### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AN D POLLUTION PRE VENTION



### MEMORANDUM

Date: 6 -J UN-20 13

SUBJECT: Abamectin. Human Health Assessment Scoping Document in Support of Registration

Review.

PC Code: 122804

Decision No.: 473543

Petition No.: NA DP Barcode: D407955 Registration No.: NA Regulatory Action : Registration Review

Case No.: 7430 Risk Assessment Typ e: NA

TXRNo.:NA

MRIDNo.:NA CAS No.: 71751-41-2

40 CFR: 180.449

FROM: Nancy Dodd, Chemist

# ~''%;It~ Whang Phang, Toxico l ogist

_,

_ ·

_**__....__~** 

### Nancy Tsaur

, Chem i st
Risk Assessment Branch III (RAB III)

Health Effects Division (7509P)

Office of Pest i c i de Prog r ams

THROUGH: Christine Olinger, Branch**Ch~'ef ~**  

### Risk Assessment Branch III '

Health Effects Division (7509

- Office of Pes ticide Programs

TO: Ne il Anderson!Khue Nguyen, Risk Manager #5 1

Risk Management and Implementation Branch I (RMIB 1 )

Pest i c id e Re-Eva l uatio n Division (PRD) (7508P)

Office of Pesticide Programs

Page 1 of26

### Executive Summary



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

insecticide/mit icide/nematic ide abamectin to determine whether sufficient data are available and

whether any updates are needed to s upport Regi s tration Review. HED has considered the most

recent human-health risk assessments for abamectin, updates to the toxicity, exposure, and usage databases, and current Agency science policy and risk assessment methodologies to determine

the scope of work necessary to support Registration Review

. In addition, HED performed a screening literature search to identify studies relevant to the human health r isk assessment and

found no relevant toxicity or exposu re information.

The registered uses of abamectin include agricultural crops, food handling establishments, cattle

ear tags, ornamentals, and lawns. Abamectin is also reg ist ered for use as a bait to control fire

ants around buildings and in landscapes ( including l awns) of residen tial, recreat i ona l

, commercia l

, industrial, and public areas.

Abamectin has high to moderate acute toxici ty by the ora l ro ut e (depending on th e vehicle), high

acute toxicity by th e inhalation route, and low acute toxicity by the dermal route

. It 

### is slightly

irritatin g to the s kin, 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 t he most frequent findings.

Neurotox i c i ty and developmental effects were detect e d in multip l e studies and species of test

animals. The dose/response curve is s t eep in seve ral studies, with effects (including death and

morbid sacrifice) seen at dose levels as low as 0.4 mg/kg/da y and 0.1 mg/kg/day in rats and
mice, respectively, following repea ted/chronic exposures. The combined data from severa l rat 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

ef

fec t (0.4 mg/kg/day). Increased susceptibility (qualitative and/or quantitative) was see n 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 acceptab l e oncogenicity and mutagenic it y s tudie s prov i des no indication that abamectin is carcinogenic or mutagenic.

In the most recent risk assessment, the Food Quality Protect ion Act (FQPA) safety factor was reduced to lx for th e acute d ietary assessment and was reduced to 3x to address residual

concerns as to all risk assess men ts other than acute dietary. For all risk assessments involving

repeat expo sures, the selected toxicity endpoint is based on the decr ease in pup body weight seen in the developmental neurotox icity study (2007) and three reproduction s tud ies in th e rat. With

respec t to acute d i etary exposure, the endpoint selecte d 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 exposu r e because steepness of the dose/response curve and seve r ity of effects

were not seen in the studies wh ere mydriasis occurred. In addition, the reduced body weights as

tox i city endpoints for other exposure scenarios are not a sing le dose effect.

The toxicology database is currently considered to be adequate. The requirement for an immunotoxici ty study has been wa i ved (Hazard and Scie nc e Po li cy Council [HASPOC], 6/6/13)

. Based on a weight of the evidence (WOE) ap proach and considering all of the availab l e

Page 2 of26

### Page 3 of 26

abamectin hazard and exposure information, the H ASPOC concluded in a meeting on November 8, 2012 that a subchronic inhalation toxicity study in mice and a subchronic dermal toxicity study are not required at this time. However, the HASPOC recommend ed that the points of departure ( PODs ) and scenarios for risk assessment be reevaluated. Depending on the results, a new risk assessment may be needed.

A new diet ary exposure and risk assessment is not expected to be needed in the registration review p rocess unless toxicological endpoints/ PODs are revised.

There is sufficient information available to assess residential exposure. A ll residential exposure

scenarios have been assessed using current HED Residential Standard Operating Procedures ( SOPs ) and current policies. A new residential assessment is not expected to be needed in the registration review process unless toxicological endpoints/points of departure are revised or the Agency develops new policies/procedures to quantitate residential pos t

- application inhalation

exposure.

A new aggregate risk assessment is not expected to be needed in the registration review process

unless t he toxicological endpoints/points of departure are revised or the Agency develops new policies/procedures to quantit ate residential post

- application inhalation exposure

.

