Document ID: EPA-HQ-OPP-2010-0619-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-11-09T05:00Z

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

Date:		7/18/11
	
SUBJECT:	Abamectin.   Human Health Risk Assessment for Proposed Uses on the Bulb Onion Subgroup 3-07A, Chives, and Dry Beans

PC Code: 122804
Decision No.: 436528
Petition No.: 0E7738
Risk Assessment Type: Single Chemical/Aggregate
TXR No.: None
MRID No.: None
DP Barcode: 380523
Registration Nos.: 100-898, 100-1351, 100-1154
Regulatory Action: Section 3 Registration
Case No.: None
CAS No.: 71751-41-2
40 CFR: 180.449
FROM:	Nancy Dodd, Chemist/Risk Assessor
		Nancy Tsaur, Chemist
		Whang Phang, Toxicologist
      Risk Assessment Branch III (RAB3)
		Health Effects Division (HED) (7509P)
			
THROUGH:	Paula Deschamp, Branch Chief
		RAB3/HED (7509P)

TO:	Barbara Madden/Laura Nollen, RM#5
	Registration Division (7505P)		
      			
The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides.  The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed use 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 on the bulb onion subgroup 3-07A, chives, and dry beans.

HED evaluated the abamectin petition and determined that potential exposure could occur via the dietary (food and drinking water), residential, and occupational 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 uses on the bulb onion subgroup 3-07A, chives, and dry beans.

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	7
2.1	Data Deficiencies/Conditions of Registration	8
2.2	Tolerance Considerations	9
2.2.1	Enforcement Analytical Method	9
2.2.2	International Harmonization	9
2.2.3	Recommended Tolerances	10
2.2.4	Revisions to Petitioned-For Tolerances	10
2.3	Label Recommendations	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	16
4.0	Hazard Characterization and Dose-Response Assessment	17
4.1 	Adequacy of the Toxicity Database	17
4.2 	Mode of Action	17
4.3	Toxicological Effects	18
4.4	FQPA Considerations	18
4.4.1	Adequacy of the toxicity database for FQPA consideration	18
4.4.2	Evidence of Neurotoxicity	19
4.4.3	Developmental Toxicity	19
4.4.4	Reproductive Toxicity	20
4.4.5	Additional Information from Literature Sources	22
4.4.6	Determination of Susceptibility	22
4.5	FQPA Safety Factor for Infants and Children	23
4.6	Dose-Response Assessment	25
4.7	Endocrine Disruption	30
5.0	Dietary Exposure and Risk Assessment	31
5.1	Metabolite/Degradate Residue Profile	31
5.1.1	Summary of Plant and Animal Metabolism Studies	31
5.1.2	Summary of Environmental Degradation	32
5.1.3	Comparison of Metabolic Pathways	33
5.1.4	Residues of Concern Summary and Rationale	33
5.2	Food Residue Profile	34
5.3	Water Residue Profile	36
5.4	Dietary Risk Assessment	37
5.4.1	Description of Residue Data Used in Dietary Assessment	37
5.4.2	Percent Crop Treated Used in Dietary Assessment	38
5.4.3	Acute Dietary Risk Assessment	39
5.4.4	Chronic Dietary Risk Assessment	39
5.4.5	Cancer Dietary Risk Assessment	39
5.4.6	Summary Table	40
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	41
6.1	Residential Handler Exposure	41
6.2	Residential Post-Application Exposure	43
6.3	Spray Drift	45
7.0	Aggregate Risk Assessments and Risk Characterization	45
7.1	Acute Aggregate Risk	45
7.2	Short- and Intermediate-Term Aggregate Risk	46
7.3	Long-Term (Chronic) Aggregate Risk	47
7.4	Cancer Risk	47
8.0	Cumulative Risk Characterization/Assessment	47
9.0	Occupational Exposure/Risk Pathway	47
9.1	Short-/Intermediate-Term Handler Risk	48
9.2	Occupational Post-Application Exposures and Risks	51
10.0	References	53
Appendix A:	Toxicology Assessment	54
Appendix B:	Toxicology Literature References	59
Appendix C:	Physical/Chemical Properties	60
Appendix D:	Review of Human Research	61
Appendix E:	International Residue Limits	62

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, leafminers, 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.
  
IR-4 proposed registration of Agri-Mek(R) 0.15 EC Miticide/Insecticide (2% ai; EPA Reg. No. 100-898), Agri-Mek(R) SC Miticide/Insecticide (8% ai; EPA Reg No. 100-1351), and Epi-Mek(R) 0.15 EC Miticide/Insecticide (2% ai; EPA Reg. No. 100-1154) on the bulb onion subgroup 3-07A, chives, and dry beans.  All formulations are currently registered for use on a variety of crops.
  
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 4.5.)  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 is not a single dose effect.

The 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.  

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 DEEM-FCID(TM), Version 2.03.  Although tolerance-level residues and 100% crop treated were used for the proposed crops 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% aPAD) at the 99.9[th] percentile of exposure.  Abamectin dietary exposure at the 99.9[th] percentile for food and drinking water is 16% of the aPAD for the general U.S. population and 30% of the aPAD for all infants (<1 year 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% cPAD) for the general U.S. population and all population subgroups.  Abamectin dietary exposure for food and drinking water is 18% of the cPAD for the general U.S. population and 50% of the cPAD for children 1-2 years old, the most highly exposed population subgroup.

Residential Exposure:  Abamectin is currently registered for a number of residential insecticidal uses.  Because the FQPA requires consideration of aggregate exposure to all likely non-occupational uses, this assessment includes contact with abamectin from residential crack and crevice and lawn treatments as the most common and worst-case contributors to such exposures.  The Margins of Exposure (MOEs) for applicable residential scenarios were calculated using exposure monitoring data and the HED Standard Operating Procedures for Residential Exposure Assessments (Draft, December 18, 1997), along with interim changes presented in HED Science Advisory Council for Exposure SOP No.11 (February 22, 2001).  In addition, for the indoor crack and crevice treatment, measured airborne and surface residue data were available to perform an assessment of post-application inhalation, dermal, and incidental oral risks.  Combined residential exposures/risks were estimated for adults and for children. Children's exposure from incidental ingestion of granules on treated lawns was compared to the acute dietary NOAEL of 0.5 mg/kg/day.  The exposure/risk from this latter scenario was not combined with other scenarios, nor was it included in the aggregate assessment, because it is considered to be a one-time, episodic event, rather than occurring for several days (or several months).  The MOEs for all residential scenarios are greater than the levels of concern (LOCs) of 300, and therefore, are not of concern.

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 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).  No chemical-specific exposure data were submitted in support of this Section 3 registration.  To assess handler exposures for regulatory actions when chemical-specific monitoring data are not available, HED relies on the most scientifically-reliable surrogate data currently available from various sources.  The abamectin labels contain specific requirements for personal protective equipment (PPE) for applicators and other handlers.  All handler activities result in MOEs >300 with baseline clothing or baseline plus gloves, and, therefore, do not exceed HED's level of concern since the occupational LOCs are 300.  
       
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 re-entry interval (REI) on all the labels is acceptable.  All MOEs are >300 on the day of application, and therefore, are not of concern to HED since the LOC is 300.  

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:  As discussed in Appendix D, this risk assessment relies on the most scientifically-reliable surrogate data currently available from various sources such as the Pesticide Handler Exposure Database (PHED), the Agricultural Handler Exposure Task Force (AHETF), and the Outdoor Residential Exposure Task Force (ORETF).  Some of this data, such as the industry task force data, is compensatory, subject to the data protection provisions of FIFRA.  HED policy on use of surrogate data is described in more detail on the Agency's website (htpp://www.epa.gov/pesticides/science/handler-exposure-data.html).  Scenario-specific surrogate exposure data, including their sources, are presented in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (http://www.epa.gov/pesticides/science/handler-exposure-table.pdf).

2.0	HED Recommendations

Provided revised Sections B (OPPTS 860.1200) and F (OPPTS 860.1550) are submitted, HED can recommend for a conditional registration of abamectin for use on the bulb onion subgroup 3-07A, chives, and dry beans except cowpea and for permanent tolerances for the proposed uses on the bulb onion subgroup 3-07A, chive, and dry bean except cowpea.  Additional data are needed as a condition of registration as outlined in Section 2.1 below.  The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.

2.1	Data Deficiencies/Conditions of Registration

The following must be provided prior to a tolerance being established or registration allowed:

	860.1200 Directions for Use

   * Label revisions are required for the EC labels to remove the statement that adjuvants may be used on chives and dry beans since the submitted crop field trials on chives and dry beans do not reflect the use of an adjuvant.   

   * The labels must be revised to specify a 7-day PHI for chives and dry beans since most of the chive and dry bean data reflect a 7-day PHI. 

   * The amount (v/v) of the non-ionic surfactant and/or horticultural oil is required to be specified in the Directions for Use for each crop on the SC label and is required to be within the range of the amount (v/v) used in the available SC field trials (D364734, N. Dodd, 1/21/10).

   * Cowpea must be removed from the label under dry bean since residue data for cowpea forage and hay must be submitted to support use on cowpea.

