
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM
	
Date:  12/20/12
 
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 Nos.:  100-1351, 100-1408
Petition No.:  2F8009
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical/Aggregate
Case No.:  NA
TXR 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 uses of abamectin, also known as avermectin B1 [a mixture of avermectins containing >=80% avermectin B1a (5-O-demethyl avermectin A1) and <=20% avermectin B1b (5-O-demethyl-25-de (1-methylpropyl)-25-(1-methylethyl) avermectin A1)], 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, higher tolerances are needed to support use of the SC formulation since higher residues occurred 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 with the SC formulation to increase photolytic degradation of abamectin and thereby reduce residues, as has been observed with 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 pathways.  HED determined that there 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 resulting 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.



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	FQPA 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
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


1.0	Executive Summary

Use Profile:  Abamectin is a mixture of avermectin B1 [a mixture of avermectins containing greater than or equal to 80% avermectin B1a (5-O-demethyl avermectin A1) and less than or equal to 20% avermectin B1b (5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) avermectin A1)] 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 miners, and other insects in commercially important crops.  Abamectin acts as an insecticide by interfering with the nervous system of the insect, causing the insect to become paralyzed.
  
Syngenta 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(R) SC Miticide/Insecticide (EPA Reg. No. 100-1351) and Epi-Mek(TM) SC Miticide/Insecticide (EPA Reg. No. 100-1408) labels.  Cotton and strawberry uses are currently registered on emulsifiable concentrate (EC) labels.  The established tolerances are based on residue data using the EC formulation.  Residues from crop 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 amendment of the established tolerances for combined residues of the insecticide avermectin B1 (a mixture of avermectins containing greater than or equal to 80% avermectin B1a (5-O- demethyl avermectin A1) and less than or equal to 20% avermectin B1b (5-O-demethyl-25- de(1-methylpropyl)-25-(1-methylethyl) avermectin A1)) and its delta-8,9-isomer to increase the tolerances on cotton, undelinted seed from 0.005 ppm to 0.015 ppm; on cotton, gin by-products from 0.15 ppm to 1.0 ppm; and on strawberry from 0.02 to 0.06 ppm.
  
Human 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 system, 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/response 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, respectively, 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 additional 3x FQPA safety factor is needed to address residual 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.

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 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 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 residues 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 processing factors and percent crop treated (%CT) were used as available.  Estimated drinking water concentrations (EDWCs) were provided by the Environmental Fate and Effects Division (EFED).  The maximum (acute) concentration of abamectin and its major soil degradate (a mixture of an 8-alpha-hydroxy and a ring opened aldehyde 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 15% 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 are below HED's level of concern [<100% of the chronic population adjusted dose (cPAD)] for the general U.S. population and all population subgroups.  Abamectin dietary exposure for food and drinking water is 17% of the cPAD for the 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.  All existing residential 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 that would lead to any residential handler or post-application risk estimates of concern.  Short-term combined (dermal + inhalation) 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 by adults and children is unlikely.

Aggregate 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 aggregate 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 likely to be carcinogenic to humans."  All potential exposure pathways 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, application).  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 < 300) 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 clothing (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).  Only 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 4,800 (no gloves, no respirator).

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 all the labels is acceptable.  The post-application MOEs do not exceed HED's LOC of 300 (MOEs ranged from 1,800 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 assessment 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 inhalation exposure assessment for abamectin.

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 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.  As indicated in Appendix D, these studies have been determined to require a review of their ethical conduct, and have received that review.

2.0	HED Recommendations

Provided revised Sections B (OCSPP 860.1200) and F (OCSPP 860.1550) and an analytical reference standard for 8,9-Z avermectin B1a (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

Residue 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 Analytical Reference Standards

Because the supply has been depleted, the registrant must submit five grams of 8,9-Z avermectin B1a (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 to conduct this study, but currently the registrant is planning 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 Analytical 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 byproducts 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 analyte, equivalent to 0.002 ppm for two analyte peaks (i.e., avermectin B1a and its delta-8,9-isomer in one peak and avermectin B1b 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 B1 [a mixture of avermectins containing greater than or equal to 80% avermectin B1a (5- O -demethyl avermectin A1 ) and less than or equal to 20% avermectin B1b (5- O -demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) avermectin A1 )] and its delta-8,9-isomer.

Table 2.2.2.  Tolerance Summary for Abamectin.
Commodity
                                  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

Strawberry 
                                     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 slightly different tolerance levels, as compared to Syngenta-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.


2.2.4	International Harmonization

The tolerance expressions for the US, Codex, and Canada include the same analytes 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 strawberry at 0.02 ppm.  The US is recommending higher tolerances for both undelinted cotton seed (0.02 ppm) and strawberry (0.05 ppm) based on residue data on the SC formulation.  Codex MRLs 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 photolytic degradation of abamectin and thereby reduce residues.  An International Residue Limit Status sheet is attached (Appendix E).

2.3	Label Recommendations

2.3.1	Recommendations from Residue Reviews

Both the Agri-Mek(R) SC Miticide/ Insecticide label [EPA Reg. No. 100-1351] and the Epi-Mek(TM) SC Miticide/ Insecticide 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 from Residential Assessment

Refer to Section 2.3.1.

3.0	Introduction

Abamectin is a mixture of avermectin B1 [a mixture of avermectins containing greater than or equal to 80% avermectin B1a (5-O-demethyl avermectin A1) and less than or equal to 20% avermectin B1b (5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) avermectin A1)] 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 commercially important crops.  Abamectin acts as an insecticide by interfering with the nervous system of the insect, causing the insect to become paralyzed.  Available mechanistic data indicate a neurotoxic mechanism of action, related to interference with GABA-mediated neurotransmission.