. There is sufficient information available to assess occupational handler and post

- application exposures. While all occupational exposure scenarios were not assessed based on current HED policies, the most recent assessments are protective of the previously unassessed scenarios. An

up

- to

- date quantitative occupational risk assessment may be required to account for the currently registered application rates, changes in unit exposures, changes in transf er coefficients (TCs), and any possible changes to endpoints and safety factors. Updated risk estimates are unlikely to

result in risks of concern.

I ntroduction

Abamectin is a mixture of avermectin B 1 

### [a mixture of avermectins containing greater than or equal to 80% avermectin B 1a 

### (5

- O

- demethyl avermectin A 1 

### ) and less than or equal to 20%

avermectin B 1b 

### (5

- O

- demethyl

- 25

- de(1

- methylpropyl)

- 25

- (1

- methylethyl) avermectin A 1 

### )] and

its delta

- 8,9

- isomer. Ab amectin is a natural fermentation product of the soil bacterium Streptomyces avermitilis. Abamectin acts as an insecticide /miticide /nematicide by interfering with the nervous system of the pest , causing the pest to become paralyzed.

The registered formul ation types include emulsifiable concentrate, suspension concentrate, granular, bait, gel, and dust formulations . The registered uses include agricultural crops, food handling establishments, cattle ear tags, ornamentals, and lawns. Abamectin is also reg istered

for use as a bait to control fire ants around buildings and in landscapes (including lawns) of

residential , recreational, commercial

, industrial

, and public areas

.

The most recent risk assessment for abamectin w as conducted in 201 2 (D P# D 402677, N . Dodd,

12/20/12 ). Refer to Attachment 1 for the chemical identity of abamectin.

### Page 4 of 26

Hazard Identification/ Toxicology

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 but reduced body weight is one of the most frequent findings in the

exper imental toxicology database . Neurotoxicity and developmental effects were detected in multiple studies and species of test animals. The dose/response curve is steep in several studies, with effects (including death and morbid sacrifice) seen at dose leve ls as low as 0.4 mg/kg /day and 0.1 mg/kg /day in rats and mice, respectively , following repeated/chronic exposures

. The combined data from several rat reproduction toxicity and developmental neurotoxicity studies have documented a very narrow dose range fr om NOAEL (0.12 mg/kg/day) to adverse effect (0.2 mg/kg/day) to severe adverse effect (0.4 mg/kg/day). Increased susceptibility (qualitative and/or quantitative) was seen in prenatal developmental toxicity studies in mice and rabbits, and an increase in qu antitative 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. Refer to Attachment 3 for a summary of toxicity endpoints and points of departure and to Attachment 4 for the toxicity profile tables

. HED anticipates re

- assessing all the endpoints and uncertainty factors.

A n additional 3x FQPA safety factor was used in the previous risk assessment to ad dress residual

concerns as to all risk assessments other than acute dietary. The additional 3x FQPA safety factor was retained for the steepness of the dose

- response curve and the severity of the effects. For all risk assessments involving repeat exposur es, 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 dietary exposures and other exposure scenarios is not applicable to acute exposure because steepness of the

dose /response curve and severity of effects were not seen in the studies where mydriasis occurred. In addition, the reduced body weights as toxicity endpoints for other exposure

scenarios are not a single dose effect.

The immunotoxicity study (OCSPP 870.7800) required und er 40 CFR Part 158 has been waived

after HED examined the entire toxicity database of abamectin

. For abamectin, a complete battery of subchronic, chronic, carcinogenicity, developmental and reproductive studies as well

as acute and subchronic neurotoxicit y 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 abame ctin does not belong to a class of chemicals that would be expected

to be immunotoxic. Because 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 depa rture for risk assessment , a n additional uncertainty factor for database uncertainties (UF DB 

### ) is not needed to account for potential immunotoxicity. Additionally, results of a retrospective analysis conducted by the agency of 170 immunotoxicity studies pr ovide strong support for not

### Page 5 of 26

applying a UF DB 

### as no immunotoxicity study available thus far provided sensitive endpoints of use in driving the POD. The HASPOC determined on 6/6/13 that the current points of departure (based on neurotoxicity and development al endpoints) are protective of any immune effects, and an additional uncertainty factor is not needed at this time.

Under the 2007 revised 40 CFR Part 158 data requirements, a subchronic dermal toxicity study is required for food use chemicals for which there is repeated human dermal exposure from occupational/residential uses . N o dermal toxicity studies are available for abamectin. The HASPOC met on November 8, 2012 (K. Rury, MPH, 1/30/13, TXR # 0056509) to discuss the

need for a subchronic dermal toxi city study. Based on a WOE approach, the HASPOC

concluded that neither a subchronic dermal toxicity study n or a subchronic dermal developmental toxicity study is required at this time. In addition , t he HASPOC recommend ed

that the Toxicology Science Advis ory Council ( ToxSAC ) reevaluate the need for a dermal exposure assessment and appropriate PODs for abamectin.

