Page 3 of 21

residual concern for pre

- and/or post

- natal toxicity, no concern fo r developmental neurotoxicity, and the completeness of the residue chemistry and environmental fate databases, the required
10X FQPA safety factor was reduced to 1X. In support of registration review, the required immunotoxicity study should be submitted, and the endpoint selection and use of safety and uncertainty factors for human health risk assessment should be confirmed

. HED is undergoing a retrospective analysis of 170 immunotoxicity stidies submitted to the Agency. The results of that analysis may impact the requirement for immunotoxicity teting; therefore, HED recommends that PRD confirm the need for an immunotoxicity study prior to issuing the data call

- in (DCI).

The residue chemistry database supporting the registered use s is complete. Metabolism data indicate that hydramethylnon is extensively metabolized in grasses and pineapple, which are the only food

- use s that are registered. The residue definition for both tolerance enforcement and risk assessment is hydramethylnon. The current t olerance definition should be revised during registration review to include coverage and compliance statements as follows :

Tolerances are established for residues of hydramethylnon , 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 hydramethylnon { tetrahydro

- 5,5

- dimethyl

- 2(1 H )

- pyrimidinone [3

- [4

- (trifluoromethyl)phenyl]

- 1

- [2

- [4

- (trifluoromethyl)phenyl]ethenyl]

- 2

- propenylidene]hydr azone }

.

Acceptable analytical method s are available to enforce tolerances for residues in/on grass and pineapple commodities.

The last risk assessment provides dietary (food only) estimates for acute and chronic aggregate
risk that are below HED’s level of concern for all population subgroups. During registration review, HED will confer with the Environmental Fate and Effects Division (EFED) regarding estimated levels of the residues of concern in drinking water. HED will evaluate the results of

t hat analysis and determine whether or not a new quantitative dietary assessment is needed

. Given current risk estimates, it is unlikely that a new analysis will be necessary.

The characteristics of the formulations containing hydramethylnon limit the t ype and degree of residential exposures that may occur. For the residential scenarios that were quantitatively assessed, estimated risks were not of concern. Previous o ccupational handler assessments result
in risk estimates that are below HED’s level of concern at the baseline level of personal protective equipment (PPE) for most scenarios, and with the addition of gloves for handlers in aerial application scenarios. Revisions to 40 CFR Part 158, which requi re dislodgeable foliar
residue data in order t o adequately assess post

- application risks , are not applicable to the registered uses of hydramethylnon because the products are formulated as granules and would
not result in foliar residues. There were no risk estimates of concern for d ermal post

- applic ation

exposure; quantitative inhalation assessments were not completed for hydramethylnon.

Pending outcome of the retrospective analysis of the utility of immunotoxicity studies, HED is recommending that the required immunotoxicity study be submitted to support registration
review.Page 4 of 21

Absent any new toxicity or exposure data, changes to the standard operating procedures, or default exposure assumptions that could impact the overall risk conclusion, updated res idential, dietary, occupational risk assessmen t s are not anticipated to be needed in registration review.

Introduction

This document summarizes HED’s evaluation of the data available for assessing human health risk from exposure to the insecticide hydramethylnon , as well as any data need ed to support registration review

. Hydramethylnon is an amidinohydrazone insecticide registered for control of ants in numerous settings, including pastures, rangelands, other non

- crop lands, fruit and nut orchards (bait station only, non

- food use), domesti c dwellings and commercial establishments, and pineapple orchards (food use). In conducting this evaluation, HED has considered the most recent human health risk assessment ( D228934

, 21 May 2003 ), HED and OPPIN/PRISM databases, and open literature (via Go ogle Scholar). Chemical nomenclature for hydramethylnon is summarized in Table 1, below.

Table 1. Chemical Nomenclature for Hydramethylnon

. Chemical Structure

IUPAC Name 5,5

- dimethylperhydropyrimidin

- 2

- one 4

- trifluoromethyl

- α

- (4

- trifluoromethylstyryl) cinnamylidenehydrazone

CAS Name tetrahydro

- 5,5

- dimethyl

- 2(1H)

- pyrimidinone [3

- [4

- (trifluoromethyl)phenyl]

- 1

- [2

- [4

- trifluoromethyl)phenyl]ethenyl]

- 2

- propenylidene]hydrazone

CAS Number 67485

- 29

- 4

Hazard Identification/ Toxicology

The tox icological database for hydramethylnon is largely complete including complete batteries of acute and mutagenicity studies. The acute neurotoxicity (ACN) , subchronic neurotoxicity ( SCN ), subchronic inhalation toxicity, and immunotoxicity studies have not been submitted to the Agency. Although t hese studies are required based on the most recent pesticide registration data requirements published in Title 40 Part 158 of the Code of Federa l Regulations

, HED’s Hazard and Science Policy Council (HASPOC) determined that the ACN, SCN, and
inhalation stud ies are not required ( TXR# 0056452 , 8/30/2012 )

. HASPOC concluded the ACN
and SCN are not required based on the lack of neurotoxicity observed in hydramethylnon toxicity database and the decreased likelihood that these studies would result in a more conservative endpoint than those currently being used for risk assessment. The HA S POC also
concluded that a subchronic inhalation study is not requ ired based on weight of evidence considerations including the high Margins of Exposure (10,000 for residential and 190,000 for occupational) that were determined in the last risk assessment.Page 5 of 21