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 at levels ranging from 0.005 ppm to 0.20 ppm.  Compliance with the tolerance levels is to be determined by measuring only avermectin B1 [a mixture of avermectins containing greater than or equal to 80% avermectin B1a (5- O -demethyl avermectin A1 ) and less than or equal to 20% avermectin B1b (5- O -demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) avermectin A1 )] and its delta-8,9-isomer.

The registered formulation types include emulsifiable concentrate, granular, bait, gel, and dust.  The registered uses include food, food handling establishments, and residential uses.  Clinch(R) Ant Bait is registered for control of fire ants in citrus, almonds, 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 Ascend Fire Ant Stopper Bait/EPA Reg. No. 499-370).  

Agri-Mek(R) SC Miticide/Insecticide [100-1351] and Epi-Mek(TM) SC Miticide/Insecticide [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 days and the preharvest interval is 20 days.

Agri-Mek(R) SC Miticide/Insecticide [100-1351] and Epi-Mek(TM) SC Miticide/Insecticide [100-1408] are to be applied 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 days and the preharvest interval is 3 days.


3.1	Chemical Identity

Table 3.1.  Abamectin Nomenclature
Chemical Structure



Empirical formula
C48H72O14 (B1a); C47H70O14 (B1b)
Common Names
abamectin, avermectin B1
Company experimental name
MK-0936
IUPAC name
mixture of (10E,14E,16E)-(1R,4S,5 'S,6S,6 'R,8R,12S,13S,20R,21R,24S)-6 '-[(S)-sec-butyl]-21,24-dihydroxy-5 ',11,13,22-tetramethyl-2-oxo-(3,7,19-trioxatetracyclo[15.6.1.1[4,8].0[20,24]]pentacosa-10,14,16,22-tetraene)-6-spiro-2 '-(5 ',6 '-dihydro-2 'H-pyran)-12-yl 2,6-dideoxy-4-O-(2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranosyl)-3-O-methyl-α-L-arabino-hexopyranoside and (10E,14E,16E)-(1R,4S,5 'S,6S,6 'R,8R,12S,13S,20R,21R,24S)-21,22-dihydroxy-6 '-isopropyl-5 ',11,13,22-tetramethyl-2-oxo-(3,7,19-trioxatetracyclo[15.6.1.1[4,8].0[20,24]]pentacosa-10,14,16,22-tetraene)-6-spiro-2 '-(5 ',6 '-dihydro-2 'H-pyran)-12-yl 2,6-dideoxy-4-O-(2,6-dideoxy-3-O-methyl-α-L-arabino-hexopyranosyl)-3-O-methyl-α-L-arabino-hexopyranoside
CAS name
Avermectin B1
CAS Registry Number
Avermectin B1 - 71751-41-2; Avermectin B1a - 65195-55-3; Avermectin B1b - 65195-56-4
End-use product/EP
Agri-Mek(R) 0.15 EC Miticide/Insecticide, EPA Reg. No. 100-898 (contains 0.15 lb ai per gallon);
Epi-Mek(TM) 0.15 EC Miticide/Insecticide, EPA Reg. No. 100-1154 (contains 0.15 lb ai per gallon);
Agri-Mek(R) SC Miticide/Insecticide, EPA Reg. No. 100-1351 (contains 0.7 lb ai per gallon);
Epi-Mek(TM) 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 crystalline powder with very low vapor pressure.  It has very low water solubility but is soluble in organic solvents.  Residues do not readily leach to groundwater due to their affinity for soil particles.  Abamectin is stable to abiotic hydrolysis.  Acceptable data are not available to determine stability via other routes.  Determination of stability to photolysis and biodegradation is pending submission of acceptable data.  Refer to Appendix C for the table of physical/chemical properties.

3.3	Pesticide Use Pattern

Syngenta Crop Protection, LLC has submitted a petition to add cotton and strawberry uses to the Agri-Mek(R) SC and Epi-Mek(R) SC labels.  Cotton and strawberry uses are currently registered on emulsifiable concentrate (EC) labels.  Both Agri-Mek[(R)] SC and Epi-Mek(TM) SC are suspension concentrate (SC) formulations which contain 0.7 lb abamectin per gallon.  Both formulations contain 8.0% active ingredient and 92.0% inerts. 

Table 3.3.  Summary 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(R) SC Miticide/ Insecticide
[100-1351]

Epi-Mek(TM) 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 always be mixed with an adjuvant.
Do not apply with aircraft in NY state.
Do not apply through any type of irrigation system.
Retreatment interval is at least 21 days.
Do not apply in fewer than 5 gals water per acre.
                                 Strawberries
Foliar:
Ground Only
Agri-Mek[(R)] SC Miticide/ Insecticide
[100-1351]

Epi-Mek(TM) 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.
Conclusions. 	Refer to Section 2.3 for recommended modifications to the proposed labels.  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 applied 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 setting, 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 have 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	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

