ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 1 of 58 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION**  **PREVENTION MEMORANDUM**  **Date :**  1 2/20 /12 **SUBJECT: Abamectin. Human Health Risk Assessment for Uses of**  **the SC Formulation** 

**on Cotton and Strawberry PC Code:**  122804 **DP Barcode:** D402677 , D405843 **Decision No.:** 463021 , 463020 **Registration No s**  **. :**  100 - 1351, 100 - 1408 **Petition No .:**  2F8009 **Regulatory Action:** Section 3 Registration **Risk A**  **ss essment Typ**  **e :**  Single Chemical/Aggregate **Case No.: NA**  **T XR No.:**  NA **CAS No.:** 71751 - 41 - 2 **MRID No.:** NA **40 CFR:** 180.449 **FROM:** Nancy

Dodd, Chemist/Risk Assessor Whang Phang, Toxicologist Nancy Tsaur, Chemist Risk Assessment Branch III (RAB3) Health Effects Division (HED) (7509P) **THROUGH:** Jeff Dawson, Acting Branch Chief

Risk Assessment Branch III (RAB3) Health Effects Division (HED) (7509P) **TO:** John Hebert/Jessica Rogala, RM#7

Registration Division (7505P) The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments , as needed, to estimate the risk to human health that will result from the proposed use s of abamectin, also known as avermectin B 1 [a mixture of avermectins containing ≥80% avermectin B 1a (5 - O - demeth yl avermectin A 1 ) and ≤20% avermectin B 1b (5 - O - demeth yl - 25 - de (1 - methylprop yl ) - 25 - (1 - methylethyl) avermectin A 1 )], and its delta - 8,9 - isomer , as the suspension concentrate (SC) formulation on cotton and strawberry . Although tolerances are established for abamectin on cotton and strawberry based on use of the emulsifiable concentrate (EC) formulation, h igher tolerances are needed to support use of the SC formulation since higher residues occur red on cotton and strawberry as a result of use of the SC formulation as compared to use of the registered EC formulation. Higher residues occurred in cotton and strawberry even though an adjuvant was used with the SC formulation;ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 2 of 58 the adjuvant was used with the SC formulation to increase photoly tic degradation of abamec tin and thereb y reduce residues, as has been observed wi th the SC formulation of abamectin on other crops. HED evaluated the abamectin petition and determined that potential exposure could occur via the dietary (food and drinking water), residential, and occupational exposure pathway s. HED determined that the re is reasonable certainty that no harm will result to the general population and to infants and children from aggregate exposure resulting from the proposed uses on cotton and strawberry . A summary

of the findings and an assessment of human health risk r esulting from the registered and proposed uses for abamectin are provided in this document. The HED team members contributing to this risk assessment include: Nancy Dodd (risk assessment/residue chemistry review/dietary

exposure assessment), Nancy Tsaur ( occupational/residential exposure assessment), and Whang Phang (toxicology assessment). Greg Orrick of the Environmental Fate & Effects Division (EFED) provided the drinking water exposure assessment.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 3 of 58 **TABLE OF CONTENTS 1.0**  **Executive Summary ................................**  **................................ ................................**  **........... 5**  **2.0 HED Recommendations**  **................................ ................................**  **................................ ....**  **8 2.1**  **Data Deficiencies ................................**  **................................ ................................**  **............ 8**  **2.2 Tolerance Considerations**  **................................ ................................**  **.............................. 9**  **2.2.1 Enforcement Analytical Method**  **................................ ................................**  **............... 9**  **2.2.2 Recommended Tolerances**  **................................ ................................**  **......................... 9**  **2.2.3 Revisions to Petitioned**  **- For**  **Tolerances ................................**  **................................ ....**  **9 2.2.4**  **International Harmonization ................................**  **................................ ...................**  **10 2.3**  **Label Recommendations ................................**  **................................ ..............................**  **10 2.3.1**  **Recommendations from Residue Reviews ................................**  **.............................. 10**  **2.3.2 Recommendations from Occupational Assessment**  **................................ ...............**  **10 2.3.3**  **Recommendations from Residential Assessment ................................**  **................... 10**  **3.0 Introduction**  **................................ ................................**  **................................ ......................**  **10 3.1**  **Chemical Identity**  **................................ ................................**  **................................ .........**  **12 3.2**  **Physical/Chemical Characteristics ................................**  **................................ .............**  **13 3.3**  **Pesticide Use Pattern ................................**  **................................ ................................**  **.... 13**  **3.4 Anticipated Exposure Pathways**  **................................ ................................**  **................. 15**  **3.5 Consideration of Environmental Justice**  **................................ ................................**  **.... 15**  **4.0 Hazard Characterization and Dose**  **- Response Assessment**  **................................ ..........**  **16 4.1**  **Summary of Toxicological Effects ................................**  **................................ ..............**  **16 4.2**  **Safety Factor for Infants and Children (FQPA Safety Factor) ...............................**  **17 4.2.1**  **Completeness of the Toxicology Database ................................**  **.............................. 17**  **4.2.2 Evidence of Neurotoxicity**  **................................ ................................**  **........................ 18**  **4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  **........ 18**  **4.2.4 FQ**  **PA Safety Factor for Infants and Children**  **................................ ......................**  **22 4.2.5**  **Residual Uncertainty in the Exposure Database ................................**  **................... 23**  **4.3 Toxicity Endpoint and Point of Departure Selections**  **................................ ..............**  **24 4.4**  **Endocrine Disruption ................................**  **................................ ................................**  **... 29**  **5.0 Dietary Exposure and Risk Assessment**  **................................ ................................**  **......... 30**  **5.1 Residues of Concern Summary and Rationale**  **................................ ..........................**  **30 5.2**  **Food Residue Profile ................................**  **................................ ................................**  **.... 32**  **5.3 Water Residue Profile**  **................................ ................................**  **................................ ..**  **35 5.4**  **Dietary Risk Assessment ................................**  **................................ ..............................**  **36 5.4.1**  **Description of Residue Data Used in Dietary Assessment ................................**  **.... 36**  **5.4.2 Percent Crop Treated Used in Dietary Assessment**  **................................ ..............**  **36 5.4.3**  **Acute Dietary Risk Assessment ................................**  **................................ ...............**  **37 5.4.4**  **Chronic Dietary Risk Assessment ................................**  **................................ ...........**  **37 5.4.5**  **Cancer Dietary Risk Assessment ................................**  **................................ .............**  **37 5.4.6**  **Summary Table ................................**  **................................ ................................**  **......... 38**  **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  **............................. 38**  **6.1 Residential Handler Exposure**  **................................ ................................**  **.................... 39**  **6.2 Residential Post**  **- Application Exposure**  **................................ ................................**  **...... 41**  **6.3 Spray Drift**  **................................ ................................**  **................................ ....................**  **41**ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 4 of 58 **7.0 Aggregate Exposure/Risk Characterization**  **................................ ................................**  **.. 42**  **7.1 Acute Aggregate Risk**  **................................ ................................**  **................................ ...**  **42 7.2**  **Short -**  **and Intermediate -**  **Term Aggregate Risk ................................**  **........................ 42**  **7.3 Chronic Aggregate Risk**  **................................ ................................**  **.............................. 43**  **7.4 Cancer Aggregate Risk**  **................................ ................................**  **................................ 43**  **8. 0**  **Cumulative Exposure/Risk Characterization ................................**  **............................... 43**  **9.0 Occupational Exposure/Risk Characterization**  **................................ ............................**  **44 9.1**  **Short -** **/Intermediate -**  **Term Handler Risk ................................**  **................................ ...**  **45 9.2**  **Short -** **/Intermediate -**  **Term Post -**  **Application Exposures and Risks**  **........................ 47**  **10.0 References**  **................................ ................................**  **................................ .........................**  **48 Appendix A. Toxicology Profile and Executive Summaries**  **................................ ..................**  **49 A.1**  **Toxicology Data Requirements ................................**  **................................ ...................**  **49 A.2**  **Toxicity Profiles ................................**  **................................ ................................**  **............ 50**  **Appendix B. Toxicology Literature References ................................**  **................................ ......**  **55 Appendix C. Physical/Chemical Properties**  **................................ ................................**  **............. 56**  **Appendix D. Review of Human Research ................................**  **................................ ...............**  **57 Appendix E. International Residue Limits Table**  **................................ ................................**  **... 58** ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 5 of 58 **1.0 Executive Summary**  **Use Profile :**  Abamectin is a mixture of avermectin B 1 [a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O - demethyl avermectin A 1 ) and less than or equal to 20% avermectin B 1b (5 - O - demeth yl - 25 - de(1 - methylpropyl) - 25 - (1 - methylethyl) avermectin A 1 )] and its delta - 8,9 - isomer. Abamectin is a natural fermentation product of the soil bacterium Streptomyces avermitilis. Abamectin is an insecticide/miticide used to control mites, leaf mine rs, and other insects in commercially important crops. Abamectin acts as an insecticide by interfering with the nervous sy stem of the insect, causing the insect to become paral yz ed. Sy ngenta Crop Protection, LLC has submitted a petition to increase the established permanent tolerances on cotton and strawberry , and to add uses on cotton and strawberry to Agri - Mek® SC Miticide/Insecticide (EPA Reg. No. 100 - 1351) and Epi - MekTM SC Miticide/Insecticide (EPA Reg. No. 100 - 1408) labels . Cotton and strawberry us es are currently registered on emulsifiable concentrate (EC) labels. The established tolerances are based on residue data using the EC formulation. Residues from c rop field trials using the suspension concentrate (SC ) formulation of abamectin plus adjuvant are higher than the established tolerances on cotton and strawberry , which are based on the EC formulation ; therefore, higher tolerances are needed for use of the SC formulation on cotton and strawberry . The petitioner has proposed am endm ent o f th e es t ab l i she d t o lerance s f o r co mb in e d r es id

ue s o f th e in s ec t i c ide av e r

m ec t in B 1 ( a mi xtur e o f av e r m ec t ins cont a ini n g gr eat e r than o r equa l t o 80 % av e r m ec t in B 1a ( 5 - O - de m e th y l av e r m ec t in A 1 ) an d le s s than o r equa l t o 20 % av e r m ec t in B 1 b ( 5 - O - de m e th y

l - 25 - de ( 1 - m e thylpro p yl) - 25 - ( 1 - m e thylethyl) av e r m ec t in A 1 ) ) an d i t s de l t a 8 , 9 - is o m e r to increase the tolerance s on cotton, undelinted se ed from 0.005 ppm to 0.015 ppm; on cotton, gin b y - products from 0.15 ppm to 1.0 ppm; and on strawberry from 0.02 to 0.06 ppm. **H uman Health Risk Assessment:**  **Toxicity/Hazard:** Abamectin has high to moderate acute toxicity by the oral route (depending on the vehicle), high acute toxicity by the inhalation route, and low acute toxicity by the dermal route. It is slightly

irritating to the skin, but is not an ocular irritant or a dermal sensitizer. The main target organ is the nervous s ys tem, and the reduced body weight effect is one of the most frequent findings. Neurotoxicity and developmental effects were detected in multiple studies and species of test animals. The dose/resp onse curve is very steep in several studies, with severe effects (including death and morbid sacrifice) seen at dose levels as low as 0.4 mg/kg/day and 0.1 mg/kg/day in rats and mice, respectivel y , following repeated/chronic exposures . (For details, refer to Section 4. 2.4 .) Increased susceptibility (qualitative and/or quantitative) was seen in prenatal developmental toxicity studies in mice and rabbits, and an increase in quantitative and qualitative susceptibility

was seen in the rat reproductive toxicity study . Review of acceptable oncogenicity and mutagenicity studies provides no indication that abamectin is carcinogenic or mutagenic. The RAB3 Risk Assessment Team has evaluated the entire toxicity database of abamectin and determined that an additio nal 3x FQPA safet y factor is needed to address residual concerns as toABAMECTIN Human Health Risk Assessment DP No. D402677

Page 6 of 58 all risk assessments other than acute dietary . For all risk assessments involving repeat exposures, the selected toxicity

endpoint is based on the decrease in pup body weight seen in the developmental neurotoxicity study (2007) and three reproduction studies in the rat. With respect to acute dietary exposure , the endpoint selected for risk assessment is based on mydriasis observed in dogs. The additional 3x factor applied to chronic and other exposure scenarios is not applicable to acute exposure because steepness of the dose /response curve and severit y of effects were not seen in the studies where m ydriasis occurred. In addition, the reduced body weights as toxicity endpoints for oth er exposure scenarios are not a single dose effect. The immunotoxicity

study ( OCSPP 870.7800) is required to fulfill current 40 CFR Part 158 data requirements. However, the RAB3 toxicity team examined the entire database of abamectin and determined that an additional uncertainty factor is not needed to account for potential immunotoxicity . **Dietary Exposure (Food/Water)** : The residue chemistry and environmental fate data are adequate to assess human exposure. Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM - FCID), Version 3.16. Although tolerance - level re sidues and 100% crop treated were used for bulb onion, chives, dry bean, and okra, the acute and chronic dietary exposure assessments were refined assessments using anticipated or average residues derived from field trial data for most crops. Default proc essing factors and percent crop treated (%CT) were used as available. Estimated drinking water concentrations (EDWCs) were provided b y the Environmental Fate and Effects Division (EFED). T he maximum (acute) concentration of abamectin and its major soil d egradate (a mixture of an 8 - alpha - hy drox y and a ring opened aldeh yde derivative) in surface water is not likely to exceed 2.3 ppb. The mean (chronic) estimated surface water concentration is 1.3 ppb. The acute dietary

exposure estimates for food and drinking water are below HED’s level of concern [ <100% of the acute population adjusted dose ( aPAD) ] at the 99.9 th percentile of exposure. Abamectin dietary exposure at the 99.9 th percentile for food and drinking water is 1 5 % of the aPAD for the general U.S. population and 24 % of the aPAD for children 1 - 2 years old, the most highly

exposed population subgroup. The chronic dietary

exposure estimates for food and drinking water ar e below HED’s level of concern [ <100% of the chronic population adjusted dose ( cPA D) ] for the general U.S. population and all population subgroups. Abamectin dietary exposure f

or food and drinking water is 17 % of the cPAD for th e general U.S. population and 53 % of the cPAD for children 1 - 2 years old, the most highly

exposed population subgroup. **Residential Exposure** : There are no expected residential exposures from the proposed uses ; however, there are existing residential uses. A ll existing r esidential exposures have been reassessed to reflect updates to HED’s 2012 Residential Standard Operating Procedures ( SOPs ) along with policy

changes for body

weight assumptions. There are no registered products thatABAMECTIN Human Health Risk Assessment DP No. D402677

Page 7 of 58 would lead to an y residential handler or post - application risk estimates of concern. Short - term combined (dermal + inhalatio n) residential handler margins of exposure ( MOEs ) range from 320,000 to 1,100,000,000 . Residential post - application exposures are not expected. For outdoor treatments, adults and children are not expected to directly contact fire ant mounds. For indoor pest control, bait placements are intended to be placed in cracks and crevices where direct contact b y adults and children is unlikely. **Aggrega te Risk**  **:** For the proposed uses, human health aggregate risk assessments have been conducted for acute aggregate exposure (food + drinking water), short - /intermediate - term aggregate exposure (food + residential exposure + drinking water), and chronic aggre gate exposure (food + drinking water) scenarios. For short - /intermediate - term aggregate exposure, the residential levels of concern ( LOCs ) are 300 and the MOEs are greater than 300, and thus are not of risk concern. A cancer aggregate risk assessment was not performed because abamectin is classified as “not likel y t o be carcinogenic to humans.” All potential exposure pathway s were assessed in the aggregate risk assessment. None of the aggregate exposure and risk estimates exceed HED's level of concern. **Occupational Exposure/Risk :**  Based on the proposed uses, there is a potential for short - and intermediate - term occupational exposure to abamectin during handling activities (e.g. mixing, loading, applicatio n). The results of the occupational handler exposure and risk assessment indicate that short - and intermediate - term dermal and inhalation risks do not exceed HED’s LOC (i.e. , an MOE < 3 00) at some level of mitigation . The abamectin product labels direct mixers, loaders, applicators and other handlers to wear a long - sleeved shirt and long pants, chemical resistant gloves, and shoes plus socks . For short - and intermediate - term exposure, the combined (dermal + inhalation) MOEs for mixer/loader scenarios range from 150 to 2,300 at baseline level of cloth ing (single layer long - sleeved shirt, long pants, and shoes plus socks). With single layer plus gloves as required by the label, the lowest MOE of 150 increases to 600. All uses have acceptable MOEs given the proposed label requirements. For flaggers, the MOE is 2 , 700 at baseline (no gloves , no respirator). Onl y engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircrafts. For ground and aerial applicators , the MOEs range from 1,900 to 4,8 00 (no gloves, no r espirator). There is a potential for short - and intermediate - term occupational exposure during post application activities. Based on a post - application assessment of common agricultural practices, the proposed 12 - hour restricted entry interval ( REI ) on a ll the label s is acceptable. The post application MOEs do not exceed HED’s LOC of 300 (MOEs ranged from 1, 8 00 to 28 ,000) on day 0 (12 hours after application). Based on the Agency 's current practices, a quantitative non - cancer occupational post - application inhalation exposure a ssessment was not performed for abamectin at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inh alation exposure assessment for abamectin.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 8 of 58 **Environmental Justice Considerations:** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment. Dietary and non dietary exposures were considered. **Review of Human Re search**  **:** This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. As indicated in Appendix D, these studies have been determined to require a review of their ethica l conduct, and have received that review. **2.0 HED**  **Recommendations** Provided revised Sections B (O CSPP 860.1200) and F (O CSPP 860.1550) and an analy tical reference standard for 8 ,9 - Z avermectin B 1a (NOA427011) are submitted, HED can recommend for registration of abamectin for use of the SC formulation on cotton and strawberry and for permanent tolerances for the proposed uses on cotton and strawberry . Additional data are needed as outlined in Section 2.1 below. The specific tolerance recommendations are discussed in Section 2.2, and the label modifications are discussed in Section 2.3. **2.1 Data Deficiencies**  **Data that needs to be submitted prior to a tolerance being established or registration allowed**  R esid ue Chemistry 860.1200 Directions for Use Refer to Section 2.3 for label recommendations. 860.1550 Proposed Tolerances The petitioner should submit a revised Section F to propose tolerances of 0.02 ppm on cotton, undelinted seed and 0.05 ppm on strawberry . 860.1650 Submittal of Analy tical Reference Standards Because the suppl y has been depleted, the registrant must submit five grams of 8,9 - Z avermectin B 1a (NOA427011) to the EPA National Pesticide Standards Repository . Toxicology 870.7800 Immunotoxicity Under the current data requirement guidelines (40 CFR §158.500), the immunotoxicity study is required. The risk assessment team was initially informed that the registrant was committed toABAMECTIN Human Health Risk Assessment DP No. D402677