An immunotoxicity study is required in the 2007 revised 40 CFR Part 158 Toxicology Data Requirements for food

- use and non

- food use chemicals and HASPOC did not consider waiving the immunotoxicity study; therefore this study is considered outstanding. The Agency acknowledges that the submission of CLA’s retrospectiv e analysis on immunotoxicity studies is currently under review. In addition, EPA is conducting an independent retrospective analysis of 170 immunotoxicity studies submitted to the Agency. The EPA retrospective analysis is anticipated to be completed in e arly 2013. The preliminary results of the retrospective analyses provide strong support for not retaining the 10X UF DB as no immunotoxicity study available thus far has provided sensitive endpoints for use in deriving points of departure. At this time,

co ncludes that the immunotoxicity study is required; however, that conclusion may change upon completion of the retrospective analysis and HED recommends that PRD confirm this requirement prior to issuing the DCI for this study

Oral toxicity has been well c haracterized in the rat, mouse, rabbit, and dog. The testes were clearly the primary target organ in rats, mice, and dogs

. Lowest observed adverse effect levels ( LOAELs ) in the subchronic studies in the rat and dog and chronic studies in the rat and mouse
included decreased testicular weight and/or testicular atrophy. In the two

- generation reproductive study in rats, the LOAEL was based on microscopic lesions and dege n er ation of the germinal cells . D ecreased reproductive perform ance at the highest dose tested resulted from longer precoital intervals and lower impregnation rates in the males and reduced gestation w e ight gain and smaller litters in females. Adverse effect s were also found on the spermatocytes and/or spermatogonia in the dominant lethal assay. All other mutagenicity studies were negative. Other effects noted in the subchronic rat study and the developmental studies in the rat and rabbit
included decreased food consumption, muscle wasting, and gastrointestinal irritation.

There was no indication of increased quantitative or qualitative susceptibility in the rat and rabbit developmental studies or in the 2

- generation reproduction study in the rat. The mat ernal and development LOAELs were similar in the developmental studies and there was no indication of toxicity in the offspring in the reproduction study. For the most recent risk assessment, HED
recommended the FQPA Safety Factor be reduced to 1X based o n the lack of fetal or offspring sensitivity, the use of conservative residue assumptions, and the completeness of the chemistry and environmental fate databases (TXR 0051786).

The Cancer Peer Review Committee (CPRC) classified hydramethylnon as a Group C

— possible human carcinogen based upon statistically significant increases in lung adenomas and combined lung adenomas/carcinomas in female mice. The CPRC recommended q uantification of risk using

a non

- linear approach ( i.e., R fD) will adequately account fo r all chronic toxicity, including carcinogenicity, that could result from exposure to hydramethylnon

Metabolism studies indicate that absorption is minimal following oral exposure, with greater
than 90% of the administered dose recovered in the feces as u nchanged parent. Dermal absorption was also low based on studies using gel formulations. Dermal absorption following 10 hours of exposure was 0.414% for 2% a.i. Maxforce Gel ® and 0.97% for 2.16% a.i. Siege ®

.

Conclusions : W ith the exception of the immunotoxicity study, the toxicology database is complete and sufficient for human health risk assessment. During registration review, thePage 6 of 21

required immunotoxicity study should be submitted, and the endpoint select ion and safety an d uncertainty factors for human health risk assessment should be confirmed.

Dietary Exposure

The residue chemistry database for hydramethylnon is complete for purpose of supporting the currently registered uses. HED has previously determined that the re sidue definition for both
tolerance enforcement and risk assessment purposes is hydramethylnon

.

Dietary exposure estimates in the previous risk assessment assume 100% percent crop treated and do not include direct incorporation of potential residues in dr inking water

. All dietary r isk
estimates were less than 1% of the acute or chronic population

- adjusted doses and were, therefore, well below HED’s level of concern. HED has identified potential residues of toxicological concern in aquatic systems . T he degradates identified in the fate studies are structurally similar to the parent compound and in the absence of additional data may be considered to have the same toxicity as the parent , for the purpose of risk assessment . As a result, HED will work with EFED to determine the estimated level of these metabolites in drinking water and evaluate their impact on the dietary risk estimates. Given the level s of the current risk estimates, it appear s unlikely that a new quantitative dietary assessment will be

ne eded.

Conclusions : No new residue chemistry data are required to support the currently registered

uses

. Although unlikely, a n ew dietary exposure analyses may be conducted to address any changes in the hazard assessment, to include estimates for residue s in drinking water (including all degradates of potential toxicological concern) directly in the exposure estimates and to update
the assessment with current policies and consumption databases

.

Residential Exposure

There are no chemical specific data available for assessing residential exposure and risk associated with registered products containing hydramethylnon. In the absence of chemical

specific data, HED has relied on information in the Pesticide Handler Exposure Database (PHED), Outdoor Residen tial Exposure Task Force (ORETF) studies, and standard assumptions with respect to the area treated and surrogate unit exposure data.