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 paralysis and death.  In the mammalian toxicity studies submitted by the registrant, paralysis is also a common finding prior to moribund sacrifice.  On the cellular level, abamectin acts by binding to gamma-aminobutyric 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 plays a critical role in nervous system development through both non-synaptic (Represa and Ben-Ari, 2005) and synaptic (Nguyen et al., 2001) mechanisms.  Within the mammalian brain, abamectin binding is widespread but particularly abundant in the cerebellum (Wang and Pong, 1982).  Abamectin also acts on GABA receptors in the enteric nervous system and induces longitudinal rhythmic 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 hypothesis, 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 with avermectin B1a. 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 blood were achieved within 4-8 h after administration. It was rapidly eliminated from the body, almost exclusively in the feces, and did not accumulate in the body after repeated exposure. The major biotransformations of avermectin B1a in the rat were demethylation, hydroxylation, cleavage of the oleandrosyl ring and oxidation reactions. There were 11 isolated metabolites. In the rat, avermectin B1a was metabolized to 24-hydroxy-methyl B1a (i.e., 24-OH-Me-B1a), which accounts for most of the radiolabeled residues.  However, the [8, 9-Z]- isomer of avermectin B1a was not found in the rat metabolism studies.  Avermectin B1a did not bioaccumulate in rat tissues. 

Toxicological Effects:  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 acute toxicity of abamectin technical is summarized 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 system, 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.  
Integral to its dose response in mammals, abamectin is also a substrate for P-glycoprotein (P-gp).  P-glycoprotein 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-hydrolysis providing the energy for active transport (Marzolini et al., 2004).  P-gp is found in the canallicular surface of hepatocytes, the apical surface of proximal tubular cells in the kidneys, brush border surface of enterocytes, luminal surface of blood capillaries of the brain (blood 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 in the brain and gonads, as well as the fetus.  Therefore, some test animals, in which genetic polymorphisms compromise P-gp expression, are particularly susceptible to abamectin-induced neurotoxicity (Lankas et al., 1997).  An example is the CF-1 mouse.  Some CF-1 mice are deficient in P-gp and are found to be highly 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 polymorphism in the gene encoding ABC (Dubin-Johnson Syndrome) (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 increase 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.  In rabbits at 2.0 mg/kg, the maternal effects consisted of deceases in  body weight and food consumption whereas 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 was 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 mutagenicity studies provide no indication that abamectin is carcinogenic or mutagenic.  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 Factor for Infants and Children (FQPA Safety Factor)

4.2.1	Completeness of 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.  

However, under the current data requirement guidelines (40 CFR §158.500), a subchronic dermal toxicity study and immunotoxicity study (OCSPP 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 structurally 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 currently the registrant is planning to submit a data waiver for the immunotoxicity study.  An inhalation study in rats was available and showed 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 is needed at this time.  

To address the issue of the immunotoxicity data gap and the associated database uncertainty 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 screening 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 of chemicals that would be expected to be immunotoxic.  Therefore, based on the above considerations, HED does not believe that conducting a special series 870.7800 immunotoxicity study will result in a NOAEL that is less than any which is used for point of departure for this risk assessment.  An additional uncertainty factor (UFDB) for database uncertainties does not need to be applied at this time. 

4.2.2	Evidence of Neurotoxicity

The findings of neurotoxic signs are consistent with mode of actions for a chemical which acts on GABA receptors.  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, ataxia, or spastic movements of the limbs are reported in various studies with different durations of abamectin exposure.  In dogs, mydriasis 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 seen 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 of Sensitivity/Susceptibility in the Developing or Young Animal

Increased 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 and 

developmental neurotoxicity studies in rats where the LOAELs 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  00130819) (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 days 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 LOAEL 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 days 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 the 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 particularly 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 levels, 0.75 mg/kg/day and 2.0 mg/kg/day, respectively.

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. LaRocca, 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.
  

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 effects (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; 1984): Groups of 30 SD rats/sex/dose were administered abamectin by 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 days while F0 females were treated for a minimum of 177 days.  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 NOAEL was 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 increased 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:APfSD 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 generally small and presented with dehydration and tremors.  Additionally, at this dose, pup body weights were decreased (p<=0.05) by 10-35% 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, 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.
Decreases (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 Analysis of Body Weight Data from the Developmental Neurotoxicity Study.  The results indicated that there was a statistically 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 biologically 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 safety factor yields 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 Analysis).

Developmental 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:APfSD 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.  Dams were allowed to deliver naturally 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.  Subsequently, 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 males and by 8-10% in the females throughout the post-weaning interval (PND 36-63).  The 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 safety 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/safety 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 NOAEL less than the NOAELs of 0.5 and 0.12 mg/kg/day already set for abamectin acute and repeated exposures, respectively.  An additional uncertainty factor (UFDB) 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 safety factor is needed to address residual 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 reproduction 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 neurotoxicity study provides little margin of safety for such a severe effect.  Retaining an additional 3x FQPA safety factor effectively provides a 10x margin between the dose which causes death (0.4 mg/kg/day) and the NOAEL adjusted by the additional safety factor (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 doses 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 protective 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-glycoprotein.  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 Exposure Database

There are no residual concerns with respect to the exposure databases. The chronic and acute dietary food exposure assessment utilizes conservative assumptions including anticipated residues, default processing factors, and percent crop treated.  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, the water exposure assessment will not underestimate the potential risks for infants 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 immunotoxicity study (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.  

