Page 2 of 40 

Executive Summary 

The HED Registration Review Team has evaluated human health assessments for the insecticide 

emamectin benzoate to determine whether sufficient data are available and whether any updates 

are needed to support Registration Review. HED has considered the most recent human-health 

risk assessments for emamectin benzoate, updates to the toxicity, exposure, and usage databases, 

and current Agency science policy and risk assessment methodologies to determine the scope of 

work necessary to support Registration Review. 

Emamectin benzoate is a semi-synthetic avermectin, consisting of two active homologous 

compounds (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). 

 

Emamectin is registered for agricultural uses, as a tree injection use, and as a cockroach bait. 

Except for OptigardTM Cockroach Bait (EPA Reg. No. 100-1290), all registered emamectin enduse products are restricted use products (RUPs; restricted to use by professional certified 

operators [PCOs] only). There are no existing residential use sites. 

The toxicology database for emamectin benzoate is largely complete. However, an 

immunotoxicity study (OPPTS Guideline Number 870.7800) is now required for conventional 

pesticide registration (40 CFR Part 158). Additionally, a subchronic (28-day) inhalation toxicity 

study (OPPTS GLN 870.3465) is needed for a more accurate assessment of toxicity via the 

inhalation route, and for inhalation risk assessments for exposures associated with the existing 

use pattern. 

The nervous system is the main target of emamectin benzoate, with neuropathology detected in 

many studies and several species. The dose/response curve was very steep in several studies 

(most notably with CF-1 mice and dogs), with severe effects (morbid sacrifice and 

neuropathology) sometimes seen at the LOAELs. Although no increased sensitivity was seen in 

developmental toxicity studies in rats and rabbits, increased qualitative and/or quantitative 

sensitivity of rat pups was seen in the reproductive toxicity study and in the developmental 

neurotoxicity study. Review of acceptable oncogenicity and mutagenicity studies provide no 

indication that emamectin is carcinogenic or mutagenic. Emamectin is classified as “not likely 

to be carcinogenic to humans.” 

The 10X FQPA safety factor has been retained for chronic/long-term and intermediate-term 

assessments due to the steepness of the dose-response curve, severity of effects at the LOAEL 

(death and neuropathology), and the use of a short-term study for long-term risk assessment. 

(HED did not use a chronic study for the point of departure because the chronic studies were 

conducted in rats, dogs, and CD-1 mice. The 15-day study employed the CF-1 mice, which do 

not have the glycoprotein. As a result, the point of departure is protective of all population 

subgroups.) The steepness of the dose-response curve and the severity of the effects at the 

LOAEL also are the basis for HED retaining a 3X FQPA safety factor for acute assessments. A 

3X FQPA factor was judged to be adequate (as opposed to a 10X) for the following reasons: (1) 

A NOAEL was established in the 15-day neurotoxicity CF-1 mouse study used to determine the 

acute toxicity endpoint for risk assessment; (2) Although the effects of concern are seen after 
Page 3 of 40 

repeated dosing, the NOAEL here is used for a single exposure risk assessment; and (3) The 

most sensitive endpoint in the most sensitive species is selected. 

The dietary-exposure database is adequate to support the existing registrations. The most recent 

chronic dietary-exposure assessment was performed in conjunction with the July 2008 humanhealth risk assessment conducted by HED. However, a new dietary assessment may be required 

during Registration Review to incorporate potential changes to the emamectin benzoate 

estimated drinking water concentrations. 

There are currently no registered residential uses of emamectin benzoate. 

There is sufficient information available to assess occupational handler exposure to emamectin 

benzoate. Occupational handler exposure has been previously assessed for cotton, pome fruit, 

tree nuts, leafy vegetables (Brassica and non-Brassica), fruiting vegetables, turnip greens, 

tobacco, tree injection, and cockroach bait use. A new handler assessment will be needed if 

toxicity endpoints are revised or if revised guidelines/procedures are implemented. 

The tolerance expression for emamectin will have to be revised to be stated in the 40 CFR 

§180.505 according to HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner) 

as follows: 

40 CFR §180.505(a)(1)

“Tolerances are established for residues of emamectin, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only the combined residues of 

emamectin (a mixture of a minimum of 90% 4'-epi-methylamino-4'-deoxyavermectin B1a

and maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B1b), the associated 8,9-Z

isomers (8,9-ZB1a +8,9-ZB1b), or 4'-deoxy-4'-epi-amino-avermectin B1a and 4'-deoxy-4'-

epi-amino-avermectin B1b; 4'-deoxy-4'-epi-amino-avermectin B1a (AB1a); 4'-deoxy-4'-epi-

(N-formyl-N-methyl)amino-avermectin (MFB1a); and 4'-deoxy-4'-epi-(N-formyl)aminoavermectin B1a (FAB1a).” 

40 CFR §180.505(a)(2)

“Tolerances are established for residues of emamectin, including its metabolites and 

degradates, in or on the commodities in the table below. Compliance with the tolerance 

levels specified below is to be determined by measuring only the combined residues of 

emamectin (MAB1a +MAB1b) and the associated 8,9-Z isomers (8,9-ZB1a +8,9-ZB1b).” 

There are no Codex or Canadian maximum residue limits (MRLs). Mexico adopts US tolerances 

and/or Codex MRLs for its export purposes. 

Introduction 

Emamectin benzoate is a semi-synthetic avermectin, consisting of two active homologous 

compounds (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). 

Emamectin benzoate is an insecticide/miticide developed for the control of lepidopteran insects. 
Page 4 of 40 

Available mechanistic data indicate a neurotoxic mechanism of action, related to interference 

with gamma-aminobutyric acid (GABA)-mediated neurotransmission in mammals and 

glutamate-mediated neurotransmission in invertebrates. Emamectin benzoate may enter the 

environment through broadcast foliar applications to agricultural crops using ground or aerial 

equipment, tree injection, or use in commercial and industrial indoor areas as a cockroach bait. 

(The cockroach bait sites are limited to Emamectin and several metabolites are expected to be 

persistent and relatively immobile in the environment due to a high degree of sorption to soil 

particles; thus, parent and degradates of toxicological concern are not expected to leach into 

ground water but may occur in surface water due to field runoff as determined by the Pesticide 

Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS). 

Tolerances are established under 40 CFR §180.505 for various plant and livestock (except 

poultry) commodities as shown in Attachment 2. 

The registered emamectin benzoate end-use product formulations (listed below) include a 

soluble granular (SG) formulation for use on various terrestrial food/feed crops; an emulsifiable 

concentrate (EC) formulation for use on cotton and tobacco; a ready-to-use gel for use as a 

cockroach bait; and an EC formulation for tree injection. The terrestrial crops are treated with 

multiple foliar sprays, using ground equipment, aircraft, or airblast equipment (for orchards). 

Proclaim® Insecticide (EPA Reg. No. 100-904), a soluble granular (SG) formulation 

containing 5% active ingredient (ai), registered for use on fruiting vegetables, leafy 

vegetables including Brassica (cole crops), pome fruit, tree nuts including pistachios, and 

turnip greens (tops, leaves) for control of lepidopterous larvae, leafminers, and spider 

mites; 

Denim® Insecticide (EPA Reg. No. 100-903), an emulsifiable concentrate (EC) 

formulation containing 2.15% ai, equivalent to 0.16 lb ai/gal, registered for use on cotton 

and tobacco to control certain lepidopterous larvae (worms/caterpillars); 

OptigardTM Cockroach Bait (EPA Reg. No. 100-1290), a ready-to-use gel bait 

formulation containing 0.1% ai for use as a crack and crevice treatment, spot treatment, 

or void treatment in commercial and industrial areas; 

and Emamectin Benzoate 4.0% Tree Injection (EPA Reg. No. 100-1309), an emulsifiable 

concentrate (EC) formulation containing 4% ai, equivalent to 0.36 lb ai/gal, registered for 

injection into ornamental/nonbearing trees (deciduous, coniferous, and palm trees) to 

control arthropod pests. 