Residential Handler Exposure and Risk

In previous risk assessments, HED did not quantitatively evaluate d ermal and inhalation exposure to residential handlers from use of the termite bait system : exposure to the active ingredient is expected to be negligible since the solid bait is packaged in a tube and does not
come in to contact with skin when installed in the ground. In addition, the active ingredient in the
solid termite bait is non

- volatile and no significant inhalation exposure is expected ( J. Arthur, D229910, 29 July 1997)

. G el baits used to control cockroaches and ants in homes were not quantitativel y assessed for handler exposure via the dermal and inhalation routes due to the lack of appropriate unit exposures. However, e xposures from such gel systems are considered to be negligible because the bait station design allows the user to deploy the bait station withoutPage 7 of 21

contacting the active ingredient in the product. For uses on turf, HED evaluated c ombined
dermal and inhalation exposure and risk from applying a granul ar formulation with a belly

grinder ; risk estimates associated with use on a home lawn for fire ant control were not of concern ( G. Bangs, D288800, 20 May 2003)

.

Residential Post

- application Exposure and Risk

End

- use p r oducts formulated with hydramethylnon can be classified into three groups: bait stations, gel formulations, an d granules. Bait stations are either installed below soil level (e.g., termite bait systems) or are pre

- filled and sold only in child

- resistant packages. These attributes, coupled with hydramethynon’s low vapor pressure, make the potential for post

- applica tion exposure from use of bait stations very low and not of concern.

The use of gel formulations has the potential to result in post

- application exposure for children
and adults when these formulations are used by homeowners and/or professional applicat ors. The previously assessed adult dermal MOE resulting from indoor use of cockroach gel bait was not of concern (D229910, 29 July 1997). Children’s dermal and oral exposures from gel baits
were not evaluated in the 1997 assessment. However, such expos ures are expected to be not of
concern because of the use of child

- resistant packag ing (CRP) or appli cation as pastes in cracks
and crevices. Due to the properties of gel formulations and h ydramethylnon itself, post

application inhalation from exposure to adults and children is not of concern.

Application of granular formulations of hydramethylnon to lawns has the potential to result in
post

- application dermal exposure as well as incidental oral exposure via hand

- to

- mouth transfer or the direct ingestion of granules themselves , which is considered to be an episodic type of

exposure . In the 2003 assessment, the risk estimates associated with these exposures were not of concern (G. Bangs, D288800, 20 May 2003).

Conclusions : There is very low potential for dermal and inhalation exposures to residential handlers from use of termite bait systems and cockroach baits because of the properties of the gel
formulation and bait

- station packaging. The dermal and inhalation risk est imates for homeowners handling fire ant control products were not of concern. Post

- application dermal and oral (children only) risk estimates for adults and children f ollowing use of gel baits and granules
for fire ant control in residential settings were not of concern. The post

- application inhalation exposures are expected to be minimal due to the low volatility of hydramethylnon and the gel or granule characteristics of the formulated products.

R ecently, HED has updated the Residential S OPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html )

. During registration review, updated residential exposure assessments may be required to address these SOPs as we ll

as potential changes in toxicological points of departure

. Based on the current risk estimates, it is HED’s position that updated quantitative assessments will not likely be necessary.Page 8 of 21

Aggregate Risk Assessment

In the most recent risk assessment, aggregate risks , which included residential exposure and risk estimates, were assessed using drinking water levels of comparison (DWLOCs) and estimated environmental concentrations (EECs) of hydramethylnon in water. For all durations (acute,
short

- term, a nd chronic) and population subgroups, the EECs were much less than the DWLOCs, indicating that aggregate risk estimates were well below HED’s level of concern.

Conclusions : During registration review, new aggregate risk estimates may be needed in order

t o address potential changes in toxicological points of departure, residential exposure estimates, and dietary exposure estimates; the last of which would include estimated exposure from drinking water sources directly in the assessment. Preliminary inform ation from EFED indicates that a total residue approach may be needed for residues in drinking water ; we note, however, that based on the current estimated risk levels a new quantitative aggregate risk assessment is not likely to be necessary

.

Occupationa l E xpos ure

There are no chemical specific data available for assessing occupational exposure and risk associated with registered products containing hydramethylnon. In the absence of chemical

specific data, HED has relied on information in the Pesticide Handler Exposure Database (Version 1.1) and standard assumptions with respect to the area treated and surrogate unit exposure data.

Occupational Handler Exposure and Risk

Termite bait systems : There were no dermal risk estimates of concern associated w ith the use of termite bait systems. W hen such systems are anchored in the ground by professional applicators around homes and other structures where termite activity is found or suspected, the dermal MOE associated with hydramethylnon termite bait system s is not of concern ( Dow, M., D309409, 7 February 2005 ). Inhalation exposure was not assessed because it is exp ected to be negligible
based on the solid formulation, enclosed packaging, and low volatility of hydramethylnon (vapor pressure = 2.0x10 - 8 mm Hg).

Gel baits : In the absence of chemical

- specific exposure data or appropriate surrogate unit exposures, occupational handler exposures could not be estimated for professional applicators using gel baits. These products are formulated as gel matrices and are packaged in small units for placement in infested areas, w h i ch does not involve touching the bait; therefore, no dermal exposure is expected. The possibility of inhalation exposure is also negligible due to the low volatility of hydrameth ylnon, and due to the method of dispensing solid baits or use of injectors to apply bait paste into cracks and crevices.