Under the 2007 revised 40 CF R Part 158 data requirements, a subchronic inhalation toxicity study is also required due to the potential for repe ated inhalation exposure. An inhalation toxicity study is available in rats. On November 8, 2012, the HASPOC discussed the need for an inhalation toxicity study in mice to support abamectin. Based on a WOE approach, the

HASPOC concluded that a subchroni c inhalation toxicity study in CF

- 1 mice is not required at

this time. The HASPOC recommended that the abamectin endpoints and the rat inhalation toxicity study be revisited with the ToxSAC.

C onclusions : The toxicology database is currently considered to be adequate . The requirement

for an immunotoxicity study has been waived

. The HASPOC determined on 6/6/13 that the current points of departure (based on neurotoxicity and developmental endpoints) are protective of any immune effec ts, and an additional uncertainty factor is not needed at this time. Based on a WOE approach and considering all of the available abamectin hazard and exposure information, the HASPOC concluded in a meeting o n November 8, 2012 that a subchronic

inhalation toxicity study in mice and a subchronic dermal toxicity study are not required at this

time. However, the HASPOC recommended that the PODs and scenarios for risk assessment be

reevaluated. Depending on the results, a new risk assessment may be needed.

Dietary Exposure

The residue chemistry d atabase is sufficient to support current registrations. The nature of the residue in plants and livestock has been defined, and adequate enforcement methods are available. Adequate storage stability, field trial, and rotational crop data are available. Since residues of concern are not expected to occur in rotational crops, rotational crop tolerances and restrictions are not required for abamectin.

The most recent dietary (food and drinking water) exposure assessment (D P# D 40 3715, N. Dodd, 12/ 19 /12) w as conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID), Version 3.16. This software uses 2003

- 2008 food consumption data from the National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA).

### Page 6 of 26

Although tolerance

- level residues and 100% crop treated were used for bulb onion, chives, dry bean, and okra, the acute and chronic dietary exposure assessments were refined assess ments 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). T he 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) es timated surface water concentration is 1.3 ppb.

The acute dietary exposure estimates for food and drinking water ar e below HED’s level of
concern [ <100% of the acute population adjusted dose ( 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 15% of the aPAD for the general U.S. population and 24% of the aPAD for children 1

- 2 years old, the most highly exposed population subgroup

.

The chronic dietary exposure estimates for food and drinking water ar e below HED’s level of
concern [ <100% of the chronic population adjusted dose ( cPAD) ] for the general U.S. population and all population sub groups. Abamectin dietary exposure for food and drinking water is 17% of the cPAD for the general U.S. population and 53% o f the cPAD for children 1

- 2 yrs old, the most highly exposed population subgroup

.

HED classified abamectin as “not likely to be car cinogenic to humans;” therefore, quantification

of human cancer risk was not conducted.

Conclusions : A new dietary exposure and risk assessment is not expected to be needed in the registration review process unless toxicological endpoints/points of departure are revised.

Residential Exposure

The products registered for residential use sites include several formulations of homeowner bait and bait station products registered under multiple companies. These p roducts include outdoor granular bait (GB) and indoor ready

- to

- use bait (RB) of both dust and gel formulations.

The existing residential uses were reassessed in the last risk assessment (D402677, N. Dodd, 12/20/12) to reflect updates to HED’s 2012 Resid ential SOPs 1 

### along with policy changes for body weight assumptions.

For res idential exposure, the duration of exposure is expected to be short

- term (1

- 30 days) ; intermediate

- term (1

- 6 months) and long

- term exposures are not anticipated. The level of

con cern (LOC) for risk estimates is a margin of exposure (MOE) of less than 300 for short

- term

exposure.

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Page 7 of 26

Residential Handlers Residential handlers are likely to be exposed to abamectin residues via dermal and inhalation routes during handling activities. The exposures and risk from applying outdoor granular baits

were assessed. Exposure from indoor ready

- to

- use gel baits is expected to be negligible ; however, exposure data for hand dispersal of granular /dust bait was chosen as a surrogate to

calculate ris k estimates from indoor RBs.

The quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios: l oading/applying GB outdoors via (1) p ush

- type spreaders

, (2) b elly grinders , (3) s poon s, (4) hand, and (5) cup or shaker ; and (6) applying granular bait indoor by hand (as a surrogate for a ready

- to

- use dust bait).

There are no registered products that would lead to any residential handler risk estimates of

concern. Short

- term combined (dermal + inhalation) resid ential handler MOEs range from 320,000 to 1,100,000,000.

Residential Post

- Application Residential post

- application exposure to adults and children is unlikely for all registered uses of abamectin. For outdoor treatments, adults and children are not expec ted to directly contact fire ant mounds. For indoor pest control, bait placements are intended to be placed in cracks and crevices where direct contact by adults and children is unlikely.