Page 9 of 58 conduct this study , but currentl y the registrant is pl anning to submit a data waiver for the immunotoxicity

study . **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  Adequate enforcement methods for abamectin in plant and livestock commodities are available in the Pesticide Analy

tical Manual, Volume II ( PAM II) . The methods have been validated for citrus and processed fractions (Method I), ginned cottonseed (Method IA), and bovine tissues and milk (Method II ). These methods determine residues in plant and livestock commodities at limits of quantitation (LOQs) of 0.02 ppm for meat and meat b yproducts and ≤0.01 ppm for other plant/livestock commodities. The limit of detection (LOD) of the methods for plant and livestock commodities is 0.001 ppm for each anal yte, equivalent to 0.002 ppm for two anal y te peaks (i.e., avermectin B 1a and its delta - 8,9 - isomer in one peak and avermectin B 1b and its delta 8,9 - isomer in the other peak). **2.2. 2**  **Recommended Tolerances** The current tolerance expression in 40 CFR §180.449 is consistent with the S. Knizner memo dated 5/27/09. Tolerances are established under 40 CFR §180.449 for residues of abamectin (avermectin), including its metabolites and degradates, in or on various crop and livestock commodities. Compliance with the tolerance levels is to be determined by measuring only avermectin B 1 [a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O - demethyl avermectin A 1 ) and less than or equal to 20% avermectin B 1b (5 - O - demeth yl 25 - de(1 - meth ylprop yl ) - 25 - (1 - methylethyl) avermectin A 1 )] and its delta - 8,9 - isomer. **Table 2.2.2**  **. Tolerance Summary for Abam**  **ectin .**  **Comm odity**  **Established Tolerance**  **(ppm) Syngenta**  ****

**Proposed Tolerance**  **(ppm) HED**  ****

**Recommended Tolerance**  **(ppm) Comments** 

**( correct commodity**  **definition )**  Cotton, undelinted seed 0.005 0.015 0.02 Cotton, gin by - products 0.15 1.0 1.0 Straw berry 0.02 0.06 0.05 **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** As shown in Table 2.2.2 above, HED is recommending slightl y different tolerance levels, as compared to S yn genta - proposed tolerance levels, for cotton, undelinted seed and strawberry . HED’s recommended tolerance levels are based on the Organization for Economic Co - operation and Development (OECD) tolerance calculation procedures .ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 10 of 58 **2.2. 4**  **International Harmonization** The tolerance expressions for the US, Codex, and Canada include the same anal yt es for plants . There are currently

maximum residue limits (MRLs) established by Codex on cotton seed at 0.01 ppm and by

Codex and Canada on s trawberry at 0.02 ppm. The US is recommending higher tolerances for both undelinted cotton seed (0.0 2 ppm) and strawberry (0.05 ppm) based on residue data on the SC formulation. Codex MRL s are established for use of the EC formulation. Higher tolerances are found in cotton and strawberry from use of the SC formulation and, therefore , the US tolerance levels cannot be harmonized with Codex MRLs , which are based on the EC formulation. Higher residues occurred in cotton and strawberry even though an adjuvant was used with the SC formulation; the adjuvant was used to increase photoly tic degradation of abamectin and thereb y reduce residues. An International Residue L imit Status sheet is attached (Appendix E). **2.3 Label Recommendations**  **2.3.1 Recommendations**  **from Residue Reviews** Both the Agri - Mek® SC Miticide/ Insecticide label [ EPA Reg. No. 100 - 1351 ] and the Epi - MekTM SC Miticide/ In secticide label [ EPA Reg. No. 100 - 1408 ] indicate under “Cotton” that 6.75 fl oz/A are 0.038 lb ai/A and under “Strawberries” that 14 fl oz/A are 0.075 lb ai/A . HED calculated that 6.75 fl oz/A are 0.037 lb ai/A and 14 fl oz/A are 0.077 lb ai/A . These calculations should be corrected on both labels. **2.3.2 Recommendations**  **from Occupational Assessment** Refer to Section 2.3.1. **2.3.3 Recommendations f**  **rom Residential**  **Assessment** Refer to Section 2.3.1. **3.0 In**  **troduction** Abamectin is a mixture of avermectin B 1 [a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O - demeth yl avermectin A 1 ) and less than or equal to 20% avermectin B 1b (5 - O - demethyl - 25 - de(1 - methylpropyl) - 25 - (1 - methylethyl) avermectin A 1 )] and its delta - 8,9 - isomer. Avermectins are macrocyclic lactones produced as natural fermentation products of the soil bacterium Streptomyces avermitilis. Abamectin is an insecticide/miticide used to control mites, leaf miners, and other insects in commerciall y important crops. Abamectin acts as an insecticide b y interfering with the nervous s ys tem of the insect, causing the in sect to become paral yz ed. Available mechanistic data indicate a neurotoxic mechanism of action, related to interference with GABA - mediated neurotransmission.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 11 of 58 Tolerances are established under 40 CFR §180.449 for residues of abamectin (avermectin), includi ng its metabolites and degradates, in or on various crop and livestock commodities at levels ranging from 0.005 ppm to 0.20 ppm. Compliance with the tolerance levels is to be determined b y measuring only avermectin B 1 [a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O - demeth yl avermectin A 1 ) and less than or equal to 20% avermectin B 1b (5 - O - demethyl - 25 - de(1 - methylpropyl) - 25 - (1 - methylethyl) avermectin A 1 )] and its delta - 8,9 - isomer. The registered formulation ty pes include emulsifiable concentrate, granular, bait, gel, and dust. The registered uses include food, food handling establishments, and residential uses. Clinch® Ant Bait is registered for control of fire ants in citrus, alm onds, walnuts, potatoes, around barns and equipment, and around chicken houses. There are registered granular products for the application of abamectin to lawns to control fire ants (e.g., Affirm Fire Ant Insecticide Bait/EPA Reg. No. 100 - 893 and PT 370 A scend Fire Ant Stopper Bait/EPA Reg. No. 499 - 370). Agri - Mek ® SC Miticide/Insecticide [ 100 - 1351 ] and Epi - MekTM SC Miticide/ In secticide [ 100 - 1408 ] are to be applied to cotton as foliar applications using ground or aerial equipment. The maximum application rates are 0.019 lb ai/A/application and 0.038 lb ai/A/season. The retreatment interval is at least 21 day s and the preharvest interval is 20 days. Agri - Mek ® SC Miticide/Insecticide [ 100 - 1351 ] and Epi - MekTM SC Miticide/ In secticide [ 100 - 1408 ] are to be app lied to strawberries as foliar applications using ground equipment only . A maximum of four applications can be made. The maximum application rates are 0.019 lb ai/A/application and 0.075 lb ai/A/season. The retreatment interval is at least 21 day s and the preharvest interval is 3 day s.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 12 of 58 **3.1 Chemical Identity**  **Table 3.1. Abam**  **ectin Nomenclature**  Chemical Structure

Em pirical formula C 48 H 72 O 14 (B 1a); C 47 H 70 O 14 (B 1b ) Common Names abamectin, avermectin B 1 Com pany experimental name MK - 0936 IUPAC name mixture of (10E ,14E ,16E) - (1 R ,4 S,5 ' S,6 S,6 'R ,8 R ,12 S,13 S,20R ,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

- py ran) - 12 - yl 2,6 - dideoxy - 4 - O - (2,6 - dideoxy - 3 - O - methyl - α - L arabino - hexopyranosyl) - 3 - O - methyl - α - L - arabino - hexopyranoside and (10E ,14E ,16E) - (1 R ,4 S,5 ' S,6 S,6 'R ,8 R ,12 S,13 S,20R ,21 R ,24 S ) - 21,22 - dihydroxy - 6 ' -ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 13 of 58 **Table 3.1. Abam**  **ectin Nomenclature**  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

- py ran) - 12 - yl 2,6 - dideoxy - 4 - O - (2,6 - dideoxy - 3 - O - methyl - α - L arabino - hexopyranosyl) - 3 - O - methyl - α - L - arabino - hexopyranoside CAS n ame Avermectin B 1 CAS Registry Number Avermectin B 1 - 71751 - 41 - 2; Avermectin B 1a - 65195 - 55 - 3; Avermectin B 1b - 65195 - 56 - 4

End - use product/EP Agri - Mek® 0.15 EC Miticide/Insecticide , EPA Reg. No. 100 - 898 (contains 0.15 lb ai per gallon); Ep i - MekTM 0 .15 EC Miticide/Insecticide , EPA Reg. No. 100 - 1154 (contains 0.15 lb ai per gallon); Agri - Mek® SC Miticide/Insecticide, EPA Reg. No. 100 - 1351 (contains 0.7 lb ai per gallon) ; Epi - MekTM SC Miticide/Insecticide, EPA Reg. No. 100 - 1408 (contains 0.7 lb ai per gallon) Chemical class Macrocyclic lactone; Insecticide/Miticide Known impurities of concern None **3.2 Physical/Chemical Characteristics**  Avermectin is a cry stalline powder with very low vapor pressure. It has very low water solubility but is soluble in organic solvents. Res idues do not readil y leach to groundwater due to their affinit y for soil particles. Abamectin is stable to abiotic hydrol ys is. Acceptable data are not available to determine stability via other routes. D etermination of stability to photoly sis and biodegradation is pending submission of acceptable data. Refer to Appendix C for the table of phy sical/chemical properties. **3.3 Pesticide Use Pattern**  Sy ngenta Crop Protection, LLC has submitted a petition to add cotton and strawberry uses to the Agri - Mek® SC and Epi - Mek® SC labels. Cotton and strawberry uses are currentl y registered on emulsifiable concentrate (EC) labels. Both Agri - Mek® SC and Epi - MekTM SC are suspension concentrate (SC) formulations which contain 0.7 lb abamectin per gallon. Both formulati ons contain 8.0% active ingredient and 92.0% inerts.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 14 of 58 **Table 3.3**  **. Su mma**  **ry of Directions for Proposed Amended Uses of Abamectin .**  Application Timing, Type, and Equipment Formulation

[EPA Reg. No.] Application

Rate Max. No.

Application per Season Maximum

Seasonal Application Rate PHI

( days ) Use Directions and Limitations 1 **Cotton** Foliar: Ground or Air Agri - Mek ®

SC Miticide/ Insecticide [ 100 - 1351 ] Epi - MekTM SC Miticide/ Insecticide [ 100 - 1408 ] 1.0 - 3.5 fl

oz/A (0.0055 - 0.019 lb ai/A) Not

stated 1 6.75 fl

oz/A (0.038 lb ai/A) 20 Agri - Mek SC and Epi Mek must alway s be mixed with an adjuvant. Do not apply

with aircraft in NY state. Do not apply

through any t yp e of irrigation sy stem. Retreatment interval is at least 21 day s. Do not apply

in fewer than 5 gals water per acre. **Strawberries** Foliar: Ground Onl y Agri - Mek ®

SC Miticide/ Insecticide [ 100 - 1351 ] Epi - MekTM SC Miticide/ Insecticide [ 100 - 1408 ] 3.5 fl

oz/A (0.019 lb ai/A) 4 14 fl oz/A

(0.075 lb ai/A) 3 Ground application

only . Do not apply

with aircraft. Apply with ground application equipment as a foliar spray

and ensure thorough coverage on upper and lower leaf surfaces. Adjust spray

volume and nozzle placement to ensure maximum coverage of tops and undersides of leaves. Retreatment interval is at least 21 days . Do not apply

in less than 50 gals water per acre with conventional ground application equipment, or in less than 10 gal of water per acre with electro - static sprayers. 1 Two applications per season could be made at the maximum application rate.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 15 of 58 Conclusions . Refer to S ection 2.3 for recommended modifications to the proposed label s . Provided the recommended label revisions are made, the labels are adequate to allow evaluation of the residue data relative to the proposed uses. **3.4 Anticipated**  **Exposure Pathways** The Registration Division has requested an assessment of human health risk to support the proposed new use of abamectin on cotton and strawberries. Humans may be exposed to abamectin in food and drinking water since abamectin may be app lied directly

to growing crops. Although significant residues are not expected to occur in groundwater because of the low water solubility of residues and their affinity to soil particles, residues may occur in surface water due to runoff, erosion, and spray drift. The proposed uses on cotton and strawberries do not include residential uses; however, there are registered residential uses of abamectin, so there is the possibility

of exposure in residential or non - occupational settings. In an occupational s etting, applicators may

be exposed while handling and applying abamectin. There is a potential for post - application exposure for workers re - entering treated fields. Risk assessments have been previously

conducted for abamectin, but no new toxicity data h ave been received since the previous risk assessment. A detailed description of the toxicity data and metabolism information may be found in the risk assessment dated 7/18/11 (N. Dodd, D380523); an amendment is dated 8/24/11 (N. Dodd, D393232). **3.5 Consi**  **deration of Environmental Justice** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Jus tice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variet y 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 anal yz ed and categorized by subgroups based on age, season of the ye ar, 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 ente ring 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 by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 16 of 58 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  No new toxicity

and/or metabolism data have been received since the last risk assessment. **4.1 Summary**  **of Toxicological Effects Mode of Action**  : In nematodes, abamectin blocks signal transmission from the central command interneurons to the peripheral motoneurons , leading to paral ys is and death. In the mammalian toxicity studies submitted by

the registrant, paraly sis is also a common finding prior to moribund sacrifice. On the cellular level, abamectin acts b y bind ing to g amma - aminobuty ric acid (GABA) gated chloride channels at two different sites, a high affinity binding site that activates the channel and a low affinity site that blocks the channel ( Pong et al., 1982; Huang and Casida , 1997 ; and Dawson et al., 2000). GABA play s a critical role in nervous s ys tem development through both non - sy

naptic (Represa and Ben - Ari, 2005) and s ynaptic (Nguyen et al ., 2001) mechanisms. Within the mammalian brain , abamectin binding is widespread but particularl y abundant in the cerebellum (Wang and Pong , 1982). Abamectin also act s on GABA receptors in the enteric nervous s ys tem and induce s longitudinal rhy thmic contractions in the isolated ileum (Kerr and Ong , 1986). Abamectin may therefore influence GABA - mediated regulation of metabolism, food intake and body weight at multiple sites (Meister , 2007 ). Although GABA receptor mediated neurotoxicity is a solid hy

pothe sis, data in mammalian preparations linking alterations in GABA receptor function to disruptions in neuronal excitability in vitro and in vivo , and ultimately

adverse outcome are currently lacking. **Metabolism in rats :**  The metabolism study was performed wi th avermectin B 1a . With oral dosing, the test material in the gastrointestinal tract of the rat was almost completely absorbed and distributed throughout all major tissues and organs, with the highest residues found in fat. Maximum concentrations in bl ood we re achieved within 4 - 8 h after administration. It was rapidly eliminated from the body , almost exclusively in the feces, and d id not accumulate in the body after repeated exposure. The major biotransformation s of avermectin B1a in the rat we re demethyl ation, hydrox yl ation, cleavage of the oleandros ylring and oxidation reactions . There were 11 isolated metabolites . Inthe rat , avermectin B 1a was metabolized to 24 - hydroxy - methyl B 1a (i.e., 24 - OH - Me - B 1a), which accounts for most of the radiolabeled residues. However, the [8, 9 - Z ] - isomer of avermectin B 1a was not found in the rat metabolism studies. Avermectin B 1a d id not bioaccumulate in rat tissues . **Toxicological Effects** : Abamectin has high to moderate acute toxicity by the oral route (dependi ng on the vehicle), high acute toxicity by the inhalation route, and low acute toxicity by the dermal route. Itis slightl y irritating to the skin, but is not an ocular irritant or a dermal sensitizer. The acute toxicity of abamectin technical is summari zed in Table A.2.1 of Appendix A. In general, the results of available toxicity studies with single or repeated dosing indicate that the main target organ is the nervous s ys tem, and that decreased body weight is also one of the most frequent findings . Neurotoxicity and developmental effects are detected in multiple studies and species of test animals.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 17 of 58 Integral to its dose response in mammals, abamectin is also a substrate for P - gl ycoprotein (P - gp). P - gl ycoprotein is a member of the ATP binding cassette transporter proteins (ABC), which reside in the plasma membrane and function as a transmembrane efflux pump, moving xenobiotics from intracellular to the extracellular domain against a steep concentration gradient with ATP - hydrol ys is providing the energy for active transport (Marzolini et al., 2004). P - gp is found in the canallicular surface of hepatocy tes, the apical surface of proximal tubular cells in the kidney s, brush border surface of enterocy tes, luminal surface of blood capillaries of the brain (b lood brain barrier), placenta, ovaries, and the testes. As an efflux transporter, P - gp acts as a protective barrier to keep xenobiotics out of the body by excreting them into bile, urine, and intestinal lumen and prevents accumulation of these compounds i n the brain and gonads, as well as the fetus. Therefore, some test animals, in which genetic pol ym orphisms compromise P - gp expression, are particularly susceptible to abamectin - induced neurotoxicity (Lankas et al ., 1997). An example is the CF - 1 m ouse. S ome CF - 1 mice are deficient in P - gp and are found to be highl y sensitive to the neurotoxicity of abamectin . A very small population of humans is also found to be deficient of ATP binding cassette transporter proteins due to poly morphism in the gene encodi ng ABC (Dubin - Johnson Sy ndrome) (S. Habashi, 2006 ; A. T . Niles, 2007) . In addition, collie dogs have been shown to be deficient in P - gp (R. Kerb, 2005). The dose/response curve is very steep in several studies, with death and morbid sacrifice seen at dose levels as low as 0.4 mg/kg/day and 0.1 mg/kg/day

