Document ID: EPA-HQ-OPP-2021-0066-0006
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2023-01-13T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND

                                                           POLLUTION PREVENTION

MEMORANDUM

Date:		June 11, 2021

SUBJECT:	Emamectin Benzoate; Human Health Risk Assessment for a Proposed New Use on Soybean   
 
PC Code: 122806  
DP Barcode: D456360  
Decision No.: 559030  
Registration No.: 100-903  
Petition No.:  9F8817
Regulatory Action: Section 3 Registration 
Risk Assessment Type: Single Chemical Aggregate
Case No.: NA 
TXR No.: NA 
CAS No.: 155569-91-8 
MRID No.: NA 
40 CFR:  §180.505

FROM:	Brent Davis, Biologist 
      Krystle Yozzo, Ph.D., Biologist
		Johnnie L Smith II, Chemist 
		Risk Assessment Branch III (RABIII)
		Health Effects Division (HED, 7509P)

THROUGH:	Thomas Moriarty, Branch Chief		
		RABIII/HED (7509P)

TO:	Jasmin Jackson, Risk Manager
	Gene Benbow, PM 7
	Invertebrate-Vertebrate Branch III (IVB 3)
	Registration Division (7505P)

The Registration Division (RD) of the Office of Pesticide Programs (OPP) has requested that the Health Effects Division (HED) evaluate hazard and exposure data and conduct occupational and residential exposure assessments, as needed, to estimate the risk to human health that will result from a proposed new use of emamectin benzoate on soybean.  This memorandum serves as HED's human health risk assessment of the dietary, occupational, and residential exposure; and aggregate risk from the registered uses of emamectin benzoate.

                               Table of Contents
1.0	Executive Summary	4
2.0	HED Recommendations	6
2.1	Tolerance Considerations	6
2.1.1	Enforcement Analytical Method	6
2.1.2	Recommended Tolerances	7
2.1.3	Revisions to Petitioned-For Tolerances	7
2.1.4	International Harmonization	7
2.2	Label Recommendations	7
2.2.1	Recommendations from Occupational Exposure Assessment	7
3.0	Introduction	7
3.1	Chemical Identity	8
3.2	Physical/Chemical Characteristics	10
3.3	Pesticide Use Pattern	10
3.4	Anticipated Exposure Pathways	11
3.5	Consideration of Environmental Justice	12
4.0	Hazard Characterization and Dose-Response Assessment	12
4.1	Toxicological Effects	13
4.2	Safety Factor for Infants and Children (FQPA Safety Factor)	14
4.3	Toxicity Endpoint and Point of Departure Selections	14
5.0	Dietary Exposure and Risk Assessment	16
5.1	Residues of Concern Summary and Rationale	16
5.2	Food Residue Profile	17
5.3	Water Residue Profile	18
5.4	Dietary Risk Assessment	18
5.4.1	Description of Residue Data Used in Dietary Assessment	18
5.4.2	Percent Crop Treated Used in Dietary Assessment	19
5.4.3	Acute Dietary Risk Assessment	19
5.4.4	Chronic Dietary Risk Assessment	19
5.4.5	Cancer Dietary Risk Assessment	19
5.4.6	Summary Table	19
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	20
7.0	Aggregate Exposure/Risk Characterization	20
8.0	Non-Occupational Spray Drift Exposure and Risk Estimates	20
9.0	Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates	21
10.0	Cumulative Exposure/Risk Characterization	21
11.0	Occupational Exposure/Risk Characterization	22
11.1	Short-/Intermediate Occupational Handler Exposure and Risk Estimates	22
11.2	Post-Application Exposure and Risk Estimates	26
11.2.1	Dermal Post-Application Exposure and Risk Estimates	26
11.2.2	Inhalation Post-Application Exposures and Risk Estimates	27
12.0 	References	27
Appendix A.  Toxicology Profile and Executive Summaries	29
A.1	Toxicology Data Requirements	29
A.2.	Toxicology Data Requirements	30
A.3.	Data Demonstrating the Sensitivity of Beagle Dogs to the Effects of Abamectin and Emamectin	36
Appendix B.  Physical/Chemical Properties	38
Appendix C.  Review of Human Research	39

 Executive Summary

The active ingredient (ai) emamectin benzoate (referred to in this assessment as emamectin) is a mixture of approximately 90% 4′-epi-methylamino-4′-deoxyavermectin B1a and 10% 4′-epi-methylamino-4′-deoxyavermectin B1b. Emamectin is a natural fermentation product of the soil bacterium Streptomyces avermitilis and is an insecticide/miticide developed to control insect species by interfering with the nervous system, specifically causing paralysis. 

The petitioner, Syngenta Crop Protection LLC, requests established tolerances for combined residues of the insecticide: emamectin benzoate (a benzoate salt mixture of a minimum of 90% 4'-epi-methylamino-4'- deoxyavermectin B1a and a maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B1b) resulting from the application of emamectin benzoate in/on soybean at 0.01 ppm.  The HED has conducted a Food Quality Protection Act (FQPA) aggregate risk assessment for pesticide petition no. 9F8817 for proposed new uses of emamectin on soybean. The most recent human health draft risk assessment (DRA) was completed in September of 2017 (L. Bacon, et. al., D438444, 09/26 /2017); emamectin's interim registration review decision was published on 05/15/2019    

Use Profile 
Syngenta has requested soybeans be added to the Denim Insecticide label (EPA Reg. No. 100-903). Denim Insecticide is an emulsifiable concentrate (EC) formulation containing 0.16 lb of ai per gallon. Denim is currently designated as a restricted use pesticide (RUP) (i.e., for use by professional certified operators only). The proposed maximum single application rate is 0.015 lb ai/acre (A) and 0.003 lb ai/gallon for handheld equipment. The proposed use is for application by aerial and ground equipment; chemigation is prohibited.  Applications may be repeated at a 7-day interval to maintain control, however no more than 0.045 lb ai/A may be applied per year. Occupational handlers (applicators, mixers/loaders, and other handlers) are required to wear "baseline attire" (i.e., long-sleeved shirt, long pants, shoes and socks) along with additional personal protective equipment (PPE) consisting of chemical-resistant gloves, coveralls, and protective eyewear. Additionally, handlers must wear a chemical-resistant apron when cleaning equipment, mixing, or loading.  

Exposure Profile 
Humans may be exposed to emamectin in food and drinking water since emamectin may be applied directly to growing crops and following harvest, and application may result in emamectin reaching surface and ground sources of drinking water. Based on the currently registered and proposed uses of emamectin, occupational handler and post-application exposure is expected to be both short- (1 to 30 days) and intermediate-term (1 to 6 months).  Potential occupational routes of exposure include both dermal and inhalation. The only registered residential use, gel bait products, is not expected to result in residential exposure. Post-application residential exposures are not anticipated based on the existing or proposed use patterns. Non-occupational exposures may occur as a result from spray drift from agricultural applications of emamectin.    

Hazard Characterization
The toxicological database for emamectin is considered complete with respect to guideline toxicity studies. In general, available toxicity data for emamectin showed that with a single dose or repeated dose administration, the primary target organ was the nervous system and that decreased body weight was one of the most frequent findings. The subchronic inhalation toxicity study has been waived for emamectin at this time (J. Leshin, TXR 0051377, 03/12/2015) due to a weight-of-evidence (WOE) consideration of toxicity and exposure. The toxicity endpoints and points of departure (PODs) for all exposure scenarios have been selected from the subchronic and chronic oral toxicity studies in dogs, based on species sensitivities and review of relevant literature information. The adverse effects seen in the dog studies included clinical signs and neuropathology findings (degeneration in the white matter of the brain, in the spinal cords, and in the peripheral nerves along with skeletal muscle atrophy). The POD selected from the dog studies is based on clear no-observed adverse effect-levels (NOAELs) of 0.25 mg/kg/day that are protective of all adverse effects seen in human-relevant studies conducted in rats, CD-1 mice, and rabbits. An available dermal absorption study in monkeys indicates that approximately 1.8% of emamectin is dermally absorbed; therefore, a dermal absorption factor of 1.8% was applied for route-to-route extrapolation. Inhalation toxicity is assumed to be equivalent to oral toxicity. The dermal, incidental oral, and inhalation POD is based on the same study, therefore, risk estimates for emamectin are combined into a total risk estimate where applicable.

The FQPA safety factor (SF) has been reduced to 1X. The level of concern (LOC) is a margin of exposure (MOE) of 100 for all exposure scenarios (10X for interspecies extrapolation and 10X for intraspecies variations). Emamectin is classified as "not likely to be carcinogenic to humans" based on the absence of compound-related increases in tumor incidence in two adequate rodent (rats and mice) carcinogenicity studies.

Dietary Exposure Assessment 
Highly refined acute probabilistic and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted for emamectin.  Acute dietary exposure to emamectin at the 99.9[th] percentile contributes an estimated 15% of the aPAD for the general U.S. population, and 30% of the acute population-adjusted dose (aPAD) for children 1-2 years of age, the most highly exposed population subgroup.
Chronic dietary exposure to emamectin contributes an estimated 1.6% of the cPAD for the general U.S. population, and 3.5% of the cPAD for children 1-2 years of age, the most highly exposed population subgroup.

Emamectin was classified as "not likely to be carcinogenic to humans" based on the absence of significant increase in tumor incidence in two adequate rodent (i.e., rat and mouse) carcinogenicity studies.  As such, a quantitative cancer assessment was neither conducted, nor required.