Granule s : The hydramethylnon Re

- registration Eligibility Document ( Arthur, J., D229910, 29 July 1997 ) and a subsequent assessment ( B angs, G., D288800, 20 May 2003) estimated combined ( dermal and inhalation) risks that are not of concern when granules are applied at 0.02 lb ai/A using aeria l and ground spreaders, and hand dispersal methods. The evaluated end

- usePage 9 of 21

product was considered representative of other hydramethylnon granular products with respect to application sites and rates.

Occupational Post

- application Exposure and Risk

T here are no occupational post

- application activit i es performed following treatment of residential, comm ercial, and industrial premises after treatment with termite bait systems and cockroach/ant gel bait stations. Therefore, there are no occupational post

- application risk s for
these formulations. However, activities such as scouting, irrigation, and harve sting in cropland and orchards and fertilizing and mowing of commercial turf areas result in the potential for post

application dermal and inhalation exposures from the use of granules on agricultural and non

agricultural sites for control of fire ants and other pests. Short

- term post

- application dermal exposure was estimated for workers harvesting pineapple and was not of concern (Bangs

, G., D288800, 20 May 2003 )

. Evaluation of short

- term exposure is considered to be protective of
intermediate

- and long

- term exposure because the endpoints and doses for risk assessment are the same for all three durations

.

A quantitative post

- application inhalation exposure as sessment was not performed for agricultural uses of hydramethylnon granules b ased on the expectation that inhalation exposure would be very low

. During registration review, HED may evaluate the multiple potential sources of inhalation exposure to workers performing post

- application activities in treated fields. These potential sources include volatilization of pesticides and re

- suspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html )

. The Agency 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 and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation expos ure 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 hydramethylnon.

Conclusions: There are no risk estimates of concern associated with hydramethylnon handler or
post

- application occupational exposure

. For granular formulations of hydramethylnon, h andler
dermal and inhalation risk estimates are not of concern at baseline PPE for most scenarios, and
wit h the addition of gloves for handlers in aerial and hand application scenarios. The baseline scenario generally represents a handler wearing long pants, a long

- sleeved shirt, and no
chemical

- resistant gloves.

Absent any new toxicity or exposure data, cha nges to the standard operating procedures, or default exposure assumptions that could impact the overall risk conclusion, updated occupational
risk assessment s are not anticipated to be needed in registration review. If any assessments are required, HED will rely on the following revised scenario

- specific surrogate handler exposurePage 10 of 21

data : ( http://www.epa.gov/pesticides/science/handler

- exposure

- table.pdf ) and ( h ttp://www.epa.gov/pesticides/science/exposac_policy3.pdf ).

Public Health and Pesticide Epidemiology Data

OPP has conducted a review of the incident data associated with hydramethylnon (S. Recore,
D40 3751

, 9 July 2012). To date, there are relatively f ew incident cases reported for hydramethylnon in either the Main (28 incidents) or Aggregate Incident Data System (IDS ; 177
incidents ) . Based on the relatively low frequency and severity on incident cases reported for hydramethylnon, t here is no concern a t this time that would warrant further investigation

. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the registration review risk assessment.

Tolerance Assessment and International Harmonization

Tolerances for residues of hydramethylnon in food/feed commodities (40 CFR 180. 395 ) are currently expressed in terms of hydramethylnon. T he available data are sufficient to support the existing tolerances for residues of hydra methylnon in foods/feeds

. During registration review, the tolerance definition should be updated to the following language to include the coverage and compliance statements as per current policy :

Tolerances are established for residues of hydramethylnon

, 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 hydramethylnon { tetrahydro

- 5,5

- dimethyl

- 2(1 H )

- pyrimidinone [3

- [4

- (trifluorome thyl)phenyl]

- 1

- [2

- [4

- (trifluoromethyl)phenyl]ethenyl]

- 2

- propenylidene]hydrazone }

.

There are no Canadian or Codex MRLs at this time for hydramethylnon ( Attachment 1. )

Tolerances for residues of hydramethylnon in foods and feeds
Commodity Parts per million
Grass, forage 2.0
Grass, hay 2.0
Pineapple 0.05

Conclusions : International harmonization of regulatory levels will not be an issue for registration review.

Environmental Justice

Potential areas of environmental justice concerns, to the extent p ossible, were considered in the 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/nepa/tools/guidance/Volume1/2

- 6

- EO_12898envjustice.pdf ) . The Office of Pesticide Programs (OPP) typically considers the highest potential exposu res from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to,Page 11 of 21

people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be expos ed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure
that the risk estimates are based on the best available information.

Endocrine Disruptor Screening Program

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, neurotoxici ty, 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 maturati on, 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), hydramethylnon is subj ect 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 simila r 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 s creening 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 s ubstance, 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. Hydramethylnon is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future
EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for hydramethylnon . For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future li sts, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

Cumulative

Hydramethylnon has not been identified as a member of a common mechanism group.Page 12 of 21

Human Studies

Hydramethylnon human health risk assessments rely, in part, on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1) and the Agricultural Handler Exposure Task Force (AHETF) database, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.

Data Requirements

HED recommends that the immunotoxicity stu dy (OCSPP Guideline 870.7800) be submitted to support registration review

.