4.3	Toxicity Endpoint and Point of Departure 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 endpoints 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 Assessment 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 departure for risk assessment for various exposure scenarios are presented in Tables 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 # 012854), 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 in 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 mydriasis was reported.  The data show that mydriasis was not reported in treated 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, mydriasis was noted only after at least 9 weeks of treatment, and at 0.5 mg/kg/day, mydriasis was seen at treatment day 7.  As treatment 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 mydriasis. With increasing dose levels, the time for mydriasis to occur was shortened.  At 8 mg/kg/day, mydriasis was seen within 24 hrs of treatment.  In dogs treated with 1 mg/kg/day, mydriasis 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, mydriasis was present.  Therefore, the LOAEL for mydriasis resulting from a single dose is 1 mg/kg and the NOAEL is 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 by 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 (LOAEL).  At the next higher dose level, 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 safety factor may be reduced to 1x, based on mydriasis 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.  Based 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 Seen in All the Available Toxicity Studies in Dogs
                                     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 was never noted.
Mydriasis was never noted.
Mydriasis was noted from 1 to 5  times/ week, beginning on week 1.
Mydriasis was noted. Food consumption was markedly reduced. 
4 mg/kg was reduced to 2 mg/kg due to marked reduction in FC.
Mydriasis was 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 died 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 hours after dosing, & 2/6 dogs died within 4 hrs.
53-Week toxicity study feeding (1987)
(0.25, 0.5, & 1.0 mg/kg/day)  (6M/6F)
On week 10, 1 dog was noted to have mydriasis, and none before that time.
On week 1, one dog was reported to have mydriasis. By week 6, 5 dogs had mydriasis. 
On week 1, 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. Dodd, 3/11/09).]  In the 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 analyzed using a statistical Mixed Model Analysis of Body Weight Data. The analysis showed that there was a statistically significant decrease in male pup body weights 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, respectively.  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 analysis was further evaluated with all the results of the pup body weight effects seen in three other reproduction 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 D362615).  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 biologically significant.  The 0.2 mg/kg/day dose is considered to be statistically and biologically 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 neurotoxicity study is established as the toxicity endpoint, and the NOAEL of 0.12 mg/kg/day is the point of departure for risk assessment.  As discussed in the FQPA Safety Factor Section, the 10x intraspecies factor is protective of the most sensitive subpopulation as represented by 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) carcinogenicity studies.

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 developmental 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 (appropriate duration), was relevant due to evidence of increased susceptibility to the offspring following pre- and postnatal exposure to abamectin, and adequately 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:  In 1998, the HIARC recommended the use of a dermal penetration factor of 1% for risk assessment purposes (HED document No. 012845; 9/15/1998)  This value was based on the results from a dermal absorption study in monkeys 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 factor for the steepness of the dose/response curve in several studies and the severity of effects [death] seen at the slightly higher dose level).

Level of Concern (LOC) for Occupational Risk Assessment:  For occupational exposure risk assessments, the uncertainty 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 severity of effects). 


Table 4.3.2.  Summary of Toxicological Doses and Endpoints for Abamectin for Use in Dietary and Non-Occupational Human Health Risk Assessments
Exposure/ Scenarios
Point of Departure
Uncertainty/FQPA Safety Factor
RFD, PAD, Level of Concern (LOC) 
Study and Toxicological Effects
Acute Dietary
(General population, including infants and children)
NOAEL = 0.5 mg/kg/day
UFA = 10x
UFH = 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
UFA = 10x
UFH = 10x
FQPA SF=3x*

cPAD = 0.0004 mg/kg/day
Combined data from three reproduction studies and two developmental 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
UFA = 10x
UFH = 10x
FQPA SF=3x*

Residential  LOC for MOE = 300
Combined data from three reproduction studies and two developmental 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
UFA = 10x
UFH = 10x
FQPA SF=3x*

Residential  LOC for MOE = 300

Combined data from three reproduction studies and two developmental neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint)
LOAEL = 0.2 mg/kg/day based on decreased pup body weight. 
Inhalation (All durations)

NOAEL = 0.12 mg/kg/day
UFA = 10x
UFH = 10x
FQPA SF=3x*

Residential  LOC for MOE = 300


Combined data from three reproduction studies and two developmental 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 observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  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.



Table 4.3.3.  Summary of Toxicological Doses and Endpoints for Abamectin for Use in Occupational Human 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
                                   UFA = 10X
                                   UFH = 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
                                   UFA = 10X
                                   UFH = 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 lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies). SF = 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.  
*	Level of Concern (LOC):  For 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 by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals.  Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity.  These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring.  For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups.  As part of its most recent registration decision, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database.  However, as required by FFDCA section 408(p), abamectin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 
EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen, or other such endocrine effects as the Administrator may designate."  The EDSP employs a two-tiered approach to making the statutorily required determinations.  Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems.  Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data.  Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect. 
Under FFDCA section 408(p), the Agency must screen all pesticide chemicals.  Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients.  Abamectin was included on that list and has been issued an order to conduct the Tier 1 testing.  Once all required 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 policies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website:  http://www.epa.gov/endo/. 

5.0	Dietary Exposure and Risk Assessment 

5.1	Residues of Concern Summary and Rationale

Metabolism in Primary Crops:  	The qualitative nature of abamectin residues in cotton and strawberry is adequately understood based on metabolism studies on cotton, citrus, and celery (PP#'s 5G3500, 5G3287, and 8F3649, respectively), as well as a report titled "Comparative Degradation of Avermectin B1a in Cotton Leaf, Citrus Fruit, Celery, and In Vitro" (PP#9F3703, S. Willett, 12/15/89).  The available studies on cotton, 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, and 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. Dykstra, 3/15/89; PP#8F3592, F. Boyd, 6/21/89; D203373, G. J. Herndon, 3/29/95).  As 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 B1a and B1b) and their delta-8,9-isomers (also known as 8,9-Z avermectin B1a and 8,9-Z avermectin B1b).