Residential Exposure and Risk Assessment 
There are no residential exposures expected from the proposed and registered uses of emamectin. 

Aggregate Risk Assessment 
Residential exposure from the gel bait product is expected to be negligible and therefore does not contribute to aggregate risk Therefore, all aggregate risk estimates are expected to be equivalent to dietary (food and drinking water) risk estimates and are not of concern.   

Occupational Exposure and Risk Assessment 
For the proposed use, occupational handler combined dermal and inhalation risk estimates are not of concern [MOEs are >= LOC of 100] with label-specified PPE including a double layer of clothing and chemical-resistant gloves (DL/G); MOEs from handler scenarios range from 200 to 27,000. Using chemical-specific dislodgeable foliar residue (DFR) data, there are no post-application dermal risk estimates of concern for the proposed use of emamectin. All post-application scenarios associated with the proposed use resulted in dermal MOEs greater than the LOC of 100 on the day-zero(12 hours following the end of the application on). The post application MOEs ranged from 48,000 to 750,000.  Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed for emamectin. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for emamectin.
   
Environmental Justice
Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations." (http://www.archives.gov/federal-register/executive-orders/pdf/12898.pdf).

Human Studies
This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their exposure.  Appendix C provides additional information on the review of human research used to complete the risk assessment.  There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA's Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied see Appendix C).

 HED Conclusions

HED has examined the toxicology, residue chemistry, and exposure databases for emamectin.    There are no human health risk issues that would preclude granting of Section 3 registration for the proposed use of emamectin on soybean, or the establishment of tolerances for residues of emamectin in/on soybean.  The specific tolerance recommendations are discussed in Section 2.1.  Label recommendations are specified in Section 2.2.1.

       Tolerance Considerations

       Enforcement Analytical Method

A high-performance liquid chromatography equipped with a fluorescence detector (HPLC/FLD) method (Method 244-92-3) is available for the enforcement of established emamectin tolerances on plant commodities. HED previously concluded that Revision 1 of this method is adequate for enforcement purposes for the determination of residues of emamectin (MAB1a and MAB1b) and its metabolites 8,9-isomer of the B1a and B1b component of the parent (8,9-ZMA)  in/on plant commodities.  The methods determine residues of emamectin in the following analyte combinations: MAB1a + 8,9-ZB1a, MAB1b + 8,9-ZB1b, AB1a, and MFB1a + FAB1a, with a limit of quantification (LOQ) of 0.005 ppm for each analyte or analyte combination, for a combined LOQ of 0.02 ppm.  

       Recommended Tolerances

HED recommends that 40 CFR §180.505(a)(1) be updated to include the following tolerance:

Table 2.2.2.  Tolerance Summary for Emamectin.
Commodity
                           Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
                                   Comments 
                        (correct commodity definition)
                            40 CFR §180.505(a)(1)
Soybean, seed 
                                      --
                                     0.01
Revised commodity definition
         Soybeans
                                     0.01
                                      --

       Revisions to Petitioned-For Tolerances

The petitioned-for tolerance was revised with respect to the correct commodity definition currently used by the Agency as indicated in Table 2.2.2. 

       International Harmonization

The U.S. and Codex residue definitions for emamectin are not harmonized. The U.S. residue definition for emamectin includes the sum of emamectin and its metabolites (8,9-isomer) for plants and livestock. The Codex residue definition includes only emamectin for plants and livestock commodities. There are no Canadian maximum residue limits (MRLs) established for emamectin. 

There are currently no maximum residue limits (MRLs) established for residues of emamectin in/on soybean under Codex; therefore, there are no issues with harmonization. 

       Label Recommendations
NONE.

       Recommendations from Occupational Exposure Assessment

Emamectin is a severe eye irritant, and according to 40 CFR 156.208 (c) (2), HED recommends that the 12-hour restricted entry interval (REI) established on the Denim Insecticide label (EPA Reg. No. 100-903) be increased to 48 hours.

 Introduction

Emamectin benzoate is an insecticide that is a benzoate salt mixture of  >=90% of 4'-epi-methylamino-4'-deoxyavermectin B1a (MAB1a) and <=10% of 4'-epi-methylamino-4'-deoxy-avermectin B1b (MAB1b).  The pesticidal mode of action is through inhibition of muscular contraction via continuous flow of chlorine ions in the GABA (γ-aminobutyric acid) and H-glutamate receptor sites.  The compound penetrates leaf tissue and has been observed to form residues within leaves (Fanigliulo, A. and Sacchetti, M. Emamectin benzoate: new insecticide against Helicoverpa armigera. Communications in Agricultural and Applied Biological Sciences. 2008;73(3):651-3).

       Chemical Identity

Table 3.1.	Nomenclature for Emamectin Benzoate and Metabolites of Interest.
Common name
Emamectin benzoate (B1a = NOA426007; B1b = NOA422390)
Identity
Mixture of >90% emamectin B1a benzoate and <10% emamectin B1b benzoate
CAS nomenclature
4′-epi-methylamino-4′-deoxyavermectin B1a 
CAS registry number
155569-91-8 (formerly 137512-74-4) 
Molecular weight
B1a = 1008.26 g/mol; B1b = 994.23 g/mol
Company experimental name
MK244
                                       
Name
Emamectin (B1a = NOA426007; B1b = NOA422390)
CAS nomenclature
4′-epi-methylamino-4′-deoxyavermectin B1b
CAS registry number
11979-41-2
Molecular weight
B1a = 886.14 g/mol; B1b = 872.12 g/mol
                                       
Metabolite name
8,9-Z isomer[1] (8,9-ZB1a; isomer for B1a; NOA438376)
CAS nomenclature
4′-deoxy-4′-epi-amino-avermectin B1a
Molecular weight
B1a = 886.14 g/mol; B1b = 872.12 g/mol
                                       
Metabolite name
AB1a (L'649; NOA438309)
CAS nomenclature
4′-deoxy-4′-epi-amino avermectin B1a
Molecular weight
872.12 g/mol
                                       
Metabolite name
MFB1a (L'599; NOA415692)
CAS nomenclature
4′-deoxy-4′-epi-(N-formyl-N-methyl)amino-avermectin
Molecular weight
914.15 g/mol
                                       
Metabolite name
FAB1a (L'831; NOA415693)
CAS nomenclature
4′-deoxy-4′-epi-(N-formyl)amino-avermectin B1a
Molecular weight
900.13 g/mol
                                       

       Physical/Chemical Characteristics

Emamectin is a solid with neutral pH at room temperature.  It is readily soluble in water below pH 9.0, and in numerous organic solvents. The vapor pressure is negligible, and it is not expected to volatilize.  

The physical/chemical characteristics of emamectin are presented below in Appendix B.
PESTICIDE USE PATTERN

Syngenta has requested a proposed new use on soybeans to be added to the Denim Insecticide label (EPA Reg. No. 100-903). Denim Insecticide is an EC formulation containing 0.16 lb of ai per gallon and is currently designated as a RUP (i.e., for use by professional certified operators only). The proposed maximum single application rate for soybeans is 0.015 lb ai/A, using aerial and ground equipment, and 0.003 lb ai/gal for handheld equipment; chemigation is prohibited. Applications may be repeated at a 7-day interval to maintain control, up to a maximum seasonal application rate of 0.045 lb ai/A. Occupational handlers are required to wear "baseline attire" (i.e., long-sleeved shirt, long pants, shoes and socks) along with additional PPE consisting of chemical-resistant gloves, coveralls, and protective eyewear. When cleaning equipment, mixing, or loading, handlers must wear a chemical-resistant apron. 

The proposed use of emamectin is summarized in Table 3.3.1.

Table 3.3.1. Use Profile for Proposed Emamectin Benzoate Use
                                   Proposed
                                      Use
                              Product Formulation
                                [EPA Reg. No.]
                             Application Equipment
                           Max. Single 
Applic. Rate
                           Max. No. Applic. Per Year
                           Max. Annual Applic. Rate 
                                    lb ai/A
                                    PHI[1] 
                                    (days)
                        Use Directions and Limitations
                                    Soybean
                   Denim Insecticide [EPA Reg. No. 100-903]
                 EC 2.15% Emamectin Benzoate, 0.16 lb ai/gal 
                     Ground, Aerial, or Handheld equipment
                                6-12 fl oz/gal 
                                   (0.015) 
                                       
                               (0.003 lb ai/gal)
                                       3
                                     0.045
                                      28
Apply Denim to plant foliage when larvae first appear, but before populations reach damaging levels.

Chemigation is prohibited. Not for use in CA. No aerial application in NY. 

Do not allow livestock to graze in treated areas. Do not harvest treated soybean forage, straw, or hay as feed for meat or dairy cattle. Do not feed treated soybean fodder or silage to meat or dairy cattle. 