Based on the Agency’s current practices, a quantitative residentia l post

- application inhalation exposure assessment was not performed for abamectin primarily because of the low proposed use rate and low vapor pressure.

I f there are Agency policy changes regarding residential exposures resulting from off

- site
transport (e.g. spray drift or volatilization), the Agency will re

- examine the need for spray drift and volatilization assessments for abamectin during registration review.

A T urf T ransferable R esidue (TRR) study is not required for abamectin at this time because

neither dermal nor hand

- to

- mouth exposure is e xpected following the registered fire ant mound

uses on turf.

Conclusion s : There is sufficient information available to assess residential exposure. A ll residential exposure scenarios have been assessed using HED’s 2012 Residential SOPs along with policy changes for body weights and cu rrent toxicological endpoints . A new residential assessment is not expected to be neede d in the registration review process unless toxicological endpoints/points of departure are revised or the Agency develops new policies/procedures to quantitate residential post

- application inhalation exposure.

Aggregate Risk Assessment

In the most recent human health risk assessment (D P# D 402677, N. Dodd, 12/20/12 ), acute, chronic, and short

- term aggregate exposures were assessed. The a ggregate assessments

### Page 8 of 26

considered exposures from food, drinking water, and residential uses (as appropriate) . All risk

estimates were below the level of concern.

A cancer aggregate risk ass essment was not performed because abamectin is classified as “not likely to be carcinogenic to humans.”

Conclusion s : A new aggregate risk as sessment is not expected to be needed in the registration review process unless the toxicological endpoints/points of departure are revised or the Agency develops new policies/procedures to quantitate residential post

- application inhalation exposure

.

Occupational Exposure

Abamectin is registered for several agricultural uses and non

- crop areas. The durations of exposure are expected to be short

- term (1

- 30 days) and intermediate

- term (1

- 6 months); long

term exposures are not anticipated. The LOC for dermal and inhalation r isk estimates is a MOE

of less than 300 for short

- and intermediate

- term exposure. Occupational handler and post

application exposure and risk assessments have been conducted on a majority of the registered occupational (agricultural and non

- crop) uses, r esulting in risk estimates that are not of concern, with the required PPE.

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

- application inhalation exposure assessment has not been performed for abamectin at this time

.

Dislodgeabl e Foliar Residue (DFR): In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in post

- application dermal exposure. As part of the rec ent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment , HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be d islodged after a foliar application (F AR 

### ). This default value is 25% and is based on an analysis of 19 DFR studies where the F AR 

### value ranged from 2% to 89%. This value is recommended for use in both residential and occupational postapplication assessmen ts. Of the analyzed DFR studies, the maximum F AR 

### value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific DFR study ( Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dis lodgeable Foliar Residue (DFR) Studies . 6/7/2012, Exposure Science Advisory Council). A DFR study is not required for abamectin at this time since dermal MOEs are greater than 1200 based on default values for the fraction of application rate available for transfer after a foliar application.

Dermal and Inhalation Exposure: Due to a lack of information about the seed treatment industry, HED cannot characterize the broad range of handler MOEs in any probabilistic distributional context. Since there is pot ential for risks of concern based on the Helix® study, dated August 2000, and Avicta® 500FS is currently registered for use on cottonseed and corn seed in closed systems, HED previously required the registrant to submit an exposure monitoring

### Page 9 of 26

study of Avic ta® 500FS as a condition of registration ( COR ) . This study must be submitted under guideline numbers 875.2400 and 875.2500.

Conclusions: There is sufficient information available to assess occupational handler and post

application exposures. While all occupational exposure scenarios were not adequately assessed based on current HED policies, the most recent assessments are protective of the previously

unassessed scenarios. An up

- to

- date quantitative occupational risk assessment may be required

to accou nt for the currently registered application rates, the changes in unit exposures, the changes in transfer coefficients (TCs), and any possible changes to endpoints and safety factors. Updated risk estimates are unlikely to result in risks of concern.

Endocrine Disruptor Screening Program (EDSP)

As required by the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ) and the Federal Food, Drug, and Cosmetic Act ( FFDCA ) , EPA reviews numerous studies to assess potential adverse outcomes from expos ure 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 ma y 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 asse ssments, 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 endp oints 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 thy roid (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 s ection 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. Abame ctin was included on that list and has been issued an order to conduct the Tier 1 testing. Once all required Tier 1 asssay 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

### Page 10 of 26

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

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

.

Public Health and Pesticide Epidemiology Data

A database search was conducted to identify potential patterns in the frequency and severity of

the health effects attributed to abamectin exposure (D 409003 , S. Recore, 2/ 20 /13). B oth the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides ( SENSOR) databases were consulted for pesticide incident data on the active ingredient abamectin (PC Code : 122804 ). Abamectin is not included in the Agricultural Health Study ( AHS ); therefore , the AHS d id not provide information for th is report

. Based on t he relatively low frequency and severity of incident cases reported for abamectin in

both IDS and NIOSH SENSOR

- Pesticides, there does not appear to be a concern that would warrant further investigation at this time

. The Agency notes that there were three incidents that occurred due to allergic reactions to peanut products in two RAID Ant Baits. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis

will be included in the risk assessment.

