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Federal Food, Drug, and Cosmetic Act (FFDCA) Considerations for Lavandulyl Senecioate

Docket ID Number: EPA-HQ-OPP-2015-0017

Date: June 30, 2015

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 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 Place, 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 rate 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 Docket ID Number EPA-HQ-OPP-2015-0017

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. Overview 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-
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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 

pheromone in an aqueous suspension of micro-bead/dispensers via normal 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 submitted in support of this petition (summarized 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 consumption 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, 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 have been fulfilled with data and scientific rationales submitted by the 

petitioner. The following is a summary of EPA’s review of the toxicity profile of this 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 (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. 47595804). Lavandulyl senecioate is classified as Toxicity Category IV

(low toxicity) for acute oral toxicity. 

2. The acute dermal LD50 in rats was greater than 5,000 mg/kg body weight (MRID 47595804). 

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

3. The acute inhalation median lethal concentration (LC50) 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 irritating to 

the eye with no effects observed at 24 hours after treatment (MRID 47595804). Lavandulyl senecioate

is classified as Toxicity Category IV 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 III for primary dermal irritation. 
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6. Data indicate that lavandulyl senecioate is not a dermal sensitizer (MRIDs 49413204 and 49519301). 

Mutagenicity: Three mutagenicity studies, using lavandulyl senecioate (98.10% purity) 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 investigate 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 

biologically 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. 49413204) 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 with 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 polychromatic 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 test 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 groups 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 relevant. 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 that 

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 annual 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 support of the data requirements. The scientific rationales are based on the following: 
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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 ft3, or 

9,869 m3

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

c. The 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 calculations 

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 already 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 for food use under 40 CFR 180.960.

9. The mode of action of the arthropod pheromone is non-toxic. It is a mating pheromone of the 

vine mealybug. 

The Agency believes that repeated 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 less 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 subchronic 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 rationales 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 per 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 application 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 developmental testing.
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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 

applications 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 acknowledged 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 petitioner’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/acre/year) will not result in detectable residues in or on all food 

commodities. There are no dietary concerns for the arthropod pheromone, lavandulyl senecioate, when 

applied in accord with EPA-approved label use directions as a aqueous suspension of microbead/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 exposure to the pheromone due to its high volatility and rapid 

biodegradation. The high volatility and rapid degradation of arthropod pheromones resulting in extremely 

low exposure to humans and the environment have been thoroughly 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 mechanism 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 from 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 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 
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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 lavandulyl senecioate as an arthropod pheromone in or on all raw agricultural 

commodities when applied/used at a rate not to exceed 150 grams 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 toxicant. 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 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 lavandulyl senecioate 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 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. EPA (2015) 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, 2015.

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