References

Cutchin, W. D., D228934, 21 May 2003. PP#: 2F2609. Human Health Risk Assessment for the Section 3 Use of Hydramethylnon in/on Pineapple.

Arthur, J. L., D229910, 9 July 1997. Hydramethylnon

– HED RED Chapter Sections III, IV, and

V.

Bangs, G., D288800, 20 May 2003. Occupational and Residential Exposure and Risk Assessment for Hydramethylnon New Uses on Pineapple.

Dow, M., D309409, 7 Febr uary 2005. ORE Assessment Regarding Proposed AMDRO ®
Interceptor Termite Baiting System.

Jaquith, D., D232251, 19 March 1997. Review of Exposure Assessment for Hydramethylnon
Termite Bait.

TXR# 0056452 . Meeting of the Hazard and Science Policy Council, 3 0 September 2012.

Attachments

Attachment 1. T oxicological D oses and E ndpoints for H uman H ealth R isk A ssessment for

H ydramethylnon

. Attachment 2. Toxicity Profile for Hydramethylnon

. Attachment 3

. Summary of US and International Tolerances and Maximum Residue Limits

. Attachment 4

. Hydramethylnon Products and Use Sites.Page 13 of 21

Attachment 1. T oxicological D oses and E ndpoints for H uman H ealth R isk A ssessment for

H ydramethylnon

.

Table A. 1

. Summary of Toxicological Doses and Endpoints for Hydramethylnon for Use in Dietary and Non

Occupational Human Health Risk Assessments.

Exposure/
Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD & PAD for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population) NA

Acute Dietary (Females 13

- 49 years of age) NOAEL =

5 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x RfD = 0. 0 5 m g/kg/day

aPAD = 0. 0 5 mg/kg/day Developmental Study

- Rabbit
LOAEL = 10 mg/kg/day based

on abortions

Chronic Dietary (All Populations) NOAEL =

1.66 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x RfD = 0.017 mg/kg/day

cPAD = 0.017 m g/kg/day 2

- Generation Reproductive Toxicity Study

- Rat
LOAEL = 3.22 mg/kg/day based

on testicular effects.

Incidental Oral (all durations) NOAEL =

1.66 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x MOE = 100 2

- Generation Reproductive

Tox i city Study

- Rat
LOAEL = 3.22 mg/kg/day based

on testicular effects.

Dermal (all durations) NOAEL =

1.66 mg/kg/day (dermal absorption = 1%) UF A = 10x

UF H =10x FQPA SF= 1x MOE = 100 2

- Generation Reproductive Toxicity Study

- Rat
LOAEL = 3.22 mg/kg/day based

on testicular effects.

Inhalation (all durations) NOAEL =

1.66 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 1x MOE = 100 2

- Generation Reproductive Toxicity Study

- Rat
LOAEL = 3.22 mg/kg/day based

on testicular effects. Cancer (oral, dermal, inhalation) Group C

— possible human carcinogen

. Reference Dose (RfD) approach should be used for quantification of human r isk

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 effe ct 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.

Table A .2 Summary of Toxicological Doses and Endpoints for Hydramethylnon for Use in Occupational Human
Health Risk Assessments. Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern for Risk

Assessment Study and Toxicological Effects

Dermal Short

- and
Intermediate

Term NOAEL =

1.66 mg/kg/day (dermal absorption = 1%) UF A = 10x

UF H =10x MOE = 100 2

- Generation Reproductive Toxicity Study

- Rat
LOAEL = 3.22 mg/kg/day based

on testicular effects.

Inhalation Short

and Intermediate

Term NOAEL =

1.66 mg/kg/day * UF A = 10x

UF H =10x MOE = 100 2

- Generation Reproductive Toxicity Study

- Rat
LOAEL = 3.22 mg/kg/day based

on testicular effects.Page 14 of 21

Table A .2 Summary of Toxicological Doses and Endpoints for Hydramethylnon for Use in Occupational Human
Health Risk Assessments. Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern for Risk

Assessment Study and Toxicological Effects

Cancer (oral, dermal, inhalation) Group C

— possible human carcinogen

. Reference Dose (RfD) approach should be used for quantification of human r isk

* Inhalation absorption assumed equivalent to oral absorption. 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 =
uncertaint y factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Page 15 of 21

Attachment 2. Toxicity Profile for Hydramethylnon

.

Table A2

- 1. Acute Toxicity Profile of Hydramethylnon Technical Grade Active Ingredient

OPPTS No./Study Type MRID Results

870.1100
Acute Oral

- Rat American Cyanamid Co. Study A90

- 117 July 19, 1990 41612503 LD 50 = 817 mg/kg ( ♂ ); 1502 mg/kg ( ♀ ), 1146 mg/kg ( ♂ + ♀ ) Clinical signs: Decreased activity, diuresis, anorexia, ataxia, epistaxis, chromodacryorrhea, salivation, and emaciation. Toxicity Category III
Guideline

870.1200
Acute Dermal

- Rabbit American Cyanamid Co. Study A90

- 114 July 1, 1993 41612504 LD 50 >2000 mg/kg (limit test) There was no evidence of toxicity. Toxicity Category III
Minimum

870.1300
Acute Inhalation

- Rat Bio/Dynamics Inc. Study 91

- 8399 July 16, 1993 42871101 LC 50 = 3.1 mg/L ( ♂ ), 3.4 mg/L ( ♀ ), 2.9 mg/L ( ♂ + ♀ ) ; 4