Proclaim® Insecticide, Denim® Insecticide, and Emamectin Benzoate 4.0% Tree Injection are 

restricted use pesticides for use only by certified applicators. OptigardTM Cockroach Bait is to be 

used only in commercial and industrial areas. 

HED has conducted four human health risk assessments for emamectin benzoate; the most recent 

one was completed in July of 2008 (DP#345943, N. Dodd, 7/31/08). There are currently no 
Page 5 of 40 

Section 18 emergency exemptions, no tolerances with regional registrations, and no indirect or 

inadvertent tolerances for emamectin benzoate. 

Note: A short-term assessment for adverse human health effects from smoking cigarettes 

containing emamectin-treated tobacco was not conducted as there is no potential for exposure via 

this route. Total residues of emamectin benzoate and its metabolites of concern in green tobacco 

leaves are expected to be <0.1 ppm from the registered use; therefore, according to OPPTS 

860.1000, residue data on cured tobacco leaves and a pyrolysis study are not required. 

Hazard Characterization 

The toxicology database for emamectin is sufficient to characterize the hazard to humans, to 

conduct an FQPA assessment, and to select toxicity endpoints for risk assessment. Data quality 

is acceptable and meets the criteria set in the OPPTS guidelines and 40 CFR §158.500. 

However, under the current data requirement guidelines, immunotoxicity data (OPPTS 

870.7800) are required. A subchronic inhalation study (OPPTS 870.3465) is also required to 

better assess inhalation risks associated with emamectin use. 

Emamectin is a semi-synthetic avermectin and is a member of the naturally derived complex of 

16-membered macrocyclic lactones, which include abamectin, avermectin, and ivermectin. The 

available mechanistic data on these compounds indicate that they have high-affinity binding to 

glutamate-gated chloride ion channels in invertebrate nerve and muscle cells leading to paralysis 

and death (Lankas et al., 1997). In the mammalian toxicity studies submitted by the registrant, 

ataxia, tremors or paralysis are also common findings prior to moribund sacrifice. In mammals, 

this group of chemicals is reported to be excluded from the central nervous system (CNS) by the 

blood-brain barrier contributing to the increased margin of safety of these compounds in 

mammals. However, among the tested mammalian species, a subgroup of CF-1 mice has been 

shown to be extremely sensitive to emamectin toxicity due to deficiency in P-glycoprotein (Pgp). 

The main target organ for emamectin is the nervous system; clinical signs (tremors, ptosis, 

ataxia, and hunched posture) and neuropathology (neuronal degeneration in the brain and in 

peripheral nerves, muscle fiber degeneration) were found in most of the studies and in rats, dogs 

and mice. The dose/response curve was very steep in several studies (most notably with CF-1 

mice and dogs), with severe effects (morbid sacrifice and neuropathology) sometimes seen at the 

LOAELs. Although no increased sensitivity was seen in developmental toxicity studies in rats 

and rabbits, increased qualitative and/or quantitative sensitivity of rat pups was seen in the 

reproductive toxicity and in the developmental neurotoxicity studies. 

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.” A toxicity profile for emamectin is presented in Appendix A. 

The acute toxicity studies indicate 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, abamectin has been shown to be a severe 
Page 6 of 40 

eye irritant. A recent (as of 2008) submission of acute toxicity six-pack tests performed on a 

new technical product (Emamectin Benzoate Technical II, EPA Reg. No. 100-1270) resulted in 

new toxicity category assignments. Specifically, the toxicity category for inhalation changed 

from Category IV to Category II. Relevant to the REI, the eye irritation study changed from 

Category I to Category III. HED had concern for the possibility that a change in manufacturers 

and technical registrations could result in a different acute toxicity outcome, while the technical 

compound itself had not changed. Detailed information has been submitted which confirms the 

appropriateness of the REI reduction. 

The most recent toxicity endpoints and points of departure for risk assessment were determined 

by HED in 2003. The available emamectin data show that there is a difference in species 

sensitivity, and the data suggest the following order: rat NOAELs/LOAELs > dog 

NOAELs/LOAELs > mouse NOAELs/LOAELs. The toxicity endpoints and points of departure 

for risk were selected from the results of the 15-day CF-1 mouse oral toxicity study. No new 

toxicity studies have been submitted since 2003, and these selections are valid based on current 

policies and available information (Tables 4.1 & 4.2). 

HED also evaluated all the relevant data and determined that there was an increase in 

susceptibility in the offspring of a 2-generation reproduction study and in the pups of the 

developmental neurotoxicity study. In the reproduction study, whole body tremors, hind limb 

extension, and hind limb splay were seen in the F1 and F2 pups while these clinical signs were 

not seen in F0 parental animals at similar dose levels. In addition, a greater incidence of 

decreased fertility was seen in the F1 parental females than in the F0 females. In the 

developmental neurotoxicity study, no maternal effect was seen at the highest dose tested 

whereas dose-related decrease in open-field motor activity was seen in the mid-dose on PND 17. 

Body tremors, hind-limb extension, and auditory startle were also found in the high dose pups. 

A degree-of-concern analysis was conducted to determine whether or not an additional safety 

factor is needed to account for the increased susceptibility in pups; it was concluded that the 

degree-of-concern was low for both 2-generation reproduction and developmental neurotoxicity 

studies. The reasons are as follows: 

· For the 2-generation reproduction study, (1) there was a clear NOAEL for the offspring 

toxicity, (2) effects unique to offspring (decreased fertility in F1 adults, and clinical signs 

[tremors and hind limb extensions during and following lactation]) were seen at the same 

dose that caused parental systemic toxicity (decreased body weight gain and 

histopathological lesions in the brain and spinal cord), and (3) the decreased fertility seen in 

F1 adults might have been due to histopathological lesions in the brain and central nervous 

system (seen in both F0 and F1 generations), rather than due to a direct effect on the 

reproductive system. 

· For the developmental neurotoxicity study, (1) although multiple offspring effects (including 

decreased pup body weight, head and body tremors, hindlimb extension and splay, changes 

in motor activity and auditory startle) were seen at the highest dose, and no maternal effects 

were seen at any dose, there was a clear NOAEL for offspring toxicity at the low dose, and 

(2) the offspring LOAEL (at the mid dose) is based on a single effect seen on only one day 
Page 7 of 40 

(decreased motor activity on PND 17) and no other offspring toxicity was seen at the 

LOAEL. 

Although HED concluded that there is a low degree of concern and lack of residual uncertainties 

for pre- and post-natal toxicity, the 10X FQPA safety factor (SF) is retained for chronic 

assessments while a 3X FQPA SF is adequate for acute assessments. 

A 10X FQPA SF has been retained for the chronic/long-term and intermediate-term risk 

assessments to account for the steepness of the dose response curve, severity of effect at the 

LOAEL (death and neuropathology), and most importantly the use of a short-term study for long 

term risk assessment. The 10X FQPA SF will also provide adequate protection for the lack of 

the new immunotoxicity study. A 3X FQPA SF has been retained for acute and short-term risk 

assessments to account for the steepness of the dose-response curve and severity of effect at the 

LOAEL (death and neuropathology). For future risk assessment, the additional safety factors 

will be evaluated according to the current HED science policy and the available data. 

Immunotoxicity

To address the issue of the immunotoxicity data gap and the associated database uncertainty 

factor, the RAB3 toxicity team examined the entire database of emamectin and determined that 

an additional uncertainty factor is not needed to account for potential immunotoxicity. For 

emamectin, a complete battery of subchronic, chronic, carcinogenicity, developmental and 

reproductive studies as well as acute and subchronic neurotoxicity screening battery and 

developmental neurotoxicity are available for consideration. At the dose levels tested, 

emamectin has not demonstrated effects which can be associated with immunotoxicity, and 

emamectin does not belong to a class of chemicals that would be expected to be immunotoxic. 