in rats and mice, respectively , following repeated exposures. Increased susceptibility (qualitative and/or quantitative) was seen in prenatal developmental toxicity studies in mice and rabbits, and an incr ease in quantitative and qualitative susceptibility

was also seen in the rat reproductive toxicity studies. In CD - 1 mice , hind limb splay

was seen at 3.0 mg/kg in dams ; a similar effect , hind limb extension , was seen at 0.75 mg/kg in the fetuses . Inrabbi ts at 2.0 mg/kg , the maternal effect s consisted of deceases in body weight and food consumption where as in the fetuses cleft palate, clubbed foot, and death were found. In the rat reproduction study , at the highest dose tested (0.4 mg/kg/day) no effect w as seen in parental animals whereas in the pups death and decreases in pub body weight were seen (please Section 4.2.3 for details). Review of acceptable oncogenicity and mutagenicit y studies provide no indication that abamectin is carcinogenic or mutagen ic. The studies, which demonstrated neurotoxicity as well as other effects, are summarized in Tables A.2 .2 & A. 2. 3 of Appendix A. **4.2 Safety**  **F actor for Infants and Children (FQPA Safety Factor)**  **4.2.1 Completeness**  **o f**  **the Toxicology Database**  The toxicology

database for abamectin is sufficient to characterize the hazard to humans, to conduct FQPA assessment, and to select toxicity endpoints for risk assessment. Some of the toxicity studies conducted in the 1980’s do not fully meet the current guideline requirements. However, when considered in conjunction with acceptable guideline studies, they provide adequate information for determining the toxicity of abamectin in adult, fetal, and young animals. Data quality is acceptable and meets the criteria set in the OCSPP guidelines and 40 CFR §158.500.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 18 of 58 However, under the current data requirement guidelines (40 CFR §158.500), a subchronic dermal toxicity

study and immunotoxicity

study (O CSPP 870.7800) are missing. A subchronic dermal toxicity

study is waived based on the results of a monkey dermal absorption study , which shows less than 1% of abamectin is absorbed (HASPOC, 11/19/12). In addition, a 22 - day dermal toxicity

study in rabbits with a structurall y related compound, emamectin, shows no adverse effect at 1000 mg/kg/day . However, the immunotoxicity study is required. The risk assessment team was initially informed that the registrant was committed to conduct this study , but currentl y the registrant is planning to submit a data waiver for the immunotoxicity study . An inhalation study

in rats was available and show ed no effect at the highest concentration tested (0.0025 mg/L) ( ≈0.68 mg/kg/day). The HASPOC considered all the available data and concluded that no additional inhalation study i s need ed at this time. To address the issue of the immunotoxicity data gap and the associated database uncertaint y factor, the RAB3 risk assessment and toxicity team examined the entire database of abamectin and determined that an additional uncertainty factor is not needed to account for potential immunotoxicity . For abamectin, a complete battery of subchronic, chronic, carcinogenicity , developmental and reproductive studies as well as acute and subchronic neurotoxicity screen ing studies are available for consideration . In addition, two developmental neurotoxicity studies have been conducted on abamectin. At the dose levels tested, abamectin did not induce effects which can be associated with immunotoxicity , and abamectin does not belong to a class o f 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 an y which is used for point of departure for this risk assessment. An additional uncertaint y factor (UF DB ) for database uncertainties does not need to be applied at this time . **4.2.2 Evidence of N**  **eurotoxicity** The findings of neurotoxic signs are consistent with mode of actions for a chemical which acts on GABA receptor s. Signs of neurotoxicity ranging from decrease in foot splay reflex, mydriasis (i.e., excessive dilation of the pupil), curvature of the spine, decreased fore - and hind limb grip strength, tip - toe gate, tremors, ataxi a, or spastic movements of the limbs are reported in various studies with different durat ions of abamectin exposure. Indogs, m ydriasis was the most common finding at doses as low as 0.5 mg/kg/day after one week of treatment. In CF - 1 mice, tremor was see n prior to death at doses of 0.1 mg/kg/day and above following repeated exposure. In comparison to dogs and CF - 1 mice, the studies which reported the neurotoxicity findings are summarized in Appendix B of D362615 (N. Dodd, 3/11/09). **4.2.3 Evidence**  **o f Se**  **nsitivity/Su sceptibility in the Developing o**  **r Young Animal** In creased susceptibility

was demonstrated in the fetuses of CD - 1 and CF - 1 mice and rabbits in the developmental toxicity studies both quantitatively and qualitatively as discussed below. Quantitative increase in susceptibility was also shown in reproductive toxicity andABAMECTIN Human Health Risk Assessment DP No. D402677

Page 19 of 58 developmental neurotoxicity studies in rats where the L OAELs were substantially lower in the pups than those in the parental animals. **Developmental Toxicity** There are several developmental toxicity studies available indicating that there is a qualitative and quantitative increase in sensitivity and susceptibility

in the developing mouse and rabbit fetuses to the effects of abamectin (MRIDs 44179901 and 001308 19) (Tables A.2.2 and A.2.3 of Appendix A). **Prenatal developmental toxicity in rabbits** (MRID 00130819; 1982): Pregnant New Zealand White rabbits were administered abamectin (94% pure) at dose levels of 0.5, 1.0, and 2.0 mg/kg/day

on gestation day s 6 through 16. At 2.0 mg/kg/day , decreases in body weights and food/water consumptions were seen. Developmental toxicity was reported in fetuses of the 2 mg/kg/day

group; the findings were cleft palate, clubbed foot, increased pup deaths at birth, and delayed ossification of sternebrae, metacarpals, and phalanges. No effects were seen in dose levels of 1.0 and 0.5 mg/kg/day . The maternal LOAEL was 2.0 mg/kg/day ; the maternal NOAEL was 1.0 mg/kg/day . The developmental toxicity L OAEL was 2.0 mg/kg/day and the NOAEL was 1.0 mg/kg/day . **Prenatal developmental toxicity study in CD -**  **1 mice** (MRID 44179901 ; 1996 ): Pregnant CD - 1 mice were administered abamectin at doses of 0, 0.75, 1.5, and 3.0 mg/kg/day from gestation day s 6 through 15. At 3.0 gm/kg/day , maternal toxicity was reported as limb splay . This dose was considered to be the maternal LOAEL, and the NOAEL was 1.5 mg/kg/day . Hindlimb extension was found in 2 fetuses from 2 litters each for 0.75, 1.5, & 3.0 mg/kg/day groups. Therefore, the developmental LOAEL was 0.75 mg/kg/day , and a NOAEL could not be established. In addition, the data indicate that th e most sensitive effect of abamectin on the fetuses is the increase in the incidence of cleft palates in mice and rabbits in the presence of no or minimal maternal toxicity . This effect is particularl y apparent in CF - 1 mice (Table A.2.3, Appendix A). In CF - 1 mice, cleft palate was seen at doses as low as 0.1 mg/kg/day in developmental toxicity studies; but no effect was seen at 0.06 mg/kg/day or below (Table A.2.3 of Appendix A). In CD 1 mice and rabbits, cleft palate was found at slightly higher dose le vels, 0.75 mg/kg/day and 2.0 mg/kg/day , respectivel y . It should be noted that the CF - 1 mouse developmental toxicity studies were thoroughly

reviewed by the Developmental and Reproductive Toxicity Peer Review group in 1993 (Memorandum: R. Gardner to G. LaR occa, July 8, 1993). Subsequently , additional data were submitted by the registrant demonstrating that the sensitivity of some CF - 1 mice to abamectin was correlated with a deficiency

in P - gp.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 20 of 58 **Reproductive Toxicity** There are three available reproduction studies in rats: two one - generation reproduction studies and a two - generation reproduction study (MRIDs 00096450, 00096451, and 00164151) (Table A.2.2, Appendix A). The results of all three studies show the effe cts (decreased pup body weights and/or survival) in the pups at lower dose levels (0.4 mg/kg/day) than the LOAELs of the parental animals (>0.4 mg/kg/day or 1.5/2.0 mg/kg/day). A similar lower offspring LOAEL, based on decreased pup body weight, than that of the maternal animals was also found in the developmental neurotoxicity study (offspring LOAEL=0.2 mg/kg/day ; maternal LOAEL >0.4 mg/kg/day). **Two -**  **generation reproduction study in rats** (MRID 00164151; 198 4 ): Groups of 30 SD rats/sex/dose were administe red abamectin b y gavage at dose levels of 0, 0.05, 0.12, and 0.4 mg/kg/day . F0 males were dosed for a total of 259 day s while F0 females were treated for a minimum of 177 day s. For F0 animals, mating and fertility indexes and body

weights were comparable among all dose groups. For the pups, F1a and F1b pups had decreases in viability and lactation indexes and a decrease in body weights at 0.4 mg/kg/day . Similar decreases were also seen in F2a and F2b groups. In the F2b weanlings, there was a treatment - related increase in the incidence of retinal rosettes. The parental NOAELwas 0.4 mg/kg/day (highest dose tested). The reproductive NOAEL was also 0.4 mg/kg/day. The offspring NOAEL was 0.12 mg/kg/day , while the LOAEL was 0.4 mg/kg/day based on increase d incidence of retinal rosettes in F2b pups, increased dead pups at birth (decreased viability index), decreased lactation index, and reduced pup body weights. **Developmental neurotoxicity study in rats**  (MRID 47116201; 2007): Abamectin (96.2% a.i. on dry basis; Batch No.: VS094KO) in sesame oil was administered via gavage (10 mL/kg) to pregnant Alpk:AP f

SD rats (30/dose) from gestation day (GD) 7 through lactation day (LD) 22 at doses of 0, 0.12, 0.20, or 0.40 mg/kg/ day . The pups were not directly dosed. Maternal toxicity **:** There were no effects of treatment on mortality , clinical signs, functional observational battery

parameters, body

weights, body

weight gains, food consumption, reproductive performance, or gestation length. The maternal LOAEL was not observed. The maternal NOAEL was 0.4 mg/kg/day . Offspring toxicity : At 0.40 mg/kg/day , pup death was seen. The pups were generall y small and presented with deh ydration and tremors. Additionally , at this dose, pup body weight s were decreased (p ≤0.05 ) b y 1 0 - 3 5 % compared to controls from post - natal day (PND) 8 to 36 for males and females. There were no surviving pups at this dose level after PND 38. Since these deaths left an insufficient number of pups to complete all of the study objectives, all dams and pups at this dose were removed from the study during PND 15 - 38. At 0.12 and 0.20 mg/kg/day , n o treatment - related effects were observed on litter parameters (number born live, number born dead, sex ratio (% male), mean litter size, live birth index, and viability index ) , clinical signs , FOB parameters, motor activity , auditory startle reflex, learning and memory , sexual maturation, brain weight, or gross or microscopic pathology .ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 21 of 58 D ecreases (p ≤0.05) in post - weaning body weight were observed in the 0.12 and 0.20 mg/kg/day males throughout the post - weaning interval (PND 36 - 63). The individual pup body weight data were re - evaluated using Mixed Model Analy sis of Body Weight Data from the Developmental Neurotoxicity

Study . The resu lts indicated that there was a statisticall y significant difference for mid - and low - dose males from the corresponding controls, and for females no statistically significant difference existed at either the low - or mid - dose level. However, the body weight decrease in low - dose males was approximately 3% relative to the controls, and it was determined not to be toxicologically

significant. The offspring LOAEL for this effect is established at 0.2 mg/kg/day

based on statistically

and biologicall y significant body weight reductions (6%). The NOAEL for this effect is established at 0.12 mg/kg/day . Because the dose - response to abamectin is pup body

weight loss (detected at the low dose, 0.2 mg/kg/day ) leading to moribundity

at the high dose (0.4 mg/kg/day), an additional 3X uncertainty factor for steepness of the dose - response curve is included in the reference dose and Level of Concern calculations. This additional 3X safet y factor yi elds a de facto NOAEL of 0.04 mg/kg/day (0.12/3) which is protective of the slight body

weight decrease seen in low - dose males (p<0.01 using Mixed Model Anal ys is). **Developmenta l neurotoxicity study in rats**  (MRIDs 46727403, 46727402, and 46727401; all 2005): Abamectin (96.2% a.i. on dry basis; Batch No.: VS094KO) in sesame oil was administered via gavage (10 mL/kg) to pregnant Alpk:AP f SD rats (30/dose) from gestation day (GD) 7 through lactation day (LD) 22 at doses of 0, 0.12, 0.20, or 0.40 mg/kg/day . The pups were not directl y dosed. Dams were allowed to deliver naturall y and were killed at weaning on LD 29. On post - natal day (PND) 5, litters were standardized to 8 pups/litter; the remaining offspring and dams were sacrificed and not examined further. S ubsequently , 1 pup/sex/litter/group (at least 10 pups/sex/dose when available) were allocated to the following subsets: Subset 1: functional observational battery (FOB) on PND 5, 12, 22, 36, 46, and 61; motor activity

on PND 14, 18, 22, and 60; and brain weight and neuropathology on PND 63. Subset 2: FOB on PND 5, 12, 22, 36, 46, and 61; water maze on PND 24 and 27; and brain weight and neuropathology on PND 63. Subset 3: FOB on PND 5 and 12; auditory startle on PND 23 and 61 (for animals not sacrificed on PND 12); and brain weight and neuropathology on PND 12. Subset 4: FOB on PND 5, 12, 22, 36, 46, and 61; water maze on PND 59 and 62. Maternal toxicity **:** There were no effects of treatment on mortality , clinical signs, functional observational battery parameters, body weights, body

weight gains, food consumption, reproductive performance, or gestation length. The maternal LOAEL was not observed. The maternal NOAEL is 0.4 mg/kg/day (highest dose tested; HDT) **.** Offspring toxicity **:** No treatment - related effects were observed on litter parameters (number born live, number born dead, sex ratio (% male), mean litter size, live birth index, and viability index ) , clinical signs , FOB parameters, motor activity , auditory startle reflex, learning and memory , sexual maturation, brain weight, or gross or microscopic pathology. On the day

of weaning (PND 29), minor decreases (p ≤ 0.05) in pup body weights of 5 - 7% were observed at 0.40 mg/kg/day . Pup body weights continued to be decreased (p<=0.01) by 5 - 6% in the mal es and b y 8 - 10% in the females throughout the post - weaning interval (PND 36 - 63). TheABAMECTIN Human Health Risk Assessment DP No. D402677

Page 22 of 58 offspring LOAEL is 0.4 mg/kg/day , due to decreased body weights in both sexes. The NOAEL is 0.2 mg/kg/day . There was no evidence of neurotoxicity in the offspring under the conditions of this study . 