- hour analytical, whole body exposure; MMAD (GSD) = 2.0 μm (2.8). Clinical signs: Labored breathing, gasping, eye closure, decreased activity, rales, excessive salivation, yellow material on the fur, and decreased weight gain. Toxicity Category IV Acceptable

870.2400 Primary Eye Irritation

- Rabbit American Cyanamid Co. Study A90

- 140 August 22, 1990 41612505 Corneal opacity and conjunctival redness, chemosis, and discharge reversed within 7 days. Hydramethylnon is a
moderate irritant. Toxicity Category III
Guideline

870.2500 Primary Skin Irritation

- Rabbit American Cyanamid Co. Study A90

- 95 June 21, 1990 41612506 There was no evidence of dermal irritation or systemic toxicity. Toxicity Category IV
Guideline

870.2600
Dermal Sensitization

- Guinea Pig Food and Drug Research
Laboratories Study 7180 May 5, 1982 101560 Not a dermal sensitizer
Minimum

Table A2

- 2. Toxicity Profile of Hydramethylnon Technical Grade Active Ingredient

OPPTS No./Study Type MRID Results

870.3100 Subchronic Feeding

- Rat Pharmacopathics Research
Laboratories Study 7866 May 31, 1979 32641 NOAEL = 2.5 mg/kg/day LOAEL = 5.0 mg/kg/day

- decreased testicular weights (34%), and testicular atrophy. Clinical signs: None Clinical pathology: Negative
Gross lesions: None Microscopic pathology: Testicular atrophy Levels tested: 0, 50, 100, 200, or 400 ppm (0, 2.5, 5.0, 10.0, or 20.0 mg/kg/day). The sponsor chose to lower the dose for the 400 ppm group to 25 ppm [sic] on day 15 due toPage 16 of 21

Table A2

- 2. Toxicity Profile of Hydramethylnon Technical Grade Active Ingredient

OPPTS No./Study Type MRID Results
significant decreases in body weight gain and food consumption. Acceptable

870.3100 Subchronic Feeding

- Mice –

–

870.3150 Subchronic Gavage

- Dog Pharmacopathics Research
Laboratories Study 7864 May 31, 1979 61794 NOAEL = 3 mg/kg/day

- LDT; decreased food consumption (11% / 20%, ♂/♀ ) and body weight gain (11% / 9%, ♂/♀ ). LOAEL = [not defined] Lethal Dose = 6 mg/kg/day

- decreased food consumption and body weight gain, SGPT, cachexia, wasting of muscle and subcutaneous fat, testicular atrophy, and death. Levels tested: 0, 3.0, 6.0, or 12.0 mg/kg/day via capsule for 91 days. Acceptable

870.3150 Subchronic Gavage

- Dog
Hazleton Laboratories Study 362

- 156 June 10, 1980 92163037 NOAEL = 1.0 mg/kg/day LOAEL = 3.0 mg/kg/day

- increased incidence of soft

stoo ls, mucoid stools, and diarrhea. Levels tested: 0, 0.33, 1.0, and 3.0 mg/kg/day via capsule for 26 weeks. The control group received 120 mg/kg/day of
lactose. Acceptable

870.3200

21

- Day Dermal

- Rabbit Hazleton Raltech, Inc. Study 80033 April 15, 1982 101559 NOAEL = 250 mg/kg/day (HDT)
A LOAEL was not determined. Food consumption was reduced in males and females at the high dose. However, the resulting decrease in body weight compared to controls was not considered to be adverse. The platelet count was also reduced in the high dose females but was not considered adverse because it is a common finding following skin
abrasion. Levels tested: 0, 10, 50, or 250 mg/kg/day on clipped skin of dorsal trunk. Half of each group was abraded prior to

treatment. Unacceptable

– The study is unacceptable because the vehicle is unknown, half of the animals had abraded skin, and
skin lesions were observed in the control animals.

870.3465
13

- Week Inhalation – –

870.3700 Developmental Toxicity

- Rat Bio/Dynamics Inc. Study 79

- 2382 September 14, 1979 92163038 Maternal NOEL = 3 mg/kg/day Maternal NOAEL = 10 mg/kg/day

- 8% decrease in body weight and yellowish discoloration of the fat. Maternal LOAEL = 30 mg/kg/day

- 16% decrease in body weight; increased incidence of na sal mucus, alopecia, soft stools, staining of the ano

- genital fur, yellowish discoloration of the fat, and small thymus. Developmental NOEL = 10 mg/kg/day Developmental LOAEL = 30 mg/kg/day

- decreased mean fetal weights and increased incidence of rudimentary structures and incompletely ossified supraoccipitals. Levels tested: 0, 3, 10, or 30 mg/kg/day on gestation days 6

- 15. Vehicle controls were dosed with corn oil. AcceptablePage 17 of 21

Table A2

- 2. Toxicity Profile of Hydramethylnon Technical Grade Active Ingredient

OPPTS No./Study Type MRID Results

870.3700

D evelopmental Toxicity

- Rabbit
International Research & Development Corp. Study 141

- 024 April 7, 1982 101558 Maternal NOAEL = 5 mg/kg/day Maternal LOAEL = 10 mg/kg/day