Therefore, based on the above considerations, HED does not believe that conducting a special 

series 870.7800 immunotoxicity study will result in a NOAEL that is less than any which is used 

for point of departure for the risk assessment. Therefore, an additional factor for database 

uncertainties (UFDB) does not need to be applied at this time. However, an immunotoxicity 

study is specifically designed to detect any deficit in the ability of the immune system to respond 

to a challenge (chemical). 

Inhalation

Since no inhalation studies are available, the Agency selected an oral NOAEL of 0.075 

mg/kg/day established in the 15-day neurotoxicity study in mice for inhalation risk assessments. 

Therefore, a 28-day subchronic inhalation study is required for the reasons that the inhalation 

study (1) may provide route specific effects (route of entry effects) and (2) may result in changes 

to the endpoints and how the risks are quantified. In addition, the acute inhalation toxicity 

category for emamectin is II, and in a 5-day preliminary inhalation study, histopathological 

changes were found in the respiratory tract at all dose levels (1μg/L to 125 μg/L). The study 

should be performed using the CF-1 mouse. In 2006, the registrant and the Agency held several 

meetings to discuss the conduct of the 28-day inhalation toxicity study (specifically the strain of 

test animal to be used). The Agency still maintains that this study should be conducted in the 

most sensitive strain of mice (i.e., the CF-1 homozygous mdr 1a (-/-) mice). 
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Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision, EPA reviewed these data and 

selected the most sensitive endpoints for relevant risk assessment scenarios from the existing 

hazard database. However, as required by FFDCA section 408(p), emamectin benzoate is 

subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Emamectin 

benzoate is not among the group of 58 pesticide active ingredients on the initial list to be 

screened under the EDSP. Accordingly, as part of registration review, EPA will issue future 

EDSP orders/data call-ins, requiring the submission of EDSP screening assays for emamectin 

benzoate. For further information on the status of the EDSP, the policies and procedures, the list 

of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website: http://www.epa.gov/endo/. 

Conclusions for Hazard Characterization

As specified in the new 40 CFR Part 158 data requirements, an immunotoxicity study (OPPTS 

870.7800) on emamectin benzoate should be conducted. Additionally, a subchronic (28-day) 

inhalation toxicity study (OPPTS 870.3465) is required to adequately characterize toxicity via 

the inhalation route. During registration review, the points of departure and safety factors used 

for risk assessment purposes should be reexamined based on current HED policy, as well as all 

new data received. 
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Residue Chemistry 

Agricultural uses include cotton, pome fruit, tree nuts, leafy vegetables (Brassica and nonBrassica), fruiting vegetables, and tobacco. Tolerances are established under 40 CFR §180.505 

for various plant and livestock (except poultry) commodities as shown in Attachment 2. 

The emamectin benzoate end-use product formulations registered on agricultural crops include a 

soluble granular (SG) formulation for use on various terrestrial food/feed crops and an 

emulsifiable concentrate (EC) formulation for use on cotton and tobacco. The terrestrial crops 

are treated with multiple foliar sprays, using ground equipment, aircraft, or airblast equipment 

(for orchards). 

Adequate plant metabolism studies on lettuce, cabbage, and sweet corn are available. Adequate 

ruminant (goat) and poultry metabolism studies are available. An adequate confined rotational 

crop study is available. Residues of concern are summarized in Table 1 below. 

 

Adequate field trials are available to support registered uses. Adequate enforcement methods 

(high performance liquid chromatography [HPLC] with fluorescence detection) are available to 

support tolerances for plants and livestock. An adequate cattle feeding study is available. A 

poultry feeding study is not needed to support registered uses because the calculated dietary 

burden for poultry is low. Based on the confined rotational crop study, there is no indication that 

emamectin residues of concern would accumulate (>0.01 ppm) in rotational crops; therefore, no 

plantback restrictions are needed on the product labels. Adequate storage stability data are 

available to support storage conditions for plant and livestock studies. 

Table 1. Summary of Metabolites and Degradates to be included in the Risk Assessment 

and Tolerance Expression

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 
Page 10 of 40 

Table 1. Summary of Metabolites and Degradates to be included in the Risk Assessment 

and Tolerance Expression

Matrix Residues included in Risk 

Assessment 

Residues included in 

Tolerance Expression 

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 

Conclusions for Residue Chemistry

The residue chemistry database is complete. There are no outstanding residue chemistry data 

deficiencies.

Dietary Exposure

 

The most recent acute and chronic dietary (food and drinking water) exposure and risk 

assessments were conducted in 2008 (DP#347924, N. Dodd, 7/24/08) using the Dietary 

Exposure Evaluation Model DEEM-FCIDTM, Version 2.03. The acute dietary exposure 

assessment was a probabilistic assessment for food and drinking water. The chronic dietary 

exposure assessment was a somewhat refined assessment for food and drinking water 

represented by a single point estimate of anticipated residues. Refinements for both the acute 

and chronic assessments included percent crop treated (% CT) for some crops (as shown in 

Attachment 3), use of DEEM default processing factors where appropriate, chemical-specific 

processing factors for apple and pear juice, and anticipated residues based on field trial data for 

all commodities except for tree nuts (which used the 0.02 ppm tolerance). The 10X FQPA safety 

factor was retained for chronic assessments and reduced to 3X for acute assessments. 

The surface water estimated drinking water concentrations (EDWCs) were derived using the Tier 

II PRZM/EXAMS model. The Tier 1 Screening Concentration in Ground Water (SCI-GROW) 

model was used to derive the ground water EDWCs. Based on sorption to soil particles, 

significant concentrations of parent or degradates of toxicological concern are not expected to 

leach into ground water. The estimated residues in drinking water were based on use of 

emamectin benzoate in a Pennsylvania apple orchard. 

The acute dietary exposure estimates for food and drinking water using the pome fruit crop 

group scenario for drinking water are below HED’s level of concern at the 99.9th percentile of 

exposure for all population subgroups (26% of the aPAD for the general U.S. population and 

45% of the aPAD for children 1-2 years old, the population with the highest exposure). 

The chronic dietary exposure estimates for food and drinking water using the pome fruit crop 

group scenario for drinking water are below HED’s level of concern for all population subgroups 

(18% of the cPAD for the general U.S. population and 44% of the cPAD for children 1-2 years 

old, the population with the highest exposure). 
Page 11 of 40 

Conclusions for Dietary Exposure

The dietary-exposure database is adequate to support the existing registrations. However, a new 

dietary assessment may be required during Registration Review to incorporate potential changes 

to the emamectin benzoate estimated drinking water concentrations. 

Residential Exposure 

Residential Handlers/Residential Post-Application

No residential exposure is expected from the registered products since they are agricultural uses 

rather than residential uses, restricted use products (restricted to use by certified applicators 

only), or limited to non-residential areas (commercial and industrial areas). 

Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander post-application 

inhalation exposure assessment has not been performed for emamectin benzoate at this time. 

However, volatilization of pesticides may be a potential source of post-application inhalation 

exposure to individuals nearby to pesticide applications. The Agency sought expert advice and 

input on issues related to volatilization of pesticides from its FIFRA SAP in December 2009. 

The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures, 

to identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for emamectin benzoate. 

Spray Drift

 

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for emamectin 

benzoate. The Agency has been working with the Spray Drift Task Force, 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 at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT® computer model 

to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic 

methods. After the policy is in place, the Agency may impose further refinements in spray drift 
Page 12 of 40 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift. 

Aggregate Risk Assessment 

The acute aggregate risk assessment takes into account exposure estimates from dietary (food 

and drinking water) consumption of emamectin as discussed above. 