No more than two apps before rotating MOA2. GPA3 5 gallons for ground; RTI4 = 7 days. REI5 = 12 hours
PPE6: "Baseline attire", coveralls, plus chemical-resistant gloves[ ]
[1] PHI - preharvest interval (PHI)
[2] MOA - mode of action 
[3] GPA - gallons per acre.
[4] RTI - Retreatment interval.
[5] REI - restricted-entry interval. 
[6] PPE - personal protective equipment

       Anticipated Exposure Pathways

Humans may be exposed to emamectin in food and drinking water, since emamectin may be applied directly to growing crops and application may result in emamectin reaching surface and ground water drinking water sources. The only existing residential use, gel bait products, are expected to result in negligible exposure and non-occupational exposure via spray drift is possible.  In occupational settings, handlers may be exposed while handling emamectin as well as during post-application activities for workers re-entering treated fields. Risk assessments have been completed for both the proposed and existing uses of emamectin.  
CONSIDERATION OF ENVIRONMENTAL JUSTICE

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (https://www.archives.gov/files/federal-register/executive-orders/pdf/12898.pdf).  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age and ethnic group.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Spray drift can also potentially result in post-application exposure and it is also being considered whenever appropriate.  Further considerations are also currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to other types of possible bystander exposures and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

 Hazard Characterization and Dose-Response Assessment
As mentioned in Section 3, emamectin is 4"-deoxy-4"-methylamino derivative of abamectin . Emamectin is a mixture of two components, B1a and B1b, which have similar biological and toxicological properties. The only difference between abamectin and emamectin is that the hydroxyl moiety at the 4'' position of the tetrahydropyran ring in abamectin is replaced by a methylamine moiety to become emamectin (circled groups in the following figures). 

Figure 4.1. Chemical Structures 

		Emamectin 						Abamectin

         								

Under registration review, the Agency re-evaluated the entire emamectin and abamectin toxicological databases to ensure consistent hazard evaluation for these structurally related pesticides. The updated hazard characterization and dose-response assessment represent a more refined analysis than previous assessments, using the literature data to enhance the characterization of the studies submitted to the Agency. In 2016, the two chemicals were screened for the potential for cumulative risk. While no common mechanism group has been established for the avermectin macrocyclic lactones of abamectin and emamectin (i.e., key events leading from the molecular initiating event to apical neurotoxicity cannot be causally determined), the Agency conducted a screening level cumulative evaluation based on screening guidance, Pesticide Cumulative Risk Assessment: Framework for Screening Analysis [https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/pesticide-cumulative-risk-assessment-framework]. The framework was used to assess the potential for cumulative risk and the extent to which additional toxicity information is needed to determine the key events for a common mechanism grouping. 

The screening level cumulative assessment was most recently updated in 2021 (B. Davis, et al., D461596, 06/11/2021).  For the new uses of emamectin, the quantitative exposures to residues of emamectin remain unchanged, and the cumulative exposures remain identical to those as assessed within the 2021 cumulative assessment. There are no risks of concern resulting from these cumulative exposures.

4.1	Toxicological Effects

The DRA was conducted in 2017 (L. Bacon, et. al.,D438444, 09/26 /2017). Since that assessment, there have been no changes in the hazard characterization and dose-response assessment, and the DRA should be referred to for complete details. A brief summary of the toxicological effects is described below. 

The emamectin database is complete and sufficient for selecting toxicity endpoints and PODs for risk assessment. The subchronic inhalation study has been recommended to be waived (J. Leshin, TXR 0051377, 03/12/2015). 

Consistent with the postulated mode of action as described in Section 4.0, the main target organ for emamectin is the nervous system; treatment-related clinical signs (tremors, ptosis, ataxia, mydriasis, and hunched posture) and neuropathology (neuronal degeneration in the brain and in peripheral nerves and muscle fiber degeneration) were found in most of the emamectin studies in rats, dogs, rabbits, and mice. Neurotoxicity was observed after oral and dermal exposures. Decreased body weight was also a frequent finding. There was no evidence of immunotoxicity in the database. The results of a Rhesus monkey study indicated that dermal absorption was minimal, and the dermal absorption factor was 1.8% which was in a similar range as that for abamectin (1%).

Emamectin did not elicit increased fetal sensitivity in developmental toxicity studies in rats and rabbits or in the reproductive toxicity study. However, in the developmental neurotoxicity study in rats, there as an increase in both quantitative and qualitative sensitivity in the pups as no adverse effect was seen at the highest dose tested in parental animals, while the pups showed a dose-related decrease in open field motor activity at post-natal day 17 at a lower dose. Body tremors, hind-limb extension, and auditory startle were also observed in the high dose pups (3.6/2.5 mg/kg/day).

The carcinogenicity and mutagenicity studies provide no indication that emamectin is carcinogenic or mutagenic. Emamectin is classified as "not likely to be carcinogenic to humans." 
  
The technical material indicates that emamectin has low to moderate acute toxicity by the oral, dermal and inhalation routes. It is not irritating to the skin, nor is it a dermal sensitizer. However, depending on the technical test substance, emamectin has been shown to be a severe eye irritant. 
4.2	Safety Factor for Infants and Children (FQPA Safety Factor)
HED recommends that the required FQPA SF of 10X for the protection of infants and children be reduced to 1X for all exposure scenarios based on the following considerations: 1) the toxicity database is complete; 2) no evidence of quantitative susceptibility in the database; and 3) although there is evidence of neurotoxicity, the concern is low because the effects and are well-characterized with clearly established NOAEL/lowest-observed adverse-effect level (LOAEL) values and selected endpoints address the observed effects and are protective of all the adverse effects seen in the studies conducted in rats, CD-1 mice, and rabbits.

4.3	Toxicity Endpoint and Point of Departure Selections

The subchronic and chronic dog studies were selected to assess all exposure scenarios. The effects seen in subchronic and chronic dog studies (skeletal atropy, brain white matter and spinal cord degeneration)[0.5 mg/kg LOAEL] were similar in lesions and degree of severity, despite longer duration of treatment in the chronic study suggesting the response could be due to each individual exposure rather than to accumulation of emamectin in tissues. Purportedly, as the peak blood level of each administered dose passed, the response diminished or disappeared accordingly. Additionally, the effects observed in the studies could be elicited by a single dose. The following support this selection: (1) kinetics data supporting rapid absorption/excretion, (2) acute neurotoxicity observed in rats, and (3) the effects produced by emamectin in beagle dogs did not progress with time. 

      Kinetic data: Given that emamectin was shown to be readily absorbed (Tmax at 4-8 hours), rapidly eliminated (≈90% by 48 hour post-dosing), and without accumulation in the body with repeated dosing; the clinical signs and neuropathological effects seen in the dog studies were likely resulting from individual dosing or single dose effect.
      
Acute neurotoxicity study in rats: The conclusion based on the kinetics data was confirmed by results from the acute neurotoxicity studies in rat (range finding and main studies) which showed that, with a single dose, the treated rats developed clinical signs of neurotoxicity such as reduced foot splay reflex, ataxia, tremors, and mydriasis.  Most of these effects were consistent with those seen in the subchronic and chronic dog studies, except in rats similar effects were observed at higher dose levels as rats were relatively less sensitive to the effects of emamectin compared to the beagle dogs. Therefore, neurotoxicity seen in the emamectin dog studies were likely due to a single dose effect.  

      Effects seen in the subchronic and chronic dog studies:  The effects seen in subchronic and chronic dog studies were similar in lesions and degree of severity, despite longer duration of treatment in the chronic study suggesting the response could be due to each individual exposure rather than to accumulation of emamectin in tissues. Purportedly, as the peak blood level of each administered dose passed, the response diminished or disappeared accordingly.

Table 4.3.1. Summary of Toxicological Doses and Endpoints for Emamectin for Use in Dietary and Non-Occupational Human Health Risk Assessments
Exposure/
Scenario
Point of Departure
Uncertainty/FQPA Safety Factors
RfD, PAD, LOC for Risk Assessment
Study and Toxicological Effects
Dietary, 
all durations

(General Population, including Infants and Children)
NOAEL = 0.25 mg/kg/day
UFA = 10X
UFH = 10X
FQPA SF= 1X

Acute RfD = 0.0025 mg/kg/day

aPAD = 0.0025 mg/kg/day

Chronic RfD = 0.0025 mg/kg/day

cPAD = 0.0025 mg/kg/day
Subchronic and chronic oral toxicity studies in dogs

Subchronic LOAEL = 0.5 mg/kg/day based skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males.

Chronic LOAEL = 0.5 mg/kg/day based on axonal degeneration in the pons, medulla, and peripheral nerves (sciatic, sural, and tibial); whole body tremors; stiffness of the hind legs, spinal cord axonal degeneration, and muscle fiber degeneration
Incidental Oral

Short-Term (1-30 days)
NOAEL = 0.25 mg/kg/day

UFA  = 10X
UFH  = 10X
FQPA SF = 1X 
Non-occupational LOC for MOE = 100

Dermal

Short-Term (1-30 days)
NOAEL= 0.25 mg/kg/day

Dermal Absorption Factor = 1.8%
UFA = 10X
UFH  = 10X
FQPA SF = 1X
Non-occupational LOC for MOE = 100

Inhalation

Short-Term 
(1-30 Days)
NOAEL = 0.25 mg/kg/day

Toxicity via the inhalation route assumed to be equivalent to oral route.
UFA = 10X
UFH  = 10X
FQPA SF = 1X
Non-occupational LOC for MOE = 100

Cancer (oral, dermal, inhalation)
Classification: "Not Likely to be Carcinogenic to Humans" based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (intraspecies). UFH = potential variation in sensitivity among members of the human population (interspecies). FQPA SF = FQPA Safety Factor. PAD = population-adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

 Table 4.3.2. Summary of Toxicological Doses and Endpoints for Emamectin for Use in Occupational Human Health Risk Assessments
                              Exposure/ Scenarios
                              Point of Departure
                          Uncertainty/ Safety Factor
                                      LOC
Study and Toxicological Effects
Dermal 
(Short-Term and Intermediate-Term)
                            NOAEL = 0.25 mg/kg/day
                                       
                        Dermal Absorption Factor = 1.8%
UFA  = 10X
UFH  = 10X
                                       
                        Occupational LOC for MOE = 100
Subchronic and chronic oral toxicity studies in dogs

Subchronic LOAEL = 0.5 mg/kg/day based skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males.

