### Page 2 of 40 Executive Summary

The HED Registration Review Team has evaluated human health assessments for the insecticide emamectin benzoate to determine whether suffici ent 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 polic y and risk assessment methodologi es to determine the scope of work necessary to support Registration Review.

Emamectin benzoate is a semi-synthetic aver mectin, consisting of two active homologous compounds (a benzoate salt mixture of a minimum of 90% 4'-epi-methylamino-4'- deoxyavermectin B 1a 

### and a maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B 1b 

### ).

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 benzoa te 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 assessmen ts for exposures associ ated with the existing use pattern.
The nervous system is the main target of emam ectin benzoate, with neuropathology detected in many studies and several species. The dose/resp onse curve was very steep in several studies (most notably with CF-1 mice and dogs), w ith 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 reprodu ctive toxicity study and in the developmental neurotoxicity study. Review of acceptable onco genicity and mutagenicity studies provide no indication that emamectin is carci nogenic 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-resp onse curve, severity of effects at the LOAEL (death and neuropathology), and the use of a shor t-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 prot ective of all population subgroups.) The steepness of the dose-response curve and the seve rity 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 (a s opposed to a 10X) for th e following reasons: (1) A NOAEL was established in the 15-day neurotoxi city 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 th e existing registrations. The most recentchronic dietary-exposure assessment was performed in conjunction with the July 2008 humanhealth risk assessment conducted by HED. Howe ver, a new dietary assessment may be required during Registration Review to incorporate po tential changes to the emamectin benzoate estimated drinking water concentrations.

There are currently no registered reside ntial uses of emamectin benzoate.

There is sufficient information available to asse ss occupational handler exposure to emamectin benzoate. Occupational handler exposure has be en previously assessed for cotton, pome fruit, tree nuts, leafy vegetables (Brassica and non-Br assica), fruiting vegeta bles, turnip greens, tobacco, tree injection, and cock roach bait use. A new handler assessment will be needed if toxicity endpoints are revise d 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 To lerance 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 ta ble 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 B 1a 

### and maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B 1b 

### ), the associated 8,9- Z isomers (8,9- Z B 1a 

### +8,9- Z B 1b 

### ), or 4'-deoxy-4'-epi-amino-avermectin B 1a 

### and 4'-deoxy-4'- epi-amino-avermectin B 1b 

### ; 4'-deoxy-4'-epi-amino-avermectin B 1a 

### (AB 1a 

### ); 4'-deoxy-4'-epi- ( N -formyl- N -methyl)amino-avermectin (MFB 1a 

### ); and 4'-deoxy-4'-epi-( N-formyl)aminoavermectin B 1a 

### (FAB 1a 

### ).”

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 ta ble below. Compliance with the tolerance levels specified below is to be determined by measuring only the combined residues of emamectin (MAB 1a 

### +MAB 1b 

### ) and the associated 8,9- Z isomers (8,9- Z B 1a 

### +8,9- Z B 1b 

### ).”

There are no Codex or Canadian maximum residu e limits (MRLs). Mexico adopts US tolerances and/or Codex MRLs for its export purposes

.

Introduction

Emamectin benzoate is a semi-synthetic aver mectin, consisting of two active homologous compounds (a benzoate salt mixture of a minimum of 90% 4'-epi-methylamino-4'- deoxyavermectin B 1a 

### and a maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B 1b 

### ). Emamectin benzoate is an insecticide/ miticide developed for the control of lepidopteran insects.

### Page 4 of 40 Available mechanistic data indicate a neurotox ic mechanism of action, related to interference with gamma-aminobutyric acid (GABA)-mediated neurotransmission in mammals and glutamate-mediated neurotransmission in invert ebrates. 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 Emamect in and several metabolites are expected to be persistent and relatively immobile in the envir onment due to a high degree of sorption to soil particles; thus, parent and degradates of toxicological con cern are not expected to leach into ground water but may occur in surf ace 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 in jection. The terrestrial crops are treated with multiple foliar sprays, using ground equipment, airc raft, 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 (c ole crops), pome fruit, tree nuts including pistachios, and turnip greens (tops, leaves) fo r control of lepidopterous la rvae, 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 lepidop terous larvae (worms/caterpillars);

OptigardTM Cockroach Bait (EPA Reg. N o. 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 commerci al and industrial areas;

and Emamectin Benzoate 4.0% Tree Injecti on (EPA Reg. No. 100-1309), an emulsifiable concentrate (EC) formulation co ntaining 4% ai, equiva lent to 0.36 lb ai/gal, registered for injection into ornamental/nonbearing trees (d eciduous, coniferous, and palm trees) to control arthropod pests.