Metabolism in Rotational Crops:  The qualitative nature of the residue in rotational crops is adequately 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 B1 and/or the delta-8,9-isomer (Memo,  P. Mastradone, 4/24/88).
  
Metabolism in Ruminants:  	The qualitative nature of abamectin residues in ruminants as a result of application to crops is adequately 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 tolerance expression and risk assessment are the parent compounds (avermectin B1a and B1b) and their delta-8,9-isomers.  An additional metabolite (24-hydroxymethyl avermectin B1a) was identified and is potentially of toxicological significance, but was not included in the tolerance expression because of its presence at low levels (PP#8F3592, F. Boyd, 6/21/89; DP#203373, G. J. Herndon, 3/29/95).  If the tolerances for residues in meat and milk need to be raised at some future time due to registration of abamectin on additional feed items, the 24-hydroxymethyl 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 byproducts of poultry and swine of 0.02 ppm were established for residues in food handling establishments.)  

Metabolism in Rats: Avermectin B1a does not bioaccumulate in rat tissues.  Avermectin B1a in rats is metabolized to 24-hydroxy-methyl B1a (i.e., 24-OH-Me-B1a), 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 B1a and B1b) and the delta-8,9-isomers (also known as 8,9-Z isomers)
Parent (avermectin B1a and B1b) and the delta-8,9-isomers (also known as 8,9-Z isomers)

Rotational Crop
Parent (avermectin B1a and B1b) and the delta-8,9-isomers (also known as 8,9-Z isomers)
Parent (avermectin B1a and B1b) and the delta-8,9-isomers (also known as 8,9-Z isomers)**
Livestock


Ruminant*
Parent (avermectin B1a and B1b) and the delta-8,9-isomers (also known as 8,9-Z isomers)
Parent (avermectin B1a and B1b) and the delta-8,9-isomers (also known as 8,9-Z isomers)

Poultry
Not applicable
Not applicable
Drinking Water

Parent (avermectin B1a and B1b)***
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.
*** The 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 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 adequately supported by the storage stability studies.  The data collection methods [liquid chromatography/tandem mass spectrometry (LC/MS/MS) for cotton; LC/MS/MS or high performance liquid chromatography (HPLC) for strawberry] are adequate for the analysis of the residues of concern.  The residue data adequately address the residues of concern.  

Residue decline in cottonseed and cotton gin byproducts was not determined because residues in the decline study were all <LOQ in cottonseed and were not determined in cotton gin byproducts.  Residues declined in strawberries with increasing PHI.  

The field trials on cotton and strawberry are summarized in Table 5.2.1 below.  Higher residues occurred 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 increase photolytic degradation of abamectin and thereby reduce residues, as has been observed with the SC formulation of abamectin on other crops.


TABLE 5.2. 1.  Summary of Combined Residues of Avermectin B1a, 8,9-Z Avermectin B1a, and Avermectin B1b  from 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 (0.002 ppm for each analyte in each matrix) was used for any results reported as <LOQ in Table C.3.
[2]  LAFT = 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 each matrix (meal, hulls, and refined oil).  Separate tolerances are not needed for the processed commodities of cotton.

TABLE 5.2.2.	Residue Data from 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/A[2]

                                       
                                       
                                     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 B1a, avermectin B1b and 8,9-Z avermectin B1a.  The LOQ was 0.002 ppm for each analyte in each matrix, for a combined LOQ of 0.006 ppm.  
[2]  N/A = Not applicable


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 byproducts).  

The available cottonseed storage stability data are adequate to support the storage intervals and conditions for undelinted seed, hulls, and oil samples from the cotton processing study.  
Although 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 B1a, avermectin B1b, and 8,9-Z avermectin B1a are stable under frozen storage conditions for 24 months in strawberries (DP# 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 B1a, avermectin B1b, and 8,9-Z avermectin B1a are stable under frozen storage conditions in/on cottonseed (avermectin B1a 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 (DP# 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 B1a, avermectin B1b, and 8,9-Z avermectin B1a are stable under frozen storage conditions in/on cottonseed (avermectin B1a 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 (DP# 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 were 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 are 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 byproducts of cattle; 0.02 ppm for meat byproducts 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 B1 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

Estimated 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.  The 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 the fate studies.  The previously included major soil degradate (a mixture of an 8-α-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. Abamectin is stable to abiotic hydrolysis; 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 PRZM/EXAMS (Pesticide Root Zone Model/Exposure Analysis Modeling System).  The Tier I SCI-GROW (Screening Concentration in Ground Water) model was used to derive the estimated concentration in groundwater.  

The modeled values used in this assessment for drinking 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%.  The 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 MI dry bean scenario.
Results from the SCI-GROW screening model predict that the maximum acute and chronic concentration of parent abamectin in shallow groundwater is not expected to exceed 1.6 x 10[-3] ug/L (ppb) based on the current maximum seasonal use rate on tomatoes and cucurbits of 0.18 lb ai/A/year.  