### 4.2.4 **FQPA Safety Factor for Infants and Children** In previous abamectin risk assessments, the 10X FQPA safet y factor was retained as a database uncertainty factor for the lack of a developmental neurotoxicity study . Two developmental neurotoxicity

studies have now been submitted and reviewed and the findings in these studies were considered in the identification of toxicological points of departure and uncertainty/ safet y factors. With the addition of the developmental neurotoxicity (DNT) studies, the toxicity database for abamectin is complete , except for immunotoxicity studies. EPA began requiring functional immunotoxicity

testing of all food and non - food use pesticides on December 26, 2007. To address the issue of an immunotoxicity data gap and the associated database uncertainty factor, RAB3 examined the entire database of abamectin and determined that an additional uncertainty factor is not needed to account for potential immunotoxicity . Abamectin has not been found to induce effects associated with immunotoxicity and abamectin 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 NOAELless than the NOAEL s of 0.5 and 0.12 mg/kg/day already s et for abamectin acute and repeated exposures, respectively. An additional uncertainty factor (UF DB ) for database uncertainties associated with immunotoxicity does not need to be applied at this time . The RAB3 Risk Assessment Team has evaluated the entire toxicity database of abamectin and determined that an additional 3x FQPA safet y factor is needed to address res idual concerns as to all risk assessments other than acute dietary . For all risk assessments involving repeat exposures, the selected toxicity

endpoint is based on the decrease in pup body weight seen in the developmental neurotoxicity study (2007) and three reproduction studies in the rat . Although the study identified a NOAEL for the effects observed in the pups, the data clearly indicate that the decrease in pup body weight seen at 0.2 mg/kg/day rapidly progresses to death at the next higher tested dose level (0.4 mg/kg/day) in both rep roduction and developmental neurotoxicity studies . As shown in Figure 1, the combined data from several reproduction toxicity and developmental neurotoxicity

studies have documented a very narrow dose range from NOAEL(0.12 mg/kg/day) to adverse effect ( 0.2 mg/kg/day) to severe adverse effect (0.4 mg/kg/day). Dose spacing is commonly

greater than the 2x between NOAEL and LOAEL. The approximately 3x difference between the NOAEL and the dose that induced mortality in the pups in the developmental neurotoxi city study provides little margin of safety for such a severe effect. Retaining an additional 3x FQPA safety factor effectivel y provides a 10x margin between the dose which causes death (0.4 mg/kg/day) and the NOAEL adjusted by the additional safety facto r (0.12 mg/kg/day

/3 = 0.04 mg/kg/day). Additionally , this adjusted point of departure (0.04 mg/kg/day) would also address the concerns for the increased susceptibility seen at higher dosesABAMECTIN Human Health Risk Assessment DP No. D402677

Page 23 of 58 in the two - generation reproduction study in rats (LOAEL = 0.4 mg/kg/day), prenatal developmental study

in CD - 1 mice (LOAEL = 0.75 mg/kg/day), the prenatal developmental toxicity study in rabbits (LOAEL = 2 mg/kg/day), and the one - generation reproduction study (LOAEL = 0.2 mg/kg/day). The 10x intraspecies factor is prot ective of the effects seen in CF - 1 mice which were found to be the most sensitive strain of test animals due to the lack of P gl ycoprotein. The data on CF - 1 mice show that most of the effects are seen at doses above 0.06 mg/kg/day

(Table A.2.3 of Appendix A.) Therefore, the additional 3x factor for the steepness of the dose - response curve and severity of effects is adequate. With respect to acute dietary exposure, the endpoint selected for risk assessment is based on mydriasis observed in dogs. The additional 3x factor applied to chronic and other exposure scenarios is not applicable to acute exposure because steepness of the dose and severity of effects were not seen in the studies where mydriasis occurred. In addition, the reduced body weights as toxicity endpoints for other exposure scenarios is not a single dose effect.

Figure 1. Dose response for pup body weight decrease and pup mortality seen in developmental neurotoxicity

study in rats (MRID 47116201). **4.2.5 Residual**  **Uncertainty in the Ex posure Datab**  **ase** There are no residual concerns with respect to the exposure databases. T he chronic and acute dietary food exposure assessment utilizes conservative assumptions including anticipated residues, default processing factors, and percent crop tr eated. The dietary drinking water assessment utilized modeling results which included conservative assumptions for the parent and all degradates of concern. Conservative assumptions were used in the water models. Therefore, **Ab am**  **ectin D ose Response** 

0 5 10 15 20 25 30 35

0. 12 0. 2 0. 4

**Do se**  **( mg/**  **kg/ da** 

**y) %** **B o** **d y** **W t** **D e** **c r** **e a** **s e** 

0

20 40 60 80 100 120**M o** **r t** **a l** **i t** **y** % Body W t D ec re as e Mo rta lityABAMECTIN Human Health Risk Assessment DP No. D402677

Page 24 of 58 the water exposure assessment will not underestimate the potential risks for infant s and children . Likewise, the use of maximum application rates and central - to - high end inputs results in calculated residential exposures that should not underestimate the risks to infants and children from these requested uses. The exposure is not expected to be underestimated in this assessment. An immuno toxicity study (870.7800) is required to fulfill current 40 CFR Part 158 data requirements ; h owever, the RAB3 toxicity team examined the entire dat abase of abamectin and determined that an additional uncertainty factor is not needed to account for potential immunotoxicity . **4.3 Toxicity Endpoint and Point of**  **D eparture Selections**  There have been no changes to the prior dose - response assessment. There have been no changes to the prior recommendations for combining routes of exposure and/or cancer classification. On June 19, 2008, the ToxSAC evaluated the previous toxicity endpoints and points of departures based on the current toxicity database with newly

added studies, such as a second developmental neurotoxicity study , and acute and subchronic neurotoxicity studies on abamectin. The Committee recommended new toxicity endp oints and points of departures for risk assessment. On September 25, 2008, the ToxSAC met a second time to discuss the decrease in pup body weight seen in the 2007 developmental neurotoxicity study . Subsequent to the ToxSAC consultation, the RAB3 Risk As sessment Team determined the toxicity endpoints presented in Tables 4.3 .2 and 4.3.3 to be most protective and appropriate for risk assessment. The rationale for the endpoint selection is summarized below, and the toxicity endpoints and the points of depar

ture for risk assessment for various exposure scenarios are presented in Table s 4 . 3.2 and 4.3.3 . **Acute Dietary Endpoint** : Previously , the acute toxicity endpoint was based on mydriasis seen in a 53 - week study

in dogs (HIARC report, Sept. 1998 , TXR # 01285 4 ), and the selected point of departure for risk assessment was a NOAEL of 0.25 mg/kg/day based on mydriasis as a likely single - dose effect. As mentioned before, at that time, acute neurotoxicity and developmental neurotoxicity

studies were not available. On June 19, 2008, the ToxSAC evaluated all the toxicity studies relevant to establishing an acute oral toxicity endpoint and focused on the mydriasis seen in the toxicity studies in the dog and other effects demonstrated in the acute neurotoxicity

study i n the rat. The results of the mydriasis seen in the dog studies are compiled and presented in Table 4.3 .1. The dog toxicity studies were conducted in the 1980’s, and significant m ydriasis was reported. The data show that mydriasis was not reported in tr eated dogs at dose levels equal to or less than 0.5 mg/kg/day with a single dose administration. However, at 0.25 mg/kg/day , m ydriasis was noted only after at least 9 weeks of treatment, and at 0.5 mg/kg/day , m ydriasis was seen at treatment day 7. As tre atment time progressed, the incidence of this effect was increased as indicated by the finding that at treatment week 6, 5/12 dogs showed signs of m ydriasis. With increasing dose levels, the time for mydriasis to occur was shortened. At 8 mg/kg/day , m ydri asis was seen within 24 hrs of treatment. In dogs treated with 1 mg/kg/day , m ydriasis was noted from 1 to 5 times during the first week of treatment. It was entirely possible that after a single dose at 1 mg/kg, m ydriasis was present. Therefore, theABAMECTIN Human Health Risk Assessment DP No. D402677

Page 25 of 58 LOA EL for m ydriasis resulting from a single dose is 1 mg/kg and the NOAELis 0.5 mg/kg. The point of departure for acute oral exposure assessment is 0.5 mg/kg/day , and the toxicity endpoint is mydriasis seen in the 12 - week dose - range - finding toxicity study . This point of departure for risk assessment is also supported b y the results of the acute neurotoxicity study in rats (MRID 46959202 ). This study

showed the reduced splay reflex in males and females at 1 .5 mg/kg/day ( LOAE L) . At the next high er dose leve l , decreased motor activity , reduced splay reflex, and tip toe gait were seen. All the data considered together, the 12 - week range - finding study in dogs and the acute neurotoxicity study in rats are considered as critical studies in establishing the acute dietary

endpoint. For acute dietary

exposure, the FQPA safet y factor may be reduced to 1x, based on m ydriasis in dogs. The additional 3x factor for chronic and other exposure scenarios is not applicable to acute exposure because steepness of the dose and severity of effects were not seen in the studies where mydriasis occurred. In addition, the reduced body weights as toxicity endpoints for other exposure scenarios is not a single dose effect. B ased on the safety factor of 100x (10x for interspecies difference and 10x for intraspecies variability), the acute RfD is 0.005 mg/kg/day . **Table 4.3**  **.1. Mydriasis S**  **een in All the Available Toxicity S**  **tudies in D**  **ogs Study**  **Dose Levels (mg/kg/day)**

**0.25 0.5**  **1 2**  **4 8**  12 - Week dose range finding study (feeding) (1984) (0.25, 0.5, 1, 4/2 mg/kg/day) (2M/2F) Mydriasis

wa s never noted. Mydriasis was

never noted. Mydriasis was

noted from 1 to 5 times/ week, beginning on week 1. Mydriasis was

noted. Food consumption wa s markedly reduced. 4 mg/kg was

reduced to 2 mg/kg due to marked reduction in FC. Mydriasis wa s noted. Tremor, rapid respiration, & weakness were seen. 18 - Week toxicity study (gavage) (1982) (0.5, 2, & 8 mg/kg/day) (3M/3F) On treatment day 7, mydriasis was seen in 1 dog. On week 2, mydriasis was seen in 4/6 dogs. Whole body tremor, ataxia, & ptyalism was seen in one dog at week 2 and persisted until the end of the study. Mydriasis, ataxia, ptyalism, and anorexia were seen in all dogs by day 3 of dosing. After the third day of dosing , 1 dog die d with signs of convulsion prior to death. Mydrasis was reported 24 hrs after dosing. 4/6 dogs had tremor, ataxia, ptyalism within 3 to 6 hour s after dosing, & 2/6 dogs died within 4 hrs.

53 - Week toxicity On week On week 1, one On w eek 1,ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 26 of 58 **Table 4.3**  **.1. Mydriasis S**  **een in All the Available Toxicity S**  **tudies in D**  **ogs Study**  **Dose Levels (mg/kg/day)**

**0.25 0.5**  **1 2**  **4 8**  study feeding (1987) (0.25, 0.5, & 1.0 mg/kg/day) (6M/6F) 10, 1 dog

wa s noted to have mydriasis, and none before that time. dog was

reported to have mydriasis. By w eek 6, 5 dogs had mydriasis. one dog had

mydriasis . By week 3, 4 dogs had mydriasis. By week 33, 3 males died. **Chronic Dietary Endpoint** : Considering all the available toxicity data, it was determined that the decrease in pup body weights in the three reproduction studies and the recent developmental neurotoxicity

study (2007; MRID 47116201) was found to be the most sensitive effect and to occur in young animals which were exposed to abamectin pre - and post - natally . [The pup body weight data are summarized in Tables C.2 (2005 DNT study) and C.3 (2007 DNT study) of Appendix C of D362615 (N. D odd, 3/11/09).] Inthe 2007 developmental neurotoxicity study , a decrease in pup body weight was demonstrated in the pups at 0.12 and 0.2 mg/kg/day starting on PND 36 to the end of the study (PND 63 ) (Table C.3 of Appendix C of D362615 ). In addition, in the high - dose group (0.4 mg/kg/day), the pup body weight decrease was present starting on PND 8 and the percent decrease relative to the controls was progressive (from 11% on PND 8 and reaching greater than 30% on PND 36). By PND 38, there were no surviving pups at this dose level. The pup body weight data of this study were anal yz ed using a statistical Mixed Model Anal ys is of Body

Weight Data. The anal ys is showed that there was a statistically significant decrease in male pup body wei ghts in 0.12 and 0.2 mg/kg dose groups relative to the controls (p<0.0001 for 0.2 mg/kg males and p<0.002 for 0.12 mg/kg males) (Table C.4 of Appendix C of D362615). The decrease was 6% and 3.3 % in 0.2 and 0.12 mg/kg males, respectivel y. The decrease in mid - and low - dose females was not statistically significant (0.12 mg/kg: 3.2 % with p<0.141; 0.2 mg/kg: 4.3% with p<0.053). The results of the anal ys is was further evaluated with all the results of the pup body weight effects seen in three other reproduct ion studies in rats. The doses tested in these three reproduction studies ranged from 0.05 to 1.5 mg/kg. The statistically and biologically

significant reduction in body weight began at 0.4 mg/kg/day

ranging from 7% to 33% (Table C.1 of Appendix C of D3626 15). No effect on pup body weight was seen at 0.12, 0.10, and 0.05 mg/kg/day levels. It was concluded that the decrease in male pup body weight at the 0.2 mg/kg/day dose in the 2007 developmental neurotoxicity

study was statistically

and biologically

significant, while decreased body weight at the 0.12 mg/kg/day

dose was not biologicall y significant. The 0.2 mg/kg/day dose is considered to be statistically

and biologicall y significant for the following reasons: 1) At 0.2 mg/kg/day, other effects such as spastic movement and delayed incisor eruption were also seen in the pups; and 2) The body weight decrease was 6%, whereas an approximately 5% decrease in body weight in pups is generally considered to be biologically significant. Therefore, the NOAEL was established at 0.12 mg/kg/day and the LOAEL was established at 0.2 mg/kg/day based on decreased pup body weight seen in the developmental neurotoxicity study . Therefore, the decrease in male pup body weight at the 0.2 mg/kg/day dose in the developmental n eurotoxicity study is established as the toxicity endpoint, and the NOAEL of 0.12 mg/kg/day is the point ofABAMECTIN Human Health Risk Assessment DP No. D402677

Page 27 of 58 departure for risk assessment. As discussed in the FQPA Safety Factor Section, the 10x intraspecies factor is protective of the most sensitive subp opulation as represented b y CF - 1 mice. An additional 3x factor for the steepness of the dose - response curve and the severity of effects is applied. With that 3x factor and the standard safety factor of 100x (10x for intraspecies and 10x for interspecies differences), the chronic RfD is 0.0004 mg/kg/day . **Carcinogenicity** : Abamectin is characterized as “not likely to be carcinogenic to humans” based on the absence of significant increase in tumor incidence in two adequate rodent (rat and mouse) carcinog enicit y s tudies. **Incidental Oral, Dermal** 

**, and Inhalation Endpoints (all durations)** : The endpoints for these routes of exposure were decreased pup body weight seen at the LOAEL of 0.2 mg/kg/day from combined results of three reproduction studies and two d evelopmental neurotoxicity studies in the rat. The details for selecting this endpoint and safety factor are discussed in the Chronic Dietary Endpoint Section . This endpoint was selected because it best represented the exposure scenario time frames (app ropriate duration), was relevant due to evidence of increased susceptibility

to the offspring following pre - and postnatal exposure to abamectin, and adequatel y reflected all the populations at risk. Because an oral study was selected for all durations of dermal and inhalation exposure, a 1% dermal absorption factor and a 100% inhalation absorption factor will be used in the route - to - route extrapolation. **Dermal Absorption** : In1998, the HIARC recommended the use of a dermal penetration factor of 1% for ri sk assessment purposes (HED document No. 012845; 9/15/1998) This value was based on the results from a dermal absorption study in monkey s which demonstrated that <1% of an applied dose was absorbed. The HASPOC at 11/19/12 meeting affirmed the use of 1% as dermal absorption factor for abamectin. **Level of Concern (LOC) for Residential Risk Assessment** : For residential exposure risk assessments, the uncertainty factor is 300 (10x for interspecies extrapolation, 10x for intraspecies variations, and a 3x facto r for the steepness of the dose/response curve in several studies and the severit y of effects [death] seen at the slightly higher dose level). **Level of Concern (LOC) for Occupational Risk Assessment** : For occupational exposure risk assessments, the uncert ainty factor is 300 (10x for interspecies extrapolation, 10x for intraspecies variations, and an additional factor of 3x for the steepness of the dose - response curve and the severit y of effects).ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 28 of 58 **Table 4.3.2 .**  **Summ ary of Toxicological Doses and Endpoints for**  **Abam ectin**  **for Use in Dietary and Non**   ** Occupational Hum** **an Health Risk Assessments Exposure/**  **Scenarios Point of** 

**Departure Uncertainty/** 

**FQPA Safety Factor**  **RFD, PAD,**

**Level of Concern**  **(LOC) Study and**  **Toxicological Effects**

Ac ute Dietary (General population, including infants and children) NOAEL =

0.5 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=1x aRfD = 0.005

mg/kg/day **12 -**  **Week dose -**  **range finding study in dogs**

LOAEL = 1.0 mg/kg/day based on mydriasis seen 1 - 5 times during the first week of treatment. **Acute neurotoxicity study in rats** LOAEL= 1.5 mg/kg/day based on increased incidence of foot splay. Chronic Dietary (All populations) NOAEL =

0.12 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=3x* cPAD =

0.0004 mg/kg/day **Combined data from three reproduction** 

**studies and two developm ental**  **neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint)**  LOAEL = 0.2 mg/kg/day based on decreased pup body weight in pups at 0.2 mg/kg/day. Short - Term

and Intermediate Term Incidental Oral NOAEL =

0.12 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=3x* Residential

LOC for MOE = 300 **Combined data from three**  **reproduction**

**studies and two developm ental**  **neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint)**  LOAEL = 0.2 mg/kg/day based on decreased pup body weight. Dermal (All Durations) NOAEL =

0.12 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=3x* Residential

LOC for MOE = 300 **Combined data from three reproduction** 

**studies and two developm ental**  **neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint)**  LOAEL = 0.2 mg/kg/day based on decreased pup body weight. Inhalation (A ll durations) NOAEL =

0.12 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=3x* Residential

LOC for MOE = 300 **Combined data from three reproduction** 

**studies and two developm ental**  **neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint)**  LOAEL = 0.2 mg/kg/day based on decreased pup body weight. Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans based on the absence of significant

increase in tumor incidence in two adequate rodent carcinogenicity studies. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no ob served 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. N/A = not applicable. * The additional FQPA safety factor of 3x is for the steepness of the dose - response curve and the severity of effects.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 29 of 58 **Table 4.3 .**  **3 .**  **Summary of Toxicol ogical Doses and Endpoints for Abam**  **ectin for Use in Occupational Hum**  **an Health Risk Assessments**  Exposure/ Scenarios Point of Departure Uncertainty/