Proclaim® Insecticide, Denim® Insecticide, an d Emamectin Benzoate 4.0% Tree Injection are restricted use pesticides for us e only by certified applicators. OptigardTM Cockroach Bait is to be used only in commercial and industrial areas.

HED has conducted four human health risk assess ments 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 w ith 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 tob acco 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 re gistered use; therefor e, 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 sufficien t to characterize the hazard to humans, to conduct an FQPA assessment, and to select toxic ity 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 requirem ent guidelines, immunotoxicity data (OPPTS 870.7800) are required. A subchronic inhalati on study (OPPTS 870.3465) is also required to better assess inhalation risks a ssociated with emamectin use.

Emamectin is a semi-synthetic avermectin and is a member of the naturally derived complex of 16-membered macrocyclic lactones, which includ e abamectin, avermectin, and ivermectin. The available mechanistic data on these compounds indi cate that they have high-affinity binding to glutamate-gated chloride ion channels in inverteb rate nerve and muscle cells leading to paralysis and death (Lankas et al., 1997). In the mammalia n toxicity studies submitted by the registrant, ataxia, tremors or paralysis ar e also common findings prior to moribund sacrifice. In mammals, this group of chemicals is reported to be exclude d 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 toxi city due to deficiency in P-glycoprotein (Pgp).

The main target organ for emamectin is the ne rvous 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 stee p 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 qualitativ e and/or quantitative sensitivit y of rat pups was seen in the reproductive toxicity and in the deve lopmental neurotoxicity studies.

The carcinogenicity and mutage nicity studies provide no in dication that emamectin is carcinogenic or mutagenic. Emamectin is classi fied as “not likely to be carcinogenic to humans.” A toxicity profile for em amectin is presented in Appendix A.

The acute toxicity studies indicate that emamectin has low to moderate ac ute 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 Te chnical 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 fo r the possibility that a change in manufacturers and technical registrations could re sult in a different acute toxic ity outcome, while the technical compound itself had not changed. Detailed inform ation 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 t oxicity endpoints and points of departure for risk were selected from the results of th e 15-day CF-1 mouse oral toxicity study. No new toxicity studies have been submitted since 2003, a nd 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-gene ration reproduction study and in the pups of the developmental neurotoxicity study. In the re production 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 animal s 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 extensi on, 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-generati on reproduction and developmental neurotoxicity studies. The reasons are as follows:



## · For the 2-generation reproduction study, (1) th ere was a clear NOAEL for the offspring toxicity, (2) effects unique to o ffspring (decreased fertility in F 1 

### adults, and clinical signs [tremors and hind limb extensions during and fo llowing lactation]) were seen at the same dose that caused parental systemic to xicity (decreased body weight gain and histopathological lesions in the brain and spinal cord), and (3) the decreased fertility seen in F 1 

### adults might have been due to histopatholog ical lesions in the br ain and central nervous system (seen in both F 0 

### and F 1 

### generations), rather than du e to a direct effect on the reproductive system.



## · For the developmental neurotoxicity study, (1) although multiple offspri ng effects (including decreased pup body weight, head and body tremor s, 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 ot her 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 toxicit y, the 10X FQPA safety factor (SF) is retained for chronic assessments while a 3X FQPA SF is ad equate for acute assessments.

A 10X FQPA SF has been retained for the ch ronic/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 impor tantly 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 severi ty of effect at the LOAEL (death and neuropathology). For future risk assessment, the a dditional 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 enti re 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 neurotox icity screening battery and developmental neurotoxicity are available for consideration. At th e 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 stud y 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 (UF DB 

### ) does not need to be applied at this time. However, an immunotoxicity study is specifically designed to de tect any deficit in the ability of the immune system to respond to a challenge (chemical).