	860.1550 Proposed Tolerances

   * The petitioner should submit a revised Section F reflecting the recommended tolerance levels and correct commodity definitions as presented in Table 2.2.4.  The proposed tolerance level for chives, dried leaves must be lowered from 0.07 ppm to 0.02 ppm.  Cowpea must be excluded from the dry bean seed tolerance since residue data for cowpea forage and hay must be submitted before cowpea can be included in the dry bean seed tolerance.

The following data are required as conditions of registration:

TOXICOLOGY

	870.7800 Immunotoxicity

       ●	Under the current data requirement guidelines, the immunotoxicity study is required to fulfill current 40 CFR Part 158 data requirements.  The registrant has committed to provide this data in 2012.
	

RESIDUE CHEMISTRY

	860.1500 Crop Field Trials

   * The petitioner needs to submit the storage temperature of the dry bean samples from the crop field trial.

The following data must be submitted for future uses on cowpea:

RESIDUE CHEMISTRY

      860.1500 Crop Field Trials
      
   * Residue data for cowpea forage and hay must be submitted before cowpea can be included in the dry bean seed tolerance.

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).
  
The plant methods used for data collection, using high performance liquid chromatography (HPLC) with fluorescence detection, adequately measure the residues of concern.  The methods have been validated at 0.002 for each analyte (avermectin B1a, avermectin B1b, and 8,9-Z avermectin B1a).

The Pestrak database indicates that abamectin and its metabolites are not recovered or not likely to be recovered by FDA multiresidue methods.  Therefore, the multiresidue methods can not be used to determine residues for dietary exposure assessment and can not be used as the primary enforcement method.

2.2.2	International Harmonization

There are currently no maximum residue limits (MRLs) established by Codex, Canada, or Mexico for abamectin on the bulb onion subgroup 3-07A, chive, or dry beans.  Therefore, there are no issues regarding international harmonization raised by this action.  An International Residue Limit Status sheet is attached (Appendix E).

2.2.3	Recommended Tolerances

HED recommends for the following tolerances and residue definition:

  "Tolerances are established for residues of abamectin, including its metabolites and degradates, in or on the commodities in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only 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."

            Onion, bulb, subgroup 3-07A	0.01 ppm
            Chive, fresh leaves	0.01 ppm
            Chive, dried leaves	0.02 ppm
            Bean, dry, seed, except cowpea	0.01 ppm

2.2.4	Revisions to Petitioned-For Tolerances

Table 2.2.4 compares proposed and recommended tolerance levels and tolerance expressions.  The recommended tolerance levels are based on the submitted magnitude of the residue data and the chive processing study.  EPA is recommending that the proposed tolerance for chive, dried leaves be reduced from 0.07 ppm to 0.02 ppm based on the results of the chive processing study.
The Agency's tolerance spreadsheet from the Guidance for Setting Pesticide Tolerances Based on Field Trial Data was not used because all of the treated samples from the field trials bore residues below the LOQ.  The correct commodity definitions were obtained from the "Food and Feed Commodity Vocabulary", which can be found at http://www.epa.gov/pesticides/foodfeed.  

Table 2.2.4.   Tolerance Summary for Abamectin
                                   Commodity
                     Established/Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                                   Comments
                         Correct Commodity Definition
Onion, bulb, subgroup 3-07A
                                     0.01*
                                     0.01
                                       
Chive, fresh leaves
                                     0.01
                                     0.01
                                       
Chive, dried leaves
                                     0.07
                                     0.02
                                       
Bean, dry, seed
                                     0.01
                                     0.01
Bean, dry, seed, except cowpea
*An established time-limited tolerance of 0.05 ppm on onion, bulb will expire on 12/31/12.

2.3	Label Recommendations

Refer to Section 2.1 above for label recommendations from residue chemistry reviews.

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, leafminers, 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 have been established in 40 CFR §180.449(a) for the 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 in/on various plant and livestock commodities at levels ranging from 0.005 to 0.20 ppm.  Time-limited tolerances are established in 40 CFR §180.449(b) for residues of avermectin B1 and its delta-8,9-isomer in/on onion, bulb at 0.005 ppm (to expire on 12/31/12) and in/on bean, lima, seed at 0.005 ppm (set to expire on 12/31/13).

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).  

New uses involving three formulations have been proposed for registration:  Agri-Mek(R) 0.15 EC, Agri-Mek(R) SC, and Epi-Mek(R) 0.15 EC.  Agri-Mek(R) 0.15 EC and and Epi-Mek(R) 0.15 EC are emulsifiable concentrate formulations containing 0.15 lb ai/gal.  Agri-Mek(R) SC is a suspension concentrate containing 0.7 lb ai/gal.  The products are to be applied as multiple foliar sprays using ground and aerial (except chive) methods.  The maximum seasonal rate is 0.056 lb ai/A for bulb onion, chives, and dry beans.  The preharvest intervals (PHIs) are 30 days for bulb onion and 6 days for chives and dry beans.  

3.1	Chemical Identity

Table 3.1.  Test Compound 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, EPA Reg. No. 100-898 (contains 0.15 lb ai per gallon);
Clinch(R) Ant Bait, EPA Reg. No. 100-894 (contains 0.011% ai);
Y-TEX BOVAMEC(TM) Cattle Ear Tags, EPA Reg. No. 39039-RT (contains 8.0% abamectin and 20.0% piperonyl butoxide technical, w/w)
Chemical Class
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.  Abamectin is stable to abiotic hydrolysis; 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

Table 3.3.  Summary of Directions for Use of Abamectin.

Applic. Timing, Type, and Equip.

                                  Formulation
                                [EPA Reg. No.]
                                 Applic. Rate 
                                   (lb ai/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ai/A)
                                    PHI[1]
                                    (days)
                      Use Directions and Limitations[2]  
                       Onion, bulb (Crop Subgroup 3-07A)
(onion, bulb including daylily, bulb; fritillaria, bulb; garlic, bulb; garlic, great-headed, bulb; garlic, serpent, bulb; lily, bulb; onion, Chinese, bulb; onion, pearl; onion, potato, bulb; shallot, bulb; cultivars, varieties, and/or hybrids of these)
Foliar spray (ground or aerial)[4,5]
Agri-Mek(R) 0.15 EC Insecticide/Miticide [EPA  Reg. No. 100-898]

Agri-Mek(R) SC Insecticide/ Miticide [EPA  Reg. No. 100-1351]

Epi-Mek(R) 0.15 EC Insecticide/Miticide [EPA  Reg. No. 100-1154]
                                     0.019
Not stated
                                     0.056
                                      30
Do not apply in less than 20 gallons of water/A with ground application equipment.  Do not apply in less than 5 gallons of water/A with aircraft.

Include a non-ionic surfactant commercially used on dry bulb onions.

RTI[3] = 7 days.

Adjuvant Requirement
SC formulation:  To avoid illegal crop residues, the SC formulations must always be mixed with a non-ionic activator type wetting, spreading and/or penetrating adjuvant.  Do not use binder sticker type adjuvants.  (See Use Information and Use Restrictions.)

EC formulation: Add a non-ionic activator type wetting, spreading and/or penetrating adjuvant approved for use on bulb onion. Do not use binder sticker type adjuvants. 
                                    Chives
Foliar spray
(ground) [4]
Agri-Mek(R) 0.15 EC Insecticide/Miticide [EPA  Reg. No. 100-898]

Agri-Mek(R) SC Insecticide/ Miticide [EPA  Reg. No. 100-1351]

Epi-Mek(R) 0.15 EC Insecticide/Miticide [EPA  Reg. No. 100-1154]
                                     0.019
Not stated
                                     0.056
                                       6
Apply as a foliar spray in a minimum of 20 gallons of water per acre.

Adjuvant Requirement
SC formulation:  To avoid illegal crop residues, the SC formulations must always be mixed with a non-ionic activator type wetting, spreading and/or penetrating adjuvant.  Do not use binder sticker type adjuvants.  (See Use Information and Use Restrictions.)6 

RTI = 7 days.

EC formulation: When necessary to improve the wetting of foliage and to smooth out spray deposits, a nonionic surfactant is recommended.
                                  Beans, dry
[Cicer arietinum (chickpea, garbanzo bean); Lupinus spp. (including sweet lupine, white sweet lupine, white lupine, and grain lupine); Phaseolus spp. (including kidney bean, lima bean, mung bean, navy bean, pinto bean, snap bean and waxbean); Vicia faba (broad bean, fava bean); Vigna spp. (including adzuki bean, asparagus bean, blackeyed pea, catjang, Chinese longbean, cowpea, crowder pea, moth bean, mung bean, rice bean, southern pea, urd bean, and yardlong bean)]
Foliar spray
(ground or aerial) [4,5]
Agri-Mek(R) 0.15 EC Insecticide/Miticide [EPA  Reg. No. 100-898]

Agri-Mek(R) SC Insecticide/ Miticide [EPA  Reg. No. 100-1351]

Epi-Mek(R) 0.15 EC Insecticide/Miticide [EPA  Reg. No. 100-1154]
                                     0.019
Not stated
                                     0.056
                                       6
Do not apply in less than 10 gallons of water/A with ground application equipment.  Do not apply in less than 5 gallons of water/A with aircraft.