Tolerance Assessment and International Harmonization

Tolerances are established under 40 CFR §180.449 for residues of abamectin (avermectin), including its metabolites and degradates, in or on various crop and livestock commodities at levels ranging from 0.005 ppm to 0.20 ppm. Several tolerances are pending, including a tolerance on cotton gin byproducts at 1.0 ppm. Compliance with the tolerance levels is to be determined by measuring only avermectin B 1 

### [a mixture of avermectins containing greater than or equal to 80% avermectin B 1a 

### (5

- O

- demethyl avermectin A 1 

### ) and less than or equal to 20%

avermectin B 1b 

### (5

- O

- demethyl

- 25

- de(1

- methylpropyl)

- 25

- (1

- methylethyl) avermectin A 1 

### )] and

its delta

- 8,9

- isome r.

There are some Codex, Canadian, or Mexican maximum residue limits ( MRLs ) establish ed for

residues of abamectin in crop or livestock commodities (see Attachment 2 )

. The tolerance expressions for the US and Canada as compared to Codex include the same a nalytes for plants

but differ for livestock commodit i es , i.e., the residue definitions are harmonized for plants but

not for livestock commodities. T here are some differences in established tolerance levels among the US, Canada, and Codex. The database will be examined during registration review to

determine if these differences can be harmonized.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible , w ill be considered in th e registration review , in accordance with US 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

### Page 11 of 26

subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are base d 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

under the National Health and Nutrition Examin ation Survey, What We Eat in America (NHANES/WWEIA) 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 and ethnic group. Additionally, OPP is able to a ssess 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 ap plicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups

.

Cumulative

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

common mechanism of toxicity (CMT) , EPA has not made a common mechanism of toxicity finding as to abamectin and any other substances and abamectin does not appear to produce a toxic metabolite produced by other substances. EPA has evaluated the available mechani stic

information available for abamectin and determined that there is not sufficient information to establish the key biological steps leading to adverse health outcomes (i.e., mammalian mechanism of 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/

.

Human Studies

The risk assessments which have been previously conducted for a bamectin have rel ied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticides, comprise generic pesticide exposur e databases such as the Pesticide

Ha ndlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF),

and the Agricultural Reentry Task Force (ARTF) Database

. EPA has reviewed all the studies supporting these multi

- pesticide generic ex posure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was

conducted. A ll applicable requirements of EPA’s Rule for the Protection of Human Subjects of

### Page 12 of 26

Research (40 CFR Part 26) have been satisfied , and t here is no regulatory barrier to continued

reliance on these studies

.

Data Requirements

As shown in Reference s below, fourteen huma n health risk assessments have been conducted for

abamectin between 1997 and 20 12

.

T he outstanding data gap s associated with the Section 3 assessments are shown below. The registrants should be aware that they are responsible for replacing analytical reference standards

at the EPA National Pesticide Standards Repository when the dates expire or the supplies are depleted.

Toxicology

None.

Residue Chemistry

None.

Occupational and Residential Exposure

875.2400 Dermal Exposure and 875.2500 Inhalation Exposure A dermal and inhalation exposure study is required for chemical

- specific abamectin seed treatment of cotton or corn in a closed system.

References

Memoranda Relevant to Registration Review of Abamectin

Author Barcode

(DP#) Date Title

Risk Assessment s N. Dodd D402677 12/20/12 Abamectin. Human Health Risk Assessment for Uses of the SC Formulation on Cotton and Strawberry

N. Dodd D393232 8/24/11 Abamectin. Amendment to the Human Health Risk Assessment for Proposed Uses on the Bulb Onion Subgroup 3

- 07A, Chives, and Dry Beans to include Cowpea in the Dry

Bean Tolerance

N. Dodd D380523 7/18/11 Abamectin. Human Health Risk Assessment for Proposed Uses on the Bulb Onion Subgroup 3

- 07A, Chives, and Dry

Beans

### Page 13 of 26

Memoranda Relevant to Registration Review of Abamectin

Author Barcode

(DP#) Date Title

N. Dodd D374426 2 /18/10 Abamectin. Human Health Risk Assessment Analysis for Proposed Use as: (1) a Soybean Seed Treatment (Non

- food); and (2) Bridging Studies from Emulsifiable Concentrate (EC) to Suspension Concentrate (SC) Formulations to Support SC Use on Almonds, Walnuts, Apples, Pears, Avocadoes, Celeriac, Citrus Fruit, Cotton, Cucurbit Vegetables, Fruiting Vegetables, Grapes, Herbs (except Chives), Hops, Leafy Vegetables, Mint, Plums, Prunes, and Potatoes