Inhalation

Since no inhalation studies are available, th e Agency selected an oral NOAEL of 0.075 mg/kg/day established in the 15-da y neurotoxicity study in mice for inhalation risk assessments. Therefore, a 28-day subchronic i nhalation 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 quantifie d. 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 respirat ory 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 inha lation toxicity study (speci fically the strain of test animal to be used). The Agency still ma intains that this study should be conducted in the most sensitive strain of mice (i.e., th e CF-1 homozygous mdr 1a (-/-) mice).

### Page 8 of 40 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of its most recent registration decision, EPA reviewed these data and selected the most sensitive endpoi nts 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 screeni ng part of the Endocrine Disrup tor Screening Program (EDSP).

EPA has developed the EDSP to determine whet her 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 ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e statutorily required determinations. Tier 1 consists of a battery of 11 scr eening assays to identify the potential of a chemical substance to interact with the estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects 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 in gredients and 9 inert ingredients. Emamectin benzoate is not among the group of 58 pesticide active ingredients on th e 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 polic ies and procedures, the list of 67 chemicals, future lists, th e test guidelines and th e Tier 1 screening ba ttery, 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 conduc ted. Additionally, a subchronic (28-day) inhalation toxicity study (OPPTS 870.3465) is required to ade quately characterize toxicity via the inhalation route. During registration review, the points of departure an d safety factors used for risk assessment purposes should be reexamin ed based on current HED policy, as well as all new data received.

### Page 9 of 40 Residue Chemistry

Agricultural uses include cotton, pome fruit, tree nuts, leafy vegetables (Brassica and nonBrassica), fruiting vegetables, and tobacco. Tolerances are establ ished under 40 CFR §180.505 for various plant and livestock (except poultry) commodities as shown in Attachment 2.

The emamectin benzoate end-use product formulati ons registered on agricu ltural 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 gr ound equipment, aircraft, or airblast equipment (for orchards).

Adequate plant metabolism studies on lettuce, ca bbage, and sweet corn are available. Adequate ruminant (goat) and poultry metabolism studies are available. An adequate confined rotational crop study is available. Residues of c oncern are summarized in Table 1 below.

Adequate field trials are availa ble to support registered uses. Adequate enforcement methods (high performance liquid chromatography [HPLC] w ith 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 re gistered uses because the calculated dietary burden for poultry is low. Based on the confined rotational crop study, ther e is no indication that emamectin residues of concern would accumulate (>0.01 ppm) in rotational crops; therefore, no plantback restrictions are need ed on the product labels. Adequa te storage stability data are available to support storage conditions for plant and livestock studies.

Table 1. Summary of Metabolites and Degradat es 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 (MAB 1a + MAB 1b ), the associated 8,9-Z isomers (8,9-ZB 1a + 8,9- ZB 1b ), and metabolites/degradates AB 1a , MFB 1a and FAB 1a emamectin (MAB 1a + MAB 1b ), the associated 8,9-Z isomers (8,9-ZB 1a + 8,9- ZB 1b ), and metabolites/degradates AB 1a , MFB 1a and FAB 1a Rotational Crops Same as for primary crops Same as for primary crops

Livestock Ruminant emamectin (MAB 1a + MAB 1b ) and its 8,9-Z isomers (8,9- ZB 1a and 8,9-ZB 1b ) emamectin (MAB 1a + MAB 1b ) and its 8,9-Z isomers (8,9- ZB 1a and 8,9-ZB 1b )
Poultry Not applicable Not applicable

### Page 10 of 40 Table 1. Summary of Metabolites and Degradat es to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression
Drinking Water emamectin (MAB 1a + MAB 1b ), the associated 8,9-Z isomers (8,9-ZB 1a + 8,9- ZB 1b ), and metabolites/degradates AB 1a , MFB 1a and FAB 1a 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 (f ood 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, Ve rsion 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 anticipat ed residues. Refinements for both the acute and chronic assessments included percent crop tr eated (% CT) for some crops (as shown in Attachment 3), use of DEEM default processi ng factors where appropriate, chemical-specific processing factors for apple and pe ar juice, and anticipated residue s 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 concentr ations (EDWCs) were derived using the Tier II PRZM/EXAMS model. The Tier 1 Screenin g Concentration in Ground Water (SCI-GROW) model was used to derive the ground water ED WCs. Based on sorpti on to soil particles, significant concentrations of pare nt or degradates of toxicological concern are not expected to leach into ground water. The estimated residu es in drinking water were based on use of emamectin benzoate in a Pe nnsylvania apple orchard.