Chronic LOAEL = 0.5 mg/kg/day based on axonal degeneration in the pons, medulla, and peripheral nerves (sciatic, sural, and tibial); whole body tremors; stiffness of the hind legs, spinal cord axonal degeneration, and muscle fiber degeneration
Inhalation 
(Short-Term and Intermediate-Term)
                            NOAEL = 0.25 mg/kg/day
                                       
   Toxicity via the inhalation route assumed to be equivalent to oral route.
UFA  = 10X
UFH  = 10X
                                       
                        Occupational LOC for MOE = 100
Subchronic and chronic oral toxicity studies in dogs

Subchronic LOAEL = 0.5 mg/kg/day based skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males.

Chronic LOAEL = 0.5 mg/kg/day based on axonal degeneration in the pons, medulla, and peripheral nerves (sciatic, sural, and tibial); whole body tremors; stiffness of the hind legs, spinal cord axonal degeneration, and muscle fiber degeneration
Cancer (oral, dermal, inhalation)
Classification: "Not Likely to be Carcinogenic To Humans" based on the absence of significant increase in tumor incidence in two adequate rodent carcinogenicity studies.
 Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no-observed adverse-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. 

 Dietary Exposure and Risk Assessment 

       Residues of Concern Summary and Rationale

The residues of concern for tolerance enforcement and risk assessment include parent emamectin, the isomers 8,9-ZB1a and 8,9-ZB1b, and photodegradants AB1a, MFB1a, and FAB1a in crops.  In ruminants, the residues of concern for tolerance enforcement and risk assessment include parent emamectin, and the isomers 8,9-ZB1a and 8,9-ZB1b only..  No decision has been made at this time concerning the residues of concern in poultry.  For drinking water, the residues of concern for risk assessment include parent emamectin, the isomers 8,9-ZB1a and 8,9-ZB1b, and photodegradants AB1a, MFB1a, and FAB1a (D245202, TXR 0050048, J. Stokes, 4/15/1998).  Table 5.1, below, summarizes these conclusions. 

Table 5.1.  Summary of Metabolites and Degradants to be included in the Risk Assessment and Tolerance Expression for Emamectin
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
Plants

Primary Crops
emamectin (MAB1a + MAB1b), the associated 8,9-Z isomers (8,9-ZB1a + 8,9-ZB1b), and metabolites/degradates AB1a, MFB1a and FAB1a
emamectin (MAB1a + MAB1b), the associated 8,9-Z isomers (8,9-ZB1a + 8,9-ZB1b), and metabolites/degradates AB1a, MFB1a and FAB1a

Rotational Crops
Same as for primary crops
Same as for primary crops
Livestock

Ruminant
emamectin (MAB1a + MAB1b) and its 8,9-Z isomers (8,9-ZB1a and 8,9-ZB1b)
emamectin (MAB1a + MAB1b) and its 8,9-Z isomers (8,9-ZB1a and 8,9-ZB1b)

Poultry
Not applicable
Not applicable
Drinking Water

emamectin (MAB1a + MAB1b), the associated 8,9-Z isomers (8,9-ZB1a + 8,9-ZB1b), and metabolites/degradates AB1a, MFB1a and FAB1a
Not applicable

       Food Residue Profile

Emamectin is used on a variety of vegetable and oil crops, with tolerances (40 CFR §180.505) ranging from 0.02 ppm to 1 ppm.  These residues include parent emamectin and numerous metabolites of concern, but the total emamectin residues are at relatively low concentrations.  Processing commodities treated with emamectin results in slight concentration in tomato pomace.  Comparison of the residues in/on the seed, the raw agricultural commodity (RAC), and aspirated grain fractions (AGF) indicate that residues of the following analytes concentrate in AGF:  emamectin MAB1a (median processing factor of >13x); 8,9-ZB1a (>2.3x); AB1a (>3.5x); MFB1a (>9.8x); and FAB1a (>2.0x). Processing factors for residues of MAB1a could not be determined as residues were below the limit of quantitation (LOQ) in/on both the seed and AGF at both trials.  Tolerances are also established for secondary residues of emamectin (parent plus 8,9-Z isomers) in livestock commodities at concentrations ranging from 0.01 ppm to 0.05 ppm.  No emamectin tolerances are established in poultry commodities.

Overall, the population is expected to be exposed to residues of emamectin at low concentrations in a limited variety of crops including green vegetables, cucurbits, fruiting vegetables, tree nuts, apples and cherries, and in most non-poultry livestock commodities.

       Water Residue Profile

The estimated drinking water concentrations used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED; D445830/446173, S. Hafner, 08/28/2018) and incorporated directly into this dietary assessment. Water residues were incorporated in the DEEM-FCID into the food categories "water, direct, all sources" and "water, indirect, all sources." These EDWCs have not been updated since the last dietary assessment, as this petition will not revise the U.S. use pattern nor impact previous drinking water concentrations.

For the acute dietary assessment, the recommended drinking water concentration of 1.5 ug/L was used.  For the chronic dietary assessment, the recommended concentration of 1.15 ug/L was used.  Both drinking water concentrations were provided using PRZM-EXAMS (Pesticide Root Zone Model  -  Exposure Analysis Modeling System).  The drinking water models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

Table 5.3.  Estimated Drinking Water Concentrations for Use in the Dietary Exposure and Risk Assessments.
                                 Use and Model
                              Acute EDWCs (ug/L)
                             Chronic EDWCs (ug/L)
Surface Water:
PRZM-EXAMS
                                      1.5
1.15 (non-cancer)

0.662 (cancer)

       Dietary Risk Assessment

       Description of Residue Data Used in Dietary Assessment

Acute probabilistic, and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted for emamectin using the DEEM-FCID Version 3.16. This software uses 2003-2008 food consumption data from the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).  

The highly refined acute probabilistic exposure assessment inputs rely upon percent crop treated (PCT) data, Pesticide Data Program (PDP) monitoring data when available, highest average field trial (HAFT) data for the proposed use and existing commodities without appropriate PDP data and HED's 2018 default processing factors.  For hog meat, a tolerance level residue was assumed.  For all other livestock commodities, anticipated residue values were used.  For all PDP inputs, point estimates were used, as PDP data indicate that no detectible residues were found in any registered commodities. Data were translated from representative commodities to the non-representative commodities according to HED's recommendations for translating monitoring data (03/15/2018)

The highly refined chronic dietary exposure assessment inputs rely upon PCT data, average PDP data when available, field trial average residues for the proposed use and existing commodities without PDP data, and HED's 2018 default processing factors.  For hog meat, the tolerance value is used for the residue concentration.  For all other livestock commodities, anticipated residue values are used.  Data were translated from representative commodities to the non-representative commodities according to HED's recommendations for translating monitoring data (03/15/2018)

       Percent Crop Treated Used in Dietary Assessment

PCT values were incorporated directly into the residue distribution files for the acute assessment, and into the food residue concentrations for the chronic assessment.  The PCT values used in the assessment were calculated August 15, 2016.  

Specific values used in the acute assessment for maximum PCT are: 10% almonds, 20% apples, 20% broccoli, 40% brussels sprouts, 25% cabbage, 20% cauliflower, 40% celery, 10% chicory, 2.5% cotton, 20% lettuce, 20% pears, 15% peppers, 2.5% pistachios, 10% spinach, 20% tomatoes, and 2.5% walnuts. However, for commodities where PDP data are available, the PDP distributions were relied upon instead of using percent crop treated inputs.

Specific values used in the chronic assessment for average PCT are: 2.5% almonds, 10% apples, 5% broccoli, 20% brussels sprouts, 10% cabbage, 5% cauliflower, 20% celery, 5% chicory, 10% lettuce, 5% pears, 5% peppers, 2.5% pistachios, 5% spinach, 15% tomatoes, 2.5% walnuts.  However, for commodities where PDP data are available, the average PDP data were relied upon instead of using PCT inputs.

        Acute Dietary Risk Assessment

Acute dietary exposure to emamectin at the 99.9[th] percentile contributes 15% of the aPAD for the general U.S. population, and 30% of the aPAD for children 1-2 years of age, the most highly exposed population subgroup.

       Chronic Dietary Risk Assessment

Chronic dietary exposure to emamectin contributes 1.6% of the cPAD for the general U.S. population, and 3.8% of the aPAD for children 1-2 years of age, the most highly exposed population subgroup.

       Cancer Dietary Risk Assessment

Based upon the cancer classification of "not likely to be carcinogenic to humans," a separate cancer assessment was neither required nor conducted for emamectin.

       Summary Table

Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Emamectin.
                              Population Subgroup
                                 Acute Dietary
                             (99.9[th] Percentile)
                                Chronic Dietary
                                        
                         Dietary Exposure (mg/kg/day)
                                    % aPAD*
                               Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
General U.S. Population
                                   0.000 376
                                       15
                                    0.000040
                                      1.6
All Infants (<1 year old)
                                   0.000 591
                                       24
                                    0.000087
                                      3.5
Children 1-2 years old
                                    0.000750
                                       30
                                    0.000096
                                      3.8
Children 3-5 years old
                                    0.000556
                                       22
                                    0.000071
                                      2.9
Children 6-12 years old
                                    0.000514
                                       21
                                    0.000045
                                      1.8
Youth 13-19 years old
                                    0.000216
                                      8.6
                                    0.000029
                                      1.2
Adults 20-49 years old
                                    0.000219
                                      8.8
                                    0.000036
                                      1.4
Adults 50-99 years old
                                    0.000235
                                      9.4
                                    0.000036
                                      1.4
Females 13-49 years old
                                    0.000218
                                      8.7
                                    0.000035
                                      1.4
*The subpopulation(s) with the highest risk estimates are bolded.
%aPAD and %cPAD are rounded to 2 significant figures.
 
