1 Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations fo r Lavandulyl Senecioate

Docket ID Number: EPA

- HQ

- OPP

- 20 1 5

- 0017

Date: June 30 , 201 5

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 drin king 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 t he 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 de termines 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 Exempt ion

In the Federal Register of March 4, 2015 (80 FR 11611) (FRL

- 9922

- 68), 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 4F8292) by Suterra, LLC, 20950 NE Talus Pla ce, Bend, OR 97701. The petition requested that 40 CFR part 180 be amended by establishing an exemption from the requirement of a tolerance for residues of lavandulyl senecioate in or on all raw agricultural commodities when applied to growing crops at a r ate not to exceed 150 grams of active ingredient per acre per year. The notice referenced a summary of the petition prepared by the Petitioner, which is available in D ocket ID Number EPA

- HQ

- OPP

- 201 5

- 0 017

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 lavandulyl senecioate , 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. Overv iew of Lavandulyl Senecioate

Lavandulyl senecioate ( 5

- methyl

- 2

- (1

- methylethenyl)

- 4

- hexenyl 3

- methyl

- 2

- butonate ) is a technical grade synthetic arthropod pheromone. This arthropod pheromone is structurally similar to and mimics a naturally occurring pheromone produced by the female vine mealybug ( Planococcus ficus ) to attract males for mating. This pheromone is used to disrupt the normal mating cycle of the vine mealybug and has a non

-2 toxic mode of action.

As an arthropod pheromone, lavandulyl senecioate is exempt from the requirement of a tolerance when used in retrievably sized polymeric matrix dispensers in or on all raw agricultural commodities when applied to growing crops only at a rate not to exceed 150 grams active ingredient/acre/year in accordance with good agricultural practices (40 CFR 180.1124). The petitioner is requesting to apply this arthropod pherom one in an aqueous suspension of micro

- bead/dispensers via nor mal spray equipment; therefore, the proposed new use of lavandulyl senecioate is not covered under the existing tolerance exemption listed in

40 CFR 180.1124

.

Based on the data submitt ed in supp ort of this petition ( s ummarized in Unit II. B. below ) and the comprehensive risk assessment conducted by the Agency (Ref. 1 ) , EPA concludes that there is a reasonable certainty of no harm from aggregate exposures to lavandulyl senecioate , including the con sumption of food

treated with this arthropod pheromone in accordance with label directions and good agricultural practices.

EPA has made this determination because available toxicology data indicate that the arthropod pheromone is of low acute toxicity and is not a developmental toxicant

, a mutagen, or toxic via repeat oral exposure

.

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 the arthropod pheromone, l avandulyl senecioate, in or on all raw agricultural commodities when applied or used in microbeads/dispensers at a rate not to exceed 150 grams active ingredient/acre/year have been fulfi lled with data and scientific rationales submitted by the petitioner. The following is a summary of EPA’s review of the toxicity profile of th is arthropod pheromone :

Acute Toxicity : Acute toxicity studies on lavandulyl senecioate ( 97.66% purity ) confirm a low toxicity profile for all routes of exposure . Therefore, it can be concluded that any acute toxicity risks associated

with this arthropod pheromone would be negligible.

1. The acute oral median lethal dose ( LD 50 ) 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. 47595804 ). Lavandulyl senecioate is classified as Toxicity Category I V (low toxicity) for acute o ral toxicity.

2. The acute dermal LD 50 in rats was greater than 5,0 00 mg/kg body weight (MRID 4 7595804 )

. Lavandulyl senecioate is classified as Toxicity Category I V (low toxicity) for acute dermal toxicity.

3. The acute inhalation median lethal concentr ation (LC 50 ) was greater than 5.21 milligrams per liter (mg/L) in rats and showed no significant inhalation toxicity (MRID 49413204 )

. Lavandulyl senecioate is classified as Toxicity Category IV (low toxicity) for acute inhalation toxicity.

4. A primary eye irritation study on rabbits indicates that lavandulyl senecioate is minimally irri ta ting to the eye with no effects observed at 24 hours after treatment (MRID 47595804 )

. Lavandulyl senecioate is classified as Toxicity Category I V for primary eye irritation.

5. A primary dermal irritation study on rabbits indicates that lavandulyl senecioate is moderately irritating

to the skin with no effects observed at day 10 after treatment (MRID 47595804 )

. Lavandulyl senecioate

is classified as Toxicity Category I II for primary dermal irritation.3 6. Data indicate that lavandulyl senecioate is not a dermal sensitizer (MRID s 49413204 and 4 9519301 ).

Mutagenicity : T hree mutagenicity studies, using lavandulyl senecioate (98.1 0 % pur ity ) 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 lavandulyl senecioate

.