Short- and intermediate-term aggregate risk assessments were not conducted because residential 

exposure is not expected from existing uses. 

The long-term aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of emamectin (food and drinking water) and residential uses. However, 

residential exposures are not expected; therefore, the chronic aggregate risk assessment will 

consider only exposure from food and drinking water, which is discussed above.

Occupational Exposure 

The following agricultural uses are on the Proclaim® Insecticide or Denim® Insecticide labels: 

Cotton 

Fruit, pome, group 11 

Nut, tree, group 14 (plus Pistachios) 

Vegetable, Brassica, leafy, group 5 (plus Turnip greens) 

Vegetable, fruiting, group 8 (including Okra as of 2010) 

Vegetable, leafy, except Brassica, group 4 

Tobacco 

In addition to the agricultural uses, emamectin is also registered for use as a cockroach bait 

(OptigardTM Cockroach Bait) for use in commercial and industrial areas, and as a tree injection 

(Emamectin Benzoate 4.0% Tree Injection) for use in ornamental/nonbearing trees (deciduous, 

coniferous, and palm). 

Three registered end-use formulations (Proclaim® Insecticide, Denim® Insecticide, and 

Emamectin Benzoate 4.0% Tree Injection) are restricted use pesticides for use only by certified 

applicators. OptigardTM Cockroach Bait is not a restricted use product (RUP) but EPA has 

indicated that it is to be used only in commercial and industrial areas. 

Except for OptigardTM Cockroach Bait, all registered emamectin end-use products are RUPs 

(restricted to use by PCOs only). Emamectin is registered for agricultural uses, as a tree 

injection use, and as a cockroach bait. There is a potential for short-term (1-30 days) and 

intermediate-term (1-6 months) exposure to emamectin during handling activities (mixing, 

loading, and applying); long-term exposures are not anticipated. Previous exposure and risk 

assessments were conducted for all of the emamectin uses. The level of concern (LOC) for risk 

is a Margin of Exposure (MOE) of less than 300 for short-term exposure, and an MOE of less 

than 1000 for intermediate-exposure. 
Page 13 of 40 

 

Occupational Handlers

No chemical-specific handler exposure data were available with which to assess potential 

exposure to pesticide handlers. Table 5.1 lists the occupational handler scenarios for each use 

site and the corresponding MOEs (indicating whether or not each scenario has been previously 

assessed). 

Some handler exposures and risks were calculated with baseline plus personal protective 

equipment (PPE; baseline with chemical-resistant gloves) unit exposures. All current uses have 

been assessed based on current HED policies. 

Conclusion for Occupational Handlers

All current uses have been assessed based on current HED policies. 

Occupational Post-Application

Occupational post-application exposure can occur via the dermal and/or inhalation route. All 

post-application dermal exposures and risks have been previously assessed and are not of 

concern to HED. Table 5.2 summarizes the most protective, previously assessed occupational 

post-application scenarios along with the corresponding MOEs, based on the activities with the 

highest dermal transfer coefficients (TCs). For all crops except for pome fruits and tree nuts, the 

interim restricted entry interval (REI) of 12 hours is acceptable. For pome fruits and tree nuts, an 

REI of 2 days is required based on the post-application dermal risk assessment. Occupational 

postapplication exposures following crack and crevice treatment and tree injection treatment are 

not expected. 

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment has not been performed for emamectin at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication 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 Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 

The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. 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. 

Public Health and Pesticide Epidemiology Data 

OPP Incident Data System (IDS)
Page 14 of 40 

There were two minor cases reported to the IDS for emamectin benzoate from January 1, 2002 to 

February 1, 2011. There were no incidents reported to the IDS resulting in higher severity 

outcomes (death or major/moderate incidents) from January 1, 2002 to February 1, 2011. 

Agricultural Health Study (AHS)

Emamectin benzoate is not included in the AHS. 

Conclusions for Public Health and Pesticide Epidemiology Data

There were very few incidents involving emamectin benzoate reported to the IDS, and they were 

of low severity. Based on the low frequency and severity of incident cases, there does not appear 

to be a concern at this time that would warrant further investigation of incidents involving 

emamectin benzoate. 

Tolerance Assessment and International Harmonization 

As shown in Attachment 2, there are no Codex or Canadian maximum residue limits (MRLs). 

Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 

Environmental Justice 

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

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.eh.doe.gov/oepa/guidance/justice/eo12898.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 USDA under the Continuing Survey of Food Intake by Individuals (CSFII) 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, season of the year, ethnic group, and region of the 

country. 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 

postapplication are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups. 
Page 15 of 40 

Cumulative 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to emamectin benzoate and any other substances and emamectin benzoate does not appear to 

produce a toxic metabolite produced by other substances. EPA has not assumed that emamectin 

benzoate has a common mechanism of toxicity with other substances. For information regarding 

EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to 

evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s 

Office of Pesticide Programs concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.

Human Studies 

The risk assessments which have been previously conducted for emamectin benzoate have relied 

in part on data from studies in which adult human subjects were intentionally exposed to a 

pesticide to determine their dermal and inhalation exposure. Many such studies, involving 

exposure to many different pesticides, comprise generic pesticide exposure databases such as the 

Pesticide Handler Exposure Database (PHED) and the Outdoor Residential Exposure Task Force 

(ORETF). EPA has reviewed all the studies supporting these multi-pesticide generic exposure 

databases, and has found no clear and convincing evidence that the conduct of any of them was 

either fundamentally unethical or significantly deficient relative to the ethical standards 

prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule 

for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and 

there is no regulatory barrier to continued reliance on these studies. 

Data Requirements 

The following data deficiencies were required as conditions of registration and remain 

outstanding or are required under current guidelines: 

Toxicology

870.3465 Subchronic Inhalation

• A subchronic inhalation study is needed. HED determined there was a data gap for a

28-day inhalation study. This study should be performed using the CF-1 mouse. 

870.7800 Immunotoxicity

• An immunotoxicity study is needed as described in Attachment 6.

Residue Chemistry 

There are no outstanding residue chemistry data deficiencies.
Page 16 of 40 

Occupational-Residential Exposure

The occupational and residential databases for emamectin benzoate are considered complete for 

risk assessment purposes. 

Recent Actions and Current/Future Submissions at EPA, California (CDPR), Canada, and 

the European Union

EPA: There was a recent expansion of Emamectin Benzoate 4.0% Tree Injection (EPA Reg. No. 

100-1309, label dated 12/16/10) to many pests on deciduous, coniferous, and palm trees. 

References 

Residue Chemistry/Occupational and Residential Exposure (ORE) References 

Memoranda Relevant to Registration Review of Emamectin Benzoate 

Author Barcode 

(DP#) 

Date Title 

S. Winfield 386649 3/1/11 Emamectin Benzoate: Review of Human Incidents. 

N. Dodd 382030 2/15/11 Emamectin Benzoate. Storage Stability Data on 

Almonds. 

R. Prieto --- 12/7/10 Usage/Use Report Package in Support of Registration 

Review for Emamectin Benzoate (122806). 

J. Arthur 360697 1/21/09 Revised. Emamectin Benzoate; Change of WPS REI 

from 48 to 12 Hours. 

N. Dodd 345943 7/31/08 Emamectin Benzoate. Human Health Risk Assessment 

for Proposed Uses on Tree Nuts and Pistachios, and as 

an Injection Treatment for Ornamental/Nonbearing 

Trees. 

N. Dodd 347924 7/24/08 Emamectin Benzoate. Acute and Chronic Aggregate 

Dietary (Food and Drinking Water) Exposure and Risk 

Assessments for the Section 3 Registration Action on 

Tree Nuts (including Pistachios). 

