Developmental and Mutagenicity Tier I requirements. 

The requirement for a 90-day oral toxicity study (OCSPP Guideline 870.3100) is satisfied by information presented by the petitioner which demonstrates that pear ester is structurally similar to straight chain lepidopteran pheromones (unbranched aliphatic chains between 9 and 18 carbons ending in an alcohol, aldehyde, or acetate functional group and containing up to three double bonds in the aliphatic backbone), which have well documented low toxicity via the oral route. 

The requirement for a 90-day dermal toxicity study (OCSPP Guideline 870.3250) is waived because the use of pear ester as a mating disruptor in pome orchards does not involve purposeful application to human skin and is not expected to result in comparable prolonged human exposure.

The requirement for a 90-day inhalation study (OCSPP Guideline 870. 3465) is satisfied by information presented by the petitioner which demonstrates that pear ester is a volatile kairomone (Henry's Law Constant estimated 7 x 10[-4] atm m[3]/mol) that dissipates rapidly in the environment and undergoes degradation in the presence of air and light. Therefore, there is no likelihood of significant levels of repeated inhalation exposure. 

The requirements for developmental toxicity and mutagenicity testing (OCSPP Guidelines 870.3700, 870.5100, 870.5300 and 870.5375) are satisfied, as in the 90-day oral requirement, above, by rationale which states that pear ester is structurally similar to straight chain lepidopteran pheromones, which have well documented low toxicity via the oral route. 


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 of pear ester is already occurring, given that this substance is used as a flavoring agent in many foods commonly consumed by humans and is emitted naturally from mature, ripening fruit (Ref. 1). In addition, the proposed use of pear ester as a codling moth mating disruptor is not expected to result in significant residues in/on edible fruit (Ref. 3). The proposed rates of application, under worst case scenarios, are not expected to produce dietary exposure to pear ester exceeding that of current exposure due to use of pear ester as a flavoring agent (Ref. 3, Ref. 4). 

Drinking Water Exposure:  Polymer dispenser products containing pear ester would not result in water residues because the product would be volatizing from the dispenser, dissipating, and degrading rapidly. Foliar spray products containing pear ester are intended for use at rates of less than one gram of active ingredient per acre with no direct applications to bodies of water. Therefore, drinking water exposure from the proposed used pattern is not expected to pose incremental risk to adults, infants and children via drinking water consumption (Ref. 4).

Other Non-occupational Exposure: 
Non-occupational dermal exposure to pear ester when used as a codling moth mating disrupter is considered negligible because agricultural treatments of pome orchards are limited by label directions to pre-harvest applications (Ref. 4). Non-occupational dermal exposure via treated food commodities is not greater than naturally occurring background levels of pear ester and not greater than exposure due to use of pear ester as a food additive (Ref. 4).


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 ethyl-2E,4Z-decadienoate (pear ester) to share a common mechanism of toxicity with any other substances, and ethyl-2E,4Z-decadienoate (pear ester) 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 ethyl-2E,4Z-decadienoate (pear ester)  does not have a common mechanism of toxicity with other substances. Following from this, therefore, the EPA concludes that there are no cumulative effects associated with ethyl-2E,4Z-decadienoate (pear ester) 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 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 pear ester as a pesticide (mating disruptor) 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 likely developmental toxicant, (2) naturally occurs in the human diet, and (3) has been approved by FDA for use in foods as a food additive without limitation. When compared to the amount of pear ester that is likely already consumed in the human diet, dietary exposure from pesticidal use 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 pear ester 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 pear ester 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 ethyl-2E,4Z-decadienoate (pear ester). Therefore, an exemption is established for residues of the biochemical pesticide ethyl-2E,4Z-decadienoate (pear ester) in or on all food commodities when used in accordance with label directions and good agricultural practices.

VII.  References

1. U.S. EPA, 2012. Memorandum from Clara Fuentes, Ph.D., to Gina Burnett. Tolerance Exemption Petition Review in support of registration of the following products: a) Bedoukian Pear Ester Technical  -  a manufacturing use product, containing 93.4 % w/w of 2,4-Decadienoic acid, ethyl ester, (2E,4Z); b) end use microencapsulated formulation Cidetrak DA-MEC, containing 5.0% w/w of Pear Ester, for foliar application to control larvae and adult Codling moth, Cydia pomonella, in apple, pear and walnut trees, and c) Cidetrack CM-DA Combo MD polymeric dispensers: Cidetrak CM-DA 115/30, containing 115 mgs of Codling Moth Pheromone and 30 mgs of Pear Ester; Cidetrak CM-DA 185/60, containing 185 mgs of Codling Moth Pheromone and 60 mgs of Pear Ester, and Cidetrak CM-DA 90/60, containing 90 mgs of Codling Moth Pheromone and 60 mgs of Pear Ester to control Codling moth, Cydia pomonella, and hickory Shuckworm, Cydia caryana, in apple, pear, walnut, pecan, quince, and other pome fruit trees. U.S. Environmental Protection Agency, Office of Pesticide Programs. June 28, 2012. 
   
2. U.S. FDA, 2013. Everything Added to Food in the United States (EAFUS) list. U.S. Food and Drug Administration (FDA), accessed on April 1, 2013. Available at: http://www.accessdata.fda.gov/scripts/fcn/fcnDetailNavigation.cfm?rpt=eafusListing&id=1183

3. Trece, 2011. Petition proposing the exemption from the requirement of a tolerance under 40 CFR § 180 for the biochemical active ingredient Ethyl 2,4 Decadienoate (CAS 3025-30-7) for pre-harvest uses on all agricultural commodities. Trece, Inc. July 8, 2011.  

4. U.S. EPA, 2013. Memorandum from Clara Fuentes, Ph.D., to Gina Burnett. Science review of registrant's response to deficiencies concerning Tolerance Exemption Petition in support of registration of Bedoukian Pear Ester Technical  -  a manufacturing use product, containing 93.4 % w/w of 2,4-Decadienoic acid, ethyl ester, (2E,4Z). U.S. Environmental Protection Agency, Office of Pesticide Programs. January 10, 2013. 

5. U.S. EPA, 2008. Biopesticide Registration Action Document Straight Chain Lepidopteran Pheromones. U.S. Environmental Protection Agency, Office of Pesticide Programs. October 2, 2008. Available at: http://www.epa.gov/pesticides/chem_search/reg_actions/registration/decision_G-109_02-Oct-08.pdf