The acute dietary exposure estimates for food and drinking water using the pome fruit crop group scenario for drinking water are be low HED’s level of concern at the 99.9 th 

### 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 f ood and drinking water us ing 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. populatio n 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 requi red during Registration Review to incorporate potential changes to the emamectin benzoate estimat ed drinking water concentrations.

Residential Exposure

Residential Handlers/Resi dential Post-Application

No residential exposure is expected from the regi stered products since they are agricultural uses rather than residential uses, re stricted use products (restricted to use by certif ied applicators only), or limited to non-residential areas (commercial and industrial areas).

Residential Bystander Post-Appl ication Inhalation Exposure

Based on the Agency's current practices, a quant itative residential bystander post-application inhalation exposure assessment has not been perfor med for emamectin benzoate at this time. However, volatilization of pestic ides 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 volat ilization 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/SA P/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, s ubsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments. If ne w policies or procedures are put into place, the Agency may revisit the need fo r a quantitative post -application inhalati on exposure assessment for emamectin benzoate.

Spray Drift

Spray drift is always a potential source of expos ure to residents nearby to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be a potential source of exposure from the gr ound 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 a nd other parties to devel op the best spray drift management practices (see the Agency’s Spra y 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 comp leted 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 appropriate ly apply the data and the AgDRIFT ® 

### computer model to its risk assessments for pe sticides applied by air, orch ard 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 drif t with specific products with significant risks associated with drift.

Aggregate Risk Assessment

The acute aggregate risk assessm ent takes into account exposur e estimates from dietary (food and drinking water) consumption of emamectin as discussed above.

Short- and intermediate-term aggregate risk as sessments 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 drin king water) and residential uses. However, residential exposures are not expected; therefor e, the chronic aggregate risk assessment will consider only exposure from food and dr inking 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 (i ncluding 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, a nd as a tree injection (Emamectin Benzoate 4.0% Tree Injection) fo r use in ornamental/nonbearing trees (deciduous, coniferous, and palm).

Three registered end-use formulations (Procl aim® Insecticide, Denim® Insecticide, and Emamectin Benzoate 4.0% Tree Injection) are rest ricted use pesticides for use only by certified applicators. OptigardTM Cockroach Bait is no t a restricted use pr oduct (RUP) but EPA has indicated that it is to be used onl y in commercial and industrial areas.

Except for OptigardTM Cockroach Bait, all regist ered 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 we re available with whic h to assess potential exposure to pesticide handlers. Table 5.1 lists th e occupational handler scenarios for each use site and the corresponding MOEs (indicating whether or not each s cenario 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 expo sure 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-appl ication dermal risk assessment. Occupational postapplication exposures following crack and crev ice treatment and tree in jection treatment are not expected.

Based on the Agency's current practices, a quant itative occupational post- application inhalation exposure assessment has not been performed for emamectin at this time. However, there aremultiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fiel ds. These potential sour ces include volatilization of pesticides and resuspension of dusts and/or pa rticulates that contain pesticides. The Agency sought expert advice and input on is sues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rode nticide 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/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post-applicat ion inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures to identify the need for and, s ubsequently, the way to incorporate occupational post-application inhalation exposur e into the Agency's risk asse ssments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation expos ure assessment for emamectin. Public Health and Pesticide Epidemiology Data

OPP Incident Data System (IDS)

### Page 14 of 40 There were two minor cases repo rted 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 incident s) 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 i nvolving emamectin benzoate reported to the IDS, and they were of low severity. Based on the low frequency and se verity of incident cases, there does not appear to be a concern at this time that would warra nt 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 ju stice concerns, to the extent po ssible, were considered in the human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d 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-esta blished procedures. In line with OPP policy, HED estimates risks to population subgroups fr om pesticide exposures that ar e based on patterns of that subgroup’s food and water consumption, and activ ities in and around the home that involve pesticide use in a residential se tting. 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 fo od 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 di etary exposure to smaller, specialized subgroups and exposure assessments are performed when c onditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for t oddlers, youths, and adults enteri ng or playing on treated areas postapplication are evaluated. Further considerat ions are currently in development as OPP has committed resources and expertise to the developm ent of specialized software and models that consider exposure to bystanders and farm worker s as well as lifestyle and traditional dietary patterns among specific subgroups.