Adjuvant Requirement
SC formulation: To avoid illegal crop residues, the SC formulations must always be mixed with a non-ionic activator type wetting, spreading and/or penetrating adjuvant. Do not use binder sticker type adjuvants.  (See Use Information and Use Restrictions.) 6

RTI = 6 days.

EC formulation: A non-ionic activator type wetting, spreading and/or penetrating adjuvant approved for use on dry beans and peas can be used to help improve control. Do not use binder sticker type adjuvants. 
1 PHI = preharvest interval.
[2] Onion, bulb - Make 2 consecutive applications then rotate to a chemistry (pesticide) with a different mode of action.  Make at least 2 applications of a chemistry (pesticide) with a different mode of action before making additional applications.  Do not make more than 2 sequential applications of any other foliarly applied abamectin containing product. 
Chives - Do not make more than 2 applications of any foliarly applied abamectin containing product per single cutting (harvest). 
Dry beans - Do not make more than 2 sequential applications of any foliarly applied abamectin containing product.
[3] RTI =retreatment interval.
[4] Do not apply through any type of irrigation system.
[5] Aerial applications are not allowed in NY.
[6] The use of an adjuvant is required on the Agri-Mek(R) SC Insecticide/Miticide label, but is not specified in the      Section B use directions for chives and dry beans.

Conclusions:  The submitted labels for Agri-Mek(R) 0.15 EC Insecticide/Miticide (EPA  Registration No. 100-898), Agri-Mek(R) SC Insecticide/ Miticide (EPA  Registration No. 100-1351), and Epi-Mek(R) 0.15 EC Insecticide/Miticide (EPA  Registration No. 100-1154) are adequate to allow evaluation of the residue data relative to the proposed uses.  

The ChemSAC determined on 5/18/11 that the available bridging studies for the SC formulation on leafy vegetables, fruiting vegetables, cucurbit vegetables, citrus fruits, and pome fruits (DP#364734, N. Dodd, 1/21/10) can be translated to support use of the SC formulation on the bulb onion subgroup 3-07A, chives, and dry beans provided the use directions for the SC formulation always require use of a non-ionic surfactant or a horticultural oil in the spray mix and the preharvest intervals are >= 7 days.   

Refer to Section 2.3 for recommended modifications to the proposed label. 

3.4	Anticipated Exposure Pathways
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 the bulb onion subgroup 3-07A, chive, and dry bean 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.  

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 post-application 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.

Although not applicable to a specific environmental justice demographic, this risk assessment gives consideration to genetic polymorphism and the potential for susceptibilities in human populations.  CF-1 mice were the most sensitive strain of test animals due to the lack of P-glycoprotein.  In mammals, P-glycoprotein 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.  Because abamectin is a substrate for p-glycoprotein, this protective mechanism may be less effective, as demonstrated in test animals where genetic polymorphisms compromise P-glycoprotein expression.  An example is the CF-1 mouse, some of which are deficient in P-glycoprotein and highly sensitive to the neurotoxicity of abamectin.  A small population of humans is also found to be deficient in p-glycoprotein due to polymorphism in the gene encoding P-glycoprotein.  It was determined that the 10x factor for intraspecies variability adequately protects the most sensitive population.

An additional factor of 3x for the steepness of the dose-response curve and the severity of effects is applied to all risk assessments other than acute dietary.    
  

4.0	Hazard Characterization and Dose-Response Assessment

4.1 	Adequacy of the Toxicity 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.  Data quality is acceptable and meets the criteria set in the OPPTS guidelines and 40 CFR §158.500.  However, under the current data requirement guidelines, immunotoxicity data (OPPTS 870.7800) shall be required as a condition of registration.  An immunotoxicity study is specifically designed to detect any deficit in the ability of the immune system to respond to a challenge (chemical).  Refer to Appendix B for toxicology citations.

To address the issue of the immunotoxicity data gap and the associated database uncertainty factor, 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.  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 	Mode of Action	

In nematodes, abamectin blocks the 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.  Consequently, abamectin may have the potential to influence GABA-mediated events important to brain development.  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).  This is consistent with the results seen in some submitted studies because the body weight effect is a frequent finding and is generally seen at dose levels lower than those producing a neurological effect in the test animals.

Integral to its mechanism of action in mammals, abamectin is also a substrate for P-glycoprotein (P-gp).  P-glycoprotein is a member of the ATP binding cassette transporter proteins, 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 small population of humans is also found to be deficient of p-glycoprotein due to polymorphism in the gene encoding P-gp (Dubin-Johnson Syndrome) (S. Habashi, 2006).  In addition, collie dogs have been known to be deficient in P-gp (R. Kerb, 2005).

4.3	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.1 of Appendix A.

In general, the results of available toxicity studies with single or repeated dosing reflect the mode of action of abamectin discussed in Section 3.2, and they 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.  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 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.  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 Section 3.4.2 and in Tables A.2 & A.3 of the Appendix A. 
 
4.4	FQPA Considerations	

4.4.1	Adequacy of the toxicity database for FQPA consideration
	
As mentioned before, the toxicology database is sufficient to conduct an FQPA 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. 

4.4.2	Evidence of Neurotoxicity	

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 duration of abamectin exposure.  These neurotoxicity signs are seen singularly or in combination in rats, mice (CD-1 and CF-1 mice), or dogs.  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, neurotoxic signs were seen at higher dose levels (1.0 mg/kg/day or above) in rats.  The studies which reported the neurotoxicity findings are summarized in Appendix B of D362615 (N. Dodd, 3/11/09).
            
4.4.3	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 and A.3 of Appendix A).  Three representative prenatal developmental toxicity studies are summarized below.

Prenatal developmental toxicity study in rats (MRID 00130819; 1982): Pregnant Crl:CD rats were dosed with avermectin B1 (95% pure, sesame oil as vehicle) at dose levels of 0.4, 0.8, and 1.6 mg/kg/day on gestation day 6 through 19.  No treatment related maternal or developmental toxicity was seen in the study.  Both maternal and developmental toxicity NOAELs were considered to be at the highest-dose tested (1.6 mg/kg/day).  A range finding study was performed; the results indicated that at 2.0 mg/kg/day, one dam had tremors and lost weight and was sacrificed after 12 doses.  The results of the dose-range-finding study indicated that the highest dose employed in the final study was approaching the level which would lead to severe toxicity.

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.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.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.  In general, most of the maternal effects were found at 2 mg/kg/day or above in CD-1 mice or rabbits. 

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.  In consideration of this information, a decision was made in 1998 by the Hazard Identification and Assessment Review Committee (HIARC) not to employ the results from the CF-1 mice studies for establishing toxicity endpoints (HIARC Report, Sept. 15, 1998). Currently, HED establishes a point of departure of 0.12 mg/kg/day for risk assessment of chronic, short, and intermediate terms of exposure based on the combined data from three reproduction studies and two developmental neurotoxicity studies.  With the intraspecies safety factor of 10x, the effects seen in the most sensitive subpopulation (CF-1 mice) are protected. (Details are presented in Section 4.5). 
      
4.4.4	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, 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 body weight loss (detected at the low dose) leading to moribundity at the high dose, 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 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 (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.

4.4.5	Additional Information from Literature Sources	

No additional information relevant to potential susceptibility in the developing young was found in open literature sources.
      
4.4.6	Determination of Susceptibility

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 in Section 4.4.3.  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.  
      
4.5	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 here, and the 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 /3x = 0.04 mg/kg/day).  A dose spacing of 10x between a NOAEL and LOAEL is as broad, if not broader, than the dose spacing generally used in animal testing and thus removes the residual concern with the steepness of the dose response curve and the severe effects seen here.  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.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).
      
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.

4.6	Dose-Response Assessment 	

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 Table 4.6.2 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 Table 4.6.2.

Acute Dietary Endpoint:  Previously, the acute toxicity endpoint was based on mydriasis seen in a 53-week study in dogs (HIARC report, Sept. 1998), 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 4.6.1.  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 4.6.1.  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, 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. 

This model takes into account the correlations of animals in the same litter and of measures of the same animal, can select the best covariance, uses all information available from the data, and is more appropriate for DNT body weight data structure than the ANOVA or Repeated Measures ANOVA.  The model provides a measurement of the rate of body weight changes with time among the test groups.  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).  To further evaluate the pup body weight reduction affected by abamectin, RAB3 conducted a comparative evaluation of all the pup body weight changes from PND 7 to 21 in all the available reproduction studies with abamectin.  The results are summarized in Table C.1 of Appendix C of D362615.  The two one-generation studies appeared to be dose-range finding studies because one study (MRID 00096450, 1982) employed dose levels which were too high (0.5, 1.00 and 1.5 mg/kg/day).  In this study, decreased body weight was seen at all dose levels and death occurred in the high dose group at PND 14.  The other one-generation study (MRID 00096451, 1982) employed dose levels of 0.10, 0.2, and 0.4 mg/kg/day, which were less than the lowest dose of the first study.  The mean pup body weights were decreased from PND 7 to 21 by as much as 16% at the highest dose tested (0.4 mg/kg/day).  No pup body weight decrease was seen in the 0.2 and 0.1 dose groups.  The two-generation studies used dose levels of 0.05, 0.12 and 0.40 mg/kg/day.  Decreased pup body weights were consistently seen in F1a, F1b, F2a, and F2b pups at 0.4 mg/kg/day.

