Page 3 of 21

residual concern for pre- and/or post-natal toxicity, no concern for 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 uses is complete. Metabolism data 

indicate that hydramethylnon is extensively metabolized in grasses and pineapple, which are the 

only food-uses that are registered. The residue definition for both tolerance enforcement and risk 

assessment is hydramethylnon. The current tolerance 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(1H)-pyrimidinone [3-[4-(trifluoromethyl)phenyl]-1-[2-[4-

(trifluoromethyl)phenyl]ethenyl]-2-propenylidene]hydrazone}.

Acceptable analytical methods 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 

that 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 type and degree of 

residential exposures that may occur. For the residential scenarios that were quantitatively 

assessed, estimated risks were not of concern. Previous occupational 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 require dislodgeable foliar 

residue data in order to 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 dermal post-application 

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 residential, 

dietary, occupational risk assessments 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 needed 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), domestic 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 Google 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 toxicological 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 these studies are required based on the most recent pesticide registration 

data requirements published in Title 40 Part 158 of the Code of Federal Regulations, 

HED’s Hazard and Science Policy Council (HASPOC) determined that the ACN, SCN, and 

inhalation studies 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 HASPOC also 

concluded that a subchronic inhalation study is not required 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 retrospective 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 early 2013. The preliminary results of the retrospective analyses 

provide strong support for not retaining the 10X UFDB as no immunotoxicity study available thus 

far has provided sensitive endpoints for use in deriving points of departure. At this time, 

concludes 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 characterized 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 degeneration of the 

germinal cells. Decreased reproductive performance at the highest dose tested resulted from

longer precoital intervals and lower impregnation rates in the males and reduced gestation weight 

gain and smaller litters in females. Adverse effects 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 maternal 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 on 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 quantification of risk using 

a non-linear approach (i.e., RfD) will adequately account for 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 unchanged 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: With the exception of the immunotoxicity study, the toxicology database is 

complete and sufficient for human health risk assessment. During registration review, the 
Page 6 of 21

required immunotoxicity study should be submitted, and the endpoint selection and safety and 

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 residue 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 drinking water. All dietary risk 

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. The 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 levels of the 

current risk estimates, it appears unlikely that a new quantitative dietary assessment will be 

needed.

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

uses. Although unlikely, a new dietary exposure analyses may be conducted to address any 

changes in the hazard assessment, to include estimates for residues 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 chemicalspecific data, HED has relied on information in the Pesticide Handler Exposure Database

(PHED), Outdoor Residential 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 dermal 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 into 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). Gel baits used to control cockroaches and ants in homes were not 

quantitatively assessed for handler exposure via the dermal and inhalation routes due to the lack 

of appropriate unit exposures. However, exposures from such gel systems are considered to be 

negligible because the bait station design allows the user to deploy the bait station without 
Page 7 of 21

contacting the active ingredient in the product. For uses on turf, HED evaluated combined 

dermal and inhalation exposure and risk from applying a granular formulation with a bellygrinder; 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 products formulated with hydramethylnon can be classified into three groups: bait 

stations, gel formulations, and 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-application 

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 applicators. 

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 exposures are expected to be not of 

concern because of the use of child-resistant packaging (CRP) or application as pastes in cracks 

and crevices. Due to the properties of gel formulations and hydramethylnon itself, postapplication 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 estimates for 

homeowners handling fire ant control products were not of concern. Post-application dermal and 

oral (children only) risk estimates for adults and children following 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.

Recently, HED has updated the Residential SOPs

(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 well 

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, and 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 

to 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 information 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.

Occupational Exposure

There are no chemical specific data available for assessing occupational exposure and risk 

associated with registered products containing hydramethylnon. In the absence of chemicalspecific 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 with the use of 

termite bait systems. When 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 systems is not of concern (Dow, M., D309409, 7 

February 2005). Inhalation exposure was not assessed because it is expected 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, which 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 hydramethylnon, and due to the method of dispensing solid baits or use of injectors 

to apply bait paste into cracks and crevices.