Safety Factor RFD, PAD,

LOC* Study and Toxicological Effects

Dermal (Short - Term and Intermediate Term) NOAEL = 0.12 mg/kg/day 1% Dermal Absorption Factor UF A = 10X

UF H = 10X SF = 3X LOC: MOE = 300 **Combined data from three**  **reproduction studies and two developmental**  **neurotoxicity studies.**  LOAEL = 0.2 mg/kg/day based on decreased pup body weight in pups. Inhalation (Short Term and Intermediate - Term) NOAEL = 0.12 mg/kg/day UF A = 10X

UF H = 10X SF = 3X LOC: MOE = 300 **Combined data from three**  **reproduction studies and two**  **developmental neurotoxicity studies.**  LOAEL = 0.2 mg/kg/day based on decreased pup body weight in pups. Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to human based on the absence of significant

increase in tumor incidence in two adequate rodent carcinogenicity studies. Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with low er environmentally relevant human exposures. N OAEL = no observed adverse effect level. L OAEL = lowest observed adverse effect level. U F = uncertainty factor. U F A = extrapolation from animal to human (interspecies). U F H = potential variation in sensiti vity among members of the human population (intraspecies). SF = Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). Rf D = reference dose. M OE = margin of exposure. L OC = level of c oncern. N/A = not applicable. * Level of Concern (LOC): F or occupational exposure risk assessments, the uncertainty factor is 300X (10X for interspecies extrapolation; 10X for intraspecies variations; and 3X for the steepness of the dose - response curve in several studies and the severity of effects [death] seen at the slightly higher dose level). **4.4 Endocrine Disruption**  As required b y 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 sy stemic toxicity . These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine targe t 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, de velopmental 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 databas e. However, as required b y FFDCA section 408(p), abamectin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 30 of 58 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 b y a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statuto rily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or th yroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems 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 an y adverse end ocrine - 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. Abamectin was included on that list and has been issued an order to conduct the Tier 1 testing. Once all requir ed Tier 1 and Tier 2 data have been received and reviewed, the endpoints and safety factors used for risk assessment purposes will be examined and a new risk assessment performed if necessary . For further information on the status of the EDSP, the policie s 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/ . **5.0 Dietary Exposure and Risk Assessment**  **5.1 R**  **esidues of Concern Summary and Rationale** Metabolism in Primary Crops : The qualitative nature of abamectin r esidue s in cotton and strawberry

i s adequately

understood based on metabolism studies on cotton, citrus, and celery (PP#'s 5G3500, 5G3287, and 8F3649, respectivel y), as well as a report titled "Comparative Degradation of Avermectin B 1 a in Cotton Leaf, Citrus Fruit, Celery , and In Vitro " (PP#9F3703, S. Willett, 12/15/89). The available studies on cott on, citrus, and celery indicate that the metabolism of abamectin in plants results in a complex mixture of residues, with the majority of the terminal residue composed of several unidentified polar degradates. The parent compound, its delta - 8,9 - isomer, an d the alpha 8 - OH degradate have been identified in plants, with only the parent and its delta - 8,9 - isomer each accounting for at least 10% of the total residue. The polar degradates generated on citrus [ 7 - day preharvest interval ( PHI) ] and in vitro (30 hour sample) have been tested for toxicity (in the developmental toxicity study in CF - 1 mice) and were found to be of no toxicological significance at the levels tested (TOX memos 7080 and 7081, W. Dy kstra, 3/15/89; PP#8F3592, F. Boyd, 6/21/89; D203373, G. J. Herndon, 3/29/95). A s stated in The Pesticide Manual , Eleventh Edition, British Crop Protection Council (1997), abamectin has limited plant systemic activity , but does exhibit some translaminar movement. For the tolerance expression and risk assessment, the residues of concern in these crops are the parent compounds (avermectin B 1a and B 1b ) and their delta - 8,9 - isomers (also known as 8,9 - Z avermectin B 1a and 8,9 - Z avermectin B 1b ).ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 31 of 58 Metabolism in Rotational Crops : The qualitative nature of the residue in r otational crops is adequatel y defined. The confined rotational crop study indicated that avermectin residues accumulated in some rotational crops at levels up to 10 - 12 ppb. However, the radioactivity was due to polar degradates that were of little toxicological concern as compared to the parent compound avermectin B 1 and/or the delta - 8,9 - isomer (Memo, P. Mastradone, 4/24/88). Metabolism in Ruminants : The qualitativ e nature of abamectin residues in ruminants as a result of application to crops is adequatel y understood based on a goat metabolism study (PP#7G3468, L. Cheng, 2/11/87; PP#9F3703, S. Willett, 12/15/89). The residues of concern in ruminants for the toleran ce expression and risk assessment are the parent compounds (avermectin B 1a and B 1b ) and their delta - 8,9 - isomers . An additional metabolite (24 - hydroxy methyl avermectin B 1a) was identified and is potentially of toxicological significance, but was not includ ed in the tolerance expression because of its presence at low levels (PP#8F3592, F. Bo yd, 6/21/89; DP#203373, G. J. Herndon, 3/29/95 ). I f the tolerances for residues in meat and milk need to be raised at some future time due to registration of abamectin o n additional feed items, the 24 - hydroxy methyl metabolite may

need to be included in the tolerance expression and appropriate enforcement methods developed. Metabolism in Poultry : No poultry metabolism study

has been submitted. Since no significant poultry feed items are associated with the proposed uses, as indicated in Table 1 Feedstuffs (June 2008) , no poultry

metabolism study

is required. (Note: The tolerances for meat and meat by products of poultry

and swine of 0.02 ppm were established for residues in food handling establishments.) Metabolism in Rats: Avermectin B 1a does not bioaccumulate in rat tissues. Avermectin B 1a in rats is m etabolized to 24 - hydrox y - methyl B 1a (i.e., 24 - OH - Me - B 1a), which accounts for most of the radiolabeled residues. Residues of concern for the risk assessment and tolerance expression are summarized in Table 5.1 below. **Table 5.1**  **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 Crop Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Rotational Crop Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers)**ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 32 of 58 **Table 5.1**  **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 Livestock Ruminant* Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Parent (avermectin B 1a and B 1b ) and the delta - 8,9 - isomers (also known as 8,9 - Z isomers) Poultry Not applicable Not applicable Drinking Water Parent (avermectin B 1a and B 1b ) *** Not applicable * Residues of concern in ruminants include both use on crops and use in cattle ear tags. ** No rotational crop tolerances have been established. *** T he delta - 8,9 - isomers (also known as 8,9 - Z isomers) are not included in the drinking water assessment because they we re not identified in the fate studies . The major soil degradate included in the previous assessment ( a mixture of an 8 - alpha - hydroxy and a ring opened aldehyde derivative ) was not included in the current assessment based on an assumption of stability of parent until acceptable environmental fate data are submitted (D380524, G. Orrick, 1/31/11). **5 .2**  **Food Residue**  **Profile** Crop Field Trials For both cotton and strawberry , the field trials reflect the proposed use pattern. The number of trials and the geographic representation are adequate. The residue data are adequatel y supported by the storage sta

bility studies. The data collection methods [liquid chromatograph y/tandem mass spectrometry (LC/MS/MS ) for cotton; L C/MS/MS or high performance liquid chromatograph y ( HPL C ) for strawberry] are adequate for the anal ys is of the residues of concern. The res idue data adequately address the residues of concern. Residue decline in cottonseed and cotton gin b yproducts w as not determined because residues in the decline study were all < LOQ in cottonseed and were not determined in cotton gin by products. Residues declined in strawberries with increasing PHI. The field trials on cotton and strawberry are summarized in Table 5.2 .1 below. H igher residues occur red on cotton and strawberry as a result of use of the SC formulation as compared to use of the registered EC formulation. Higher residues occurred in cotton and strawberry even though an adjuvant was used with the SC formulation; the adjuvant was used to in crease photol yt ic degradation of abamect in and thereb y reduce residues, as has been observed with the SC formulation of abamectin on other crops.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 33 of 58 **TABLE 5.2. 1.**  **Summary of Combined Residues of**  **Avermectin B 1a**  **, 8,9**  **- Z Avermectin B**  **1a , and**  **Avermectin B 1b**  **fr om** **Field Trials with Abamectin.** Commodity Total Applic.

Rate (lb a.i./A) PHI

(days) Residue Levels 1 (ppm) n Sample Min. Sample

Max. LAFT 2 HAFT 2 Median Mean Std. Dev. **COTTON Proposed Use = 0.038 lb ai/acre/season total application rate, 20 -**  **day PHI.**  Cotton, undelinted seed 0.038 - 0.039 19 - 20 11 <0.006 <0.014 <0.006 <0.014 <0.006 <0.007 0.002 Cotton, gin byproducts 0.038 - 0.039 20 7 <0.009 0.688 <0.014 0.632 <0.018 <0.129 0.226

**STRAWBERRY Proposed Use = 0.075 lb ai/acre/season total application rate, 3**  **- day PHI.**  Strawberry 0.075 - 0.078 3 6 <0.008 <0.028 <0.010 <0.025 <0.015 <0.017 0.006 1 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LOQ (0. 0 0 2 ppm for each analyte in each matrix) was used for any results reported as <LOQ in Table C.3. 2 LAF T = lowest average field trial; HAFT = highest average field trial. Processing Studies There are no processed commodities associated with strawberries. As shown in Table 5.2.2 below, residues are not expected to concentrate in the processed commodities of cotton (meal, hulls, or refined oil). The average processing factor is 0.6x for eac h matrix (meal, hulls, and refined oil). Separate tolerances are not needed for the processed commodities of cotton. **TABLE 5.**  **2.2. Residue Data fr**  **om Cotton Processing Study with Abamectin**  **.** Location (County, State; Year) Trial ID RAC Total Rate (lb a . i . /A) Commodity PHI (days) Total Abamectin Residues (ppm) 1 Processing Factor Replicates Average Uvalde, TX; 2008 (W07TX081024) Cotton 0.190 Undelinted seed 20 <0.006, <0.013, <0.006 <0.009 N/A2 Hulls 20 <0.006, <0.006 <0.006 0.7x Meal 20 < 0.006, <0.006 <0.006 0.7x Refined oil 20 <0.006, <0.006 <0.006 0.7x Groom, TX; 2008 (E13TX081026) Cotton 0.191 Undelinted seed 20 <0.018, <0.014, <0.014 <0.016 N/A Hulls 20 <0.006, <0.006 <0.006 0.4x Meal 20 <0.006, <0.006 <0.006 0.4x Refined oil 20 <0.006, <0.006 <0.006 0.4x 1 Total residues of avermectin B 1a , avermectin B 1b and 8,9 - Z avermectin B 1a . The LOQ was 0.002 ppm for each analyte in each matrix, for a combined LOQ of 0.006 ppm. 2 N/A = N ot applicableABAMECTIN Human Health Risk Assessment DP No. D402677

Page 34 of 58 Storage Stability The storage stability data are adequate to support the storage intervals and conditions for the field trials on strawberry

and cotton (cottonseed and cotton gin by products). The available cotton seed storage stability data are adequate to support the s torage intervals and conditions for undelinted seed, hulls, and oil samples from the cotton processing study . A lthough storage stability data demonstrating the stability of abamectin in processed cotton meal frozen for up to 17.5 months are not available , the available storage stability data on cottonseed (14 months) and on other crops (fruits and vegetables) for longer intervals (24 - 35 months) allow HED to expect that residues in cotton meal will be stable for 17.5 months under frozen storage. Storage stability

data are summarized in Table 5.2.3 below. **TABLE 5.2.3. Summary of Storage Conditions**  **.** Matrix Storage Temperature (°C) Actual Storage

Duration 1 Interval of Demonstrated Storage Stability Strawberry

 20  5 45 - 141 days 1 (1.5 - 4.6 months) Data are available demonstrating that residues of

avermectin B 1a , avermectin B 1b , and 8,9 - Z avermectin B 1a are stable under frozen storage conditions for 24 months in strawberries (D P# 191433 , G. J. Herndon, 5/19/94 ). Cotton, undelinted seed

 20  5 142 - 220 days 2 (4.7 - 7.2 months) Data are available demonstrating that residues of

avermectin B 1a , avermectin B 1b , and 8,9 - Z avermectin B 1a are stable under frozen storage conditions in/on cottonseed (avermectin B 1a only) for 14 months; in/on celery, tomato, and strawberries for 24 months; in/on oranges, lemons, and grapefruits for 29 months; and in/on pears for 35 months (D P# 191433 , G. J. Herndon, 5/19/94 ). Cotton, gin byproducts

 20  5 297 - 437 days 2 (9.8 - 14.4 months) Cotton, undelinted seed for processing  20  5 148 - 219 days 3 (4.9 - 7.2 months) Data are available demonstrating that residues of

avermectin B 1a , avermectin B 1b , and 8,9 - Z avermectin B 1a are stable under frozen storage conditions in/on cottonseed (avermectin B 1a only) for 14 months; in/on celery, tomato, and strawberries for 24 months; in/on oranges, lemons, and grapefruits for 29 months; and in/on pears for 35 months (D P# 191433 , G. J. Herndon, 5/19/94 ). Cottonseed, hulls 59 - 152 days 3 (1.9 - 5.0 months) Cottonseed, meal 438 - 531 days 3 (14.4 - 17.5 months) Cottonseed, refined oil 313 - 406 days 3 (10.3 - 13.3 months) 1 Interval from harvest to extraction for analysis. Samples were analyzed within 0 - 5 days of extraction. 2 Interval from sample collection to extraction for analysis. Extracts were analyzed within 0 - 7 days of extraction. 3 Interval from sample collection (at harvest for RAC; after processing for processed commodities) to extraction for analysis. Extracts w ere analyzed within 0 - 16 days of extraction. Meat, Milk, Poultry, and Eggs An adequate ruminant feeding study was conducted. An adequate cattle ear tag study was conducted. No poultry

feeding studies were submitted or required. The livestock dietary burdens were calculated based on the maximum reasonably balanced diets ( Table 1 Feedstuffs , June 2008). The established tolerances on livestock commodities areABAMECTIN Human Health Risk Assessment DP No. D402677

Page 35 of 58 adequate to cover expected residues from livestock feed items and from the cattle ear tag use. The established tolerances for ruminants are 0.03 ppm for fat of cattle; 0.01 ppm for fat of goat, hog, horse, and sheep; 0.02 ppm for meat of cattle, goat, hog, horse, poultry , and sheep; 0.06 ppm for meat b yproducts of cattle; 0.02 ppm for meat byprodu cts of goat, hog, horse, poultry , and sheep; and 0.005 ppm for milk. Rotational Crops The confined rotational crop study indicated that avermectin residues accumulated in some rotational crops at levels up to 10 - 12 ppb. However, the radioactivity was due to polar degradates that were of little toxicological concern as compared to the parent compound avermectin B 1 and/or the delta - 8,9 - isomer (Memo, P. Mastradone, 4/24/88). Therefore, field rotational crop studies are not required (PP#7F3500, PP#8F3592, and PP#5E4566, DP#s 230333, 230352, and 230880, G. Herndon, 1/10/97). **5.3 Water Residue Profile**  E stimated drinking water concentrations (EDWCs) were provided for abamectin. The aquatic photodegradation products, which are polar and of low molecular weight, appear to be sugars with low toxicity

relative to the parent. T he delta - 8,9 - isomers (also known as 8,9 - Z isomers) are not included in the drinking water assessment because they were not identified in th e fate studies. The previousl y included major soil degradate (a mixture of an 8 - α - hydrox y and a ring opened aldeh yde derivative) was not included in the current assessment based on an assumption of stability of parent until acceptable environmental fate d ata are submitted . Abamectin is stable to abiotic hydrol ys is; acceptable data are not available to estimate the formation and decline of residues of concern via other degradataion routes. Groundwater and surface water monitoring data are not available for abamectin at this time. Therefore, screening models were used to determine estimated concentrations for abamectin in groundwater and surface water for the proposed uses. The estimated residues in surface water were derived using the Tier II model PRZ M/EXAMS (Pesticide Root Zone Model/Exposure Analy sis Modeling S ys tem). The Tier I SCI - GROW (Screening Concentration in Ground Water) model was used to derive the es timated concentration in groundwater. The modeled values used in this assessment for dri nking water were based on residues in surface water from the use of abamectin on dry beans in Michigan. The surface water residue estimates were adjusted for the national default percent cropped area (PCA) adjustment factor of 87%. T he estimated residues in groundwater were lower than those in surface water. Results from the PRZM/EXAMS screening model predict that the maximum acute (1 - in - 10 year peak) concentration of parent abamectin in surface water is not expected to exceed 2.3 ug/L (ppb), based on the current maximum seasonal use rate of 0.056 lb ai/A/year on dry beans in MI. The maximum chronic (1 - in - 10 year annual mean) concentration of parent abamectin in surface water is not expected to exceed 1.3 ug/L (ppb), based on the one - in - 10 year annual mean and the current maximum seasonal use rate in the M I dry bean scenario.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 36 of 58 Results from the SCI - GROW screening model predict that the maximum acute and chronic concentration of par ent abamectin in shallow groundwater is not expected to exceed 1.6 x 10 - 3 u g/ L (ppb) based on the current maximum seasonal use rate on tomatoes and cucurbits of 0.18 lb ai/A/year. **Table 5.3. Summ**  **ary of Estimated Surface Water and Groundwater Concentrations for Abam ectin**  **c ,d**  Abamectin Surface Water Conc., ppb a Groundwater Conc., ppb b Ac ute **2.3** 1.6 x 10 - 3 Chronic (non - cancer) **1.3** 1.6 x 10 - 3 Chronic (cancer) 0.94 1.6 x 10 - 3 a From the Tier II PRZM - EXAMS model. Input parameters for acute and chronic are based on the MI dry bean scenario of 0.056 lb ai/A/year with the percent cropped area adjustment factor of 87%. b From the SCI - GROW model based on the tomato and cucurbits scen ario of 0.18 lb ai/A/year. c Data source: D380524, G. Orrick, 1/31/11. d Bolded values are estimates used in the assessment. **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  Acute assessment: A refi ned acute dietary (food and drinking water) exposure assessment was conducted. Tolerance level residues were used for bulb onions, chives, dry beans, and okra . Acute anticipated residues for the remaining commodities were derived from field trial data. Empirical and default processing factors and percent crop treated (% CT) were used as available. EDWCs from EFED were also included. Surface drinking water concentrations were estimated using the Tier II PRZM/EXAMS (Pesticide Root Zone Model/Exposure Ana ly sis Modeling Sy stem) computer model and a percent c ropped area (PCA) value of 87%. The model predicts that the maximum concentration of total residues of abamectin in surface water (the 1 - in - 10 - ye ar peak exposure) is not likely to exceed 2.3 ppb from the use of aerial/ground application s to dry beans in Michigan. Chronic assessment: A refined chronic dietary (food and drinking water) exposure assessment was conducted. Tolerance level residues were used for bulb onions, chives, dry beans, and okra. Average residues from field trials were used for the remaining crops. Empirical and default processing factors and % CT were used as available. Drinking water was represented b y a single point estimate of average abam e ctin residues (the 1 - in - ten - ye ar annual mean) . The estimated surface water concentration of 1.3 ppb was based on the a pplication to dry