The above data and discussion were presented to the ToxSAC on Sept. 25, 2008, to request the Committee's opinion on determining the offspring LOAEL based on the pup body weight data for offspring toxicity.  The ToxSAC recommended three scenarios for choosing the NOAEL/LOAEL for the DNT study which were then thoroughly considered by the RAB3 Risk Assessment Team.  The RAB3 Risk Assessment Team 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 (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:  According to the HIARC report dated September 15, 1998 (HED document No. 012845), a dermal penetration factor of 1% should be used for risk assessment purposes.  This value was based on the results from a dermal absorption study in monkeys which demonstrated that <1% of an applied dose is absorbed.  Because of the physical-chemical properties, and known pharmacokinetics and excretion pattern of avermectin B1a, the monkey is considered to be an appropriate model to use in determining dermal absorption for this chemical.

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 4.6.2.1.  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 4.6.2.2.  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).

Recommendation for Aggregate Exposure Risk Assessments

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.

4.7	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	Metabolite/Degradate Residue Profile

5.1.1	Summary of Plant and Animal Metabolism Studies

Metabolism in Primary Crops:  	No new plant metabolism data were submitted with this registration request.  The qualitative nature of the abamectin residues in the bulb onion subgroup 3-07A, chives, and dry beans 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 indicate that the metabolism of abamectin in plants results in a complex mixture of residues. The majority of the terminal residue is 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 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:  	No rotational crop studies were submitted with this registration request.  Review of the results of 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).

Metabolism in Livestock:  	No new livestock metabolism data were submitted with this registration request.  The qualitative nature of abamectin residues in ruminants as a result of application to crops is adequately understood based on a goat metabolism study which was previously submitted (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.

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.

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.  

5.1.2	Summary of Environmental Degradation

Abamectin is stable to abiotic hydrolysis; determination of stability to photolysis and biodegradation is pending submission of acceptable data.  Abamectin has very low water solubility but is soluble in organic solvents.  Abamectin is not expected to leach since it is not soluble in water and binds to soil.  Abamectin is degraded by soil microorganisms.  

The previous screening assessment of estimated drinking water concentrations (EDWCs) included abamectin and its major soil degradate (a mixture of an 8-α-hydroxy and a ring opened aldehyde derivative).   The delta-8,9-isomers (also known as 8,9-Z isomers) were not included in the drinking water assessment because they were not identified in the fate studies.

This current drinking water exposure assessment conservatively models only parent abamectin based on an assumption of stability until acceptable environmental fate data are submitted (D380524, G. Orrick, 1/31/11).     
      
5.1.3	Comparison of Metabolic Pathways

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.  
 
Metabolism of abamectin in ruminants (goats) appears to be similar to its metabolism in rats in that the 24-hydroxy-methyl metabolite is formed, although it is a minor metabolite in ruminants.  Based on the goat metabolism study, 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.  

A poultry metabolism study has not been conducted.  Since no significant poultry feed items, as indicated in Table 1 Feedstuffs (June 2008), are associated with the proposed uses, no poultry metabolism study is required.

Metabolism studies on cottonseed, citrus, and celery indicate that the metabolism of abamectin in plants results in a complex mixture of residues.  The majority of the terminal residue is 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.  In citrus, the majority of the residue remained in the peel but a small amount translocated into the pulp.  For the tolerance assessment 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 isomers).

The results of a 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.  It is not likely that residues of concern will occur in rotational crops.

5.1.4	Residues of Concern Summary and Rationale

The metabolism 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 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).  

Table 5.1.4  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

References:   Abamectin.  Petition for Tolerances/Section 3 Registration on the Bulb Onion Subgroup 3-07A, Chives, and Dry Beans.  Summary of Analytical Chemistry and Residue Data, DP#380795, N. Dodd, 5/18/11.
          
DER References: 48135001.der (onion, bulb), 48135002.der (chives, fresh), 48135003.der (beans, dry)

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.  In the citrus metabolism study, the majority of the residues remained in the peel but a small amount translocated into the pulp.

Residues from application to dry bulb onion, chive (fresh), and dry bean are reported in Table 5.2 below.  The number and geographic representation of the field trials are adequate. 

The field trials were conducted using the emulsifiable concentrate (EC) formulation.  The ChemSAC determined on 5/18/11 that the available bridging studies for the suspension concentrate (SC) formulation on leafy vegetables, fruiting vegetables, cucurbit vegetables, citrus fruits, and pome fruits (DP#364734, N. Dodd, 1/21/10) can be translated to support use of the SC formulation on the bulb onion subgroup 3-07A, chive, and dry bean provided the use directions for the SC formulation always require use of a non-ionic surfactant or a horticultural oil in the spray mix and the preharvest intervals are >= 7 days.   

The dry bulb onion field trials reflect the proposed use pattern, including the use of an adjuvant in all trials.

The fresh chive field trials reflect the proposed use pattern, including application rate and PHI.  An adjuvant was not used in the field trials.  Label revisions are required for the EC labels to remove the statement that adjuvants may be used on chives since the submitted chive field trials do not reflect the use of an adjuvant.  Also, the labels must be revised to specify a 7-day PHI for chives since most of the chive data reflect a 7-day PHI.  

The dry bean field trials reflect the proposed use pattern, including application rate and PHI.  An adjuvant was not used in the field trials.  The EC label indicates than an adjuvant can be used with the applications, but is not required.  Label revisions are required for the EC labels to remove the statement that adjuvants may be used on dry beans since the submitted dry bean field trials do not reflect the use of an adjuvant.  The labels must be revised to specify a 7-day PHI for dry beans since most of the dry bean data reflect a 7-day PHI.  The petitioner should also submit the storage temperature of the dry bean samples.  Residue data for cowpea forage and hay must be submitted before cowpea can be included in the dry bean seed tolerance.

The residue data for fresh chive, dry bulb onion, and dry bean were not entered into the tolerance spreadsheet since >15% of treated samples bore residues below the LOQ.  For the purpose of setting tolerances, HED will rely on the maximum residues observed in the field trials (i.e., 0.0046 ppm for dry bulb onion; 0.0045 ppm for fresh chives; and 0.006 ppm for dry bean).  Based on these data, HED recommends tolerances of 0.01 ppm for dry bulb onion, chive, and dry bean.

Table 5.2.	Summary of Residue Data from Crop Field Trials with an Abamectin Formulation 
                            (EC formulation).
Commodity
                              Total Applic. Rate
                                  (lb ai/A) 
                                  PHI (days)
                             Residue Levels  (ppm)

                                       
                                       
                                       n
                                     Min.
                                     Max.
                                     HAFT
                                    Median
                                     Mean
                                   Std. Dev.
                            Total Combined Residues
  Bean, dry (proposed use = 0.056 lb ai/A total application rate, 6-day PHI)
                                   Bean, dry
                                  0.054-0.061
                                      5-7
                                      24
                                   <0.004
                                     0.006
                                     0.005
                                     0.004
                                    0.0041
                                      0.0
    Chive (proposed use = 0.056 lb ai/A total application rate, 6-day PHI)
                              Chive, fresh leaves
                                  0.057-0.059
                                      5-7
                                       6
                                   <0.004
                                    0.0045
                                    0.0042
                                     0.004
                                    0.0041
                                      0.0
Onion, dry bulb (proposed use = 0.056 lb ai/A total application rate, 30-day PHI)
                                Onion, dry bulb
                                 0.0567-0.0767
                                     29-31
                                      16
                                   <0.004
                                    0.0046
                                    0.0043
                                     0.004
                                    0.0040
                                    0.0002

5.3	Water Residue Profile

Reference:  Abamectin: Drinking Water Exposure Assessment for Proposed Section 3 New Uses on Chives, Dried Beans, and the Bulb Onion Subgroup 3-07A, DP#380524, G. Orrick, 1/31/11.

Estimated drinking water concentrations (EDWCs) were provided for parent 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.    

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 ground water.  

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 ground water 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 ground water 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 and its Major Soil Degradates.[c]

                                   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
                                Not applicable
[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.

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment

References:  Abamectin: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 on Bulb Onions, Chives, and Dry Beans, DP#380796, N. Dodd, 6/13/11.

Abamectin:  Drinking Water Exposure Assessment for Proposed Section 3 New Uses on Chives, Dried Beans, and the Bulb Onion Subgroup 3-07A, DP#380524, G. Orrick, 1/31/11.
Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM-FCID(TM), Version 2.03 which uses food consumption data from the U.S. Department of Agriculture's Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998.  These analyses were performed to support Section 3 requests for use on the bulb onion subgroup 3-07A, chives, and dry bean.  
Tolerance-level residues and 100% crop treated were used for the proposed crops.  No monitoring data were used.  Anticipated residues based on field trial data were used.  Empirical/default processing factors and percent crop treated (%CT) data were also used.  Also, for the chronic dietary assessment, residues of abamectin in foods exposed in a food-handling establishment were assumed to be (1/2) LOD (0.0002 ppm) (DP#283668, J. Morales, 20-NOV-2003).  As shown in Section 5.3 above, drinking water values were 2.3 ppb for the acute assessment and 1.3 ppb for the chronic assessment.

5.4.2	Percent Crop Treated Used in Dietary Assessment

Reference:	Usage Report Package in Support of Registration for the Insecticide Abamectin (122804), DP#382732, Arthur H. Grube, 10/21/10.