1. A Bacterial Reverse Gene Mutation Test (MRID No. 49413204 ) was performed to investigat e the potential of lavandulyl senecioate to induce gene mutations using Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and tester strain E. coli WP2 uvrA with and without metabolic activation. No

bio logically relevant increases in revertant colony numbers of any of the five tester strains were observed following treatment of lavandulyl senecioate at any concentration level with or without metabolic activation. Lavandulyl senecioate did not cause gene mutations by base pair changes or frameshifts in the genome of the tester strains used; therefore, lavandulyl senecioate is considered to be non

- mutagenic under

the conditions of this assay.

2. An in vitro Mammalian Cell Gene Mutation Assay (MRID No. 49413 204 ) tested lavandulyl senecioate for its potential to induce mutations at the mouse lymphoma thymidine kinase locus using the cell line

L5178Y with and without metabolic activation. No biologically relevant increase of mutants was found

after treatment wi th lavandulyl senecioate with or without metabolic activation. No dose

- response relationship was observed. Colony sizing showed no clastogenic effects induced by lavandulyl senecioate under the experimental conditions with or without metabolic activation. Therefore, lavandulyl senecioate is

considered to be non

- mutagenic under the conditions of this assay.

3. An in vivo Mammalian Cytogenetics Test (MRID 49413204) was performed to investigate the potential of lavandulyl senecioate to induce micronuclei in p olychromatic erythrocytes (PCE) in the bone marrow of the mouse to assess genotoxicity. The dosing groups were 2000, 1000, and 400 mg/kg bw and bone marrow samples were collected for micronuclei analysis 24 and 48 hours after a single application of the te st item. No biologically relevant increase of micronuclei was found after treatment with lavandulyl senecioate in any of the dose groups evaluated. No statistically significant increases/decreases (p<0.05) of cells with micronuclei were noted in the dose g roups except the value observed for the 2,000 mg/kg bw male dose group (24 hours). This significant decrease compared to the negative control was within the range of the historical negative control data; therefore, it was regarded as not biologically relev ant. Lavandulyl senecioate did not induce structural and/or numerical chromosomal damage in the immature erythrocytes of the mouse; therefore, lavandulyl senecioate is considered to be non

- mutagenic with respect to clastogenicity and/or aneugenicity in the Mammalian Erythrocyte Micronucleus Test.

Subchronic Toxicity : In the preamble to the final rule that exempted arthropod pheromones from the requirement of a tolerance when used in retrievably sized polymeric matrix dispensers, the Agency indicated that it did not have a toxicology database for arthropod pheromones th at addressed the potential risk of repeated, direct dietary exposure with sprayable formulations; therefore, at that time, the Agency limited the tolerance exemption to arthropod pheromones used in retrievably sized polymeric matrix dispensers with an annu al rate limitation of 150 grams of active ingredient per acre. The Agency concluded that the limitations would not result in dietary exposure any greater than what may be found naturally as a result of heavy infestations of the pest arthropod. 59 FR 14757, 15758 (Mar. 30, 1994).

To address the subchronic toxicity data requirements for this exemption from the requirement of a tolerance for this arthropod pheromone, lavandulyl senecioate, the petitioner submitted scientific

rationales in s upport of the data requirements. The scientific rationales are based on the following:4 1. The acute oral LD50 is > 5000; the acute inhalation LC50 is >5.21 mg/L; and the acute dermal LD50 is >5000 mg/kg

2. The maximum application rate is no more than 10 grams active ingredient ( a.i. ) per acre per application (see calculations in MRID 49413204, p 42)

. 3. The maximum estimated emission rate from the microbeads is 0.48 grams (480 mg) a.i. per acre per day over a 21 day period (see calculations in MRID 49413204, p 43)

. 4. The Estimated Environmental Concentration (EEC) within a treated grape orchard is 0.0000486 mg/L , assuming :

a. An average grape orchard height = 8 ft and a calculated cubic area = 348, 480 ft 3 , or 9,869 m 3

b. All of the daily pheromone emission (480 mg/ acre /day) remains within the orchard

c. T he product is applied at the maximum label rate (10 g a.i. per acre per application; see all calculations in MRID 49413204, p 43) NOTE: A hypothetical grape orchard was chosen as the basis for the EEC ca lculations because the product label specifies that the product is intended for use on grapes.

5. The arthropod pheromone volatilizes and dissipates rapidly in the atmosphere rapidly after

emission from the microbead.

6. The arthropod pheromone readily biodegrades in the environment.

7. Lavandulyl senecioate is already present in the environment wherever Vine Mealy Bugs are present and mating, and humans are alre ady exposed on a repeated basis.

8. Significant direct exposure to the arthropod pheromone is highly unlikely. The active ingredient is encapsulated in a microbead, from which it is emitted slowly, over a period of 21 days. The microbead is a polymer cleared fo r food use under 40 CFR 180.960.

9. The mode of action of the arthropod pher omone is non

- toxic. It is a mating pheromone of the vine mealybug

.