Table 5.3.   Summary of Estimated Surface Water and Groundwater Concentrations for Abamectin[c][,d]

                                   Abamectin

                          Surface Water Conc., ppb a
                           Groundwater Conc., ppb b
Acute
                                      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 scenario 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 refined 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 Analysis Modeling System) computer model and a percent cropped area (PCA) value of 87%.  The model predicts that the maximum concentration of total residues of abamectin in surface water (the 1-in-10-year peak exposure) is not likely to exceed 2.3 ppb from the use of aerial/ground applications 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 by a single point estimate of average abamectin residues (the 1-in-ten-year annual mean).  The estimated surface water concentration of 1.3 ppb was based on the application 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 currently registered for abamectin: almonds: 75%; apples: 10%; apricots: 5%; avocados: 60%; cantaloupes: 30%; celery: 65%; cherries: 2.5%; cotton: 20%; cucumbers: 10%; grapefruit: 80%; grapes: 25%; honeydew: 35%; lemons: 55%; lettuce: 20%; oranges: 45%; peaches: 2.5%; pears: 80%; pecans: 2.5%; peppers: 25%; potatoes: 2.5%; prunes: 10%; pumpkins: 10%; spinach: 45%; squash: 10%; strawberries: 45%; tangerines: 65%; tomatoes: 20%; walnuts: 20%; and watermelons: 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: almonds: 50%; apples: 5%; apricots: 5%; avocados: 40%; cantaloupes: 15%; celery: 40%; cherries: 1%; cotton: 5%; cucumbers: 5%; grapefruit: 60%; grapes: 10%; honeydew: 20%; lemons: 35%; lettuce: 10 %; oranges: 25%; peaches: 1%; pears: 70%; pecans: 1%; peppers: 10%; potatoes: 1%; prunes: 2.5%; pumpkins: 2.5%; spinach: 20%; squash: 5%; strawberries: 30%; tangerines: 60%; tomatoes: 10%; walnuts: 10%; and watermelons: 5%.

Percent crop treated data are available for 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 years 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 years 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 concern.

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.


5.4.6	Summary Table

 Table 5.4.6.  Summary of Dietary (Food and Drinking Water) Exposure and Risk for Abamectin[1]
                              Population Subgroup
                                 Acute Dietary
                              99.9[th] Percentile)
                                Chronic Dietary
                                        
                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
 General U.S. Population
                                    0.000726
                                       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 along with policy changes for body weight assumptions.  The revision 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 homeowner 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 applying outdoor granular baits are assessed using the 2012 Residential SOPs 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 estimates from indoor RBs.

There 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-application exposures are not expected.
6.1	Residential Handler Exposure

The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios: loading/applying GB outdoors via (1) push-type spreaders, (2) belly grinders, (3) spoons, (4) hand, and (5) cup or shaker; and (6) applying 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.  Short-term combined (dermal + inhalation) residential handler MOEs range from 320,000 to 1,100,000,000.








Table 6.1.  Residential Handler Non-Cancer Exposure and Risk Estimates for Abamectin.
                                   Exposure
                                   Scenario
                               Level of Concern
                             Dermal Unit Exposure
                                  (mg/lb ai)
                      Inhalation Unit Exposure (mg/lb ai)
                           Maximum Application Rate
                                 (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]
             Mixer/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
              Mixer/Loader/Applicator for Indoor Bait Application
                                Bait (granular;
                                hand dispersal)
                                      300
                                      160
                                     0.38
                                   0.000013
                               lb ai/package/day
                                  0.00000031
                                    390,000
                                  0.000000073
                                   1,600,000
                                    320,000
a	Based on registered 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 x 7 tbsp product/mound x 0.4 oz product/tbsp product x 0.0625 lb product/oz product x 50 mg ai/lb product x 2.20462x10[-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 x 0.05% ai/product x 0.00220462 lb ai/g ai = 0.000013 lb ai/day).
b	Exposure Science Advisory Council Policy #9.1. Based on HED's SOPs: Lawns/Turf (January 2012).  0.023 A = 1000 ft[2].  0.0023 A = 100 ft[2].
c	Dermal Dose = Dermal Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled  (A or gallons/day) x 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 Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or gal) x 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/Inhalation NOAEL = 0.12 mg/kg/day. Level of concern = 300.
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.

Residential Bystander 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 rate 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 pesticides 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.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for abamectin.

6.3	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for abamectin.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information).  On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift 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 fields, 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 inhalation exposure scenarios.
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 years old at 24% of the aPAD, which is below the level of concern.

58.2 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 therefore, 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]
                          Total 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 (UFA and UFH, 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)]
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 exposures are expected.  Therefore, the chronic aggregate risk assessment will consider exposure from food and drinking water only.

The chronic aggregate food and drinking water assessment results 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.
 
6.0 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 for 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 leading to an effect do not need to be specifically 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 by 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 major 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 insecticidal mechanism of action for avermectin: its insecticidal actions are mediated by interaction with the glutamate-gated chloride channels and GABAA 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 GABAA and possibly glycine gated chloride channels (Kamijima M, Casida JE, 2000).  There is evidence that avermectin B1a binds to GABAA 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 pyrethroids), as well as in vivo measurements of altered excitability associated with adverse outcomes.  Thus, while the downstream steps leading to toxicity via disruption of GABAA receptor function for avermectin can be postulated, experimental data supporting these actions are lacking.  In addition, specific data demonstrating GABAA 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.  GABAA receptors have multiple binding sites which have been proposed to relate to adverse outcomes.  For example, Dawson et al (2000) 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 hypothesized that these findings may be related to differential affinity or efficacy at subtypes of the GABAA receptor. Other reports have indicated species differences in abamectin effects on GABAA receptor function in the mouse as compared to the rat (Soderlund et al., 1987).