 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed residential uses of emamectin that would result in residential exposures at this time. Emamectin is primarily registered for agricultural or non-residential use sites. While emamectin is registered as a crack and crevice RTU gel bait for use in and around residential areas, residential exposure is expected to be negligible. Therefore, a residential exposure assessment was not previously required nor conducted. As a result, there are no residential risk estimates recommended for use in the aggregate risk assessment for emamectin.

 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

There are no residential exposures for emamectin; therefore, aggregate exposure and risk estimates are equivalent to the dietary exposure and risk estimates as described in Section 5 and are not of concern.

 Non-Occupational Spray Drift Exposure and Risk Estimates
 
Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for emamectin. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency's Spray Drift website for more information). The Agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.  The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non-occupational exposure to drift.

 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk Estimates 

Volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (FIFRA SAP) in December 2009, and received the SAP's final report on March 2, 2010 (http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2009-0687-0037).  The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219).  
During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for emamectin.

 Cumulative Exposure/Risk Characterization

The Agency is required to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. In 2016, EPA's Office of Pesticide Programs released a guidance document entitled Pesticide Cumulative Risk Assessment: Framework for Screening Analysis [https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/pesticide-cumulative-risk- assessment-framework]. This document provides guidance on how to screen groups of pesticides for cumulative evaluation using a two-step approach beginning with the evaluation of available toxicological information and if necessary, followed by a risk-based screening approach.  This framework supplements the existing guidance documents for establishing common mechanism groups (CMGs) and conducting cumulative risk assessments (CRA)  The Agency has utilized this framework for abamectin and determined that abamectin along with emamectin form a candidate CMG of the avermectin macrocyclic lactones. This group of pesticides is considered a candidate CMG because they share characteristics to support a testable hypothesis for a common mechanism of action and there is sufficient toxicological data to suggest a common pathway. However, there is not adequate data to establish those key events in a pathway as described in the mode of action/adverse outcome pathway (MOA/AOP) framework (e.g., lack of dose or temporal concordance of proposed key events).

In 2019, the Agency conducted a screening-level cumulative exposure analysis consistent with the guidance described in the cumulative screening framework (L. Bacon, et al., D451451, 08/07/2019).  The screening-level cumulative assessment for the avermectin macrocyclic lactones, abamectin, and emamectin indicated that cumulative aggregate dietary and residential exposures for abamectin and emamectin were below the Agency's LOC. 

Based upon updated use information (i.e., new uses), the Agency has updated its screening-level cumulative exposure analysis for the avermectin macrocyclic lactones, including abamectin and emamectin (B. Davis, et al., D461596, 06/11/2021).  This updated screening-level cumulative exposure assessment for the avermectin macrocyclic lactones, abamectin and emamectin, indicated that that cumulative aggregate dietary and residential exposures for abamectin and emamectin were below the Agency's LOC.

 Occupational Exposure/Risk Characterization

Emamectin is proposed for new use on soybeans.  Application methods, maximum application rates, and use sites are summarized in Section 3.3 and Table 3.3.1.  Based on application rate and label information, occupational handler exposure is expected to occur for short- (1 to 30 days) and intermediate-term (1 to 6 months) durations during mixing, loading, applying, and other handling activities.  Additionally, there is a potential for short- and intermediate-term occupational exposure during occupational post-application activities.  For both dermal and inhalation exposures the same endpoint and POD were selected for short- and intermediate-term durations, and therefore, short-term exposure and risk estimates are considered to be protective of intermediate-term exposure and risk estimates. 

 Short-/Intermediate Occupational Handler Exposure and Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task.  Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed use. The quantitative exposure/risk assessment developed for occupational handlers is based on the exposure scenarios summarized in Table 11.1.1. 

Occupational Handler Exposure Data and Assumptions 
A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor are detailed below on an individual basis. 
 
Application Rate:  The application rates for the proposed use is described in Table 3.3.1. 
 
Unit Exposures:  It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant-submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures", are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website.  
 
Area Treated or Amount Handled: The inputs for area treated or amount handled are based on information in ExpoSAC Policy 9.1. 

Exposure Duration: HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term.  Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site.  For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one-month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region). For emamectin, based on the proposed use, short- and intermediate-term exposures are expected.  Additionally, since the same endpoint and POD were selected for short- and intermediate-term durations, short-term exposure and risk estimates are considered to be protective of intermediate-term exposure and risk.

Personal Protective Equipment: Estimates of dermal and inhalation exposure were calculated and presented for coveralls plus label-required PPE (i.e., chemical-resistant gloves, and protective eyewear). The emamectin product labels direct mixers, loaders, applicators, and other handlers to wear baseline attire (i.e., long-sleeved shirt, long pants, shoes plus socks and no respirator), coveralls and PPE including chemical-resistant gloves, chemical-resistant apron, and protective eyewear. 

Combining Exposures/Risk Estimates
Dermal and inhalation exposures were combined in this assessment since the toxicological PODs are based on the same effects. Dermal and inhalation risk estimates were combined using the following formula:

Total MOE = Point of Departure (mg/kg/day) / (Combined dermal + inhalation dose (mg/kg/day))

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates 
For occupational handlers, there are no combined dermal and inhalation risks of concern using label specified PPE (MOEs are >= LOC of 100). Combined occupational handler dermal and inhalation MOEs ranged from 200 to 27,000. 

Occupational handler exposures and risk assessment data are summarized in Table 11.1.1.

Table 11.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Emamectin Benzoate. 
                               Exposure Scenario
                                Crop or Target
                               Unit Exposure[1]
                                  (μg/lb ai)
                             Max 
App. Rate[2] 
                   Area Treated or 
Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                     Total

                                    Dermal
                                     [PPE]
                                  Inhalation
                                     [PPE]

                              Dose[4] (mg/kg/day)
                                    MOE[5]
                                   LOC = 100
                              Dose[6] (mg/kg/day)
                                    MOE[7]
                                   LOC = 100
                                    MOE[8]
                                   LOC = 100
                                 Mixer/Loader
                           Liquid, Aerial, Broadcast
                                    Soybean
                          (Field, crop high acreage)
                                     29.1
                                     DL/G
                                     0.219
                                     No-R
                                     0.015
                                    lb ai/A
                                     1,200
                                     acres
                                   0.000118
                                     2,100
                                   0.0000493
                                     5,100
                                     1,500
                         Liquid, Groundboom, Broadcast
                                       
                                     29.1
                                     DL/G
                                     0.219
                                     No-R
                                     0.015
                                    lb ai/A
                                      200
                                     acres
                                   0.0000196
                                    13,000
                                  0.00000821
                                    30,000
                                     9,100
                                  Applicator
             Spray
 (all starting formulations), Aerial, Broadcast
                                    Soybean
                          (Field, crop high acreage) 
                                     2.08
                                      EC
                                    0.0049
                                      EC
                                     0.015
                                    lb ai/A
                                     1,200
                                     acres
                                  0.00000842
                                    30,000
                                   0.0000011
                                    230,000
                                    27,000
           Spray
 (all starting formulations), Groundboom, Broadcast
                                       
                                     12.6
                                     DL/G
                                     0.34
                                     No-R
                                     0.015
                                    lb ai/A
                                      200
                                     acres
                                  0.00000851
                                    29,000
                                   0.0000128
                                    20,000
                                    12,000
                                    Flagger
           Spray 
(all starting formulations), Aerial, Broadcast 
                                    Soybean
                          (Field, crop high acreage)
                                     10.6
                                     DL/G
                                     0.202
                                     No-R
                                     0.015
                                    lb ai/A
                                      350
                                     acres
                                   0.0000125
                                    20,000
                                   0.0000133
                                    19,000
                                     9,700
                           Mixer/Loader/Applicator 
         Liquid, Mechanically-pressurized Handgun, Broadcast (foliar)
                                    Soybean
                          (Field, crop high acreage)
                                     1,360
                                     DL/G
                                     8.68
                                     No-R
                                     0.003
                                   lb ai/gal
                                     1,000
                                    gallons
                                   0.000918
                                      270
                                   0.000325
                                      770
                                      200
           Liquid, Mechanically pressurized Handgun, Ground-Directed
                                       
                                     1,360
                                     DL/G
                                     8.68
                                     No-R
                                     0.003
                                   lb ai/gal
                                     1,000
                                    gallons
                                   0.000918
                                      270
                                   0.000325
                                      770
                                      200
1  Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table  -  Update March 2020 " (https://www.epa.gov/pesticide-science-and-assessing-pesticide-risks/occupational-pesticide-handler-exposure-data); Level of PPE: No-R = no respirator (baseline inhalation PPE). DL/G = double layer clothes with gloves (label required PPE).  EC = engineering controls
2	Based on the proposed end-use product label [EPA Reg. No. 100-903]. See Table 4.1. 
3	Exposure Science Advisory Council Policy #9.1. 
4	Dermal Dose = Dermal Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated or Amount Handled (A/day)xDAF (1.8%) / BW (80 kg).
5	Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).
6	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated or Amount Handled (A /day) / BW (80 kg).
7	Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).
8	Total MOE = NOAEL (mg/kg/day) / Dermal Dose + Inhalation Dose

       Post-Application Exposure and Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

       Dermal Post-Application Exposure and Risk Estimates

Based on the proposed use patterns, short- and intermediate-term post-application dermal exposures to workers re-entering treated areas is possible.
  