N. Dodd D 365712 6/2/09 Abamectin. Addendum to 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

N. Dodd D362615 3/11/09 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 Sub group 1C

and Request for Cattle Ear Tag Use

N. Dodd D315734 1/27/09 Abamectin. 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

K. O’Rourke D317742 9/15/05 Abamectin Abamectin (Avermectin B 1 ). Human Health Risk Assessment

for the New Use Seed Treatment of Cucurbits and Tomatoes

N. Dodd D313175 2/16/05 Abamectin. 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

K. O’Rourke D297225 11/2/04 Abamectin (Avermectin B 1 ). Human Health Risk Assessment for New Uses on Plums/Prunes, Leafy Vegetables, Fruiting Vegetables, Herb Subgroup (except chives), Avocado, Mint, and Food Handling Establishments

G. J. Herndon D259195 9/3/99 Avermectin . Revised Risk Estimates for Human Health Risk Assessment for the Request for Tolerances on Grapes, Raisins, and Peppers. Update of Memo of G.J.

Herndon Dated 6/28/99

G. J. Herndon D257267 6/28/99 Avermectin . Revised Risk Estimates for Human Health Risk Assessment for the Request for Tolerances on Grapes, Raisins, and Peppers

W. Cutchin D248844 2/24/99 Avermectin. Human Health Risk Assessment for the Request for Tolerances on Grapes, Raisins, and Peppers

G.J. Herndon D232674 1/24/97 PP#5F04508. Use of Averrmectin B1 on Potatoes. Section 3 Registration and Permanent Tolerance Request

### Page 14 of 26

Memoranda Relevant to Registration Review of Abamectin

Author Barcode

(DP#) Date Title

Residue Chemistry

N. Dodd D401832 12/17/12 Abamectin. Petition to Increase the Established Permanent Tolerances on Strawberry and Cotton and to Add Uses on Strawberry and Cotton to Agri

- Mek® SC and Epi

- MekTM SC Labels. Summary of Analytical Chemistry and Residue Data Dietary Exposure Assessment

N. Dodd D403715 12/19/12 Abamectin. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action for Use of a Suspension Concentrate (SC) Formulation on Cotton and Strawberry Occupational Residential Exposure

N. Tsaur D405841 12/20/12 Abamectin. Occupational Exposure Assessment for a Label

Amendment for Use on Cotton and Strawberries with an Updated Residential Exposure Assessment of All Existing Residential Uses (Lawns/Turf and Indoor Environments) Toxicology

S. Recore D 409003 2/ 20 /13 Abamectin: Review of Human Incidents

K. Rury, MPH TXR #

0056509 1/30/13 Abamectin: Summary of Hazard and Science Policy Council (HASPOC) Meeting of November 8, 2012: Recommendations on the Requirement of a Subchronic Inhalation Study and Dermal Toxicity Study.
Van Alstine,
J., MPH 410367 June

2013 Abamectin

– Report of the Hazard and Science Policy Council

(HASPOC) Meeting of June 6, 2013; Waiver for the Immunotoxicity Study (870.7800)



### Attachment s 1. Chemical Identity Table

2. Tolerance /MRL Summary Table

3 . Endpoint Selection Table

4. To x icity Profile Table s

### Page 15 of 26 Attachment 1 Chemical Identity Table

Table 1. Chemical Identity

- Abamectin

Common Name abamectin, avermectin B 1 Chemical Name (CAS) a vermectin B 1
PC Code 122804

Chemical Abstracts No. a vermectin B 1 - 71751

- 41

- 2; a vermectin B 1a - 65195

- 55

- 3; a vermectin B 1b - 65195

- 56

- 4
Registration Review Case No. 7430

Chemical Class avermectin insecticide/miticide /nematicide

Chemical Structure

Abamectin

### Page 16 of 26 Attachment 2

Tolerance /MRL Summary Table

The Codex, Canadian, or Mexican maximum residue limits (MRLs) established for residues of

abamectin in crop or livestock commodities are shown in the table below

.

ABAMECTIN (122804; 2/ 04 /2013)

Table 2 . Summary of US and International Tolerances and Maximum Residue Limits Residue Defi nition :
US Canada Mexico 1 Codex 2

40 CFR §180.449:

Plants/Livestock: avermectin B 1 [a mixture of avermectins containing greater than or equal

to 80% avermectin B 1a (5

- O

- demethyl

avermectin A 1 ) and less than or equal to 20%

avermectin B 1b (5

- O

- demethyl

- 25

- de(1

- methylpropyl)

- 25

- (1

- methylethyl) avermectin

A 1 )] and its delta

- 8,9

- isomer avermectin B 1 (a mixture of avermectins containing greater than or equal to

80% avermectin B 1a (5

- O

demethyl avermectin A 1a ) and less than or equal to

20% averme ctin B 1b (5

- O

- demethyl

- 25

- de(1

- methylpropyl)

- 25

- ( 1

- methylethyl ) avermectin

A 1a ) 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.