In conclusion, although GABAA receptor mediated neurotoxicity is a strong hypothesis as a common mechanism endpoint for the macrocyclic lactone pesticides, data demonstrating the interactions of emamectin and abamectin with mammalian GABAA receptors are not available, and data in mammalian preparations linking alterations in GABAA receptor function to disruptions in neuronal excitability in vitro and in vivo, and ultimately adverse outcome, are also currently lacking for 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 by extension a CMT cannot be established.

For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

7.0 Occupational Exposure/Risk Characterization

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses.  The quantitative exposure/risk assessment developed for occupational 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 sprays with groundboom equipment (cotton/strawberries), and
   5. Applying sprays with aerial equipment (cotton only).

Agricultural workers performing typical post-application activities (e.g. scouting, irrigation, transplanting/harvesting, etc.) may receive 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 < 300) 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 clothing (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).  Only 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 4,800 (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, flaggers are still used in approximately 10 to 15 percent of aerial application operations.  In cases like these, the Agency strongly encourages the use of the engineering control system but will continue to evaluate risks for flaggers and any other population where 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 timely 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 engineering 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.
   
Table 9.1.  Short- and Intermediate-Term Occupational Exposure and Risk Estimates for Abamectin Use on Cotton and Strawberries.[a]  
                                     Crop
                               Exposure Scenario
                            Dermal Unit Exposure[b]
                          Inhalation Unit Exposure[b]
                          Maximum Application Rate[c]
                             Area Treated Daily[d]
                                    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)
                                 Strawberries
               Mixing/Loading Liquids for Groundboom Application
                                      220
                                     0.219
                                     0.019
                                      80
                                   0.0000488
                                     2,500
                                  0.00000486
                                    25,000
                                     2,300
                                    Cotton
               Mixing/Loading Liquids for Groundboom Application
                                      220
                                     0.219
                                     0.019
                                      200
                                   0.000122
                                      980
                                   0.0000121
                                     9,900
                                      890
                                    Cotton
                 Mixing/Loading Liquids for Aerial Application
                                      220
                                     0.219
                                     0.019
                                     1200
                                   0.000732
                                      160
                                   0.0000729
                                     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)
                                 Strawberries
                   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
                                   0.0000188
                                     6,400
                                     1,900
                                    Cotton
                              Applying Sprays via
                              Aerial Equipment[*]
                                       5
                                     0.068
                                     0.019
                                     1200
                                   0.0000167
                                     7200
                                   0.0000226
                                     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 which includes the engineering control of enclosed cockpits.
b	Unit Exposures 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 (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre) x Area Treated or Amount Handled (A) x 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 (μg/lb ai) x Conversion Factor (0.001 mg/μg) x 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/kg/day) / (Dermal Dose + Inhalation Dose). ST/IT NOAEL = 0.12 mg/kg/day. LOC = 300.

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 1,800 to 28,000) on day 0 (12 hours after application).

Table 9.2.  Summary of Short- and Intermediate-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/Strawberries
                                   Scouting
                                      70
                                    0.0533
                                  0.00000433
                                    28,000
                                       
                                 Hand Weeding
                                      210
                                       
                                   0.0000130
                                     9,200
                                 Strawberries
                          Scouting, Canopy Management
                                      70
                                       
                                  0.00000433
                                    28,000
                                       
                                 Hand Weeding
                                      210
                                       
                                   0.0000130
                                     9,200
                                       
                                 Transplanting
                                      230
                                       
                                   0.0000142
                                     8,500
                                       
                                Hand Harvesting
                                     1,100
                                       
                                   0.0000680
                                     1,800
a	DFR = Application Rate x F x (1-D)t x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day.
b	Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x dermal absorption (1%)]  BW (69 kg).
c	MOE = NOAEL (mg/kg/day) / Daily Dermal Dose.  Daily Dermal Dose = [DFR/TTR (ug/cm[2]) x TC x 0.001 mg/ug x 8 hrs/day x 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-application 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 irritation and primary skin irrigation are assigned a 12-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to abamectin.

Occupational 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 rate (0.019 lb ai/A) and low vapor pressure (1.13 x 10[-9] mmHg at 25ºC).  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 Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010. The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the the Agricultural 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 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 performed, 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 expected 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 Health Risk Assessment for Proposed Uses on the Bulb Onion Subgroup 3-07A, Chives, and 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(R)  SC and Epi-Mek(TM) SC Labels.  Summary of Analytical Chemistry and Residue Data.

N. Dodd, 12/19/12, DP No. D403715, Abamectin.  Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action for Use of a Suspension Concentrate (SC) Formulation on Cotton and Strawberry.

	N. Tsaur, 12/20/2012, DP No. D405841,  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 (Lawns/Turf and Indoor Environments).

G. Orrick, 1/31/11, DP No. D380524, Abamectin.  Drinking Water Exposure Assessment for Proposed Section 3 New Uses on Chives, Dried Beans, and the Bulb Onion Subgroup 3-07A.
Appendix 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	
                                      yes
                                      yes
                                      yes
                                      CR
                                      CR
                                      yes
                                      yes
                                       a
                                       -
                                      yes
870.3700a  Prenatal Developmental Toxicity (rodent)	
870.3700b  Prenatal Developmental Toxicity (nonrodent)	
870.3800    Reproduction and Fertility Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (nonrodent)	
870.4200a  Carcinogenicity (rat)	
870.4200b  Carcinogenicity (mouse)	
870.4300    Combined Chronic Toxicity/Carcinogenicity	
                                      yes
                                      no
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Bacterial Reverse Mutation Test	
870.5300    Mutagenicity -- Mammalian Cell Gene Mutation Test	
870.5xxx    Mutagenicity -- Structural Chromosomal Aberrations	
870.5xxx    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Developmental Neurotoxicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.7485    Metabolism and Pharmacokinetics	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      CR
                                      Yes
                                      yes
                                      yes
                                      no
[a]: This study was waived.
A.2	Toxicity Profiles