beans in Michigan. **5.4.2 Percent Crop Treated Used in Dietary Assessment**  The following maximum percent crop treated estimates ( D382732, Arthur H. Grube, 10/21/10) were used in the acute dietary risk assessment for the following crops that are currentl y registered for abamectin: a lmonds : 75%; a pples : 10%; a

pricots : 5%; avocados : 60%;ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 37 of 58 c antaloupes : 30%; c elery : 65%; c herries : 2.5%; c otton : 20%; c ucumbe rs : 10%; grapefruit : 80%; grapes : 25%; h oneydew : 35%; l emons : 55%; l ettuce : 20%; o ranges : 45%; p eaches : 2.5%; p ears : 80%; p ecans : 2.5%; p eppers : 25%; p otatoes : 2.5%; p runes : 10%; p umpkins : 10%; s pinach : 45%; s quash : 10%; s trawberries : 45%; t angerines : 65%; t omatoes : 20%; w alnuts : 20%; and w atermelons : 10%. The following average percent crop treated estimates ( D382732, Arthur H. Grube, 10/21/10) were used in the chronic dietary risk assessment for the following crops that are currently registered for abamectin: a lmonds : 50%; a pples : 5%; a

pricots : 5%; avocados : 40%; c antaloupes : 15%; c elery : 40%; c herries : 1%; c otton : 5%; c ucumbers : 5%; grapefruit : 60%; grapes : 10%; h oneydew : 20%; l emons : 35%; l ettuce : 10 %; o ranges : 25%; p eaches : 1%; p ears : 70%; p ecans : 1%; p eppers : 10%; p otatoes : 1%; p runes : 2.5%; p umpkins : 2.5%; s pinach : 20%; s quash : 5%; s trawberries : 30%; t angerines : 60%; t omatoes : 10%; w alnuts : 10%; and w atermelons : 5%. Percent crop treated data are available f or cotton and strawberry

as registered crops since they are registered for use of the EC formulation. **5.4.3 Acute Dietary Risk Assessment**  The general U.S. population and the following population subgroups were assessed: all infants (<1 year old), children 1 - 2 years old, children 3 - 5 years old, children 6 - 12 years old, youth 13 - 19 ye ars old, adults 20 - 49 years old, females 13 - 49 years old, and adults 50 - 99 years old. As shown in Table 5.4.6, the most highly exposed subgroup was children 1 - 2 years old, with exposure of 24% of the acute population adjusted dose (aPAD). The risk estimates for all populations assessed were below the level of concern. **5.4.4 Chronic Dietary Risk Assessment**  The general U.S. population and the following population subgroups were assessed: all infants (<1 year old), children 1 - 2 years old, children 3 - 5 years old, children 6 - 12 years old, youth 13 - 19 ye ars old, adults 20 - 49 years old, females 13 - 49 years old, and adults 50 - 99 years old. As shown in Table 5.4.6, the most highly exposed subgroup was children 1 - 2 years old, with exposure of 53% of the acute population adjusted dose (aPAD). The risk estimates for all populations assessed were below the level of c oncern. **5.4.5 Cancer Dietary Risk Assessment**  Abamectin is classified as “not likely to be carcinogenic to humans” based on the absence of a significant increase in tumor incidence in two adequate rodent carcinogenicity studies.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 38 of 58 **5.4.6 Summary Table**  **Table 5.4.6.**  **Summary of Dietary (Food and Drinking Water)**  **Exposure and Risk for Abamectin 1**  Population Subgroup Ac ute Dietary 99.9 th Percentile) Chronic Dietary Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD* General U.S. Population 0.000726 15 0.000068 17 All Infants (< 1 year old) 0.001079 22 0.000127 32 **Children 1 -**  **2 years old*** **0.001215 24**  **0.000213 53**  Children 3 - 5 years old 0.000882 18 0.000146 36 Children 6 - 12 years old 0.000544 11 0.000091 23 Youth 13 - 19 years old 0.000398 8.0 0.000055 14 Adults 20 - 49 years old 0.000409 8.2 0.000057 14 Adults 50 - 99 years old 0.000354 7.1 0.000054 13 Females 13 - 49 years old 0.000398 8.0 0.000055 14 * The subpopulation with the highest risk estimates is bolded. **6.0 Residential**  **(Non -**  **Occupational) Exposure/Risk Characterization** There are no proposed residential uses at this time; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 1 along with po licy

changes for body

weight assumptions. The r evision of residential exposure risk estimates will impact the human health aggregate risk assessment for abamectin . The products registered for residential use sites include several formulations of homeowne r bait and bait station products registered under multiple companies. These products include outdoor granular bait (GB) and indoor ready - to - use bait (RB) of both dust and gel formulations. For this assessment, the exposures and risk estimates for applyin g outdoor granular baits are assessed using the 2012 Residential SOPs 2 and exposure from indoor ready - to - use gel baits is considered negligible. In addition, exposure data for hand dispersal of granular bait is chosen as a surrogate to calculate risk esti mates from indoor RBs.

1 Available: http://www.epa.gov/pesticid es/science/residential - exposure - sop.html 2 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlABAMECTIN Human Health Risk Assessment DP No. D402677

Page 39 of 58 T here are no registered products that would lead to any residential handler risk estimates of concern. Short - term combined (dermal + inhalation) residential handler MOEs range from 320,000 to 1,100,000,000 . Residential post - applic ation exposures are not expected. **6 .1**  **Residential Handler Exposure** The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios: l oading/appl yi ng GB outdoor s via (1) p ush - ty pe spreaders , (2) b elly grinders , (3) s poon s, (4) hand, and (5) cup or shaker; and (6) appl yi ng granular bait indoor by hand (as a surrogate for a ready - to - use dust bait). There are no registered products that would lead to any residential handler risk estimates of concern. Sho rt - term combined (dermal + inhalation) residential handler MOEs range from 320,000 to 1,100,000,000.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 40 of 58 **Table 6**  **.1. Residential Handler**  **Non -**  **C ancer E**  **xposure and Risk Estimates for Abamectin .**  Exposure Scenario Level of

Concern Dermal Unit

Exposure ( m g/lb ai) Inhalation

Unit Exposure (m g/lb ai) Maximum

Application Rat e (lb ai/A) a Area Treated or

Amount Handled Daily b Dermal Inhalation Total

Dose (mg/kg/day) c MOE d Dose (mg/kg/day) e MOE f MOE g **Mi xer/Loader/Applicator for Outdoor Bait Application**  Push - Type Spreaders 300 0.81 0.0026 0.5 0.5 0.000000014 8,800,000 0.0000000044 28,000,000 6,700,000 Belly Grinders 360 0.039 0.023 0.023 0.00000028 430,000 0.0000000030 40,000,000 430,000 Spoon 6.2 0.087 0.00023 0.0023 0.00000000048 250,000,000 0.00000000067 180,000,000 100,000,000 Cup 0.11 0.013 0.0023 0.0000000000085 14,000,000,000 0.00000000010 1,200,000,000 1,100,000,000 Hand Dispersal 160 0.38 0.0023 0.000000012 9,700,000 0.0000000029 41,000,000 7,900,000 Shaker Can 0.11 0.013 0.0023 0.0000000000085 14,000,000,000 0.00000000010 1,200,000,000 1,100,000,000 **Mi xer/Loader/Applicator for Indoor Bait Application**  Bait (granular; hand dispersal) 300 160 0.38 0.00 00 13 lb ai/package/day 0.00000031 390,000 0.000000073 1,600,000 320,000 a Based on register ed labels: EPA Reg. Nos. 100 - 893, 100 - 1029, 100 - 1452 (50 mg ai/lb product): Apply 7 tbsp/mound (1 tbsp ≈ 0.4 oz ). Do not treat more than 12 ant mounds per acre (i.e. 12 mounds/A × 7 tbsp product/mound × 0.4 oz product/tbsp product × 0.0625 lb product/oz product × 50 mg ai/lb product × 2.20462×10 - 6 lb ai/mg ai = 0.00023 lb ai/A) EPA Reg. No. 499 - 383 (0.05% ai bait dust): Package contains 100 bait placements (12 grams of product) . The label recommends up to 30 bait placements in an average sized kitchen (i.e. assuming one package can be used in one day, 12 g product/day × 0.05% ai/product × 0.00220462 lb ai/g ai = 0.00 0013 lb ai/day). b Exposure Science Advisory Council Policy #9.1. Based on HED’s SOPs: Lawns/Turf (January 2012). 0.023 A = 1000 ft2 . 0.0023 A = 100 ft2

. c Derma l Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gallons/day) × DAF ( 1 %) ÷ BW ( 69 kg). d Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day). ST/IT Dermal NOAEL = 0.12 mg/kg/day. Level of concern = 300. e Inhalation Do se = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gallons/day) ÷ BW ( 69 kg). f Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). ST/IT Inhalation NOAEL = 0.12 mg/kg/day. Level of concern = 300. g Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhalation Dose) . ST/IT Combined Dermal/Inh alation NOAEL = 0.12 mg/kg/day. Level of concern = 300.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 41 of 58 **6 .2**  **Residential Post -**  **Application Exposure** Residential post - application exposure to adults and children is unlikely for all registered uses of abamectin. For outdoor treatments, adults and children are not expected to directly contact fire ant mounds. For indoor pest control, bait placements are intended to be placed in cracks and crevices where direct contact by adults and children is unlikely . R esidential By stander Post - Application Inhalation Exposure Based on the Agency 's current practices, a quantitative post - application inhalation exposure assessment was not performed for abamectin at this time primarily because of the low proposed use rat e and low vapor pressure. However, volatilization of pesticides may be a source of post application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pestici des from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3

. The Agency is in the process of evaluating the SAP report and may , as appropriate, de velop policies and procedures to identify the need for and, subsequently , the way to incorporate post - application inhalation exposure into the Agency's risk assessments. I f new policies or procedures are developed, the Agency may revisit the need for a qu antitative post - application inhalation exposure assessment for abamectin . **6.3 Spray Drift**  Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a l esser extent, could also be a potential source of exposure from the ground application method employed for abamectin . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices , and State Lead Agencies for pesticide regulation and o ther parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information) 4

. On a chemical b y chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be p laced on product labels/labeling. The Agency has completed its evaluation of the new database submitted b y the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast , and ground h ydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray

drift management practices to reduce off - target drift with specific products with significant risk estimates associated with drift. Although a quantitative residential post - application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fi elds, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post - application inhalati on exposure scenarios . 3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html 4 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmABAMECTIN Human Health Risk Assessment DP No. D402677

Page 42 of 58 **7.0 Aggregate Exposure/Risk Characterization**  As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. The toxicity

endpoints selected for these routes of exposure may be aggregated as follows: the oral, dermal, and inhalation routes of exposure can be combined to assess aggregate risks because of the selection of a common toxicity endpoint for all routes and durations of exposure. **7.1 Acute Aggregate Risk**  The acute aggregate risk assessment considers exposure estimates from dietary consumption of abamectin (food and drinking water). The acute aggregate food and drinking water assessment results are presented in Section 5.4 above. The most highly exposed subgroup is children 1 - 2 ye ars old at 24 % of th e aPAD , which is below the level of concern. **7.2 Short**  **- and Intermediate**  **- Term Aggregate Risk**  The short - /intermediate - term aggregate risk assessment estimates risks likely to result from exposure to abamectin residues from food, drinking water, and residential pesticide uses. High end estimates of residential exposure are used, while average values are used for food and drinking water exposure. A short - /intermediate - term risk assessment is required for adults because there are potential residential handler and post - application exposures from the crack and crevice use. In addition, a short - /intermediate - term risk assessment is required for infants and children because there is a residential post - application exposure scenario for crack and crevice treatment. The results of the short - /intermediate - term aggregate assessments are presented in Table 7.2. HED is generally

not concerned if the MOEs remain above the LOC, which for this assessment is 300. The MOEs for all scenarios are greater than 300, and theref ore, are not of concern. **Table 7.2 Short -**  **Term and/or Intermediate Term Aggregate Risk Calculations Population**  **Short -**  **or Intermediate -**  **Term Scenario**

**NOAEL mg/kg/day**  **LOC 1**  **Max**

**Allowable Exposure**  **2 mg/kg/day**  **Average**

**Food and Water**  **Exposure mg/kg/day**  **Residential**

**Exposure mg/kg/day**  **3 Tota**  **l**

**Exposure mg/kg/day**  **4 Aggregate** 

**MOE (food, water, and**  **residential) 5**  U.S. Population 0.12 300 0.0004 0.000068 0.00000038 0.000068 1800 1 The LOC includes the standard inter - and intra - species uncertainty factors (UF A and UF H , respectively) totaling 100, and an additional factor of 3x for the steepness of the dose - response curve and the severity of effects. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC 3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation exposure]. Refer to Table 6. 1 for residential exposure values used in the aggregate assessment. 4 Total Exposure = Avg Food & Water Exposure + Residential Exposure) 5 Aggregate MOE = [NOAEL  (Avg Food & Water Exposure + Residential Exposure)]ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 43 of 58 **7.3 Chronic Aggregate Risk**  The chronic aggregate risk assessment considers average exposure estimates from dietary consumption of abamectin (food and drinking water) and residential uses. However, due to the use patterns, no chronic residential exposure s are expected. Therefore, the chronic aggregate risk assessment will consider exposure from food and drinking water onl y. The chronic aggregate food and drinking water assessment resu lts are presented in Section 5.4 above. The most highly

exposed subgroup is children 1 - 2 years old at 53% of the cPAD, which is below the level of concern. **7.4 Cancer Aggregate Risk**  Abamectin is classified as “not likely to be carcinogenic to humans ” based on the absence of a significant increase in tumor incidence in two adequate rodent carcinogenicity studies. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity (CMT) , EPA has not made a common mechanism of toxicity finding as to abamectin and any other substances and abamectin does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that abamectin has a common mechanism of toxicity with other substances. OPP’s Guidance For Identifying Pesticide Chemicals and Other Substances that have a Common Mechanism of Toxicity (USEPA, 1999) describes the weight of the evidence approach f or determining whether or not a group of pesticides share a common mechanism of toxicity . This guidance defines mechanism of toxicity as the major steps leading to a toxic effect following interaction of a pesticide with biological targets. All steps lea ding to an effect do not need to be specificall y understood. Rather, it is the identification of the crucial events following chemical interaction that are required in order to describe a mechanism of toxicity . For example, a mechanism of toxicity

may be described b y knowing the following: a chemical binds to a given biological target in vitro, and causes the receptor - related molecular response; in vivo it also leads to the molecular response and causes a number of intervening biological and morphological steps that result in an adverse effect. In this context a common mechanism of toxicity pertains to two or more pesticide chemicals or other substances that cause a common toxic effect to human health by the same, or essentially

the same, sequence of maj or biochemical events. Hence, the underlying basis of the toxicity is the same, or essentially the same, for each chemical. In the case of the macrocyclic lactone pesticides (e.g ., abamectin, emamectin, and avermectin) , there is a wealth of data on the i nsecticidal mechanism of action for avermectin: its insecticidal actions are mediated b y interaction with the glutamate - gated chloride channels and GABA A gated chloride channels. This is presumed to be the insecticidal mechanism of action of emamectin and abamectin as well. Mammals lack glutamate - gated chloride channels; the toxic actions of avermectin appear to be mediated via interaction with GABA A and possibly glycine gatedABAMECTIN Human Health Risk Assessment DP No. D402677