K. O’Rourke 347923, 

354525 

7/24/08 Emamectin Benzoate; Occupational and Residential 

Risk Assessment for Proposed Use of Emamectin 

Benzoate on Tree Nuts and as a Tree Injection. 

N. Dodd 328149 7/17/08 Emamectin Benzoate. Petition for Tolerances on the 

Tree Nuts Crop Group and Pistachios; and Responses to 

Conditions for Registrations on Leafy Vegetables 

(except Brassica), Fruiting Vegetables, Cotton and Pome 

Fruits. Summary of Analytical Chemistry and Residue 

Data. 

A. Grube 354010 7/8/08 Usage Report in Support of Registration Review for the 

Insecticide Emamectin benzoate (122806). 
Page 17 of 40 

Memoranda Relevant to Registration Review of Emamectin Benzoate 

Author Barcode 

(DP#) 

Date Title 

K. O’Rourke 341633 4/29/08 Emamectin Benzoate; Occupational and Residential 

Risk Assessment for Proposed Use of Emamectin 

Benzoate as a Cockroach Bait. 

N. Dodd 327785 3/28/06 Emamectin on Pome Fruit. Response to Review of 

PP#3F06574 for the Establishment of a Permanent 

Tolerance. 

N. Dodd 320557 10/27/05 Human Health Risk Assessment for Emamectin in/on 

Pome Fruit. 

K. O’Rourke 320799 9/14/05 Occupational and Residential Risk Assessment to 

Support Request for Establishment of Tolerance for 

Emamectin Benzoate on Pome Fruit. 

M. Xue 309150 4/26/05 Emamectin Benzoate. Petition for the Establishment of 

a Permanent Tolerance on Pome Fruit. Summary of 

Analytical Chemistry and Residue Data. PP#3F06574. 

E. Kolbe 2880045 7/17/03 PP#7F4845. Emamectin Benzoate on Livestock 

Commodities. Tolerance Method Review. 

K. O’Rourke 291065 6/24/03 PP#7F04845. Section 3 Registration for Emamectin 

in/on Brassica Leafy Vegetables, Fruiting Vegetables, 

Leafy Vegetables, Cotton, and Tobacco. 

J. Arthur 281275 3/12/03 Revised Occupational and Residential Risk Assessment 

to Support Request for Establishment of Tolerance for 

Emamectin Benzoate on Cotton, Fruiting Vegetables, 

Leafy Vegetables and Tobacco. 

M. Xue 282201 5/24/02 PP#7F04845: Evaluation of ACB Method Validation 

Report for Emamectin Benzoate and its Metabolites 

in/on Representative Samples of the Leafy Vegetables 

(Except Brassica Vegetables) Crop Group 4 and the 

Brassica (Cole) Leafy Vegetable Crop Group 5. 

M. Xue 267346 2/19/02 PP#7F04845: Emamectin Benzoate in/on Brassica 

Leafy Vegetables, Fruiting Vegetables, Leafy 

Vegetables, Cotton, and Tobacco. Evaluation of 

Analytical Method and Magnitude of the Residue Data 

to Support Permanent Tolerances for Use of Emamectin 

Benzoate. 

M. Rust 241907 4/6/99 PP#6F4628. Section 3 Registration for Emamectin 

Benzoate on Broccoli, Brussels Sprouts, Cabbage, 

Cauliflower, Lettuce, and Celery. 

Toxicology References 

 
Page 18 of 40 

Albers-Schonbery, G., Arison, B, Chabala, J., Douglas, A., Eskola, P., Fisher, M., Lusi, A., 

Mrozik, H., Smith, J., and Tolman, R. (1981) Avermectin structure determination. J. Am. 

Chem. Soc. 103, 4216-4211. 

Dawson GR, Wafford KA, Smith A, Marshall GR, Bayley PJ, Schaeffer JM, Meinke PT, 

 McKernan RM. (2000) Anticonvulsant and adverse effects of avermectin analogs in mice 

 are mediated through the gama-aminobutyric acid (A) receptor. J. Pharmacol. Exp. Ther. 

295: 1051-1060. 

Habashi, SL (2006) Dubin-Johnson Syndrome. http://www.emedicine.com/med/topic 588.htm 

Huang J, Casida JE. (1997) Avermectin B1a binds to high- and low-affinity sites with dual 

 effects on the gama-aminobutyric acid-gated chloride channel of cultured cerebellar 

 granule neurons. J. Pharmacol. Exp. Ther. 281: 261-266. 

Kerb R (2006) Implication of genetic polymorphism in drug transporters for pharmacotherapy. 

 Cancer Lett. 234: 4-33. 

Kerr DI and Ong J. (1986) Gama-aminobutyric acid-dependent motility induced by avermectin 

B1a in the isolated intestine of the guinea pigs. Neurosci. Lett. 65: 7-10. 

Lankas GR, Cartwright ME, and Umbenhauer D (1997) P-Glycoprotein deficiency in a 

 subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. Toxicol. and 

Appl. Pharmacol. 143: 357-365. 

Marzolini C, Paus E, Buclin T, and Kim RB (2004) Polymorphism I human MDR1 (P- 

 glycoprotein): Recent advances and clinical relevance. Clin. Pharmacol. and Ther. 

 75: 13-33. 

Meister B. (2007) Neurotransmitters in key neurons of the hypothalamus that regulate feeding 

behavior and body weight. Physiol. Behav. 92: 263-271. 

Nguyen L, Rigo JM, Rocher V, Belachew S, Malgrange B, Rogister B, Leprince P, Moonen G. 

 (2001) Neurotransmitters as early signals for central nervous system development. Cell 

 Tissue Res. 305: 187-202. 

 

Pong SS, DeHaven R, Wang CC. (1982) A comparative study of avermectin B1a and other 

 modulators of the gama-aminobutyric receptor- chloride ion channel complex. J. 

 Neurosci. 2: 966-971. 

Report (3rd ) of Hazard Identification Assessment Review Committee; TXR No. 0051605; March 

5, 2003. 

Report of the Hazard Identification Assessment Review Committee; TXR No. 012539; March 

19, 1998. 
Page 19 of 40 

Represa A, Ben-Ari Y.(2005) Trophic actions of GABA on neuronal development. Trends 

 Neurosci. 28: 278-283. 

Attachments

1. Chemical Identity Table 

2. Tolerance Summary Table 

3. Percent Crop Treated Data Comparison Table 

4. Endpoint Selection Table 

5. Occupational Exposure Tables 

6. Data Call-In Tables 

Appendix A- Acute Toxicity Profile Tables and Table on Repeated Dosing and Other Studies 

 
Page 20 of 40 

Attachment 1 

Chemical Identity Table 

Table 1. Chemical Identity – Emamectin, Emamectin Benzoate, and Metabolites/Degradates 

Common Name emamectin 

Chemical Name (CAS) (4''R)-4''-deoxy-4''-(methylamino)avermectin B1 

IUPAC name Mixture of ≥ 90% (10E,14E,16E)-(1R,4S,5'S,6S,6'R,8R,12S,13S,20R,21R,24S)-6'-

[(S)-sec-butyl]-21,24-dihydroxy-5',11,13,22-tetramethyl-2-oxo-(3,7,19-

trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene)-6-spiro-2'-(5',6'-

dihydro-2'H-pyran)-12-yl 2,6-dideoxy-3-O-methyl-4-O-(2,4,6-trideoxy-3-Omethyl-4-methylamino-α-L-lyxo-hexapyranosyl)-α-L-arabino-hexapyranoside 

and ≤10% (10E,14E,16E)-(1R,4S,5'S,6S,6'R,8R,12S,13S,20R,21R,24S)-21,24-

dihydroxy-6'-isopropyl-5',11,13,22-tetramethyl-2-oxo-(3,7,19-

trioxatetracyclo[15.6.1.14,8.020,24]pentacosa-10,14,16,22-tetraene)-6-spiro-2'-(5',6'-

dihydro-2'H-pyran)-12-yl 2,6-dideoxy-3-O-methyl-4-O-(2,4,6-trideoxy-3-Omethyl-4-methylamino-α-L-lyxo-hexapyranosyl)-α-L-arabino-hexapyranoside 

PC Code 122806 

Chemical Abstracts No. emamectin: 119791-41-2 (formerly 123997-28-4 and 137335-79-6) 

emamectin benzoate: 155569-91-8 (formerly 137512-74-4) 

Registration Review Case 

No. 