### Page 15 of 40 Cumulative

Unlike other pesticides for which EPA has fo llowed 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 substa nces. 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 ha ve 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 ha ve a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Human Studies

The risk assessments which have been previous ly conducted for emamectin benzoate have relied in part on data from studies in which adult hum an subjects were inte ntionally exposed to a pesticide to determine their dermal and inha lation exposure. Many such studies, involving exposure to many different pesticides, comprise ge neric 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 ev idence that the conduct of any of them was either fundamentally unethical or significantly deficient relati ve 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 c ontinued reliance on these studies.

Data Requirements

The following data deficiencies were require d as conditions of registration and remain outstanding or are required under current guidelines:

Toxicology

870.3465 Subchronic Inhalation

• A subchronic inhalation study is needed. HE D 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 em amectin 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 Benz oate: Review of Human Incidents. N. Dodd 382030 2/15/11 Emamectin Benzoate. Storage Stability Data on Almonds. R. Prieto --- 12/7/10 Usage/Use Repor t Package in Support of Registration Review for Emamectin Benzoate (122806). J. Arthur 360697 1/21/09 Revised. Emam ectin 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 Benzoa te. 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 a nd 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 Ve getables, Cotton and Pome Fruits. Summary of Analytical Chemistry and Residue Data. A. Grube 354010 7/8/08 Usage Report in S upport 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 Be nzoate; 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 Ri sk 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. S ection 3 Registration for Emamectin in/on Brassica Leafy Vegetables, Fruiting Vegetables, Leafy Vegetables, Cotton, and Tobacco. J. Arthur 281275 3/12/03 Revised Occupati onal 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: Eval uation 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 T obacco. Evaluation of Analytical Method and Magnitu de of the Residue Data to Support Permanent Toleran ces 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., Do uglas, 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) Anticonvulsa nt and adverse effects of av ermectin 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 B 1a 

### binds to high- and low-a ffinity sites with dual effects on the gama-aminobutyric acid-gated chloride channel of cultured cer ebellar granule neurons. J. Pharmacol. Exp. Ther. 281: 261-266.

Kerb R (2006) Implication of genetic polymorphi sm in drug transporters for pharmacotherapy. Cancer Lett. 234: 4-33.

Kerr DI and Ong J. (1986) Gama-aminobutyric ac id-dependent motility induced by avermectin B 1a 

### in the isolated intestine of the gu inea pigs. Neurosci. Lett. 65: 7-10.

Lankas GR, Cartwright ME, a nd Umbenhauer D (1997) P-Glycopr otein deficiency in a subpopulation of CF-1 mice enhances averm ectin-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 neur ons of the hypothalamus that regulate feeding behavior and body weight. P hysiol. Behav. 92: 263-271.

Nguyen L, Rigo JM, Rocher V, Belachew S, Malg range B, Rogister B, Leprince P, Moonen G. (2001) Neurotransmitters as early signals fo r central nervous system development. Cell Tissue Res. 305: 187-202.

Pong SS, DeHaven R, Wang CC. (1982) A comparative study of avermectin B 1a 

### and other modulators of the gama-aminobutyric recepto r- chloride ion channel complex. J. Neurosci. 2: 966-971.

Report (3 rd 

### ) of Hazard Identification Assessment Review Committee; TXR No. 0051605; March 5, 2003.

Report of the Hazard Identification Assessm ent 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 Tabl e 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 B 1 IUPAC name Mixture of ≥ 90% (10 E ,14 E ,16 E )-(1 R ,4 S ,5' S ,6 S ,6' R ,8 R ,12 S ,13 S ,20 R ,21 R ,24 S )-6'- [( S )- sec -butyl]-21,24-dihydroxy-5',11,13,22-tetramethyl-2-oxo-(3,7,19- trioxatetracyclo[15.6.1.1 4,8 .0 20,24 ]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- O

methyl-4-methylamino- α -L- lyxo -hexapyranosyl)- α -L- arabino -hexapyranoside and ≤ 10% (10 E ,14 E ,16 E )-(1 R ,4 S ,5' S ,6 S ,6' R ,8 R ,12 S ,13 S ,20 R ,21 R ,24 S )-21,24- dihydroxy-6'-isopropyl-5',11,13,22-tetramethyl-2-oxo-(3,7,19- trioxatetracyclo[15.6.1.1 4,8 .0 20,24 ]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- O