A Screening Level Usage Analysis (SLUA) was provided by BEAD based on data years 2001-2008; the SLUA as provided by BEAD is included in the dietary exposure assessment memo (DP#380796, N. Dodd, 6/13/11).  The estimated maximum percent crop treated was used for the acute dietary risk assessment; the estimated weighted average percent crop treated was used for the chronic dietary risk assessment.  The percent crop treated data, as used in the acute and chronic food residue input files in the DEEM, are summarized in Table 5.4.2 below.  For other crops, 100% CT was assumed.

 Table 5.4.2.  Screening Level Estimates of Agricultural Uses of Abamectin dated October 6, 2010[1,2]
 Crop
                              Percent Crop Treated
 
                                    Average
                                    Maximum
 Almonds
                                       50
                                       75
 Apples
                                       5
                                       10
 Apricots
                                       5
                                       5
 Avocados
                                       40
                                       60
 Cantaloupes
                                       15
                                       30
 Celery
                                       40
                                       65
 Cherries
                                     <1
                                    <2.5
 Cotton
                                       5
                                       20
 Cucumbers
                                       5
                                       10
 Grapefruit
                                       60
                                       80
 Grapes
                                       10
                                       25
 Honeydew
                                       20
                                       35
 Lemons
                                       35
                                       55
 Lettuce
                                       10
                                       20
 Oranges
                                       25
                                       45
 Peaches
                                     <1
                                    <2.5
 Pears
                                       70
                                       80
 Pecans
                                     <1
                                    <2.5
 Peppers
                                       10
                                       25
 Potatoes
                                     <1
                                    <2.5
 Prunes
                                    <2.5
                                       10
 Pumpkins
                                    <2.5
                                       10
 Spinach
                                       20
                                       45
 Squash
                                       5
                                       10
 Strawberries
                                       30
                                       45
 Tangerines
                                       60
                                       65
 Tomatoes
                                       10
                                       20
 Walnuts
                                       10
                                       20
 Watermelons
                                       5
                                       10
 [1]SLUA data sources include the USDA-NASS (United States Department of Agriculture's National Agricultural Statistics Service); Private Pesticide Market Research; and California DPR (Department of Pesticide Regulation).
[2] For chronic, the % CT was used in calculations; if the food handling establishment (FHE) value of 0.0002 ppm was greater than the product of residue level x processing factor x % crop treated, then the FHE value was used.

 

5.4.3	Acute Dietary Risk Assessment

A refined acute dietary (food and drinking water) exposure assessment was conducted for all proposed and established food uses of abamectin.  Tolerance level residues were used for the proposed crops 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.  Estimated drinking water concentrations (EDWCs) from the Environmental Fate and Effects Division (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 percent cropped area (PCA) 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 application to dry beans in Michigan.  

As shown in Table 5.4.6, the acute dietary exposure estimates for food and drinking water are below HED's level of concern (<100% aPAD) at the 99.9[th] percentile of exposure for the general U.S. population and all population subgroups.  Abamectin dietary exposure at the 99.9[th] percentile for food and drinking water is 16% of the aPAD for the general U.S. population and 30% of the aPAD for all infants (<1 year old), the most highly exposed population subgroup.

5.4.4	Chronic Dietary Risk Assessment

A refined chronic dietary (food and drinking water) exposure assessment was conducted for all proposed and established food uses of abamectin.  Tolerance level residues were used for the proposed crops 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-10-year annual mean).  The estimated surface water concentration of 1.3 ppb was based on the application to dry beans in Michigan.

As shown in Table 5.4.6, the chronic dietary exposure estimates for food and drinking water are below HED's level of concern (<100% cPAD) for the general U.S. population and all population subgroups.  Abamectin dietary exposure for food and drinking water is 18% of the cPAD for the general U.S. population and 50% of the cPAD for children 1-2 yrs old, the most highly exposed population subgroup.	

5.4.5	Cancer Dietary Risk Assessment

The HED RfD/Peer Review Committee classified abamectin 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.  Results of Acute and Chronic Dietary (Food and Drinking Water) Exposure      and Risk Estimates for Abamectin.
                              Population Subgroup
                                PAD, mg/kg/day
                                   DEEM-FCID

                              Exposure, mg/kg/day
                                     % PAD
           Acute Dietary Estimates (99.9[th] Percentile of Exposure)
U.S. Population
                                     0.005
                                   0.000777
                                      16
All infants (< 1 yr)
                                     0.005
                                   0.001501
                                      30
Children 1-2 yrs
                                     0.005
                                   0.001230
                                      25
Children 3-5 yrs
                                     0.005
                                   0.000976
                                      20
Children 6-12 yrs
                                     0.005
                                   0.000599
                                      12
Youth 13-19 yrs
                                     0.005
                                   0.000554
                                      11
Adults 20-49 yrs
                                     0.005
                                   0.000464
                                       9
Adults 50+ yrs
                                     0.005
                                   0.000355
                                       7
Females 13-49 yrs
                                     0.005
                                   0.000467
                                       9
                           Chronic Dietary Estimates
U.S. Population
                                    0.0004
                                   0.000070
                                      18
All infants (< 1 yr)
                                    0.0004
                                   0.000151
                                      38
Children 1-2 yrs
                                    0.0004
                                   0.000199
                                      50
Children 3-5 yrs
                                    0.0004
                                   0.000152
                                      38
Children 6-12 yrs
                                    0.0004
                                   0.000098
                                      24
Youth 13-19 yrs
                                    0.0004
                                   0.000059
                                      15
Adults 20-49 yrs
                                    0.0004
                                   0.000056
                                      14
Adults 50+ yrs
                                    0.0004
                                   0.000054
                                      13
Females 13-49 yrs
                                    0.0004
                                   0.000054
                                      13
                            Cancer Dietary Estimate
U.S. Population
Classification: "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 Residential (Non-Occupational) Exposure/Risk Characterization

References:	Abamectin.  Occupational and Residential Exposure Assessment for Proposed IR-4 Foliar Uses on Bulb Onions (Subgroup 3-07A), Chives, and Dry Beans, N. Tsaur, DP#380797, 3/29/11.

		Abamectin: Occupational and Residential Risk Assessment to Support Section 3 Request for Uses on Various Food Crops and Food-Handling Establishments, J. Arthur, DP#306906, 10/29/04
		
6.1	Residential Handler Exposure
            
While no residential uses are proposed in the current petition, there are residential uses currently registered for abamectin.  Short- to intermediate-term exposures may occur to adults from handling the pesticide.  Residential handler exposures are assessed below for two uses which are considered to represent the reasonable high-end residential exposure potential: 1) granular baits used to treat lawns; and 2) indoor crack and crevice dust products.  The critical exposure (worst case scenario) of all residential uses are accounted for in the aggregate. 

      Lawn Applications

Short-/Intermediate-term total MOEs (dermal + inhalation exposures) for residential handlers range from 110,000 to 17,000,000 which are greater than the LOC of 300, and are not of concern.  Exposure and risk assessment inputs and results for residential lawn applicators are summarized in Table 6.1.1.

      Crack and Crevice Applications

The short- and intermediate-term MOEs for dermal and inhalation exposure are each 5,000,000.  The combined dermal and inhalation MOE is 2,500,000, which is greater than the LOC of 300 and is not of concern.  Exposure and risk inputs and estimates are summarized in Table 6.1.2.
   Table 6.1.1.  Exposure and Risk Estimate for Residential Lawn Applicators

PHED Scenario
Exposure Scenario 

                         Personal Protective Equipment

                                 Exposure Route

                               Application Rate
                                 (lb ai/acre) 

                                 Acres Treated
                                    (acres/
                                     day)

                                 Unit Exposure
                                  (mg/lb ai) 

                                     Data
                                  Confidence

                               Absorption Factor

                                     Body
                                  Weight (kg)

                                 Daily Dose[1]
                                  (mg/kg/day)

                                  Short- and 
                                 Intermediate-
                                  Term NOAEL
                                  (mg/kg/day)

                         Short- and Intermediate Term
                                     MOE 2

Granular Bait Dispersed by Hand

short sleeves
short pants
no gloves

Dermal

                                    1.1E-4

                                     0.023

                                      430

                                    Medium

                                     0.01

                                      60

                                   1.8.0E-7

                                     0.12

                                    6.7E+5

Inhalation

                                    1.1E-4

                                     0.023

                                     0.47

                                    Medium

                                      1.0

                                      60

                                    2.0E-8

                                     0.12

                                    6.0E+6

	Total

                                    2.0E-7

                                     0.12

                                    6.0E+5

Belly Grinder Granular Open Pour (Mix, Load, and Apply)

short sleeves
short pants
no gloves

Dermal

                                    1.1E-4

                                      0.5

                                      110

                                    Medium

                                     0.01

                                      60

                                    1.0E-6

                                     0.12

                                    1.2E+5

Inhalation

                                    1.1E-4

                                      0.5

                                     0.062

                                     High

                                      1.0

                                      60

                                    5.7E-8 

                                     0.12

                                    2.2E+6

	Total

                                    1.1E-6

                                     0.12

                                    1.1E+5

Push Type Granular (Mix, Load, and Apply)

short sleeves short pants
no gloves

Dermal

                                    1.1E-4

                                      0.5

                                     0.68

                                    Note 1.