7607-1 

Chemical Class avermectin insecticide 

Chemical structure of 

emamectin 

B1a = NOA426007; 

B1b = NOA422390 

OCH3

O O

O

O

CH3

OH

3CH

O

CH3

CH3

R1

O

O

H3CO

O

CH O 3 CH3

OH

CH3

N

H 3CH

B1a Component: R1 = CH2CH3

B1b Component: R1 = CH3
Page 21 of 40 

Table 1. Chemical Identity – Emamectin, Emamectin Benzoate, and Metabolites/Degradates 

Chemical structure of 

emamectin benzoate 

Chemical structure of 8,9-

ZMA metabolite 

isomer for B1a = 

NOA438376 

Chemical structure of AB1a

metabolite 

L’649 = NOA438309 

COOOCH3

O O

O

O

CH3

OH

3CH

O

CH3

CH3

R1

O

O

H3CO

O

CH O 3 CH3

OH

CH3

H3CH2N+

B1a Component: R1 = CH2CH3

B1b Component: R1 = CH3

CH3

OH

OH

OCH3

O

O

CH3

O

CH3

CH3

O

O

H3CO

O

3CH O

NH

CH3

3CH

R

O

O

3CH

B1a Component: R = CH2CH3

B1b Component: R = CH3

OCH3

O O

O

O

CH3

CH3

OH

3CH

O

CH3

CH3

O

O

H3CO

O

CH O 3

NH2

H3CH2C

CH3

OH
Page 22 of 40 

Table 1. Chemical Identity – Emamectin, Emamectin Benzoate, and Metabolites/Degradates 

Chemical structure of MFB1a

metabolite 

L’599 = NOA415692 

Chemical structure of FAB1a

metabolite 

L’831 = NOA415693 

 

OCH3

O O

O

O

CH3

CH3

OH

3CH

O

CH3

CH3

O

O

H3CO

O

3CH O

N

H3CH2C

CH3

H

O

CH3

OH

OCH3

O O

O

O

CH3

CH3

OH

3CH

O

CH3

O

O

H3CO

O

3

CH O

NH

H3CH2C

CH3

H

O

OH
Page 23 of 40 

Attachment 2 

Tolerance Summary Table 

Table 2. Summary of US and International Tolerances and Maximum Residue Limits for Emamectin 

Benzoate 

Residue Definition 

US [40 CFR §180.505(a)(1)] US Canada Mexico1 Codex

emamectin (a mixture of a minimum of 90% 4'-epimethylamino-4'-deoxyavermectin B1a and maximum of 10% 

4'-epi-methylamino-4'-deoxyavermectin B1b) and its 

metabolites 8,9-isomer of the B1a and B1b component of the 

parent (8,9-ZMA), or 4'-deoxy-4'-epi-amino-avermectin B1a 

and 4'-deoxy-4'-epi-amino-avermectin B1b; 4'-deoxy-4'-epiamino avermectin B1a (AB1a); 4'-deoxy-4'-epi-(N-formyl-Nmethyl)amino-avermectin (MFB1a); and 4'-deoxy-4'-epi-Nformyl)amino-avermectin B1a (FAB1a) 

None None 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) 

Commodity US Canada Mexico Codex 

Almond, hulls 0.20 

Apple, wet pomace 0.075 

Cotton, gin byproducts 0.050 

Cotton, undelinted seed 0.025 

Fruit, pome, group 11 0.025 

Nut, tree, group 14 0.02 

Pistachio 0.02 

Tomato, paste 0.150 

Turnip, greens 0.050 

Vegetable, Brassica, leafy, group 5 0.050 

Vegetable, fruiting, group 8 0.020 

Vegetable, leafy, except Brassica, 

group 4 0.100 

Residue Definition 

US [40 CFR §180.505(a)(2)] US Canada Mexico1 Codex

Livestock: emamectin (MAB1a+ MAB1b isomers) and the 

associated 8,9-Z isomers (8,9-ZB1a+ 8,9-ZB1b) in/on the 

following commodities when present therein as a result of the 

application of emamectin to crops listed in the table in 

paragraph (a)(1) 

None None 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) 

Commodity US Canada Mexico Codex 

Cattle, fat 0.010 

Cattle, liver 0.050 

Cattle, meat 0.003 

Cattle, meat byproducts, except liver 0.020 

Goat, fat 0.010 

Goat, liver 0.050 

Goat, meat 0.003 

Goat, meat byproducts, except liver 0.020 
Page 24 of 40 

Residue Definition 

US [40 CFR §180.505(a)(2)] US Canada Mexico1 Codex

Hog, fat 0.003 

Hog, liver 0.020 

Hog, meat 0.002 

Hog, meat byproducts, except liver 0.005 

Horse, fat 0.010 

Horse, liver 0.050 

Horse, meat 0.003 

Horse, meat byproducts, except liver 0.020 

Milk 0.003 

Sheep, fat 0.010 

Sheep, liver 0.050 

Sheep, meat 0.003 

Sheep, meat byproducts, except liver 0.020 

Completed by: M. Negussie; 02/24/2011 

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 

 
Page 25 of 40 

Attachment 3 

Percent Crop Treated Data Comparison Tables 

Table 3. Percent Crop Treated for Emamectin Benzoate 

Crop 

Percent Crop Treated 

June 23, 2008 July 29, 2010 

Average Maximum Average Maximum 

Apples 5 5 10 20 

Broccoli 10 20 10 25 

Cabbage 10 20 10 25 

Cauliflower 10 25 10 30 

Celery 15 35 20 40 

Cotton <1 <2.5 <1 <2.5 

Lettuce 10 15 10 20 

Pears <1 <2.5 10 20 

Peppers 5 10 10 20 

Spinach 5 5 5 10 

Tobacco <1 <2.5 

Tomatoes 10 15 10 20 

 
Page 26 of 40 

Attachment 4 

Summary of Toxicity Endpoints and Points of Departure of Emamectin Benzoate

Table 4.1. Summary of Toxicological Doses and Endpoints for Emamectin Benzoate for 

Use in Dietary and Non-Occupational Human Health Risk Assessments1, 2 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological Effects 

Acute Dietary 

(All 

Populations) 

NOAEL = 

0.075 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 3x 

Acute RfD = 

0.00025 

mg/kg/day 

aPAD 

=0.00025mg/

kg/day 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

tremors on day 3 of dosing. 

Chronic 

Dietary (All 

Populations) 

NOAEL = 

0.075 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 10x 

Chronic RfD 

= 0.000075 

mg/kg/day 

cPAD = 

0.000075 

mg/kg/day 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve. 

Incidental Oral 

Short-Term 

(1-30 days) 

NOAEL = 

0.075 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 3x 

Residential 

LOC for 

MOE = 300 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve. 

Dermal ShortTerm (1-30 

days) 

NOAEL = 

0.075 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 3x 

Residential 

LOC for 

MOE = 300 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve.

Dermal 

IntermediateTerm (1-6 

months) 

NOAEL = 

0.075 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 10x 

Residential 

LOC for 

MOE = 1000 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve.