Dislodgeable Foliar Residues (DFR): A chemical-specific DFR study for the use of emamectin on celery (MRID 44007903) has been previously found acceptable and determined appropriate for use in risk assessment (T. Swackhammer, HED, 11/23/01, D279209). 

In the study, an EC formulation containing 2.15% emamectin was applied by groundboom at a single rate of 0.015 lbs ai/A to celery in California. Two applications were made, with an interval of 7 days between applications. Following the second application, four replicate samples were taken from the treated plot at each sampling interval. Leaf punch samples were collected at 24 hours before sampling, then at 2-4 hours and 1, 3, 7 and 14 days after the second application. All but one replicate was below the level of detection by day 14. 

The secondary review results from 2001 (i.e., the raw residue data adjusted based on field fortification recoveries) were re-analyzed by HED via regression analysis of total corrected residues. The predicted Day 0 DFR value of 0.003 (ug/cm[2]) was chosen for risk assessment. The residue value did not need to be adjusted for differences in application rate for the purposes of the post-application occupational exposure and risk assessment. Further details and results are provided in the recently completed ORE assessment for the registration review of emamectin (L. Bacon, 08/18/17, D438859).

Occupational Post-Application Non-Cancer Dermal Risk Estimates
There are no occupational post-application dermal risk estimates of concern (MOEs >= LOC 100) on the day of application (12 hours following the end of the application on Day 0).

Table 11.2.1.1.  Occupational Post-application Non-Cancer Exposure and Risk Estimates for Emamectin.
                                   Crop/Site
                                  Activities
                             Transfer Coefficient
                                  (cm[2]/hr)
                                    DFR[1]
                                  (ug/cm[2])
                                  Dermal Dose
                                (mg/kg/day)[2]
                                    MOE[3]
                                   LOC = 100
                                    Soybean
                                 Hand Weeding
                                      70
                                  2.7x10[-3]
                                  3.4x10[-7]
                                    48,000
                                       
                                   Scouting
                                     1,100
                                       
                                  5.3x10[-6]
                                    750,000
1 Chemical-specific dislodgeable foliar residue (DFR) study (MRID: 44007903).
2 Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hr/day x dermal absorption (1.8%)] ¸ BW (80 kg).
3 MOE = POD (0.25 mg/kg/day) / Daily Dermal Dose.  

Restricted-Entry Interval
Emamectin is classified as Toxicity Category III via the dermal route, Toxicity Category IV for skin irritation potential, and Toxicity Category I for acute eye irritation. It is not a skin sensitizer. Short- and intermediate-term post-application risk estimates were not of concern on Day 0 for all post-application activities.  However, under 40 CFR 156.208 (c) (2), ai's classified as Category I for acute, eye irritation or primary skin irritation are assigned a 48-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is not adequate to protect agricultural workers from post-application exposures to emamectin, and a 48-hour REI is recommended.

 Inhalation Post-Application Exposures and Risk Estimates

There are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009, and received the SAP's final report on March 2, 2010 (http://archive.epa.gov/scipoly/sap/meetings/web/pdf/120309meetingminutes.pdf). The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (https://www.regulations.gov/contentStreamer?documentId=EPA-HQ-OPP-2014-0219-0003&disposition=attachment&contentType=pdf). During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for emamectin.

In addition, the Agency is continuing to evaluate the available post-application inhalation exposure data generated by the ARTF.  Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers (Table 11.1.1.).  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.

12.0 	References

J. Troy Swackhammer, 11/23/2001, D279209. Review of the Merck Research Laboratories study, "Dissipation of Dislodgeable MK-0244 0.16 EC Residues from Foliage of Celery when Applied with Non-Ionic Surfactant by Ground Equipment."

J. Leshin, 03/12/2015, TXR # 0051377. Emamectin: Summary of Hazard and Science Policy Council (HASPOC) Meeting on February 19, 2015:  Recommendations on the Need for a Subchronic Inhalation Toxicity Study and if so, which species/strain.

L. Bacon, 08/18/2017, D438859. Emamectin (Emamectin Benzoate). Occupational and
Residential Exposure Assessment in Support of Registration Review.

L. Bacon, et al., 08/07/2019, D451209. Avermectin Macrocyclic Lactones, Abamectin and Emamectin. Cumulative Screening Risk Assessment.

L. Bacon, et al., 08/07/2019, D451451. Avermectin Macrocyclic Lactones, Abamectin and Emamectin. Cumulative Screening Risk Assessment.

J. Smith, Pending, D461599. Emamectin Benzoate Acute Probabilistic, and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Petition of a Tolerance for Residues in/on Soybeans.  
J. Smith, Pending, D461598. Emamectin Benzoate.  Petition for the Establishment of a Permanent Tolerance for Residues in/on Soybeans.  Summary of Analytical Chemistry and Residue Data.
B. Davis, et al., 06/11/2021, D461596. Avermectin Macrocyclic Lactones, Abamectin and Emamectin. Cumulative Screening Risk Assessment.

Appendix A.  Toxicology Profile and Executive Summaries

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.500) for food use for emamectin are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.
	
Table A.1. Toxicology Data Requirements for Emamectin
                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Acute Eye Irritation	
870.2500    Acute Dermal Irritation	
870.2600    Skin Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    90-Day Oral Toxicity in Rodents	
870.3150    90-Day Oral Toxicity in Nonrodents	
870.3200    21/28-Day Dermal Toxicity	
870.3250    90-Day Dermal Toxicity	
870.3465    90-Day Inhalation Toxicity	
                                      yes
                                      yes
                                      yes
                                      CR
                                      CR
                                      yes
                                      yes
                                      yes
                                       
                                   waived[a]
870.3700a  Prenatal Developmental Toxicity (rodent)	
870.3700b  Prenatal Developmental Toxicity (nonrodent)	
870.3800    Reproduction and Fertility Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (nonrodent)	
870.4200a  Carcinogenicity (rat)	
870.4200b  Carcinogenicity (mouse)	
870.4300    Combined Chronic Toxicity/Carcinogenicity	
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Bacterial Reverse Mutation Test	
870.5300    Mutagenicity -- Mammalian Cell Gene Mutation Test	
870.5xxx    Mutagenicity -- Structural Chromosomal Aberrations	
870.5xxx    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Developmental Neurotoxicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.7485    Metabolism and Pharmacokinetics	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      CR
                                      yes
                                      yes
                                     yes 
                                      yes
   a HASPOC Report: TXR 0051377, 03/12/2015. 
   
A.2.	Toxicology Data Requirements

Acute Toxicity Profile - Emamectin Benzoate Technical  
                                   Guideline
                                  Study Type
                                     MRID
                                    Results
                               Toxicity Category
870.1100
Acute oral - Rats
                                   49212307
LD50 = 151 mg/kg (F)
                                      II
870.1200
Acute dermal  -  Rats
                                   49212308
LD50 = 2167 mg/kg (M & F)
                                      III
870.1300
Acute inhalation - Rats
                                   50599207
LC50 Combined = 0.94 mg/L
LC50 Male > 1.0 and < 2.0 mg/L
LC50 Female > 0.53 and < 1.0 mg/L
                                      III
870.2400
Acute eye irritation - Rabbits
                                   49212310
Corneal opacity at 24 hours, persisting through day 21.
                                       I
870.2500
Acute dermal irritation - Rabbits
                                   49212311
No dermal irritation
                                      IV
870.2600
Skin sensitization  -  Guinea pigs (Maximization)
                                   49212312
Not a dermal sensitizer
                                      --
                                       
Skin sensitization - Guinea pigs (Buehler)
                                   50599210
Not a dermal sensitizer
                                      --
                                       
Skin sensitization  -  Mice (LLNA)
                                   47002110
Not a dermal sensitizer
                                      --

Table A.2.2. Repeated Dosing and Other Studies on Emamectin
                                 Guideline No
Study Type
MRID No. (Year)/ Classification/Doses
Results
Acute dermal toxicity study (Not a LD50 study)

Acute dermal tox.- rabbits 
MK-0243 0.16 EC formulation
42743611 (1991)
Acceptable 
0, 0.5, 1.0, & 2.0 mg/kg
(2 groups: 4 hr exposure & 24 hr exposure) with collar on the test animals.
4 hr. exposure
NOAEL = 2.0 mg/kg/day (highest dose tested,  HDT).

24 hr. exposure
NOAEL = 0.5 mg/kg/day.
LOAEL = 1.0 mg/kg/day one rabbit had neuron lesion occurred in cerebellar peduncle. Similar effect was not seen in 2.mg/kg group.

Acute dermal tox.  -  rabbits (24 hrs exposure with collar on all test animals)  
43850111 (1995)
Acceptable 
0, 10.4, 21.0, or 42.1 mg/kg  MK-0244  0.16 EC
NOAEL = 42.1 mg/kg. No treatment-related systemic toxicity was seen in any dosed animals. 
The acute dermal LD50 > 2,000 mg/kg for MK-0244
Subchronic toxicity studies
870.3100

13-Wk oral-CD rats
42794201 (1992)
Acceptable
0, 0.5, 2.5, and 12.5 mg/kg/day. 12.5 mg/kg/day was reduced to 8 mg/kg/day at wk 3 then to 5.0 mg/kg/day  at wk 9.
Systemic Toxicity NOAEL = 2.5 mg/kg/day; Systemic Toxicity LOAEL = 5 mg/kg/day based on moribundity, tremors, hindlimb splaying, urogenital staining, histological changes in brain and spinal cord, sciatic and optic nerves and skeletal muscles in males, emaciation, reduced body weight and reduced food consumption in both sexes.