Granules: The hydramethylnon Re-registration Eligibility Document (Arthur, J., D229910, 29 

July 1997) and a subsequent assessment (Bangs, 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 aerial and ground spreaders, and hand dispersal methods. The evaluated end-use 
Page 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

There are no occupational post-application activities performed following treatment of 

residential, commercial, and industrial premises after treatment with termite bait systems and 

cockroach/ant gel bait stations. Therefore, there are no occupational post-application risks for 

these formulations. However, activities such as scouting, irrigation, and harvesting in cropland 

and orchards and fertilizing and mowing of commercial turf areas result in the potential for postapplication dermal and inhalation exposures from the use of granules on agricultural and nonagricultural 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 assessment was not performed for 

agricultural uses of hydramethylnon granules based 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 exposure into the Agency's risk 

assessments. If new policies or procedures are put into place, the Agency may revisit the need 

for a quantitative occupational post-application inhalation exposure assessment for 

hydramethylnon.

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

post-application occupational exposure. For granular formulations of hydramethylnon, handler 

dermal and inhalation risk estimates are not of concern at baseline PPE for most scenarios, and 

with 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, changes to the standard operating procedures, or 

default exposure assumptions that could impact the overall risk conclusion, updated occupational

risk assessments 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 exposure 
Page 10 of 21

data: (http://www.epa.gov/pesticides/science/handler-exposure-table.pdf) and 

(http://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, 

D403751, 9 July 2012). To date, there are relatively few 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, there is no concern at 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. The available data are sufficient to support the 

existing tolerances for residues of hydramethylnon 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(1H)-pyrimidinone [3-[4-(trifluoromethyl)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 possible, 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 exposures 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 exposed 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, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision, EPA reviewed these data and 

selected the most sensitive endpoints for relevant risk assessment scenarios from the existing 

hazard database. However, as required by FFDCA section 408(p), hydramethylnon is subject to 

the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between 

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 

chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

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 lists, 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 study (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 February 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, 30 September 2012.

Attachments

Attachment 1. Toxicological Doses and Endpoints for Human Health Risk Assessment for 

Hydramethylnon.

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. Toxicological Doses and Endpoints for Human Health Risk Assessment for 

Hydramethylnon.

Table A.1. Summary of Toxicological Doses and Endpoints for Hydramethylnon for Use in Dietary and NonOccupational 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

UFA= 10x

UFH=10x

FQPA SF= 1x

RfD = 0.05 mg/kg/day

aPAD = 0.05 mg/kg/day

Developmental Study - Rabbit

LOAEL = 10 mg/kg/day based 

on abortions

Chronic Dietary 

(All Populations)

NOAEL = 

1.66 mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

RfD = 0.017 mg/kg/day

cPAD = 0.017 mg/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

UFA= 10x

UFH=10x

FQPA SF= 1x

MOE = 100

2-Generation Reproductive 

Toxicity Study - Rat

LOAEL = 3.22 mg/kg/day based 

on testicular effects.

Dermal (all 

durations)

NOAEL = 

1.66 mg/kg/day

(dermal 

absorption = 1%)

UFA= 10x

UFH=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

UFA= 10x

UFH=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 risk

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.

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%)

UFA= 10x

UFH=10x MOE = 100

2-Generation Reproductive 

Toxicity Study - Rat

LOAEL = 3.22 mg/kg/day based 

on testicular effects.

Inhalation Shortand Intermediate 

Term 

NOAEL = 

1.66 mg/kg/day*

UFA= 10x

UFH=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 risk

* 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 = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 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 LD50 = 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 LD50 >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 LC50 = 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 to 
Page 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 

stools, 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 nasal 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.

Acceptable
Page 17 of 21

Table A2-2. Toxicity Profile of Hydramethylnon Technical Grade Active Ingredient

OPPTS No./Study Type MRID Results

870.3700

Developmental 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 

discharge.

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 

pyrimidinyl14C-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 retained 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 of 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 14C in either the phenyl or pyrimidinyl ring. Rats 

received either a single low-dose (3 mg/kg), a single highdose (100 mg/kg), or 14 consecutive doses of 2 mg/kg/day 

unlabeled test material followed by a single 2 mg/kg dose 
Page 19 of 21

Table A2-2. Toxicity Profile of Hydramethylnon Technical Grade Active Ingredient

OPPTS No./Study Type MRID Results

with the 14C 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%

Acceptable
Page 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 Mexico2 Codex3

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

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 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 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.
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%), 64240-27 

(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, D288800, 5/20/2003.

Indoor 

and/or 

outdoor

241-270 (98.0%), 12455-134 

(99.5%)

Technical

NA NA NA