Table A.2.1.  Acute Toxicity Profile of Abamectin Technical
Guideline No.
Study Type
MRID #
Results
Toxicity Category
870.1100
Acute Oral - rat 
(sesame oil vehicle)
006894
LD50 = 13.6 mg/kg
 I
870.1100
Acute Oral - rat
(methyl cellulose vehicle)
45607202
LD50=214-232 mg/kg
 II
870.1200
Acute Dermal - rabbit
00255978
LD50 = 2000 mg/kg
 III
870.1300
Acute Inhalation - rat
45623501
LC50 =<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
Acute Neurotoxicity
none
none
 none
                                       
Table A.2.2.  Toxicity Profile of Abamectin 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 was 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 effect 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)

870.4300a
Combined Chronic toxicity/carcinogenicity- 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
Combined Chronic toxicity/Carcinogenicity- 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
Developmental 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

Developmental NOAEL < 0.75 mg/kg/day
Developmental 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 
Developmental 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/Systemic 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/Systemic 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 eyes
870.3800c
1-Generation Reproduction and fertility effects- rat
00096451
Unacceptable/Non-guideline

0, 0.1, 0.2, 0.4 mg/kg/day
Parental/Systemic 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 isomer
0, 0.06, 0.12, 0.40 mg/kg/day
Parental/Systemic 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 
Acute 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. 
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
Cytogenetics 
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 was 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 B1a 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 B1 in rats results in the formation of 24-OH-Me-B1a and accounts for most of the radiolabeled residues.  Avermectin B1a 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.




     Table A.2.3.  Toxicity Profile of Abamectin 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)
Developmental 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)
Developmental 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)
Developmental 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
Developmental 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)
Developmental 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
Developmental 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
Developmental NOAEL > 1.0  mg/kg/day
LOAEL = not established

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-aminobutyric acid (A) receptor. J. Pharmacol. Exp. Ther. 
      295: 1051-1060.

Huang J, Casida JE. (1997) Avermectin B1a	binds to high- and low-affinity sites with dual 
	effects on the gama-aminobutyric acid-gated chloride channel of cultured cerebellar 
	granule neurons. J. Pharmacol. Exp. Ther. 281: 261-266.

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

Kerr DI and Ong J. (1986) Gama-aminobutyric acid-dependent motility induced by avermectin B1a in the isolated intestine of the guinea pigs. Neurosci. Lett. 65: 7-10.

Lankas GR, Cartwright ME, and Umbenhauer D (1997) P-Glycoprotein deficiency in a 
	subpopulation of CF-1 mice enhances avermectin-induced neurotoxicity. Toxicol. and Appl. Pharmacol. 143: 357-365.

Marzolini C, Paus E, Buclin T, and Kim RB (2004) Polymorphism I human MDR1 (P-
	glycoprotein): Recent advances and clinical relevance. Clin. Pharmacol. and Ther. 
	75: 13-33.

Meister B. (2007) Neurotransmitters in key neurons of the hypothalamus that regulate feeding 
      behavior and body weight. Physiol. Behav. 92: 263-271.

Niles, AT and Keppler, D (2007) The apical conjugate efflux pump ABCC2 (MRP2). Pfluger 
	Arch-Eur J Physiol (2007) 453: 643-659.

Nguyen L, Rigo JM, Rocher V, Belachew S, Malgrange B, Rogister B, Leprince P, Moonen G.
	(2001) Neurotransmitters as early signals for central nervous system development. Cell 
	Tissue Res. 305: 187-202.
 
Pong SS, DeHaven R, Wang CC. (1982) A comparative study of avermectin B1a and other 
	modulators of the gama-aminobutyric receptor- chloride ion channel complex. J. 
	Neurosci. 2: 966-971.

Represa A, Ben-Ari Y. (2005) Trophic actions of GABA on neuronal development. Trends 
	Neurosci. 28: 278-283. 

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

Wang CC, Pong SS. (1982) Actions of avermectin B1a on GABA nerves. Prog. Clin. Biol. Res. 
		97: 373-395.

Appendix C.  Physical/Chemical Properties

Table C.  Physicochemical Properties of the Technical Grade of Abamectin
Parameter
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/cm[3] 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).

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 PHED 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 requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.

Appendix E.  International Residue Limits Table

                        Abamectin (122804; 11/01/2012)
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US
Canada
Mexico[2]
Codex[3]
40 CFR §180.449: avermectin B1 [a mixture of avermectins containing greater than or equal to 80% avermectin B1a (5- O -demethyl avermectin A1 ) and less than or equal to 20% avermectin B1b (5- O -demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) avermectin A1 )] and its delta-8,9-isomer
avermectin B1 (a mixture of avermectins containing greater than or equal to 80% avermectin B1a (5-O-demethyl avermectin A1a) and less than or equal to 20% avermectin B1b (5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl) avermectin A1a) and its delta-8,9-isomer)

Plants: sum of avermectin B1a, avermectin B1b, 8,9-Z-avermectin 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
0.02


0.01 (*)
Cotton, gin by-products
1.0



Strawberry 
0.05
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.