13-Wk oral-CD-1 mice
42743621 (1992)
Acceptable
0, 0.5, 4.5, & 15.0 mg/kg/day. An additional group received a time weighted dose 5.4 mg/kg/day

NOAEL = 5.4 mg/kg/day.
LOAEL = 15.0 mg/kg/day based on mean body weight decrease and decreased in cumulative body weight gain.
870.3150

90-Day oral  -  dogs  (gavage)
42743623 (1992)
Acceptable
0, 1.0, or 1.5 mg/kg/day for the first 2 wks then reduced to 0.25, 0.5, or 1.0 for the rest of the study.

NOAEL = 0.25 mg/kg/day.
LOAEL = 0.50  mg/kg/day based skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males.

14-Wk oral-dogs (gavage)
43868103 (1994)
Acceptable
0.5, 1.0, or 1.5 mg/kg/day for 2 wks for mid and high dose groups and for  3 wks for low dose, then they were  reduced to 0.25, 0.5, or 2.0 mg/kg/day. The time weighted doses were 0.29. 0.58, or 0.1.08 mg/kg/day.

NOAEL = 0.29 mg/kg/day.
LOAEL = 0.58 mg/kg/day based on microscopic lesions in the brain (multifocal white matter degeneration), atrophy of skeletal muscle, and spinal cord lesions. 
870.3200
21-Day dermal tox-rabbits 
MK-0244  0.16 EC formulation 
42743625 (1992
Acceptable 
0, 50, 100, or 250 mg/kg/day (6 hrs/day)
Systemic tox. NOAEL = 100 mg/kg/day.
LOAEL = 250 mg/kg/day based on axonal degeneration of the sciatic nerve. 

Application site irritation was seen in all treated rabbits.

22-Day dermal tox.  -  rabbits 
MK-0244  0.16 EC  formulation 
44007902 (1996)
Acceptable
0, 250, 500, or 1,000 mg/kg/day (6 hrs/day)
NOAEL = 1,000 mg/kg/day (highest dose tested [HDT]). No systemic toxicity was seen in any dose groups. 
Note: The test animals were collared to prevent oral ingestion of the test material. 
870.3465
5-Day inhalation tox.
49395601(2014)
Acceptable/non-guideline
0, 1, 3, 10, or 30 ug/L
Systemic tox: NOAEL =10 ug/L.
LOAEL = 30 ug/L base on ↓ body weight, tremors, hunched posture, rolling gaits, and abnormal vocalizations.

Portal of entry effects: NOAEL= 3 ug/L.
LOAEL = 10 ug/L based on squamous metaplasia and/or inflammatory cell infiltration in the larynx and nasal cavity, and olfactory epithelium degeneration in the nasal cavity.

90-day inhalation 
Recommended to be waived (HASPOC report:  TXR 0051377, 03/12/2015).
Chronic toxicity studies
870.4100
1-Year oral tox.  -  dogs (gavage) 
42743624 (1992)
Acceptable
0, 0.25, 0.5, 0.75, or 1.0 mg/kg/day (4 dogs/sex/dose)
NOAEL = 0.25 mg/kg/day.
LOAEL= 0.5 mg/kg/day based on axonal degeneration in the pons, medulla, and peripheral nerves (sciatic, sural, and tibial); whole body tremors; stiffness of the hind legs, spinal cord axonal degeneration, and muscle fiber degeneration.

Chronic oral tox.  -  rats (dietary)
 (1 year)
42868902 (1992)
Acceptable
0, 0.1, 1.0, 2.5 mg/kg (initially females received 5.0 mg/kg then reduced to 2.5 mg/kg at wk 18 due to excessive toxicity )
 
NOAEL = 1.0 mg/kg/day.
LOAEL = 2.5 mg/kg/day, based on increased incidence of neuronal degeneration in the brain and spinal cord, decreased rearing, and an increased incidence of animals with low arousal.
870.4200
Carcinogenicity study-mice (CD-1)
(dietary)
43868105 (1994)
Acceptable
0, 0.5, 2.5, or 12.5 mg/kg/day (The highest dose was reduced to 7.5 and 5.0 mg/kg/day for males at wk 9 and females at wk 3, respectively)

NOAEL = 2.5 mg/kg/day.
LOAEL = 5.0 mg/kg/day for males and 7.5 mg/kg/day for females based on increased mortality, decreased weight gain, tremors, sciatic nerve degeneration, and increased incidence of severity of infections. 

No treatment-related increase in tumor incidence was seen.

Combined Chronic/ 
Carcinogenicity-Rat

43868104 (1994)
Acceptable
0, 0.25, 1.0, 2.5/5.0 mg/kg  (Initially, high dose level was 5.0 mg/kg; it was reduced to 2.5 mg/kg on wk 6 for males and wk 10 for females due to tremors seen in another study  at 5 mg/kg). 
NOAEL = 1.0 mg/kg/day.
LOAEL = 2.5/5.0 mg/kg/day[1] based on marked neural degeneration in the brain and spinal cord of both sexes, brain white matter degeneration in males, and on decreased body weight, body weight gain, and food efficiency in males. 

No treatment-related increase in tumor incidence was seen.
Developmental and Reproduction Studies
870.3700
Developmental tox.  - rat
42743632 (1992)
Acceptable
0, 2, 4, or 8 mg/kg/day

42743631 (range finding study)

Maternal Toxicity NOAEL = 2 mg/kg/day. Maternal Toxicity LOAEL = 4 mg/kg/day based on a significant trend towards decreased body weight gain during the dosing period.

Developmental Toxicity NOAEL = 4 mg/kg/day. Developmental Toxicity LOAEL = 8 mg/kg/day based on altered growth and an increased incidence of supernumerary rib.

Developmental tox.- rabbits
42743636 (1992)
Acceptable 
0, 1.5, 3, or 6 mg/kg/day

42743635 (Range finding study)
Maternal Tox. NOAEL = 3 mg/kg/day. Maternal Tox. LOAEL = 6 mg/kg/day based on a significant trend towards decreased body weight gain during dosing period and increased clinical signs (mydriasis and decreased pupillary reaction).

Developmental Tox. NOAEL =6 mg/kg/day (HDT).

870.3800
2-Gen. reproduction study - rats
42851511 (1993)
Acceptable 
0, 0.1, 0.6, or 3.8/1.8 mg/kg/day (F0 & F1a females initially received 3.8 mg/kg, but it was reduced to 1.8 mg/kg/day on GD 0 following the second cohabitation of F0 females).
Parental  NOAEL = 0.6 mg/kg/day.
Parental LOAEL = 1.8 mg/kg/day based on neuronal degeneration in the brain and spinal cord in both sexes and generations.

Reproductive NOAEL = 0.6 mg/kg/day. Reproductive LOAEL = 1.8 mg/kg/day based on decreased fecundity and fertility indices.

Offspring NOAEL = 0.6 mg/kg/day.
Offspring LOAEL = 1.8 mg/kg/day based on tremors and hind limb extension in the offspring of both generations, neuronal degeneration in the brain and spinal cord.

Mutagenicity Studies
870.5100

870.5100
Gene Mutation - Salmonella
MK-0243 and L-660,599; L-657,831; L-695,638; L-930,905 (photometabolites of MK-0244)

42743637
42851514
42851515
42851516
42851517
Negative for the induction of reverse gene mutation.
870.5300

Gene Mutation in Cultured V-79 Chinese Hamster Lung Cells
MK-0243
42743638
Negative for the induction of forward gene mutations in Chinese hamster lung fibroblast cells up to a severely cytotoxic nonactivated dose of 0.01 mM or a severely cytotoxic S9-activated dose of 0.04 mM.

870.5385

Structural Chromosome Aberration-in vivo mouse bone marrow
MK-0244
42851513
Negative for the induction of chromosome aberrations in the bone marrow cells of male CD-1 mice.
Neurotoxicity Studies
870.6200
Acute neurotox. study-rats (gavage)
42743618 (1992)
Acceptable
0, 27.4, 54.8 or 82.2 mg/kg (range finding study)

NOAEL was not established. LOAEL= 27.4 mg/kg/day (lowest dose tested, LDT); clinical signs (tremors, ataxia, loss of righting reflex, and reduced activities) and as histological lesions in the brain, spinal cord and sciatic nerve occurred at all doses tested.

Acute neurotox. study- rats 
(gavage)
42743619 (1992)
Supplementary
0, 0.5, 2.5, 5.0, 10.0, or 25.0 mg/kg/day

NOAEL = 5.0 mg/kg/day.
LOAEL = 10 mg/kg/day based on tremors irritability. At 25 mg/kg, all rats had tremor and neuronal lesions (white matter degeneration of the brain, degeneration of the spinal cord and sciatic nerve.

Subchronic neurotox.  - SD rats
(dietary) (14 day)
42743628 (1992)
Acceptable 
0, 0.25, 1.0, or 5.0 mg/kg/day 
NOAEL = 1.0 mg/kg/day.
LOAEL = 5.0 mg/kg/day based on tremors, posture, rearing, excessive salivation, fur appearance, gait, strength, mobility and righting reflex. Neuronal vacuolation in brain and spinal cord; degeneration of nerve fiber in spinal cord and sciatic nerves. Skeletal muscle atrophy. Male rats appeared to be more affected than females.