Inhalation 

Short-Term 

(1-30 days) 

NOAEL = 

0.075 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 3x 

Residential 

LOC for 

MOE = 300 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve.
Page 27 of 40 

Table 4.1. Summary of Toxicological Doses and Endpoints for Emamectin Benzoate for 

Use in Dietary and Non-Occupational Human Health Risk Assessments1, 2 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment 

Study and Toxicological Effects 

Inhalation 

IntermediateTerm (1-6 

months) 

NOAEL = 

0.075 

mg/kg/day 

UFA = 10x 

UFH = 10x 

FQPA SF = 10x 

Residential 

LOC for 

MOE = 1000 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve.

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. 

1

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). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. 

2 Dermal absorption of 1.8% is assumed. 

 

Table 4.2 Summary of Toxicological Doses and Endpoints for Emamectin Benzoate for Use 

in Occupational Human Health Risk Assessments1, 2 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment 

Study and Toxicological Effects 

Dermal ShortTerm (1-30 

days) 

NOAEL = 

0.075 

mg/kg/day 

(dermal 

absorption 

rate =1.8%) 

UFA = 10x 

UFH = 10x 

UFM = 3x 

Occupational LOC 

for MOE = 300 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve. 

Dermal 

IntermediateTerm (1-6 

months) 

NOAEL = 

0.075 

mg/kg/day 

(dermal 

absorption 

rate = 1.8%) 

UFA = 10x 

UFH = 10x 

UFM = 10x 

Occupational LOC 

for MOE = 1000 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve. 

Inhalation 

Short-Term (1-

30 days) 

NOAEL = 

0.075 

mg/kg/day 

(assumed 

equivalent 

to oral 

absorption) 

UFA = 10x 

UFH = 10x 

UFM = 3x 

Occupational LOC 

for MOE = 300 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve. 
Page 28 of 40 

Table 4.2 Summary of Toxicological Doses and Endpoints for Emamectin Benzoate for Use 

in Occupational Human Health Risk Assessments1, 2 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment 

Study and Toxicological Effects 

Inhalation 

IntermediateTerm (1-6 

months) 

NOAEL = 

0.075 

mg/kg/day 

(assumed 

equivalent 

to oral 

absorption) 

UFA = 10x 

UFH = 10x 

UFM = 10x 

Occupational LOC 

for MOE = 1000 

15-day mouse 

LOAEL = 0.1 mg/kg/day based on 

moribund sacrifices, clinical signs of 

neurotoxicity, decreases in body weight 

and food consumption and 

histopathological lesions in the sciatic 

nerve. 

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. 

1

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). UFM = Modifying factor to account for the 

steepness of the dose-response curve, severity of effects at the LOAEL (death and neuropathology), and the use of a 

short-term study for intermediate-term risk assessment . MOE = margin of exposure. LOC = level of concern. 2 Dermal absorption of 1.8% is assumed. 

 
Page 29 of 40 

Attachment 5 

Occupational Exposure Tables 

Table 5.1. Occupational Exposure Scenarios for Emamectin 

Crop/Use Site Application 

Equipment Formulation 1

Maximum 

Application 

Rate Assessed

lb ai/gal 

Scenario Combined (Dermal + Inhalation) 

MOE 2

Mixer/ 

Loader Applicator Flagger DP Barcode 

Agricultural Uses – RACs 

Cotton 

ground EC 0.015 1100 1800 NA 281275 

aerial EC 0.015 1200 1900 1800 281275 

Tobacco ground EC 0.015 2700 4400 NA 281275 

Vegetable, 

fruiting, 

group 8 

ground WDG 0.015 2300 4400 NA 281275 

aerial WDG 0.015 2400 6300 1800 281275 

chemigation WDG 0.015 2400 NA NA 281275 

Vegetable, 

leafy, except 

Brassica, 

group 4 

ground WDG 0.015 2300 4400 NA 281275 

aerial WDG 0.015 2400 6300 1800 281275 

chemigation WDG 0.015 2400 NA NA 281275 

Vegetable, 

Brassica, leafy, 

group 5 

ground WDG 0.015 2300 4400 NA 281275 

aerial WDG 0.015 2400 6300 1800 281275 

chemigation WDG 0.015 2400 NA NA 281275 

Turnip greens 

ground WDG 0.015 2300 4400 NA 281275 

aerial WDG 0.015 2400 6300 1800 281275 

chemigation WDG 0.015 2400 NA NA 281275 

Fruit, pome, 

group 11 

chemigation WDG 0.015 1000 NA NA 320799 

airblast WDG 0.015 4500 1000 NA 320799 

Nut, tree, 

group 14 

chemigation WDG 0.015 1000 NA NA 347923 

airblast WDG 0.015 4500 11000 NA 347923 

Pistachio 

chemigation WDG 0.015 1000 NA NA 347923 

airblast WDG 0.015 4500 11000 NA 347923 

Non-Agricultural Use – Trees 

Deciduous, 

coniferous, and 

palm trees 

(ornamental, 

ash, palm, pine, 

spruce) 

tree injector EC 0.36 6000 NA NA 354525 
Page 30 of 40 

Table 5.1. Occupational Exposure Scenarios for Emamectin 

Crop/Use Site Application 

Equipment Formulation 1

Maximum 

Application 

Rate Assessed

lb ai/gal 

Scenario Combined (Dermal + Inhalation) 

MOE 2

Mixer/ 

Loader Applicator Flagger DP Barcode 

Non-Agricultural Use – Cockroach Bait 

Cockroach bait Syringe or 

bait injector 

Ready-To-Use 

0.10% 

4.9E-07 

lb ai/ft2 NA 

26,000 

dermal; 

1,100,000 

inhalation 

NA 341633 

1

 EC = emulsifiable concentrate; WDG = water dispersible granule. 2 Bold numbers are calculated using dermal PPE (baseline + gloves). Highlighted numbers are calculated using engineering 

controls in addition to baseline + gloves (e.g. water soluble bags, closed mixing, enclosed cab). NA = not applicable. The level 

of concern = 100. 

Table 5.2. Occupational Post-Application Exposure Scenarios for Emamectin

Use Site 

(TC Group) Activity 

Dermal 

TC1 

(cm2/hr) 

Day 

After 

App. 

DFR2 

(ug/cm2) 

PostApplication 

Dermal 

MOE3 

DP 

Barcode 

Tobacco 

(bunch/bundle) 

hand harvesting, stripping, 

thinning, topping, hand weeding 2000 0 0.00591 3100 281275 

Cotton 

(field/row crops, 

low/medium) 

hand harvesting 2500 0 0.00591 2500 281275 

Fruiting Vegetables 

(vegetable, fruiting) 

hand harvesting, hand pruning, 

thinning, staking, tying, training 1000 0 0.00591 6200 281275 

Leafy Vegetables 

(vegetable, leafy) 

hand harvesting, 

hand pruning, thinning 2500 0 0.00591 2500 281275 

Brassica Vegetables 

(vegetable, head and 

stem Brassica) 

hand harvesting, irrigation, hand 

pruning, topping, thinning, tying 5000 0 0.00591 1200 281275 

Pome Fruits 

(trees, fruit, 

deciduous) 

thinning 3000 

0 0.034 360 

1 0.017 720 320799 

2 0.0084 1400 

Tree Nuts 

(tree, “nut”) 

hand harvesting, 

hand pruning, thinning 2500 

0 0.034 430 

1 0.017 870 347923 

2 0.0084 1700 1

 TC = transfer coefficient. 

2 DFR = dislodgeable foliar residue. 

3

 The level of concern = 100. 
Page 31 of 40 

Attachment 6 

Data Call-In Tables 

Guideline Number: 870.7800 

Study Title: Immunotoxicity

Rationale for Requiring the Data 

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a 

pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is 

designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., 

suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to 

respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired 

Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies 

assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential 

immunotoxicity. These data will be used in combination with data from hematology, lymphoid organ 

weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential 

immunotoxic effects. 