- abortions, soft stools, reduced amount of stools, and anogenital matting and discharg e. Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 10 mg/kg/day

- abortions, decreased fetal weight (16%). Levels tested: 0, 5, 10, or 20 mg/kg/day on gestation days 6

- 18. Vehicle controls were dosed with corn oil. Acceptable

870.3800

2

- Generation Reproductive Toxicity

- Rat
Pharmaco

- LSR Ltd. Study 92

- 4026 July 19, 1995 43741501 Reproductive/Systemic NOAEL = 25 ppm (1.66 / 2.01 mg/kg/day, ♂/♀ ) Reproductive/Systemic LOAEL = 50 ppm (3.32 / 4.13 mg/kg/day, ♂/♀ )

- degeneration of the germinal epithelium (1/29) and aspermia (1/29) There was no evidence of systemic toxicity, or direct toxicity in the offspring. Levels tested: 0, 2, 50, or 75 ppm (0, 1.66, 3.32, or 5.05 mg/kg/day in males; 0, 2.02, 4.13, or 6.19 mg/kg/ day in females) in diet. Acceptable

870.4100 Chronic Feeding Toxicity

- Dog

– See 870.3150

870.4200 Carcinogenicity Feeding

- Mouse (18 months)
International Research & Development Corp. Study 141

- 013 May 6, 1982 101563 NOAEL = 25 ppm (3.57 mg/kg/day) in males
NOAEL = not defined in females. LOAEL = 50 ppm (6.93 mg/kg/day) in males

- testicular
lesions LOAEL = 25 ppm (4.45 mg/kg/day) in females

- LDT; combined lung adenomas and carcinomas Levels tested: 0, 25, 50, 100, or 200 ppm (0, 3.57, 6.93, 14.2, and 28.6 mg/kg/day in males, and 0, 4.45, 6.87, 17.3, and 33.1 mg/kg/day in females) in diet. Acceptable

870.4300 Chronic Feeding Toxicity/Carcinogenicity

- Rat
International Research and Development Corporation Study 141

- 014 May 12, 1982 101565 NOAEL = 50 ppm (2.4 mg/kg/day in ♂ , 3.0 mg/kg/day in ♀ ) LOAEL = 100 ppm (4.9 mg/kg/day in ♂ , 6.2 mg/kg/day in ♀ )

- small, soft testes, decreased testicular weights ( 27%), and testicular atrophy in males; decreased body weight gain
in females Levels tested: 0, 25, 50 , 100, or 200 ppm (0, 1.2, 2.4, 4.9, or 10.0 mg/kg/day in males; 0, 1.5, 3.0, 6.2, or 12.1 mg/kg/day in females) in feed. Acceptable

870.5100
Bacterial Reverse Mutation Test (Ames Assay) BASF Corporation Study GTOX
1982 42132701 Negative up to an insoluble dose (1000 μg/plate with or without S9 activation) in S. typhimurium TA1535, TA1537,
TA98 and TA100 and E. coli WP2 uvrA.

870.5375

In Vitro Chromosomal 40422401 Negative up to a cytotoxic dose (500 ng/mL

- /+S9)Page 18 of 21

Table A2

- 2. Toxicity Profile of Hydramethylnon Technical Grade Active Ingredient

OPPTS No./Study Type MRID Results

Aberration in Chinese Hamster Ovary (CHO) Cells Litton Bionetics, Inc. Study 20990 October 1, 1985

870.5450 Rodent Dominant Lethal Assay

- Rat American Cyanamid Company Study 79163 June 24, 1980 35897 Negative in male rats administered 3 or 30 mg/kg of CL 217,300 once daily for 5 days by oral gavage. The highest assayed dose (90 mg/kg) caused a decrease in fertility at mating week 6 and 100% infertility at mating week 7. Fifty percent of the high

- dose males regained fertility by week 17 (120 days after treatment had ceased). At necropsy (week 17), 80% of the high

- dose group had smaller testes and epididymides. There was, however, no indication of a dominant lethal effect at any dose. Overall, these findings suggest an adverse effect on spermatocytes and/or spermatogonia.
Minimum

870.5575
D4 Mitotic Gene Conversion Assay
Life Science Research Study 129006

- M

- 07685 January 14, 1986 40407602 Negative in Saccharomyces cerevisiae up to the highest dose tested (25 μg/plate +/

- S9).

P1 Forward Gene Mutation Assay 40407603 Negative in Schizosaccharomyces pombe up to the highest assayed levels (12.5 μg/mL

- S9; 50 μg/mL +S9).