Page 44 of 58 chloride channels (Kamijima M, Casida JE, 2000). There is evidence that avermectin B 1a binds to GABA A receptors and activates Cl flux into neurons (Abalis et al., 1986; Huang and Casida, 1997). However, there is a paucity of data regarding the resultant alterations in cellular excitability

of mammalian neurons and neural networks (i.e. , changes in cellular excitability and altered network function as documented with p yr ethroids), as well as in vivo measurements of altered excitabil ity

associated with adverse outcomes. Thus, while the downstream steps leading to toxicity

via disruption of GABA A receptor function for avermectin can be postulated, experimental data supporting these actions are lacking. In addition , specific data demo nstrating GABA A receptor interaction in mammalian preparations are lacking for abamectin and emamectin. Moreover, the specificity of such interaction on the adverse outcome would need to be shown experimentally. GABA A receptors have multiple binding site s which have been proposed to relate to adverse outcomes. For example, Dawson et al (20 00) showed for a group of avermectin - like compounds that rank order for anticonvulsant activity did not parallel the rank order for affinity

at the [3H]ivermectin site. The authors hy pothesized that these findings may be related to differential affinity or efficacy

at subt yp es of the GABA A receptor. Other reports have indicated species differences in abamectin effects on GABA A receptor function in the mouse as compared to the rat (Soderlund et al., 1987). In conclusion, although GABA A receptor mediated neurotoxicity is a strong h ypothesis as a common mechanism endpoint for the macrocyclic lactone pesticides, data demonstrating the interactions of emamectin and abamectin with mammalian GABA A receptors are not available, and data in mammalian preparations linking alterations in GABA A receptor function to disruptions in neuronal excitability in vitro and in vivo , and ultimately adverse outcome, are also currentl y lacking fo r this class of compounds. In the absence of such data, the key biological steps leading to the adverse outcome (i.e, the mammalian mechanism of action) cannot be established and b y extension a CM T cannot be established. For information regarding EPA’s e fforts to determine which chemicals have a common mechanism of toxicity

and to evaluate the cumulative effects of such chemicals, see the policy statements released b y EPA’s Office of Pesticide Programs concerning common mechanism determinations and proced ures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/ . **9.0 Occupational Exposure/Risk Characterization**  Based on the anticipated use patterns and current labeling, typ es of equipment and techniques that can potentially

be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupatio nal handlers is based on the following scenarios: 1. Mixing/loading liquids to support groundboom applications (cotton/strawberries) , 2. Mixing/loading liquids to support aerial applications (cotton only), 3. Flagging to support aerial application (cotton only), 4. Applying spray s with groundboom equipment (cotton/strawberries), and 5. Applying spray s with aerial equipment (cotton only).ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 45 of 58 Agricultural workers performing typical post - application activities (e.g. scouting, irrigation, transplanting/harvesting, etc.) may r eceive short - and intermediate - term exposure to abamectin residues. **9.1 Short**  **- /Intermediate**  **- Term**  **Handler Risk** The results of the occupational handler exposure and risk assessment indicate that short - and intermediate - term dermal and inhalation risks do not exceed HED’s LOC (i.e. , an MOE < 3 00) at some level of mitigation . The abamectin product labels direct mixers, loaders, applicators and other handlers to wear a long - sleeved shirt and long pants, chemical - resistant gloves, and shoes plus socks . For s hort - and intermediate - term exposure, the combined (dermal + inhalation) MOEs for mixer/loader scenarios range from 150 to 2,300 at baseline level of clothing (single layer long - sleeved shirt, long pants, and shoes plus socks). With single layer plus glov es as required b y the label, the lowest MOE of 150 increases to 600. All uses have acceptable MOEs given the proposed label requirements. For flaggers, the MOE is 2 , 700 at baseline (no gloves , no respirator). Onl y engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircrafts. For ground and aerial applicators the MOEs range from 1,900 to 4,8 00 (no gloves, no respirator). The Agency

has evaluated scenarios that may be limited in nature such as flagging during aerial applications because engineering controls (i.e., Global Positioning Satellite technology) are now predominantly

used as indicated by

the 1998 National Agricultural Aviation Association (NAAA) survey

of their membership. It appears, however, flagger s are still used in approximately

10 to 15 percent of aerial application operations. In cases like these, the Agency strongl y encourages the use of the engineering control system but will continue to evaluate risks for flaggers and an y other population wh ere a clear exposure pathway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey on exposure issues and will consider those results as are timel y and appropriate. HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engin eering control (enclosed cockpits) and baseline attire (long - sleeve shirt, long pants, shoes, and socks); pilots are not required to wear protective gloves. With this level of protection, there are no risk estimates of concern for applicators.ABAMECTIN Human Health Risk Assessment DP No. D402677

Page 46 of 58 **Table 9**  **.1 . Short**  **- and Intermediate**  **- Term Occupational Exposure and Risk Estimates for Abam**  **ectin Use on Cotton and Strawberries. a**  Crop Exposure Scenario Dermal Unit Exposure b Inhalation Unit

Exposure b Maximum

Application Rate c Area

Treated Dailyd Dermal Inhalation Total

Dose e MOE f Dose g MOE h MOE i ug/lb ai ug/lb ai lb ai/A A mg/kg/day mg/kg/day **Mixer/Loader at Baseline (No Gloves, No Respirator)**  Straw berries Mixing/Loading Liquids for

Groundboom Application 220 0.219 0.019 80 0.0000488 2,500 0.000004 86 25,000 2,300 Cotton Mixing/Loading Liquids for

Groundboom Application 220 0.219 0.019 200 0.000122 980 0.0000 121 9 , 900 890 Cotton Mixing/Loading Liquids for

Aerial Application 220 0.219 0.019 1200 0.000732 160 0.0000 729 1 , 600 **150 Mixer/Loader**  **with PPE (Single Layer + Gloves, No Respirator)** Cotton Mixing/Loading Liquids for

Aerial Application 37.6 0.219 0.019 1200 0.000125 960 0.0000729 1,600 600 **Applicator at Baseline (No Gloves, No Respirator)** Straw berries Applying Sprays via

Groundboom Equipment 78.6 0.34 0.019 80 0.0000174 6,900 0.00000755 16,000 4,800 Cotton Applying Sprays via

Groundboom Equipment 78.6 0.34 0.019 200 0.0000436 2800 0.0000 188 6 , 400 1 , 900 Cotton Applying Sprays via

Aerial Equipment * 5 0.068 0.019 1200 0.0000167 7200 0.0000 226 5 , 300 3 , 100 **Flagger at Baseline (No Gloves, No Respirator)**  Cotton Flagging for

Aerial Application 11 0.35 0.019 350 0.0000107 11,000 0.0000339 3,500 2,700 a All estimates are at baseline mitigation except for aerial applicator wh ich includes the engineering control of enclosed cockpits. b Unit Expos ures based on PHED Version 1.1 . Baseline = no gloves, no respirator. * Baseline aircraft = engineering controls. c Based on proposed label amendments (Reg. Nos. 100 - 1351 and 100 - 1408). d Acres Treated Per Day is taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 9.1 . e Dermal Dose = Dermal Unit Exposure (μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) × Area Treated or Amount Handled (A) × DAF (%) ÷ BW ( 69 kg). Dermal absorption factor = 1%. f Dermal MOE = Dermal NOAEL (mg/kg/day)/Dermal Dose (mg/kg/day). ST/IT Dermal NOAEL = 0.12 mg/kg/day. LOC = 300. g Inhalation Dose = Inhalation Unit Exposure (μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre) x Area Treated (A) ÷ BW ( 69 kg). h Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). ST/IT Inhalation NOAEL = 0.12 mg/kg/day. LOC = 300. i Total MOE = NOAEL (mg/k g/day) ÷ ( Dermal Dose + Inhalation Dose ) . ST/IT NOAEL = 0.12 mg/kg/day. LOC = 300.ABAMECTIN Human Health Risk Assessment DP No. 402677

Page 47 of 58 **9.2 Short**  **- /Intermediate**  **- Term Post**  **- Application Exposures and Risks**  The post - application MOEs do not exceed HED’s LOC of 300 (MOEs ranged from 1, 8 00 to 28 ,000) on day

0 (12 hours after application). **Table 9.2.**  **Summ ary of**  **Short -**  **and Interm ediate**  **- Term**  **Occupational/Commercial Post**  **- Application**  **Risk Estimates**  **for Abamectin**  **.** Crop Activities Transfer Coefficient (cm 2 /hr) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3 Cotton/Straw

berries Scouting 70 0.0533 0.00000 433 28,000

Hand Weeding 210 0.000013 0 9,200 Straw berries Scouting , Canopy

Management 70 0.00000 433 28,000 Hand Weeding 210 0.000013 0 9,200 Transplanting 230 0.0000142 8,500 Hand Harvesting 1,100 0.000068 0 1,800 a DFR = Application Rate × F × (1 - D) t × 4.54E8 μg/lb × 2.47E - 8 acre/cm2 ; where F = 0.25 and D = 0.10 per day. b Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption ( 1 %)]  BW (69 kg). c MOE = NOAEL (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm2 ) × TC × 0.001 mg/μg × 8 hrs/day × dermal absorption]  BW (69 kg). ST/IT Dermal NOAEL = 0.12 mg/kg/day. LOC = 300. Restricted Entry

Interval The REI specified on the proposed label is based on the acute toxicity of abamectin . Abamectin is classified as Toxicity

Category III via the dermal route and Toxicity Category III for skin irritation potential. It is not a skin sensitizer. Short - and intermediate - term post - app lication risk estimates were not a concern on day 0 (12 hours following application) for all post - application activities. Under 40 CFR 156.208 (c) (2) (iii) , active ingredients classified as Acute Toxicity Category III or IV for acute dermal, eye irritati on and primary skin irrigation are assigned a 12 - hour REI . Therefore, the [156 subpart K] Worker Protection Statement interim REIof 12 hours is adequate to protect agricultural workers from post - application exposures to abamectin. Occupational Post - Appl ication Inhalation Exposure Based on the Agency 's current practices, a quantitative post - application inhalation exposure assessment was not performed for abamectin at this time primarily because of the low proposed use rate (0.019 lb ai/A) and low vapor pressure ( 1.13 x 10 - 9 mmHg at 25 o C). However, there are multiple potential sources of post - application inhalation exposure to individuals performing post application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Sc ientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 5

. The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the the Agricultura l Reentry Task Force ( ARTF ) 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

5 Availabl e: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlABAMECTIN Human Health Risk Assessment DP No. 402677

Page 48 of 58 policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for abamectin . Although a quantitative occupational post - application inhalation exposure assessment was not p erformed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is exp ected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. **10.0 References**  N. Dodd, 8/24/11, DP No. D393232, Abamectin. Amendment to the Human Health Risk Assessment for Proposed Uses on the Bulb Onion Subgroup 3 - 07A, Chives, and Dry Beans to include Cowpea in the Dry Bean Tolerance . N. Dodd, 7/18/11, DP No. D380523, Abamectin. Human H ealth Risk Assessment for Proposed Uses on the Bulb Onion Subgroup 3 - 07A, Chives, a nd Dry Beans . N. Dodd, 12/17 /12, DP No. D401832, Abamectin. Petition to Increase the Established Permanent Tolerances on Strawberry and Cotton and to Add Uses on Strawberry and Cotton to Agri - Mek® SC and Epi -MekTM SC Labels. Summary of Analytical Chemistry and Residue Data . N. Dodd, 12/1 9 /12, DP No. D403715, Abamectin. Acute and Chronic Aggregate Dietary (Food and Drinking W

ater) Exposure and Risk Assessments for the Section 3 Registration Action for Use of a Suspension Concentrate (SC) Formulati on on Cotton and Strawberry . N. Tsaur, 12/20 /2012 , D P No. D 405841 , Abamectin. Occupational Exposure Assessment for a Label Amendment for Use on Cotton and Strawberries with An Updated Residential Exposure Assessment of All Existing Residential Uses (La wns/Turf and Indoor Environments). G. Orrick, 1/31/11, DP No. D380524, Abamectin. Drinking W ater Exposure Assessment for Proposed Section 3 New Uses on Chives, Dried Beans, and the Bulb Onion Subgroup 3 - 07A.ABAMECTIN Human Health Risk Assessment DP No. 402677

Page 49 of 58 **A ppendix**  **A .**  **Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR 158.340) for [Type of Use (e.g., food vs. non food)] for abamectin are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Acute Eye Irritation ................................ ....................... 870.2500 Acute Dermal Irritation ................................ ................. 870.2600 Skin Sensitization ................................ .......................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 90 - Day

Oral Toxicity in Rodents ................................ .. 870.3150 90 - Day

Oral Toxicity in Nonrodents ............................. 870.3200 21/28 - Day Dermal Toxicity ................................ ........... 870.3250 90 - Day

Dermal Toxicity ................................ ................ 870.3465 90 - Day

Inhalation Toxicity ................................ ........... ye s y es y es CR CR y es

y es a

- yes 870.3700a Prenatal Developmental Toxicity (rodent) ..................... 870.3700b Prenatal Developmental Toxicity (nonrodent) ............... 870.3800 Reproduction and Fertility Effects ................................ . y es yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Carcinogenicity (rat) ................................ ...................... 870.4200b Carcinogenicity (mouse) ................................ ................ 870.4300 Combined Chronic Toxicity/Carcinogenicity ................ yes no yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Bacterial Reverse Mutation Test .......... 870.5300 Mutagenicity

—Mammalian Cell Gene Mutation Test .. 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations ... 870.5xxx Mutagenicity

— Other Genotoxic Effects ....................... yes yes yes yes yes

yes yes yes 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90 - Day

Neurotoxicity Screening Battery (rat) ............... 870.6300 Developmental Neurotoxicity ................................ ........ yes yes yes yes

yes yes 870.7485 Metabolism and Pharmacokinetics ................................ 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes CR Yes yes

yes no a : This study was waived.ABAMECTIN Human Health Risk Assessment DP No. 402677

Page 50 of 58 **A.2 Toxicity Profiles**  **Table A. 2.**  **1. Acute Toxicity Profile**  **of Abam ectin Technical**  **Guideline No. Study Type**  **MRID # Results**  **Toxicity Category** 870.1100 Ac ute Oral - rat

(sesame oil vehicle) 006894 LD 50 = 13.6 mg/kg I 870.1100 Ac ute Oral - rat

(methyl cellulose vehicle) 45607202 LD 50 =214 - 232 mg/kg II 870.1200 Ac ute Dermal - rabbit 00255978 LD 50 = 2000 mg/kg III 870.1300 Ac ute Inhalation - rat 45623501 LC 50 =< 0.21 mg/L (nose only) I 870.2400 Primary Eye Irritation 45063501 not an irritant IV 870.2500 Primary Skin Irritation 41123904 slight irritation III 870.2600 Dermal Sensitization 00139564 negative in Buehler Negative 870.6200a Ac ute Neurotoxicity none none none **Table A.2. 2.**  **Toxicity Profile of Abam ectin Technical for Repeated Dosing and**  **Genotoxicity Studies Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  870.3100 Subchronic feeding study - rats 00131081 (1982)

Acceptable/Non - guideline 0, 0.10, 0.20, 0.40 mg/kg/day NOAEL > 0.40 mg/kg/day LOAEL = not established 870.3150 Subchronic toxicity Dogs (18 week gavage study) 00131082 (1982)

Acceptable/Guideline 0, 0.25, 0.5, 2.0, 8.0 mg/kg/day NOAEL = 0.25 mg/kg/day LOAEL = 0.50 mg/kg/day based on body tremors, one death, liver pathology, decreased body weight. Mydriasis was seen during week one in one dog. 870.3150 12 - Week dose range finding study - dogs (feeding) 00164152 (1982)

0.25, 0.50, 1.0, and 4.0/2.0 mg/kg/day (during week 4, 4.0 mg/kg/day wa s reduced to 2.0 mg/kg/day due to tremor, weakness, incoordination, and disorientation) The report stated that mydriasis was seen in 1.0 and 4.0 mg/kg/day dogs during week 1.The effec t was not seen at each examination day for any dog, but it was generally noted from 1 to 5 times a week. However, mydriasis was never noted at 0.5 and 0.25 mg/kg/day.