                                     0.01

                                      60

                                    6.0E-9

                                     0.12

                                    2.0E+7

Inhalation

                                    1.1E-4

                                      0.5

                                    9.1E-4

                                    Note 1.

                                      1.0

                                      60

                                    1.0E-9

                                     0.12

                                    1.2E+8

                                                                          Total

                                    7.0E-9

                                     0.12

                                    1.7E+7

[1] Daily Dose =[Application Rate (lb ai/A) x Acres Treated (A/day) x Unit Exposure (mg/lb ai handled) x Absorption Factor]/Body Weight 
[2] Short- and Intermediate-Term MOE = Short- and Intermediate-Term NOAEL/Daily Dose
Note 1.  Unit exposure values taken from ORETF study (OMA003) and are considered to be more reliable and applicable than PHED values for this scenario.

Table 6.1.2.  Exposure and Risk Estimate for Residential Application of 0.05% Crack & Crevice Powder

PHED Scenario
Selected from Draft SOP for Residential Exposure Assessments 

                                   Clothing

                                Exposure Route

                              Application Rate[1]
                                 (lb ai/day) 

                              PHED Unit Exposure
                                  (mg/lb ai) 

                                     PHED
                                     Data
                                  Confidence

                               Absorption Factor

                                     Body
                                    Weight 
                                     (kg)

                                 Daily Dose [2]
                                  (mg/kg/day)

                                  Short- and 
                                 Intermediate-
                                  Term NOAEL
                                  (mg/kg/day)

                         Short- and Intermediate-Term
                                    MOE [3]

Wettable powder, open mixing and loading 

short sleeves
short pants
no gloves

Dermal

                                    3.3 E-5

                                      4.4

                                      Low

                                     0.01

                                      60

                                    2.4E-8

                                     0.12

                                    5.0E+6

Inhalation

                                    3.3 E-5

                                     0.043

                                    Medium

                                      1.0

                                      60

                                    2.4E-8

                                     0.12

                                    5.0E+6

	Total:

                                    4.8E-8

                                     0.12

                                    2.5E+6
[1]Application rate  =   5.0E-4 (0.05% ai) x 30 g/day (weight of 1 package) x 2.2E-3 lb/g = 3.3E-5 lb ai/day	
[2] Daily Dose =[Application rate (lb ai handled/day) x PHED Unit Exposure (mg/lb ai handled) x Absorption Factor]/Body Weight (BW)  
[3]Short- & Intermediate-Term Dermal or Inhalation MOE = Short- & Intermediate-Term Dermal or Inhalation NOAEL/Daily Dose 

6.2	Residential Post-Application Exposure	

Since residential uses of abamectin are currently registered, short- to intermediate-term exposures may occur to both adults and children from contact with treated areas following application.  Residential post-application exposures are assessed below for two uses which are considered to represent the reasonable high-end residential exposure potential: 1) granular baits used to treat lawns; and 2) indoor crack and crevice dust products.  Recreational exposures to turf are expected to be similar to, or less than, those evaluated in this section. 

      Treated Lawns
      
The only post-application scenario applicable to the granular abamectin formulations used on lawns is ingestion of granules by toddlers.  The maximum rate for all registered lawn uses and representative high end exposures were used to calculate the margin of exposure.

Children's exposure and risk from incidental ingestion of granules from treated lawns is summarized in Table 6.2.1.  The acute ingestion MOE for children is 68,000.  Since this MOE is above 300, the risk presented by children's incidental ingestion of granules is not of concern to HED.

Table 6.2.1.  Incidental Ingestion of Granules Exposure and Risk for Children from Treated Lawns 

                              Fraction Available

                                Ingestion Rate
                                    (g/day)

                                  Body Weight
                                     (kg)

                                 Daily Dose[1]
                                  (mg/kg/day)

                                    NOAEL 
                                  (mg/kg/day)

                                    MOE[2]

                                    0.00011

                                    0.001*

                                      15

                                   0.0000073

                                      0.5

                                    68,000
[1] Daily Dose  = [Fraction available x Ingestion rate (g/day) x 1000 mg/g] / [Body Weight (kg)]
2  MOE = Acute Dietary NOAEL/Daily Dose. 
* It should be noted that HED's Draft Residential SOPs give a standard value of 0.3 g product/day for the ingestion rate (IgR).  This value is based on the application of 300 lbs of product distributed evenly over an acre, which results in approximately 3 grams of product per ft[2].  An assumption that a child will ingest one-tenth of what is available in one ft[2] of lawn leads to the IgR value of 0.3 g product/day.  Because the abamectin lawn product application rate is only 1 pound of product per acre, it is appropriate to scale down the standard IgR value, proportionately.  Using the SOP methodology, one pound of product, spread evenly over an acre results in 0.01 g/ft[2].  One tenth of this gives an ingestion rate of 0.001 g/day. 

      Crack and Crevice

Post-application exposure from the use of Avert Prescription Treatment 310 for crack and crevice applications was estimated for adults (dermal and inhalation routes) and children (dermal, inhalation, and incidental oral routes).
  
Children's combined post-application exposure (dermal, incidental oral, and inhalation) and risk, and adults combined post-application exposure (dermal and inhalation) and risk are summarized in Table 6.2.2.  Since short-/intermediate-term MOEs from all exposure scenarios are above 300, the risk from combined adult and combined children's post-application exposure to crack and crevice products containing abamectin are not of concern.  
            

  Table 6.2.2. Combined Exposure and Risk from Crack & Crevice Treatment

                                Exposure Route

	

                                Data Source [1]

                            Daily Dose (mg/kg/day)

                Short- and Intermediate-Term  NOAEL (mg/kg/day)

                       Short- and Intermediate-Term MOE

Children's Combined Dermal, Oral and Inhalation Post-Application Exposure and Risk

Dermal

                                   1990 Study

                                    2.2E-7

                                       
                                     0.12

                                    5.5E+5

                                  1995 Study

                                    4.4E-8
                                       

                                    2.5E+6

Oral Hand-to-Mouth

                                   1990 Study

                                    7.5E-7

                                       
                                     0.12

                                    1.6E+5

                                  1995 Study

                                    1.6E-7
                                       

                                    7.5E+5

Oral Object-to-Mouth

                                   1990 Study

                                    4.7E-8

                                       
                                     0.12

                                    2.6E+6

                                  1995 Study

                                    1.0E-8
                                       

                                    1.2E+7

Inhalation

                                   1990 Study

                                    1.3E-4

                                       
                                     0.12

                                      920

                                  1995 Study

                                    4.7E-5
                                       

                                     2,600

Total:

                                   1990 Study

                                    1.3E-4

                                       
                                     0.12

                                      920

                                  1995 Study

                                    4.7E-5
                                       

                                     2,600

Adult Combined Handler and Post-Application Dermal and Inhalation Exposure and Risk

Handler Dermal

                                     PHED

                                    2.4E-8

                                     0.12

                                    5.0E+6

Handler Inhalation

                                     PHED

                                    2.4E-8

                                     0.12

                                    5.0E+6

Post-application Dermal

                                   1990 Study

                                    1.6E-7

                                     0.12

                                    7.5E+5

                                  1995 Study

                                    2.9E-8
                                       

                                    4.1E+6

Post-application Inhalation

                                   1990 Study

                                    8.4E-5

                                     0.12

                                     1,400

                                  1995 Study

                                    3.0E-5
                                       

                                     4,000

Total:

                             PHED & 1990 Study

                                    8.4E-5

                                     0.12

                                     1,400

                            PHED & 1995 Study 

                                    3.0E-5
                                       

                                     4,000
[1]  1990 Study:	Evaluation of Avert Prescription Treatment 310 Residual Study in Air, Food and on Surfaces, November 8, 1990 (MRID No. 44665901)
   1995 Study:	Evaluation of Indoor Exposure to a Crack and Crevice Application of Whitmire Avert Crack and Crevice Prescription Treatment 310 and Prescription TC 93A Bait, October 27, 1995 (MRID No. 44147801)  

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 at http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast, and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks 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.   

Sometimes the risk presented from direct application of lawn treatment products can supersede potential risk concerns from agricultural spray drift.  However, in the case of abamectin, agricultural use rates are higher than those for residential lawn treatment, and the assessment of post-application risks for abamectin lawn products did not include a dermal exposure component.

7.0	Aggregate Risk Assessments and Risk Characterization	

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

7.1	Acute Aggregate Risk	

The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of abamectin (food and drinking water).  The acute aggregate food and drinking water assessment results are presented in Section 5.2 above.  The most highly exposed subgroup is all infants (<1 year old) at 30% of the aPAD, which is below the level of concern.

7.2	Short- and Intermediate-Term Aggregate Risk	

The short-/intermediate-term aggregate risk assessment estimates risks likely to result from exposure to abamectin residues from food, drinking water, and residential pesticide uses.  High-end estimates of residential exposure are used, while average values are used for food and drinking water exposure.