870.6200 Acute Neurotoxicity

- Rats

– –
870.6200 Feeding Subchronic Neurotoxicity

- Rats

– –
870.7485
Metabolism

- Rat Xenobiotic Laboratories, Inc. Study XBL 90043 May 2, 1992 42448902 The majority of the administered dose of phenyl

- or pyrimidinyl

14 C

- Cl 217,300 was recovered in the feces (85

- 98%). Recovery in the urine was minimal (1

- 2% of the administered dose). There were no sex or dose

- related differences in urinary or fecal elimination. Radiolabel retention in the tissues was somewhat greater in the females.
Distribution of the residues reta ined by all tissues accounted for <10% of the administered dose, with most of the radio labeled material accumulating in the carcass. Most of the radioactivity (94

- 99%) in the feces was unchanged parent compound. In contrast, the urine contained traces o f parent compound and polar metabolites which may be benzoate, cinnamate, or pyrimidinone derivates. Polar metabolites in the tissue were probably ketone, pyrimidinone, cinnamate,
and benzoate derivatives. Levels tested: Groups of male and female Sprague

- Dawley rats were dosed by gavage with Amdro (CL 217,300) labeled
with 14 C in either the phenyl or pyrimidinyl ring. Rats received either a single low

- dose (3 mg/kg), a single high

dose (100 mg/kg), or 14 consecutive doses of 2 mg/kg/day
unlabeled test mat erial followed by a single 2 mg/kg dosePage 19 of 21

Table A2

- 2. Toxicity Profile of Hydramethylnon Technical Grade Active Ingredient

OPPTS No./Study Type MRID Results

with the 14 C in either ring. Acceptable

870.7600
Dermal Penetration

- Rat Bushy Run Research Center Study 92N1073 October 13, 1993 42989101 Sprague

- Dawley rats were dermally dosed with a gel formulation containing 2% a.i. (Maxforce Gel®). Total dose
absorbed after 10 hours was 0.414% Acceptable

870.7600
Dermal Penetration

- Rat Hazleton Wisconsin, Inc. Study HWI/6123/180
1993 43093901 Sprague

- Dawley rats were dermally dosed with a gel formulation containing 2.16% a.i. (Siege®). Total dose
absorbed after 10 hours was 0.97% AcceptablePage 20 of 21

Attachment 3 . International Residue Limits for Hydramethylnon



### Hydramethylnon (PC Code : 118401 ; Date of Request : 8 August 2012 )
Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180. 395 : Plant: Hydramethylnon { tetrahydro

- 5,5

- dimethyl

- 2(1 H )

- pyrimidinone(3

- (4

- (trifluoromethyl)phenyl)

- 1

- (2

- (4

- (trifluoromethyl)phenyl)ethenyl)

- 2

- propenylidene)hydrazone }
Livestock: No Tolerances None (registered
for ant and roach control) - None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex Grass, forage 2.0

- - Grass, hay 2.0

- - Pineapple 0.05

- -

Completed: Name/Date S.Funk/08

- 08

- 2012.

1 Includes only commodities with established tolerances or MRLs.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated store d 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.Page 21 of 21

Attachment 4

. Hydramethylnon Products and Use Sites.

Table 1 . Use Patterns for the End

- use Product Formulations Containing Hydramethylnon

. EPA Reg. No., (AI%) & Formulation type Pests Controlled & Application Sites Application Equipment, Rate, & Applicable ORE Review Comment

241

- 371 (0.30% and 7969

- 230 (0.30%)
Bait matrix Termites
Residential and commercial buildings
and structures Appl. method: Used as remedial, preventive, and supplemental

treatments. Max. appl. rate = one station per
10 linear ft. D. Jaquith, D232251, 3/18/1997.

M

. Dow

, D309409

, 2

/ 7 / 2005

. Outdoor

termite baits

241

- 313 (2.0%), 432

- 1251 (2.0%),
432

- 1252 (1.0%), 432

- 1253 (1.0%),
432

- 1254 (2.15%), 432

- 1265 (1.0%),
1663

- 33 (1.0%), 1663

- 36 (1.0%),

2724

- 498 (2.15%), 4822

- 540 (0.5%), 4822

- 541 (0.25%), 54240

- 3 (1.0%), 64240

- 2 (2.0%), 64240

- 4 (1.0%), 64240

- 5 (1.0%), 64 240

- 27 (0.5%), 64240

- 35 (2.15%), 64240

- 46 (2.0%).
Gel bait stations Cockroaches and ants Residential, commercial, transportation vehicles,
and industrial Appl. method: Apply gel baits stations using a syringe where
roaches hide and near ant trails. Max. appl. rate = Inject 0.5 g of gel per 9 sq. ft. equal to 0.1147 lb ai/A for a 2.15% gel bait (Reg.
No. 432

- 1254). J. Arthur, D229910, 7/29/1997. Indoor
and/or
outdoor

241

- 260 (0.88%), 241

- 261 (0.88%),

241

- 322 (0.73%) 432

- 1255 (1.0%)
432

- 1262 (1.0%), 499

- 530 (1.0%),
2724

- 496 (0.365%) 64240

- 1 (1.0%)
64240

- 25 (1.0%), 73342

- 1 (0.73%)
73342

- 2 (0.88%), 73342

- 3 (0.9%)
73342

- 5 (0.036%), 73342

- 6 (0.036%)
73342

- 7 (0.9%)
Granular baits Fire ants Residential (lawns), commercial (sod farms, etc.),
industrial (food processing plants), orchards, poultry and livestock houses, and

non

- crop areas Appl. method: Sprinkle using table spoon, ground and aerial spreader Max. appl. rate = sprinkle 8.0 oz. Max. appl. rate = 0.022 lb ai/A

G

. Bangs , D2 88800

, 5

/ 20 / 2003

. Ind oor

and/or
outdoor

241

- 270 (98.0%), 12455

- 134 (99.5%)
Technical NA NA NA