870.3200 21/28 - Day dermal toxicity Study not available. Study requirement was waived due to very low dermal absorption (<1%). 870.3465 30 - Day inhalation tox. - rats 46921502 (2006)

Acceptable/Guideline NOAEL = >2.5 μg/L (0.0025 mg/L) (HDT) (≈0.68 mg/kg/day)ABAMECTIN Human Health Risk Assessment DP No. 402677

Page 51 of 58 **Table A.2. 2.**  **Toxicity Profile of Abam ectin Technical for Repeated Dosing and**  **Genotoxicity Studies Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  870.4300a Com bined Chronic toxicity/carcinogenici ty - rats 40069601, 40375511,

40517801 (1985) Acceptable/Guideline 0, 0.75, 1.5, 2.0 mg/kg/day NOAEL = 1.5 mg/kg/day LOAEL = 2.0 mg/kg/day based on tremors **No evidence of carcinogenicity** 870.4100b Chronic toxicity dogs 40375510 (1987)

Acceptable/Guideline 0, 0.25, 0.5, 1.0 mg/kg/day NOAEL = 0.25 mg/kg/day LOAEL = 0.5 mg/kg/day based on mydriasis during week one, death at 1.0 mg/kg/day 870.4300b Com bined Chronic toxicity/Carcinogenic ity - mice 40069602, 40375512,

40517801 (1985) Acceptable/Guideline 0, 2, 4, 8 mg/kg/day NOAEL = 4.0 mg/kg/day LOAEL = 8.0 mg/kg/day based on increased mortality in males, tremors, body weight decreases in females, dermatitis in males, extramedullary hematopoiesis in spleen of males **No evidence of carcinogenicity** 870.3700a Prenatal developmental in rodents - rats Accession: 00130819

(1982) Acceptable/guideline 0, 0.4, 0.8, 1.6 mg/kg/day **Maternal** NOAEL > 1.6 mg/kg/day **Maternal** LOAEL = not established **Developm ental**  NOAEL > 1.6 mg/kg/day LOAEL = not established 870.3700a Prenatal developmental in rodents - CD - 1 mouse 44179901 (1999)

Acceptable/Non - Guideline 0, 0.75, 1.5, 3.0 mg/kg/day **Maternal** NOAEL = 1.5 mg/kg/day **Maternal** LOAEL = 3.0 mg/kg/day based on hind limb splay **Developm ental**  NOAEL < 0.75 mg/kg/day **Developm ental**  LOAEL = 0.75 mg/kg/day based on hind limb extension 870.3700b Prenatal developmental in nonrodents - rabbits Accession: 00130819

(1982) Acceptable./Guideline 0, 0.5, 1.0, 2.0 mg/kg/day **Maternal** NOAEL = 1.0 mg/kg/day **Maternal** LOAEL = 2.0 mg/kg/day based on decreased body weight, food consumption and water consumption **Developm ental**  NOAEL = 1.0 mg/kg/day LOAEL = 2.0 mg/kg/day based on cleft palate, clubbed foot, delayed ossification of sternebrae, metacarpals, phalanges 870.3800a 2 - Generation Reproduction and fertility effects - rat 00164151 (1984)

Acceptable/Guideline 0, 0.05, 0.12, 0.40 mg/kg/day **Parental/System ic**  NOAEL = 0.40 mg/kg/day LOAEL =not established **Reproductive** NOAEL = 0.40 mg/kg/day LOAEL = not established **Offspring** NOAEL = 0.12 mg/kg/day LOAEL = 0.40 mg/kg/day based on increased retinal folds, increased dead pups at birth, decreased viability and lactation indices, decreased pup body weight 870.3800b 1 - Generation Reproduction and fertility effects - rat 00096450

Unacceptable/Non Guideline 0, 0.5, 1.0, 1.5/2.0 mg/kg/day **Parental/System ic**  NOAEL = 1.0 mg/kg/day. LOAEL=1.5/2.0 based on whole body tremors, ataxia, ptyalis, ocular/nasal discharges and mortality **Reproductive** NOAEL = 3.0 mg/kg/day **Offspring** NOAEL < 0.5 mg/kg/day LOAEL = 0.5 mg/kg/day based on decreased pup survival and body weight between days 1 - 21 and delay in opening of eyesABAMECTIN Human Health Risk Assessment DP No. 402677

Page 52 of 58 **Table A.2. 2.**  **Toxicity Profile of Abam ectin Technical for Repeated Dosing and**  **Genotoxicity Studies Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  870.3800c 1 - Generation Reproduction and fertility effects - rat 00096451

Unacceptable/Non guideline 0, 0.1, 0.2, 0.4 mg/kg/day **Parental/System ic**  NOAEL = 0.4 mg/kg/day LOAEL = not established **Reproductive** NOAEL = 0.4 mg/kg/day **Offspring** NOAEL =0.1 mg/kg/day LOAEL = 0.2 mg/kg/day based on spastic movements and, delayed incisor eruption 870.3800c 1 - Generation Reproduction and fertility effects - rat 40713404 (1988)

Acceptable/Non - guideline 0, 0.1, 0.2, 0.4 mg/kg/day with **delta -**  **8,9 isom er**  0, 0.06, 0.12, 0.40 mg/kg/day **Parental/System ic**  NOAEL = 0.4 mg/kg/day LOAEL = not established **Reproductive** NOAEL = 0.4 mg/kg/day **Offspring** NOAEL =0.4 mg/kg/day LOAEL = not established Gene Mutation 870.5100 Ames/Salmonella E.coli/mammalian gene mutation assay Accession: 246894,

265568, 265569 (1986) Acceptable/Guideline Three studies: (1) 0, 3, 10, 30, 100, 1000 ug/plate, (2) 0, 100, 300, 1000, 3000, 10,000 ug/plate both with and without S - 9, (3) doses not specified. negative both with and without S - 9

870 - 6100 Ac ute neurotoxicity in rats (gavage) 46959202 (2006)

Acceptable/guideline 0.5, 1.5, and 6.0 mg/kg NOAEL = 0.5 mg/kg/day LOAEL = 1.5 mg/kg/day based on reduced splay reflex in males and females. At high dose, decreased motor activity, reduced splay reflex, & tip toe gait were seen. No death or histopathological changes in nervous system were found. 870 - 6200 Subchronic neurotoxicity in rats (gavage) 46959201 (2006)

Acceptable/guideline 0.4, 1.6, and 4.0 mg/kg/day NOAEL = 1.6 mg/kg/day LOAEL = 4.0 mg/kg/day based on upward curvature of the spine, tip - toe gate, decreased fore - and hind - limb grip strength. Decreased body was also seen. This dose group was terminated prematurely at week 7. 870 - 630 Developmental neurotoxicity study in rats 46727403, 46727402,

46727401 (2005) Acceptable/nonguideline 0.12, 0.20, and 0.40 mg/kg/day. Pups were not directly dose. Maternal NOAEL = 0.4 mg/kg/day (HDT) Offspring NOAEL = 0.2 mg/kg/day. Offspring LOAEL= 0.4 mg/kg/day based on decreased body weight in males and females.. 870 - 6200 Developmental neurotoxicity study in rats 47116201 (2007)

Acceptable/nonguideline 0.12, 0.20, and 0.40 mg/kg/day. Pups were not directly dosed. Maternal NOAEL = 0.4 mg/kg/day (HDT) Offspring NOAEL =0.12 mg/kg/day. Offspring LOAEL = 0.2 mg/kg/day based on slight but statistically significant decrease in pup body weight.ABAMECTIN Human Health Risk Assessment DP No. 402677

Page 53 of 58 **Table A.2. 2.**  **Toxicity Profile of Abam ectin Technical for Repeated Dosing and**  **Genotoxicity Studies Guideline No./**  **Study Type MRID No. (year)/** 

**Classification /Doses Results**  Gene Mutation 870.5100 Ames/Salmonella E.coli/mammalian gene mutation assay 40713402 (1988)

Acceptable/Guideline doses not specified up to 3000 ug/plate both with and without S - 9 using delta - 8,9 isomer negative both with and without S - 9 up to 3000 ug/plate

Gene Mutation 870.5100 Ames/Salmonella E.coli/mammalian gene mutation assay 40713405 (1988)

Acceptable/Guideline doses up to 10,000 ug/plate both with and without S - 9 using polar degradates negative both with and without S - 9

Gene Mutation 870.5300 CHO/HGPRT Forward Mutation Assay 265570 (1986)

Acceptable/Guideline both with and without S - 9 Negative

Gene Mutation 870.5300 Mammalian cells in culture in V79 cells MRID Unavailable

1983 Acceptable/Guideline Not mutagenic for V79 cells in absence of S - 9, but in the presence of S - 9 appeared to have a mutagenic potential, provided the test cells had an appropriate level of sensitivity Cy togenetics 870.5395 in vivo micronucleus assay - male mice MRID Unavailable

Acceptable/non - Guideline 0, 1.2, 12.0 mg/kg i.p. No chromosomal aberrations in male mice, but females not tested

Other Effects 870.5550 MRID Unavailable

(1983) 0.3 and 0.6 mM single strand DNA breaks at 0.3 and 0.6 mM in rat hepatocytes in vitro, but negative when hepatocytes from rat at LD50 dose level wa s used Metabolism Accession: 252114

Unacceptable/Non Guideline 69 - 82% of label is excreted in feces by day 7; T 1⁄2 =1.2 days. The reliability of these data is questionable. Metabolism No MRID

(1985) Nonguideline Avermectin B 1a did not bioaccumulate in rat tissues. Half - life slightly longer in females than in males for several tissues. Metabolism No MRID

(1985) Nonguideline The metabolism of avermectin B 1 in rats results in the formation of 24 - OH - Me - B 1a and accounts for most of the radiolabeled residues. Avermectin B 1a does not bioaccumulate. 870.7600 Dermal penetration Accession: 265590 (1986)

Acceptable/ Nonguideline in Monkeys The result showed the dermal absorption to be <1% of the applied dose. For risk assessment, a dermal penetration factor of 1% was recommended.ABAMECTIN Human Health Risk Assessment DP No. 402677

Page 54 of 58 **Table A .2**  **.3. Toxicity Profile of Abam ectin Technical**  **- for CF1 Mice**  **Guideline No./ Study Type**  **MRID No. / Classification /Doses**  **Results** 870.3700a Prenatal developmental in rodents - CF1 mouse 44160501 (1996)

Acceptable/Non - Guideline 0, 1.5 mg/kg/day on gestation days (GD) 6 - 15 to females which were heterozygous (+/ - ) and homozygous ( - / - , +/+) for p - glycoprotein and then mated to heterozygous and homozygous males **Maternal** NOAEL = 1.5 mg/kg/day **Maternal** LOAEL = not established 97% of ( - , - ) fetuses, 40% of (+, - ) fetuses, and 0% of (+,+) fetuses had cleft palate. It was determined that the observed increase in cleft palate in CF - 1 mice following treatment appears to be a consequence of fetal P glycoprotein genotype. 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 265564 (1986)

Acceptable/Guideline 0, 1.5, 3.0, 6.25, 12.5, 25, 50 mg/kg/day with delta - 8,9 isomer **Maternal** NOAEL < 1.5 mg/kg/day **Maternal** LOAEL = 1.5 mg/kg/day (mortality) **Developm ental**  NOAEL < 1.5 mg/kg/day LOAEL = 1.5 mg/kg/day based on increased cleft palate 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 265564 (1986)

Acceptable/Guideline 0, 0.03, 0.1, 0.5 mg/kg/day with delta - 8,9 isomer **Maternal** NOAEL = 0.1 mg/kg/day **Maternal** LOAEL = 0.5 mg/kg/day (mortality) **Developm ental**  NOAEL = 0.03 mg/kg/day LOAEL = 0.1 mg/kg/day based on increased cleft palate 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 265564 (1985)

Acceptable/Guideline 0, 0.05, 0.1, 0.5, 1.0 mg/kg/day with deta - 8,9 isomer **Maternal** NOAEL = 0.1 mg/kg/day **Maternal** LOAEL = 0.5 mg/kg/day (mortality) **Developm ental**  NOAEL = 0.05 mg/kg/day LOAEL = 0.1 mg/kg/day based on increased cleft palate 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 40912701 (1988)

Acceptable/Guideline 0, 0.25, 0.50, 1.0 mg/kg/day with citrus derived polar degradates **Maternal** NOAEL > 1.0 mg/kg/day **Maternal** LOAEL = not established **Developm ental**  NOAEL > 1.0 mg/kg/day LOAEL =not established 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 073759, 073761 (1984)

Acceptable/Non - Guideline 0, 0.1, 0.3, 0.6 mg/kg/day **Maternal** NOAEL = 0.1 mg/kg/day **Maternal** LOAEL = 0.3 mg/kg/day (mortality, tremors) 870.3700a Prenatal developmental in rodents - CF1 mouse 00096446 (1986)

Acceptable/Guideline 0, 0.1, 0.2, 0.4, 0.8 mg/kg/day **Maternal** NOAEL < 0.1 mg/kg/day **Maternal** LOAEL = 0.1 mg/kg/day (mortality) **Developm ental**  NOAEL = 0.2 mg/kg/day LOAEL = 0.4 mg/kg/day based on increased cleft palate 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 265564 (1985)

Acceptable/Guideline 0, 0.01, 0.03, 0.06 mg/kg/day with delta - 8,9 isomer **Maternal** NOAEL > 0.06 mg/kg/day **Maternal** LOAEL = not established **Developm ental**  NOAEL > 0.06 mg/kg/day LOAEL = not established 870.3700a Prenatal developmental in rodents - CF1 mouse Accession: 40713406 (1986)

Acceptable/Guideline 0, 0.25, 0.50, 1.0 mg/kg/day with polar degradates of abamectin **Maternal** NOAEL > 1.0 mg/kg/day **Maternal** LOAEL = not established **Developm ental**  NOAEL > 1.0 mg/kg/day LOAEL = not establishedABAMECTIN Human Health Risk Assessment DP No. 402677

Page 55 of 58 **Appendix B .**  **Toxicology Literature References** 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 - aminobut yric acid (A) receptor. J . Pharmacol . Exp . Ther. 295: 1051 - 10 60. Huang J, Casida JE. (1997) Avermectin B 1 a binds to high - and low - affinity sites with dual effects on the gama - aminobuty ric acid - gated chloride channel of cultured cerebellar granule neurons. J. Pharmacol. Exp. Ther. 281: 261 - 266. Kerb R (2006) Implication of genetic pol ym orphism in drug trans porters for pharmacotherap y. Cancer Lett. 234: 4 - 33. Kerr D I and Ong J. (1986) Gama - aminobuty ric acid - dependent motility induced by

avermectin B 1a in the isolated intestine of the guinea pigs. Neurosci . Lett. 65: 7 - 10. Lankas GR, Cartwright ME, and Umbe nhauer D (1997) P - Gl ycoprotein 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) Poly morphism I human MDR1 (P gl ycoprotein): Recent advances and clinical relevance. Clin. Pharmacol. and Ther. 75: 13 - 33. Meister B. (2007) Neurotransmitters in key neurons of the hy

pothalamus that regulate feeding behavior and body weight. Physiol . Behav. 92: 263 - 2 71. Niles, AT and Keppler, D (2007) The apical conjugate efflux pump ABCC2 (MRP2). Pfluger Arch - Eur J Physiol (2007) 453: 643 - 659. Ngu ye n L, Rigo JM, Rocher V, Belachew S, Malgrange B, Rogister B, Leprince P, Moonen G. (2001) Neurotransmitters as earl y signals for central nervous s ys tem 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 - aminobuty ric receptor - chlorid e ion channel complex. J . Neurosci. 2: 966 - 9 71 . Represa A, Ben - Ari Y. (2005) Trophic actions of GABA on neuronal development. Trends Neurosci. 28: 278 - 2 83. Habashi, SL(2006) Dubin - Johnson Sy ndrome. http://www.emedicine.com/med/topic 588.htm Wang CC, Pong SS. (1982) Actions of avermectin B 1a on GABA nerves. Prog . Clin . Biol . Res. 97: 373 - 3 95.ABAMECTIN Human Health Risk Assessment DP No. 402677

Page 56 of 58 **Appendix C**  **. Physical/Chemical Properties**  **Table C**  **. Physicochemical Properties of the Technical Grade of Abam**  **ectin Param**  **eter Value**  **Reference 1**  Molecular weight (g/mole) 873.11 Melting point/range (°C) 155 - 157°C Accession No. 260785 pH Not available Density (g/cm 3 ) 1.16 g/cm3 at 21°C Accession No. 260785 Water solubility (20°C) < 0.01 mg/mL in distilled water < 0.001 mg/mL in tap water < 0.001 mg/mL in buffer system pH 6, 7.4 & 9.0 < 0.001 mg/mL in 0.9% NaCl Accession No. 260785

Solvent solubility (20°C to 25°C) > 3 mg/mL in ethanol; >2 mg/mL in isopropyl myristate, chloroform, dimethylacetamide, dimethylformamide, glycerol formal & polyethylene glycol 400. Accession No. 260785 Vapor pressure (25°C) 1.5 x 10 - 9 hPa Accession No. 260785 Dissociation constant, pKa Not available Octanol/water partition coefficient, Log(KOW ) 9.9 x 10 - 3 Accession No. 260785 Aerobic soil metabolism half - life Not available DP No. D380524, G. Orrick, 1/31/11 1 Product Chemistry data were reviewed by Leung Cheng (Accession No. 260785, RCB No. 388, 5/1/1986).ABAMECTIN Human Health Risk Assessment DP No. 402677

Page 57 of 58 **Appendix D**  **. Review of Human Research**  This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data, which include studies from PHE D 1.1; the Agricultural Reentry Task Force (ARTF) database; and the Residential SOPs (Lawns/Turf and Indoor Environments) are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics re quirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 6

.

6 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.htmlABAMECTIN Human Health Risk Assessment DP No. 402677

Page 58 of 58 **Appendix E . International Residue**  **Limits Table**



### Abamectin ( 122804 ; 11/01/20 12 ) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3 40 CFR §180.449: avermectin B 1 [a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O - demethyl avermectin A 1 ) and less than or equal to 20% avermectin B 1b (5 - O - demethyl - 25 - de(1 - methylpropyl) - 25 - (1 - methylethyl) avermectin A 1 )] and its delta - 8,9 - isomer avermectin B 1 (a mixture of avermectins containing greater than or equal to 80% avermectin B 1a (5 - O demethyl avermectin A 1a ) and less than or equal to 20% avermectin B 1b (5 - O demethyl - 25 - de(1 - methylpropyl) - 25 - ( 1 - methylethyl ) av ermectin A 1a ) and its delta - 8,9 - isomer) Plants: sum of avermectin B1a, avermectin B1b, 8,9 - Z - av ermectin B1a and 8,9 - Z avermectin B1b. Animal commodities: sum of avermectin B1a and 8,9 - Z avermectin B1a. Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3 Cotton, undelinted seed 0.0 2 0.01 (*) Cotton, gin by -products 1.0 Strawberry 0.0 5 0.02 0.02 Completed: M. Negussie; 11/01/2012 1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.