A short-/intermediate-term risk assessment is required for adults because there are potential residential handler and post-application exposures from the crack and crevice use.  In addition, a short-/intermediate-term risk assessment is required for infants and children because there is a residential post-application exposure scenario for crack and crevice treatment.  The ingestion of granules (from the lawn treatment for fire ants) is not included in the aggregate assessment because it is considered to be a one-time, episodic event, rather than occurring for several days (or several months).

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
                      (Inhalation/Oral/Dermal Endpoints and NOAELs are the Same.)

Population
                     Short- or Intermediate-Term Scenario

NOAEL
mg/kg/day
LOC[1]
Max Allowable
Exposure[2]
mg/kg/day
Average
Food & Water
Exposure
mg/kg/day
Residential Exposure[3]
mg/kg/day
Aggregate MOE
(food and
residential)[4]
U.S. Population
0.12
300
0.0004
0.000070
0.000030
1200
Children (1-2 years old)
0.12
300
0.0004
0.000200
0.000047
500
[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 6.2.2 for residential exposure values used in the aggregate assessment.  
[4] Aggregate MOE = [NOAEL  (Avg Food & Water Exposure + Residential Exposure)]

7.3	Long-Term (Chronic) Aggregate Risk
	
The chronic aggregate risk assessment takes into account 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 5.2 above.  The most highly exposed subgroup is children 1-2 years old at 50% of the cPAD, which is below the level of concern. 

7.4	Cancer Risk	

Abamectin is classified as "not likely to be carcinogenic to humans" based on the absence of a significant increase in tumor incidence in two adequate rodent carcinogenicity studies. 

8.0	Cumulative Risk Characterization/Assessment	

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to 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. 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/.

9.0	Occupational Exposure/Risk Pathway	

Reference:	Abamectin.  Occupational and Residential Exposure Assessment for Proposed IR-4 Foliar Uses on Bulb Onions (Subgroup 3-07A), Chives, and Dry Beans, D380797, N. Tsaur, 3/29/11.

Occupational handler exposure to abamectin is expected for individuals involved in foliar applications to bulb onions (subgroup 3-07A), chives, and dry beans (mixing, loading, and applying).  Handler exposure is expected to be short- or intermediate-term based on information provided on the proposed label.  

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

Handler's exposure and risk were estimated for the following scenarios: mixer/loaders (mixing/ loading liquid to support groundboom or aerial applications); flaggers (flagging to support aerial application); applicators (applying sprays with groundboom or aerial equipment with enclosed cockpit).

The minimum level of PPE for handlers is based on acute toxicity for the end-use product.  All three labels state that all handlers must wear the proper PPE: coveralls worn over a short-sleeved shirt with short pants, chemical resistant gloves, chemical-resistant footwear with socks, protective eyewear, chemical-resistant headgear for overhead exposure, and a chemical resistant apron when cleaning equipment, mixing, or loading.  The Registration Division (RD) is responsible for ensuring that PPE listed on the label is in compliance with the Worker Protection Standard (WPS).

No chemical-specific handler exposure data were submitted in support of this Section 3 registration.  In accordance with HED's Exposure Science Advisory Council (SAC) policy, exposure data from the Pesticide Handlers Exposure Database (PHED), Version 1.1, as presented in PHED Surrogate Exposure Guide (8/98), were used with other HED standard values for acres treated per day, body weight, and the level of personal protective equipment to assess handler exposures. 

Exposure/risk assessments were performed using applicable toxicity endpoints.  Daily dermal and inhalation exposures were calculated separately, applying a dermal absorption factor of 1%, and an inhalation absorption factor of 100%.  The dermal and inhalation exposures were added together and compared to the common NOAEL of 0.12 mg/kg/day (from combined data from three reproduction studies and two developmental neurotoxicity studies where the LOAEL = 0.2 mg/kg/day based on decreased pup body weight) to determine the handler risk (from total dermal and inhalation exposure) for short- and intermediate-term exposures.
      
The total MOEs (when gloves are added to the mixing/loading scenarios) range from 750 (for open mixing/loading of liquid to support aerial application with PPE including gloves) to 9100 (for applying sprays via aerial equipment (enclosed cockpit).  These MOEs do not exceed HED's level of concern of 300 (when gloves are added to the mixing/loading scenarios).    

Assumptions and estimates for occupational handler exposure are summarized in Tables 9.1.1 and 9.1.2.
   

Table 9.1.1.  Abamectin Short- and Intermediate-Term Agricultural Occupational Exposures and Risks (Baseline: single layer, no gloves, no respirator).
                               Exposure Scenario
                             Application Rate [a]
                            Area Treated Daily [b]
                                    Dermal
                                    UE [c]
                               Inhalation UE [c]
                                Dermal Dose [d]
                                 Dermal MOE e
                              Inhalation Dose [f]
                               Inhalation MOE g
                                Combined Dose h
                            ST/IT Combined MOE [i]
                                       
                                    lb ai/A
                                     acres
                                   mg/lb ai
                                   mg/lb ai
                                   mg/kg/day
                                   LOC = 300
                                   mg/kg/day
                                   LOC = 300
                                   mg/kg/day
                                   LOC = 300
                                 Mixer/Loader
                           Mixing/Loading Liquid for
                            Groundboom Applications
                                    0.0191
                                      80
                                      2.9
                                    0.0012
                                    0.00074
                                      160
                                   0.000031
                                     3900
                                    0.00077
                                      160
                           Mixing/Loading Liquid for
                              Aerial Applications
                                    0.0191
                                      350
                                      2.9
                                    0.0012
                                    0.0032
                                      37
                                    0.00013
                                      900
                                    0.0034
                                      36
                                    Flagger
                                 Flagging for
                              Aerial Application
                                    0.0191
                                      350
                                     0.011
                                    0.00035
                                   0.000012
                                     9800
                                   0.000039
                                     3100
                                   0.000051
                                     2300
                                  Applicator
                              Applying Sprays via
                             Groundboom Equipment
                                    0.0191
                                      80
                                     0.014
                                    0.00074
                                   0.0000036
                                    34,000
                                   0.000019
                                     6000
                                   0.000022
                                     5300
                              Applying Sprays via
                              Aerial Equipment j
                                    0.0191
                                      350
                                    0.0050
                                    0.00007
                                   0.0000056
                                    21,000
                                   0.0000076
                                    16,000
                                   0.000013
                                     9100
a  Application Rates based on maximum proposed use rates for abamectin labels: EPA Reg. No. 100-898, EPA Reg. No. 100-1351, EPA Reg. No. 100-1154. 
b  Acres Treated Per Day is taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 9.1.
c  UE = Unit Exposures based on PHED Version 1.1 data.  Baseline = single layer, no gloves, no respirator.
d  Dermal Dose (mg/kg/day) = application rate (lb ai/acre) x amount handled /day (acres/day) x daily unit exposure (mg/lb ai) x absorption factor (1%) / body weight (60 kg).
e  Dermal Margin of Exposure = NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day). Level of concern = 300. Short- and Intermediate-Term NOAEL = 0.12 mg/kg/day.
f  Inhalation Dose (mg/kg/day) = application rate (lb ai/acre) x amount handled /day (acres/day) x daily unit exposure (mg/lb ai) x absorption factor (100%) / body weight (60 kg).
g  Inhalation Margin of Exposure = NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day). Level of concern = 300. Short- and Intermediate-Term NOAEL = 0.12 mg/kg/day.
h  Combined Dose = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day).
i  Short- and Intermediate-Term Combined Margin of Exposure = NOAEL (mg/kg/day) / Combined Dose (mg/kg/day). Level of concern = 300. ST/IT NOAEL = 0.12 mg/kg/day.
j  Only engineering control (enclosed cockpit) data are available to assess risks to handlers operating aircraft (enclosed cab, no gloves, no respirator).

Table 9.1.2.  Abamectin Short- and Intermediate-Term Agricultural Occupational Exposures and Risks (PPE: single layer, gloves, no respirator).
                               Exposure Scenario
                             Application Rate [a]
                            Area Treated Daily [b]
                                    Dermal
                                    UEs [c]
                              Inhalation UEs [c]
                                Dermal Dose [d]
                                 Dermal MOE e
                              Inhalation Dose [f]
                               Inhalation MOE g
                                Combined Dose h
                            ST/IT Combined MOE [i]
                                       
                                    lb ai/A
                                     acres
                                   mg/lb ai
                                   mg/lb ai
                                   mg/kg/day
                                   LOC = 300
                                   mg/kg/day
                                   LOC = 300
                                   mg/kg/day
                                   LOC = 300
                                 Mixer/Loader
                           Mixing/Loading Liquid for
                            Groundboom Applications
                                    0.0191
                                      80
                                     0.023
                                    0.0012
                                   0.0000059
                                    20,000
                                   0.000031
                                     3900
                                   0.000036
                                     3300
                           Mixing/Loading Liquid for
                              Aerial Applications
                                    0.0191
                                      350
                                     0.023
                                    0.0012
                                   0.000026
                                     4700
                                    0.00013
                                      900
                                    0.00016
                                      750
a  Application Rates based on maximum proposed use rates for abamectin labels: EPA Reg. No. 100-898, EPA Reg. No. 100-1351, EPA Reg. No. 100-1154. 
b  Acres Treated Per Day is taken from Exposure Science Advisory Council (ExpoSAC) Policy No. 9.1.
c  UE = Unit Exposures based on PHED Version 1.1 data.  PPE = single layer, gloves, no respirator.
d  Dermal Dose (mg/kg/day) = application rate (lb ai/acre) x amount handled /day (acres/day) x daily unit exposure (mg/lb ai) x absorption factor (1%) / body weight (60 kg).
e  Dermal Margin of Exposure = NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day). Level of concern = 300. Short- and Intermediate-Term NOAEL = 0.12 mg/kg/day.
f   Inhalation Dose (mg/kg/day) = application rate (lb ai/acre) x amount handled /day (acres/day) x daily unit exposure (mg/lb ai) x absorption factor (100%) / body weight (60 kg).
g  Inhalation Margin of Exposure = NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day). Level of concern = 300. Short- and Intermediate-Term NOAEL = 0.12 mg/kg/day.
h  Combined Dose = Dermal Dose (mg/kg/day) + Inhalation Dose (mg/kg/day).
i  Short- and Intermediate-Term Combined Margin of Exposure = NOAEL (mg/kg/day) / Combined Dose (mg/kg/day). Level of concern = 300. ST/IT NOAEL = 0.12 mg/kg/day.