methyl-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

B 1a = NOA426007;
B 1b = NOA422390

OCH 3

O O O

O CH 3
OH CH

3 O CH 3 CH 3 R1

O O H 3 CO

O

O CH

3 CH 3

OH CH 3

N H CH

3

B 1a Component: R1 = CH 2 CH 3 B 1b Component: R1 = CH 3

### 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 B 1a = NOA438376

Chemical structure of AB 1a metabolite

L’649 = NOA438309 COO OCH 3

O O O

O CH 3
OH CH

3 O CH 3 CH 3 R1

O O H 3 CO

O

O CH

3 CH 3

OH CH 3

H 3 CH 2 N +

B 1a Component: R1 = CH 2 CH 3 B 1b Component: R1 = CH 3

CH 3
OH OH OCH 3

O O CH 3 O CH 3 CH 3

O O H 3 CO

O

O CH

3

NH CH 3

CH

3 R

O

O CH

3

B 1a Component: R = CH 2 CH 3 B 1b Component: R = CH 3

OCH 3

O O O

O CH 3 CH 3

OH CH

3 O CH 3 CH 3

O O H 3 CO

O

O CH

3

NH 2 H 3 CH 2 C

CH 3

OH

### Page 22 of 40 Table 1. Chemical Identity – Emamectin, Emamectin Benzoate, and Metabolites/Degradates

Chemical structure of MFB 1a metabolite

L’599 = NOA415692

Chemical structure of FAB 1a metabolite

L’831 = NOA415693 OCH 3

O O O

O CH 3 CH 3

OH CH

3 O CH 3 CH 3

O O H 3 CO

O

O CH

3

N H 3 CH 2 C

CH 3

H O

CH 3

OH

OCH 3

O O O

O CH 3 CH 3

OH CH

3 O CH 3
O O H 3 CO

O

O CH

3

NH H 3 CH 2 C

CH 3

H O

OH

### Page 23 of 40 Attachment 2 Tolerance Summary Table

Table 2. Summary of US and International Tol erances and Maximum Residue Limits for Emamectin Benzoate

Residue Definition US [40 CFR §180.505(a)(1)] US Canada Mexico 1 Codexemamectin (a mixture of a minimum of 90% 4'-epimethylamino-4'-deoxyavermectin B 1a and maximum of 10% 4'-epi-methylamino-4'-deoxyavermectin B 1b ) and its metabolites 8,9-isomer of the B 1a and B 1b component of the parent (8,9-ZMA), or 4'-deoxy-4'-epi-amino-avermectin B 1a and 4'-deoxy-4'-epi- amino-avermectin B 1b ; 4'-deoxy-4'-epiamino avermectin B 1a (AB 1a ); 4'-deoxy-4'-epi-( N -formyl- N

methyl)amino-avermectin (MFB 1a ); and 4'-deoxy-4'-epi- N

formyl)amino-avermectin B 1a (FAB 1a ) None None

Commodity Tolerance (ppm) /Max imum 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 Mexico 1 Codex Livestock: emamectin (MAB 1a + MAB 1b isomers) and the associated 8,9-Z isomers (8,9-ZB 1a + 8,9-ZB 1b ) 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) /Max imum 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 Mexico 1 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 Poin ts 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 Assessments 1, 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 UF A = 10x UF H = 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 UF A = 10x UF H = 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 UF A = 10x UF H = 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 UF A = 10x UF H = 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. DermalIntermediateTerm (1-6 months) NOAEL = 0.075 mg/kg/day UF A = 10x UF H = 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 UF A = 10x UF H = 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 Assessments 1, 2 Exposure/ Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level of Concern for Risk Assessment Study and Toxicological Effects