Commodi ty Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 Codex 2

Almond, hulls 0.10 0.1 Apple 0.020 0.02 0.02
Apple, wet pomace 0.10

Avocado 0.020 Bean, dry, seed 0.01
Cattle, fat 0.03 0.1 3

Cattle, meat 0.02 0.01 (*) Cattle, meat byproducts 0.06 0.05 3 cattle kidney

0.1 3 cattle liver
Celeriac, roots 0.05 Celeriac, tops 0.05
Chive, dried leaves 0.02
Chive, fresh leaves 0.01 Citrus, dried pulp 0.10
Citrus, oil 0.10

Citrus 0.02 0.02 citrus fruits 0.01 (*) citrus

fruits Cotton, gin byproducts 0.15
Cotton, undelinted seed 0.005 0.01 (*) Food products in food handling establishments (other than those already covered by higher

tolerances as a result of use on growing crops, and other than those already covered by tolerances on milk, meat, and meat byproducts) 0.01

Fruit, stone, group 12 0.09

### Page 17 of 26

Table 2 . Summary of US and International Tolerances and Maximum Residue Limits Residue Defi nition :
US Canada Mexico 1 Codex 2

Goat, fat 0.01
Goat, meat 0.02 0.01 (*) Goat, meat byproducts 0.02 0.1 goat, edible

offal of Grape 0.02 0.02 Herb subgroup 19A, except chive 0.030 Hog, fat 0.01 Hog, meat 0.02 Hog, meat byproducts 0.02 Hop, dried cones 0.20 0.1 hops, dry
Horse, fat 0.01
Horse, meat 0.02 Horse, meat byproducts 0.02

Milk 0.005 0.005 cattle milk Nut, tree, group 14 0.01 0.005 almond nuts,

walnuts 0.01 (*) almonds,

walnuts Onion, bulb, subgroup 3

- 07A 0.01

Pear 0.02 0.02 0.02 Peppermint, tops 0.010

Pistachio 0.01 Plum, prune, dried 0.025 Poultry, meat 0.02 Poultry, meat byproducts 0.02 Sheep, fat 0.01 Sheep, meat 0.02 Sheep, meat byproducts 0.02
Spearmint, tops 0.010 Strawberry 0.02 0.02 0.02 Vegetable, cucurbit, group 9 0.005 0.005 cucumbers 0.01 cucumber 0.01 (*) melons,

except watermelon; watermelon, squash summer Vegetable, fruiting, group 8 0.020 0.01 peppers, tomatoes 0.2 peppers chili,

dried 0.02 Peppers, sweet (including pimento or pimiento), tomato Vegetable, leafy, except brassica, group 4 0.10 0.05 celery, head lettuce 0.05 lettuce leaf

Vegetable, tuberous and corm, subgroup 01C 0.01 0.01 potatoes 0.01 (*) potato

MRLs with NO US Equivalent

Goat milk 0.005

Completed by: M. Negussie; 2/06/13

### Page 18 of 26 1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample . MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

3 The MRL accommodates external animal treatment.

### Page 19 of 26 Attachment 3

Summary of Toxic ity Endpoints and Points of Departure of Abamectin

Table 3

. 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 UF A = 10x

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

mg/kg/day 12

- Week dose

- range finding study in dogs

LOAEL = 1.0 mg/kg/day based on mydriasis

seen 1

- 5 times during the first week of

treatment. Acute neurotoxicity study in rats LOAEL= 1.5 mg/kg/day based on increased incidence of foot splay.

Chronic Dietary (All populations) NOAEL =

0.12 mg/kg/day UF A = 10x

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

0.0004 mg/kg/day Combined data from three reproduction

studies and two developmental neurotoxicity studies (please see the discussion on Chronic Dietary Endpoint) LOAEL = 0.2 mg/kg/day based on decreased pup body weight i n pups at 0.2 mg/kg/day.

Short

- Term and

Intermediate

Term

Incidental Oral NOAEL =

0.12 mg/kg/day UF A = 10x

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

LOC for

MOE = 300 Combined data from three reproduction

studies and two 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 UF A = 10x

UF H = 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 UF A = 10x

UF H = 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. * The additional FQPA safety factor of 3x is for the steepness of the dose

- response curve and the severity of effects.

### Page 20 of 26

Table 4

. Summary of Toxicol ogical 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 UF A = 10X

UF H = 10X

SF = 3X LOC: MOE = 300 Combined data from three reproduction studies and two developmental neurotoxicity

studies. LOAEL = 0.2 mg/kg/day based on decreased pup body weight in

pups.

Inhalation (Short

Term and

Intermediate

- Term) NOAEL = 0.12 mg/kg/day UF A = 10X

UF H = 10X

SF = 3X LOC: MOE = 300 Combined data from three reproduction studies and two developmenta l 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in

sensitivit y 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 (LO C): 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).