Practical Utility of the Data 

How will the data be used? 

These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure 

scenarios and are considered a primary data source for reliable reference dose calculation. For example, 

animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations 

of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive, and endocrinologic 

toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) 

based on observed immunotoxicity in animal studies (IRIS, 1997). 

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that 

given in the interim decision’s conclusion, the risk assessments for the test material may need to be revised 

to reflect the magnitude of potential risk derived from the new data. 

 

 
Page 32 of 40 

Guideline Number: 870.3465 

Study Title: 28-Day Inhalation Toxicity 

Rationale for Requiring the Data 

Instead of conducting this study for 90-days, the Agency only needs a 28-day inhalation study because only 

intermediate-term (but not long-term) exposure to workers is expected based on emamectin benzoate’s use 

pattern. 

In the assessment and evaluation of the toxic characteristics of a gas, volatile substance, or 

aerosol/particulate, determination of subchronic inhalation toxicity may be carried out after initial 

information on toxicity has been obtained by acute testing. The subchronic inhalation study has been 

designed to permit the determination of the no-observed adverse effect-level (NOAEL) and toxic effects 

associated with continuous or repeated exposure to a test substance for a period of 28 days. This study is not 

capable of determining those effects that have a long latency period for development (e.g., carcinogenicity 

and life shortening). Extrapolation from the results of this study to humans is valid only to a limited degree. 

It can, however, provide useful information on health hazards likely to arise from repeated exposures by the 

inhalation route over a limited period of time. It will provide information on target organs and the 

possibilities of accumulation, and can be of use in selecting concentration levels for chronic studies and 

establishing safety criteria for human exposure. Hazards of inhaled substances are influenced by the inherent 

toxicity and by physical factors such as volatility and particle size. In addition, the acute inhalation toxicity 

category for emamectin is II, and in a 5-day preliminary inhalation study, histopathological changes were 

found in the respiratory tract at all dose levels (1μg/L to 125 μg/L). 

 

Practical Utility of the Data 

How will the data be used? 

 

An inhalation study may result in changes to the endpoints and how the risks are quantified. Because no 

inhalation studies are available, the Agency selected an oral NOAEL of 0.075 mg/kg/day established in the 

15-day neurotoxicity study in mice for inhalation risk assessments. 

How could the data impact the Agency’s future decision-making? 

The Agency does not have a full picture of the potential effects which could occur as a result of exposure via 

the inhalation route. In many cases, toxicity observed via the inhalation route is higher than toxicity observed 

via oral exposure, which means that the route-to-route extrapolation used in the emamectin benzoate risk 

assessment could have resulted in an underestimation of risks from inhalation. 

 
Page 33 of 40 

Appendix A 

Toxicology Profile for Emamectin 

Table A.1.1. Acute Toxicity Profile – Emamectin Benzoate Technical (EPA Reg. No. 

100-902)

Guideline No. Study Type MRID Results Toxicity Category 

870.1100 Acute oral - Rats 42851519 LD50 for L-656,748-

038 = 53 mg/kg 

II 

870.1200 Acute dermal - Rabbits (EC) 43850111 LD50 > 2.0 g/kg III 

870.1300 Acute inhalation - Rats 43868101 0.44 mg/L <LC50<2.12 

mg/L 

III 

870.2400 Acute eye irritation - Rabbits 42743615 Severe irritation I 

870.2500 Acute dermal irritation - Rabbits 42743616 No dermal irritation IV 

870.2600 Skin sensitization - Guinea pigs 42743617 Not a dermal sensitizer - 

Table A.1.2. Acute Toxicity Profile – Emamectin Benzoate Technical II (EPA Reg. No. 

100-1270)

Guideline No. Study Type MRID Results Toxicity Category 

870.1100 Acute oral - Rats 47002104 LD50 for L-656,748-

038 = 53 mg/kg 

II 

870.1200 Acute dermal - Rabbits (EC) 47002106 LD50 > 2.0 g/kg III 

870.1300 Acute inhalation - Rats 47002107 LC50 0.10 mg/L II 

870.2400 Acute eye irritation - Rabbits 47002108 Severe irritation III 

870.2500 Acute dermal irritation - Rabbits 47002109 No dermal irritation IV 

870.2600 Skin sensitization - Guinea pigs 47002110 Not a dermal sensitizer Negative 

 
Page 34 of 40 

Table A. 1. 3. Repeated Dosing and Other Studies on Emamectin2, 3 

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 (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. 

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 > 2000 mg/kg for MK0244 

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 

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. 
Page 35 of 40 

Table A. 1. 3. Repeated Dosing and Other Studies on Emamectin2, 3 

Guideline 

No 

Study Type MRID No. (Year)/ 

Classification/Doses

Results

were 0.29. 0.58, or 

0.1.08 mg/kg/day. 

870.3200 21-Day dermal toxrabbits 

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 1000 

mg/kg/day (6 hrs/day) 

NOAEL = 1000 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. 

Chronic toxicity studies 

870.4100 1-Year oral tox. – 

dogs (gavage) 

42763624 (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) 

4386805 (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 

NOAEL=1.0 mg/kg/day 

LOAEL=2.5/5.0 mg/kg/day1

 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 
Page 36 of 40 

Table A. 1. 3. Repeated Dosing and Other Studies on Emamectin2, 3 

Guideline 

No 

Study Type MRID No. (Year)/ 

Classification/Doses

Results

females due to tremors 

seen in another study at 

5 mg/kg). 

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 

decreased body weight gain and 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 L660,599; L-657,831; 

L-695,638; L930,905 

42743637 

42851514 

42851515 

42851516 

42851517 

Negative for the induction of reverse gene 

mutation. 
Page 37 of 40 

Table A. 1. 3. Repeated Dosing and Other Studies on Emamectin2, 3 

Guideline 

No 

Study Type MRID No. (Year)/ 

Classification/Doses

Results

(photometabolites of 

MK-0244) 

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 (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 

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-0243a

 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 
Page 38 of 40 

Table A. 1. 3. Repeated Dosing and Other Studies on Emamectin2, 3 

Guideline 

No 

Study Type MRID No. (Year)/ 

Classification/Doses

Results

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-Nmethyl)- 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”-epimethylaminoavermectin B1adelta-8,9-isomer); 

photoproduct of 

MK-0244b 

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”-epimethylaminoavermectin B1adelta-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 MK0244 ) 

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 complex 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) 

42743630 (1992) 

Acceptable 

NOAEL = 0.1 mg/kg/day 

LOAEL = 0.30 mg/kg/day based on tremors, 
Page 39 of 40 

Table A. 1. 3. Repeated Dosing and Other Studies on Emamectin2, 3 

Guideline 

No 

Study Type MRID No. (Year)/ 

Classification/Doses

Results

MK-0243 0, 0.05, 0.10, 0.30, or 

0.90 mg/kg/day 

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 MK0244 

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 (highest 

dose tested) 

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 Ndemethylation 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. monohydrate 

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 AbsorptionRhesus Monkey 43850113 (1994) Dermal Absorption was approximated at 1.79% 

of the administered dose. 

870.7800 Immunotoxicity 

study 

Not available 
Page 40 of 40 

1

 The initial dose of the high dose group was 5.0 mg/kg/day. Due to unacceptable weight loss and/or tremors 

occurring at this dose in another concurrent study (TT#91-006-0) during week 9 in males and week 11 in females, 

the dose was lowered to 2.5 mg/kg/day starting at week 6 in males and week 10 in females. 

2

 MK-243: 4” epi-methylamino avermectin (L-656,748) ; L-682-901: 4” epi-methylamino ivermectin; 

 L-653, 648: 4” epi-acetyl avermectin; L-653,649: 4” epi-amino avermectin ; 

 L-655,372: 4” epi-dimethylamino avermectin 

3

 MK-0244: emamectin benzoate