InhalationIntermediateTerm (1-6 months) NOAEL = 0.075 mg/kg/day UF A = 10x UF H = 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 dete rmine risk associated with lo wer environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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 a nd Endpoints for Emamectin Benzoate for Use in Occupational Human He alth Risk Assessments 1, 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%) UF A = 10x UF H = 10x UF M = 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. DermalIntermediateTerm (1-6 months) NOAEL = 0.075 mg/kg/day (dermal absorption rate = 1.8%) UF A = 10x UF H = 10x UF M = 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) UF A = 10x UF H = 10x UF M = 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 a nd Endpoints for Emamectin Benzoate for Use in Occupational Human He alth Risk Assessments 1, 2 Exposure/ Scenario Point of Departure Uncertainty Factors Level of Concern for Risk Assessment Study and Toxicological Effects

InhalationIntermediateTerm (1-6 months) NOAEL = 0.075 mg/kg/day (assumed equivalent to oral absorption) UF A = 10x UF H = 10x UF M = 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 dete rmine risk associated with lo wer environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF M = Modifying factor to account for the steepness of the dose-response curve, se verity 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 A ttachment 5 Occupational Exposure Tables

Table 5.1. Occupational Expo sure 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 Expo sure 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 Us e – Cockroach Bait

Cockroach bait Syringe or bait injector Ready-To-Use 0.10% 4.9E-07 lb ai/ft 2 NA 26,000 dermal; 1,100,000 inhalation NA 341633

1 EC = emulsifiable concentrate; WDG = water dispersible granule.
2 Bold numbers are calculated usin g 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 lev el of concern = 100.

Table 5.2. Occupational Post-Applicat ion Exposure Scenarios for Emamectin

Use Site (TC Group) Activity Dermal TC 1 (cm 2 /hr) Day After App. DFR 2 (ug/cm 2 ) PostApplication

Dermal MOE 3 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
320799 1 0.017 720
2 0.0084 1400

Tree Nuts (tree, “nut”) hand harvesting, hand pruning, thinning 2500 0 0.034 430
347923 1 0.017 870
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 ch emical exposure to produc e 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 infec tions such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or ne oplasia. Because the immune sy stem is highly complex, studies assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential immunotoxicity. These data will be used in combin ation with data from he matology, 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 endpoint s and doses for use in risk assessment of all exposure scenarios and are considered a primary data source fo r 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 or al reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Ag ency'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 ch aracteristics of a gas, volatile substance, or aerosol/particulate, determination of subchronic in halation 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-obser ved 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 fr om 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 concentratio n 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 pa rticle size. In addition, the acute inhalation toxicity category for emamectin is II, and in a 5-day preliminary inhalation stud y, 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 end points 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 Ag ency’s future decision-making?

The Agency does not have a full pict ure 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 – Em amectin Benzoate Technical (EPA Reg. No. 100-902)

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute oral - Rats 42851519 LD 50 for L-656,748- 038 = 53 mg/kg II

870.1200 Acute dermal - Rabbits (EC) 43850111 LD 50 > 2.0 g/kg III

870.1300 Acute inhalation - Rats 43868101 0.44 mg/L <LC 50 <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 LD 50 for L-656,748- 038 = 53 mg/kg II

870.1200 Acute dermal - Rabbits (EC) 47002106 LD 50 > 2.0 g/kg III

870.1300 Acute inhalation - Rats 47002107 LC 50 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 Emamectin 2, 3

Guideline No Study Type MRID No. (Year)/ Classification/Doses Results

Acute dermal toxicity study (Not a LD 50 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 LD 50 > 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 Emamectin 2, 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 an imals 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/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 ef ficiency in males.

No treatment-related increase in tumor incidence

### Page 36 of 40 Table A. 1. 3. Repeated Dosing and Other Studies on Emamectin 2, 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 (F 0 & F 1a 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 F 0 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 - SalmonellaMK-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 Emamectin 2, 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); clin ical 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 vacuola tion in brain and spinal cord; degeneration of nerve fiber in spinal cord and sciatic nerves. Skelet al 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

### Page 38 of 40 Table A. 1. 3. Repeated Dosing and Other Studies on Emamectin 2, 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- 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”-epimethylaminoavermectin B1adelta-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”-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 4285150 4 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 plantmetabolite 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 post ure 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 Emamectin 2, 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 aminoderivative 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 [ 14 C] 4”-deoxy-4’- epi-methylamino avermectin B1a benzoate, (MAB1a) 42851523 & 42852524 (1993) Acceptable Radiolabeled MAB1a benzoate is rapidly absorbed, distributed an d 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 abenzoate 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-0243solvate 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 administ ration 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 af ter 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