Comparative neurotox.  -  dogs
(gavage) (14 days)
42743626 (1992)
Acceptable
2 dogs/sex/compound were given 1.5 mg/kg/day of testing compound.
The following effects were seen with different compounds:
                                      Tremors           Mydriasis 
MK-0243[a]                         2/4                  0/4 
L-682,901                          0/4                  0/4
L-653,648                          0/4                  4/4
L-653,649                          2/4                  3/4
L-655. 372                         3/4                  0/4   
Histopathology findings were not seen in L-682, 901 and L-653,648 treated dogs. Neuronal degeneration of the brain, spinal cord, and sciatic nerves were seen in dogs treated with MK-0234, L-653, 649, and L-655,372.

15-Day neurotox.  - CD-1 mice
(dietary)
42743629 (1992)
Acceptable
0,  0.6, 1.2, & 2.0 mg/kg/day
NOAEL = 2.0 mg/kg/day (HDT). No characteristic neuronal lesions in the brain, spinal cord or sciatic nerve in mice of high dose group. 

15-Day neurotox.- CF-1 mice  (dietary)
(L-660,599: 4"-epi-(N-formyl-N-methyl)- amino4"-deoxy-avermectin B1
42851503 (1993)
Acceptable
0, 0.05, 0.075, 0.10, or 0.30 mg/kg/day 

NOAEL = 0.075 mg/kg/day.
LOAEL = 0.10 mg/kg/day based on tremors observed beginning on day 3, ptosis, hunched posture, decreases in body weight and food consumption as well as degeneration of the sciatic nerve. At 0.3 mg/kg, tremors were seen on day 2 and followed by hunched posture and ptosis, ataxia, and labored breathing.

15-Day neurotox.  - CF-1 mice (dietary)
(L695-638: 4"-deoxy-4"-epi-methylamino- avermectin B1a-delta-8,9-isomer); photoproduct of MK-0244[b]

42851504 (1993)
Acceptable 
0, 0.05, 0.075, 0.10, & 0.30 mg/kg/day
NOAEL = 0.30 mg/kg/day (HDT). 
No treatment-related effects were seen in any dose groups.

15-Day  neurotox.  - CF-1 mice (dietary)
(L695-638: 4"-deoxy-4"-epi-methylamino- avermectin B1a-delta-8,9-isomer); photoproduct of MK-0244
42851505(1993)
Acceptable
0, 0.05, 0.075, 0.10, & 0.30 mg/kg/day

NOAEL = 0.243 (HDT). The targeted dose was 0.30 mg/kg/day. No treatment-related effects were seen in any dose groups.

Female mice only to repeat the exposure dose levels of MRID 42851504 because female mice received 15% less than the targeted dose in that study.

15-Day neurotox.- CF-1 mice (dietary) (L-660,599; formyl methylamino plant metabolite of MK-0244 )

42851506 (1993)
Acceptable 
0, 0.10, 0.30, 0.90 mg/kg/day
LOAEL < 0.1 mg/kg/day LDT) based on tremors, hunched posture and piloerection. However no treatment-related findings in histopathology were present.

15-Day neurotox.- CF-1 mice (gavage) L-930,905; a com-plex mixture of polar MK-244 photodegradates)    
42851507 (1993)
Acceptable 
0, 3, 6, 12, or 18 mg/kg/day
NOAEL = 18 mg/kg/day (HDT).
No treatment-related effects were found.

16-Day neurotox.-CF-1 mice  (dietary)
MK-0243
42743630 (1992)
Acceptable
0, 0.05, 0.10, 0.30, or 0.90  mg/kg/day
NOAEL = 0.1 mg/kg/day.
LOAEL = 0.30 mg/kg/day based on tremors, decreased activity, and moribund sacrifice starting on day 2. However, no histopathology findings were present. 
 

15-Day neurotox.- CF-1 mice (dietary)
Formyl amino derivative of MK-0244

42868901 (1991)
Acceptable 
0, 0.050, 0.075, 0.100,  & 0.300 mg/kg/day
NOAEL = 0.07 mg/kg/day.
LOAEL = 0.23 mg/kg/day based on decreased body weight gain.

870.6300
Develop. Neurotox.-rats (SD) (gavage 
for maternal animals; no direct dosing for neonates)
MK-0244
42851508 (1993)
Acceptable
0, 0.1, 0.6, 3.6/2.5 mg/kg/day (3.6 mg/kg was reduced to 2.5 mg/kg between GD 17 and 20)

Maternal NOAEL= 3.6/2.5 mg/kg/day (HDT).
Develo. Neurotox. NOAEL = 0.10 mg/kg/day. 
 Develo. Neurotox. LOAEL = 0.60 mg/kg/day based on the dose-related decrease in open field motor activity in females at postnatal day 17. 
870.7485

Metabolism  - rats
[ 14C] 4''deoxy-4'-epi-methylamino avermectin B1a benzoate,  (MAB1a)
42851523  &  42852524
(1993)
Acceptable 
Radiolabeled MAB1a benzoate is rapidly absorbed, distributed and excreted following oral and i.v. administration. The feces was the major route of excretion in oral and i.v. groups, while <1% of the administered dose was recovered in the urine 7 days post dosing. Tissue distribution and bioaccumulation appeared minimal. The metabolism of MAB1 a benzoate appears to involve primarily N-demethylation to AB1a. AB1a was the only metabolite detected in the feces while unmetabolized parent compound represented a large amount of the radioactivity.

Bioequivalence -Dog
MK-0243 
solvate vs. monohy-drate

42743641(1992)
Supplemental
The study demonstrated that MK-0243 benzoate MTBE solvate and MK-0243 benzoate monohydrate were bioequivalent in male dogs following oral administration as indicated by similar plasma levels for the two compounds.

Bioequivalence-Dog
MK-0243 benzoate vs. HCL salts
42743640 (1992)
Supplemental
The study demonstrated that benzoate and HCl salts are bioequivalent after oral administration in male beagle dogs.

870.7600
Dermal Absorption-Rhesus Monkey
43850113 (1994)
Dermal Absorption was approximated at 1.79% of the administered dose.

870.7800
Immunotoxicity study- CD-1 mice
48980301 (2012)
Acceptable/guideline
0, 10, 30, or 60 ppm (0, 1.7, 4.8, or 10.6 mg/kg/day expressed as free base)

Systemic toxicity NOAEL = 10.6 mg/kg/day (HDT).
Immunotoxicity: NOAEL = 10.6 mg/kg/day (HDT). No LOAEL was established.

A.3.	Data Demonstrating the Sensitivity of Beagle Dogs to the Effects of Abamectin and Emamectin

To illustrate the order of sensitivity to the effects of abamectin and emamectin in test animals that have fully functioning P-gp, the results of the subchronic (90-day) oral toxicity studies on emamectin with rats, CD-1 mice, and dogs were used for comparison. The data indicate that the effects produced in the dogs are qualitatively more severe and have a substantially lower LOAEL relative to those produced in the rats and CD-1 mice, as shown in the table below. Similar data on abamectin also demonstrate this order of sensitivity.

Table A.3.  Comparison of the results of subchronic (90-day) oral toxicity studies on emamectin
Test species
NOAEL (mg/kg/day)
LOAEL
                             Effects seen at LOAEL
Beagle dogs
0.25
0.50
Skeletal muscle atrophy and white matter multifocal degeneration in the brains of both sexes and white matter multifocal degeneration in the spinal cords of males.
Rats 
2.5 
5.0
Tremors, hindlimb splaying, urogenital staining, histological changes in brain and spinal cord, sciatic and optic nerves and skeletal muscles in males, emaciation, reduced body weight and reduced food consumption in both sexes, and moribundity,
CD-1 mice
5.4
15.0
Mean body weight decrease 
       
       

Appendix B.  Physical/Chemical Properties

Table X.1.  Physicochemical Properties of Emamectin
Parameter
Value
Reference
Melting point/range
141-146°C
47002103
pH (at 25°C)
6-7

Density
1.20 g/cm[3]

Water solubility 
(average of emamectin B1a + B1b at 21°C)
105 mg/L at pure water
101 mg/L at pH 5.0
93 mg/L at pH 7.0

No peaks were observed at pH 9.0.

Solvent solubility (at 25°C)
Toluene                       20.8 mg/mL
Cyclohexane               0.23 mg/mL
NMP                          576 mg/mL
Acetone	140 g/L
Dichloromethane     >500 g/L
Ethyl acetate	  81 g/L
Hexane	  77 g/L
Methanol	270 g/L
Octanol	  48 g/L
Toluene	                       26 g/L

Vapor pressure (at 21°C)
3.0 x 10[-8] torr or 3.0 x 10[-8] mmHg

Dissociation constant, pKa
4.2 (benzoic acid)
7.6 (methyl-amino)

Octanol/water partition coefficient
Shake Flask Method
Log Pow = 5.7 (emamectin B1a)
Log Pow = 5.2 (emamectin B1b)

UV/visible absorption (molar absorption coefficients at the absorbance maxima)
Neutral:	37,367 L/mol::cm at 245 nm
	22,584 L/mol::cm at 245 nm
Acidic: 	36,841 L/mol::cm at 245 nm
	22,131 L/mol::cm at 245 nm
Basic: 	28,952 L/mol::cm at 245 nm

No further absorption maximum between 280 and 750 nm was observed.

Appendix C.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from 
PHED 1.1; the AHETF database; and the ARTF database; are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.