9.2	Occupational Post-Application Exposures and Risks 	 

Short-/Intermediate-/Long-Term Post-Application Risk	

There is a potential for post-application exposure to scouts, harvesters and other field workers following foliar application to agricultural crops.  Chemical-specific post-application exposure data were not provided.  The transfer coefficients used in this assessment are from the transfer coefficient standard operating procedure (SOP) developed by HED's Science Advisory Council (SAC) for Exposure (Exposure SAC Policy No. 3.1, "Agricultural Transfer Coefficients," August 2000) using proprietary data from the Agricultural Re-entry Task Force (ARTF) database).  Also, this assessment uses HED's default assumption that 20% of the application rate is available for transfer on the day of treatment, and that the residue dissipates at a rate of 10% per day thereafter. 

The short- and intermediate-term MOEs for post-application exposure on day 0 (12 hours after application) range from 840 to 21,000.  Since these calculated MOEs are greater than 300 on the day of application, they do not exceed HED's level of concern.  A summary of the post-application exposure and risk assessment is presented in Table 9.2.

HED's post-application exposure estimates are based on surrogate data.  The transfer coefficients are considered to be central tendency.  Maximum application rates were used in this assessment.  Overall, the post-application risks are characterized as being central to high-end estimates.

The post-application exposure associated with agricultural crops is summarized in Table 9.2.  All scenarios resulted in MOEs greater than 300 (ranging from 840 to 21,000) on day 0 (12 hours after application) and, therefore, are not of concern to HED.  

Table 9.2.  Short- and Intermediate-Term Post-Application Exposures and Risk for Abamectin.
                              Crop Grouping/Crop
                                   Activity
                                   Transfer
                                  Coefficient
                             Days After Treatment
                                   DFR [a] 
                             Daily Dermal Dose [b]
                                    Dermal
                                    MOE [c]
                                       
                                       
                                       
                                       
                                   ug/cm[2]
                                   mg/kg/day
                                   LOC = 300
                                  Bulb Onions
                               (Subgroup 3-07A)
                             irrigation, scouting,
                            thinning, hand weeding
                                      300
                                       0
                                  (12 hours)
                                    0.0429
                                   0.000017
                                     7,000
                                       
                                    Chives
                           hand harvesting, thinning
                                     2500
                                       0
                                  (12 hours)
                                    0.0429
                                   0.000143
                                      840
                                       
                             irrigation, scouting
                                     1500
                                       0
                                  (12 hours)
                                    0.0429
                                   0.000086
                                     1,400
                                       
                                 hand weeding
                                      500
                                       0
                                  (12 hours)
                                    0.0429
                                   0.000029
                                     4,200
                                   Dry Beans
                                hand harvesting
                                     2500
                                       0
                                  (12 hours)
                                    0.0429
                                   0.000143
                                      840
                                       
                             irrigation, scouting
                                     1500
                                       0
                                  (12 hours)
                                    0.0429
                                   0.000086
                                     1,400
                                       
                                 hand weeding
                                      100
                                       0
                                  (12 hours)
                                    0.0429
                                   0.0000057
                                    21,000
a	DFR (ug/cm[2]) = application rate (lb ai/acre) x fraction of application rate dislodgeable on day 0 (20%) x (1 - fraction of residue that dissipates daily 10%)t x 4.54E8 ug/lb x 2.47E-8 acre/cm2.
b	Short-/Intermediate-Term Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x dermal absorption 1%]  body weight (60 kg adult).
c	Short-/Intermediate-Term MOE = NOAEL (mg/kg/day)/Daily Dermal Dose (mg/kg/day). ST/IT NOAEL = 0.12 mg/kg/day.

Restricted Entry Interval
Since both short- and intermediate-term post-application risks were not a concern on day 0 (12 hours following application), the REI is based on the acute toxicity of abamectin technical material.  Under WPS for Agricultural Pesticides, active ingredients classified as acute Toxicity Category III or IV for Acute Dermal, Eye Irritation, and Primary Skin Irritation are assigned a 12-hour REI.  Thus, the 12-hour REI on the proposed labels are acceptable.

Occupational Post-Application Inhalation Exposure
Based on the Agency's current practices, a quantitative occupational post-application inhalation exposure assessment was not performed for abamectin at this time.  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.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html) and is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the Agricultural Reentry Task Force.  The Agency 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.

10.0		References

 N. Dodd, 5/18/11, DP#380795, Abamectin.  Petition for Tolerances/Section 3 Registration on the Bulb Onion Subgroup 3-07A, Chives, and Dry Beans.  Summary of Analytical Chemistry and Residue Data.

N. Dodd, 6/13/11, DP#380796, Abamectin.  Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 on Bulb Onions, Chives, and Dry Beans.

A. Grube, 10/21/10, DP#382732, Usage Report Package in Support of Registration for the Insecticide Abamectin (122804).

N. Tsaur, 3/29/11, DP#380797, Abamectin.  Occupational and Residential Exposure Assessment for Proposed IR-4 Foliar Uses on Bulb Onions (Subgroup 3-07A), Chives, and Dry Beans.

J. Arthur, 10/29/04, DP#306906, Abamectin: Occupational and Residential Risk Assessment to Support Section 3 Request for Uses on Various Food Crops and Food-Handling Establishments.
                                       
G. Orrick, 1/31/11, DP#380524, Abamectin: Drinking Water Exposure Assessment for Proposed Section 3 New Uses on Chives, Dried Beans, and the Bulb Onion Subgroup 3-07A.

N. Dodd et al., 3/11/09, DP#362615, Abamectin.  Revised Human Health Risk Assessment for Proposed Uses on Pasture and Rangeland Grass, Stone Fruit Crop Group 12, Tree Nut Crop Group 14, Pistachio, Tuberous and Corm Vegetables Subgroup 1C and Request for Cattle Ear Tag Use.
                       Appendix A:	Toxicology Assessment
                                       
               Table A.1.  Acute Toxicity 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.  Toxicity Profile of Abamectin Technical for Repeated Dosing and Genotoxicity Studies
                           Guideline No./ Study Type
                       MRID No. / Classification /Doses
                                    Results
870.3100
Subchronic feeding study-rats
00131081 (1982)
Unacceptable/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 not available.
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
Dermal penetration is 1%.  

      Table A.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.

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.  Physiochemical Properties
Parameter
                                     Value
                                 Reference[1]
Molecular Weight
873.11
                                       
Melting point/range
155-157°C
Accession No. 260785
pH
Not available

Density
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
UV/visible absorption spectrum
Not available

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 Pesticide Handlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) database in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies have been reviewed for ethical conduct and have been determined to be ethical.

The two studies used to estimate residential post-application exposure from abamectin crack and crevice products [ref: "Evaluation of Avert Prescription Treatment 310 Residual Study in Air, Food and on Surfaces," dated November 8, 1990 (MRID No. 44665901), and "Evaluation of Indoor Exposure to a Crack and Crevice Application of Whitmire Avert Crack and Crevice Prescription Treatment 310 and Prescription TC 93A Bait," dated October 27, 1995 (MRID No. 44147801)] measured only ambient concentrations of abamectin in treated areas and did not involve collection of data for estimation of direct human exposure from the application activity.  Therefore, the requirements for ethical review or for review by the Human Studies Review Board are not applicable to these studies. 

Appendix E:	International Residue Limits
                                       
                    Abamectin (PC Code 122804; 03/31/2011)
Summary of US and International Tolerances and Maximum Residue Limits 
Residue Definition:
US
Canada
Mexico
Codex
40 CFR 180.449:
Plant/Livestock:  sum 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 
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
Tolerance (ppm) /Maximum Residue Limit (mg/kg)

                                      US
Canada
Mexico
Codex
Onion, bulb, subgroup 3-07A
                                     0.01

                                                                               
Chive, fresh leaves
                                     0.01

                                                                               
Chive, dried leaves
                                     0.02

                                                                               
Bean, dry, seed, except cowpea
                                     0.01

                                                                               

                                                                               

                                                                               

                                                                               

                                                                               

                                                                               

                                                                               

                                                                               

                                                                               

                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               

                                                                               
                                                                               

                                                                               
Completed:  M. Negussie; 03/31/2011