The Agency believes that r epeated oral and dermal exposure is highly unlikely, based on the extremely low application rate (10 g a.i. per acre per application), low emission rate (480 mg a.i. per acre per day), rapid volatilization after emission from the microbeads and rapid biodegradation. Residues on edible commodities are highly unlikely. In addition, the calculated atmospheric EEC (0.0000486 mg/L, or 0.0000486 ppm) is over 100000x le ss than the non

- definitive acute inhalation endpoint of >5.21 mg/L. Taking into account the petitioner’s rationale, EPA has concluded that there is unlikely to be exposure that could result in subchronic effects and so has waived the requirements for subch ronic testing.

Developmental Toxicity : To address the prenatal developmental toxicity data requirement for this exemption from the requirement of a tolerance for this arthropod pheromone, lavandulyl senecioate, the petitioner submitted scientific rational es in support of the data requirement. The rationale is essentially the same as discussed above for the subchronic toxicity data requirements. Based on the low application rate (10 g a.i. per acre per application), low emission rate (480 mg a.i. per acre p er day), extremely low atmospheric EEC (0.0000486 mg/L, or 0.0000486 ppm), rapid volatilization after emission from the microbeads and rapid biodegradation, it is highly unlikely that there will be significant exposure to female humans following applicatio n of the product according to approved EPA

- label rates. Taking into account the petitioner’s rationale, EPA has concluded that there is unlikely to be exposure that could result in developmental effects and so has waived the requirement for prenatal develo pmental testing.5 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 : In the preamble to the final rule, the Agency stated that limiting the exemption to

ap plications of arthropod pheromones in retrievably sized dispensers would severely limit the possibility of direct dietary exposure. The Agency believed that restriction was necessary to protect public health due to a lack of data on repeat exposure but ack nowledged that petitioners wanting to use other application methods or formulations could petition for an amendment by demonstrating that the new formulation did not increase the likely dietary exposure. For this tolerance exemption, based on the petitione r’s submission concerning the proposed use, the Agency has determined that the proposed use (applying this arthropod pheromone in an aqueous suspension of micro

- bead/dispensers via normal spray equipment with a limitation of 150 grams active ingredient/acr e/year) will not result in detectable residues in or on all food

commodities. There are no dietary concerns for the arthropod pheromone, lavandulyl s enecioate

, when applied in accord with EPA

- approved label use directions as a aqueous suspension of micro

b ead/dispensers via normal spray equipment based upon: 1) extremely low application rate of no more than 10 grams a.i. per acre per application; 2) extremely low potential for residues; 3) minimal toxicity; and 4) the extremely low likelihood of oral exposu re to the pheromone due to its high volatility and rapid biodegradation. T he high volatility and rapid degradation of arthropod pheromones resulting in extremely low exposure to humans and the environment have been th o roughly examined previously (Ref. 2).

Drinking Water Exposure : No significant exposure via drinking water is expected based on the previous

information for food exposure and the fact that the arthropod pheromone is not to be applied directly to

water.

Other Non

- occupational Exposure : Other non

- occupational exposure (other than dietary) is not expected because the arthropod pheromone, lavandulyl senecioate, is not approved for residential uses.

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 m echanism of toxicity.”

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

senecioate does not have a common mechanism of toxicity with other substances. Following f rom this, the

EPA concludes that there are no cumulative effects associated with lavandulyl senecioate 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 t he 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

FFDC A section 408(b)(2)(C) provides that, in considering the establishment of a tolerance or tolerance6 exemption for a pesticide chemical residue, the EPA shall assess the available information about consumption patterns among infants and children, special sus ceptibility 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

s hall 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 us es 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 lavandulyl senecioate as an arthropod pheromone in or on all raw agricultural

commodities when applied/used at a rate not to exceed 150 gr ams active ingredient/acre/year when label instructions and good agricultural practices are followed. The available data and information indicate that

the chemical is of low toxicity and not a developmental t oxicant

. 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 lavandulyl senecioate when it is used as labeled and in accor dance 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 lavandulyl se necioate 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 a ggregate exposure to residues of lavandulyl senecioate

. Therefore, an exemption is established for residues of the arthropod pheromone, lavandulyl senecioate, in or on all raw agricultural commodities when applied or used in microbeads/dispensers at a rate not to exceed 150 grams active ingredient/acre/year.

VII . References

1. E PA (201 5 ) Environmental Protection Agency (EPA) Risk Assessment: Science Review in Support of the Registration of Checkmate VMB

- F, An End

- Use Product (EP) Containing 19.35% 2

- Butenoic, 3

- Methyl

- , 5

- Methyl

- 2

- (1

- Methylethenyl)

- 4

- hexenyl Ester (Lavandulyl Senecioate); Vine Mealy Bug Pheromone. Review of New Food Use

. March 16 , 201 5

.

2. OECD (2002) Organisation of Economic and Co

- Operation and Development Guidance Document: Guidance for Registration Requirements for Pheromones and Other Semiochemicals Used for Arthropod Pest Control. OECD Series on Pesticides, Number 12. ENV /JM/MOMO(2001)12