### Page 21 of 26 Attachment 4

Tox icity Profile Table s

Table 5 . Acute Toxicity Profile of Abamectin Technical

Guideline No. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral

- rat

(sesame oil vehicle) 006894 LD 50 = 13.6 mg/kg I

870.1100 Acute Oral

- rat

(methyl cellulose vehicle) 45607202 LD 50 =214

- 232 mg/kg II

870.1200 Acute Dermal

- rabbit 00255978 LD 50 = 2000 mg/kg III

870.1300 Acute Inhalation

- rat 45623501 LC 50 =<0.21 mg/L (nose only) I

870.2400 Primary Eye Irritation 45063501 not an irritant IV

870.2500 Primary Skin Irritation 41123904 slight irritation III

870.2600 Dermal Sensitization 00139564 negative in Buehler Negative

870.6200a Acute Neurotoxicity none none none

Table 6. Toxicity Profile of Abamectin Technical for Repeated Dosing and Genotoxicity Studies

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100 Subchronic feeding study

- rats 00131081 (1982)

Acceptable/Non

- guideline 0, 0.10, 0.20, 0.40 mg/kg/day NOAEL > 0.40 mg/kg/day

LOAEL = not established

870.3150 Subchronic toxicity

Dogs (18 week gavage study) 00131082 (1982)

Acceptable/Guideline

0, 0.25, 0.5, 2.0, 8.0 mg/kg/day NOAEL = 0.25 mg/kg/day

LOAEL = 0.50 mg/kg/day based on body tremors, one death, liver pathology, decreased body weight. Mydriasis was seen during week one in one dog.

870.3150

12

- Week dose range finding study

- dogs (feeding) 00164152 (1982)

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

870.3200

21/28

- Day dermal toxicity Study not available. Study requirement was waived due to very low dermal absorption (<1%).

### Page 22 of 26

Table 6. Toxicity Profile of Abamectin Technical for Repeated Dosing and Genotoxicity Studies

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3465

30

- Day inhalation

tox.

- rats 46921502 (2006)

Acceptable/Guideline NOAEL = >2.5 μg/L (0.0025 mg/L) (HDT) (≈0.68 mg/kg/day)

.

870.4300a

Combined Chronic toxicity/carcinogenici
ty

- rats 40069601, 40375511,

40517801 (1985) Acceptable/Guideline 0, 0.75, 1.5, 2.0 mg/kg/day NOAEL = 1.5 mg/kg/day LOAEL = 2.0 mg/kg/day based on tremors No evidence of carcinogenicity

870.4100b Chronic toxicity dogs 40375510 (1987)

Acceptable/Guideline 0, 0.25, 0.5, 1.0 mg/kg/day NOAEL = 0.25 mg/kg/day LOAEL = 0.5 mg/kg/day based on mydriasis during week one, death at 1.0 mg/kg/day

870.4300b

Combined Chronic toxicity/Carcinogenic ity

- mice 40069602, 40375512,

40517801 (1985) Acceptable/Guideline 0, 2, 4, 8 mg/kg/day NOAEL = 4.0 mg/kg/day LOAEL = 8.0 mg/kg/day based on increased mortality in males, tremors, body weight decreases in females, dermatitis in males, extramedullary hematopoies is in spleen of males No evidence of carcinogenicity

870.3700a

Prenatal developmental

in rodents

- rats Accession: 00130819

(1982) Acceptable/G uideline 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

- g uideline 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

### Page 23 of 26

Table 6. Toxicity Profile of Abamectin Technical for Repeated Dosing and Genotoxicity Studies

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3800b

1

- Generation Reproduction and fertility effects

- rat 00096450

Unacceptable/Non

g uideline 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/G uideline

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 spla y 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/G uideline

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/N onguideline

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..

### Page 24 of 26

Table 6. Toxicity Profile of Abamectin Technical for Repeated Dosing and Genotoxicity Studies

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870

- 6200

Developmental neurotoxicity study in

rats 47116201 (2007)

Acceptable/N onguideline

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/N on

- g uideline 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

g uideline 69

- 82% of label is excreted in feces by day 7; T 1⁄2 =1.2 days. The reliability of these data is questionable.

Metabolism No MRID

(1985) Nonguideline Avermectin B 1a did not bioaccumulate in rat tissues. Half

- life slightly longer in females than in males for several tissues.

Metabolism No MRID

(1985) Nonguideline The metabolism of avermectin B 1 in rats results in the formation

of 24

- OH

- Me

- B 1a and accounts for most of the radiolabeled

residues. Avermectin B 1a does not bioaccumulate.

### Page 25 of 26

Table 6. Toxicity Profile of Abamectin Technical for Repeated Dosing and Genotoxicity Studies

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.7600 Dermal penetration Accession: 265590 (1986)

Acceptable/ Nonguideline in Monkeys The result showed the dermal absorption to be <1% of the applied dose. For risk assessment, a dermal penetration factor of

1% was recommended.

Table 7 . 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 f etal 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)

### Page 26 of 26

Table 7 . 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 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