Meta]dehyde Human Health Risk Assessment DP No. 0417506 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: December 17, 20 14 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Metaldehyde. Human Health Risk Assessment for Proposed New Uses on 

Vegetable, Legume, Edible Podded [Subgroup 6A], Pea and Bean, Succulent Shelled [Subgroup 

6B], Vegetable, Foliage of Legume, Except Soybean [Subgroup 7A], Clover Forage and Hay, 

and Ginseng; and for Amendments to Existing Tolerances [Tomato and Crop Group 1 0]. 

0417506 

PC Code: 053001 

Decision No.: 486426 

Petition No.: 3E8223 

DP Barcode: 0417506 

Registration No.: 6 I 096-13 

Regulatory Action: Section 3 

Risk Assessment Type: Single Chemical Aggregate CaseNo.: NA 

TXR No.: NA CAS No.: 108-62-3 

MRID No.: NA 40 CFR: 180.523 

FROM: 

THROUGH: 

Matthew Lloyd, CIH; Risk Assessor 

William Donovan, Chemist ~qt{ · ~ 

Linda Taylor, Ph.D, Toxicologist fFJ 

Risk Assessment Branches V & VII 

-~ 

Health Effects Division (7509P) 

Ideliz Negron-Encarnacion, Ph.D., ~e 1ist 17 J a L / 

John Liccione, Ph.D., Toxicologist tJ!I- ;{ U 

Mjchael Metzger, Chief ;If ,-)att~v m;lhtu/ lh·b_L 

Risk Assessment Branches V & Vlf V "'J 1 1 .t7l t--;t c.--

Health Effects Division (7509P) 

TO: Laura Nollen/Barbara Madden, RM 05 

Risk Integration and Minor Use Emergency Response Branch 

Registration Division (7505P) 

The Health Effects Division (HED) of the Office of Pesticide Programs (OPP) is charged with 

estimating the risk to human health from exposure to pesticides. 

The following human health assessments were conducted in support of the registration action for 

metaldehyde: the aggregate risk, and occupational and residential exposure assessments by Matt 

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Metaldehyde Human Health Risk Assessment DP No. D4l 7506 

Lloyd (RABVII); the residue chemistry and dietary exposure assessment by William Donovan 

(RABV); the hazard characterization and endpoint selection by Linda Taylor (RABVII). 

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1.0 Executive Summary ........................................................................................................... 5

2.0 HED Recommendations .................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................ 7

2.2 Tolerance Considerations.............................................................................................. 7

2.2.1 Enforcement Analytical Method ............................................................................... 7

2.2.2 Recommended Tolerances......................................................................................... 8

2.2.3 Revisions to Petitioned-For Tolerances.................................................................... 9

2.2.4 International Harmonization..................................................................................... 9

2.3 Label Recommendations................................................................................................ 9

2.3.1 Recommendations from Residue Reviews................................................................ 9

2.3.2 Recommendations from Occupational/Residential Assessment............................. 9

3.0 Introduction........................................................................................................................ 9

3.1 Chemical Identity ........................................................................................................... 9

3.2 Physical/Chemical Characteristics ............................................................................. 10

3.3 Pesticide Use Pattern.................................................................................................... 10

3.4 Anticipated Exposure Pathways................................................................................. 11

3.5 Consideration of Environmental Justice.................................................................... 12

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 12

4.1 Toxicology Studies Available for Analysis................................................................. 12

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)............................. 13

4.2.1 Dermal Absorption................................................................................................... 13

4.3 Toxicological Effects .................................................................................................... 13

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 14

4.4.1 Completeness of the Toxicology Database.............................................................. 15

4.4.2 Evidence of Neurotoxicity ........................................................................................ 15

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal........ 15

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 16

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 16

4.5.1 Dose-Response Assessment...................................................................................... 16

4.5.3 Cancer Classification and Risk Assessment Recommendation............................ 17

5.0 Dietary Exposure and Risk Assessment......................................................................... 20

5.1 Metabolite/Degradate Residue Profile ....................................................................... 20

5.1.1 Summary of Plant and Animal Metabolism Studies............................................. 20

5.1.2 Summary of Environmental Degradation.............................................................. 20

5.1.3 Comparison of Metabolic Pathways....................................................................... 20

5.1.4 Residues of Concern Summary and Rationale ...................................................... 20

5.2 Food Residue Profile .................................................................................................... 21

5.3 Water Residue Profile.................................................................................................. 21

5.4 Dietary Risk Assessment.............................................................................................. 22

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 22

5.4.2 Acute Dietary Risk Assessment............................................................................... 22

5.4.3 Chronic Dietary Risk Assessment........................................................................... 23

5.4.4 Cancer Dietary Risk Assessment............................................................................. 23

5.4.5 Summary Table......................................................................................................... 23

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 24

6.1 Residential Handler Exposure .................................................................................... 24
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6.2 Post-Application Exposure .......................................................................................... 25

6.4 Residential Risk Estimates for Use in Aggregate Assessment.................................. 25

6.5 Residential Bystander Post-application Inhalation Exposure ................................. 27

6.6 Spray Drift.................................................................................................................... 27

7.0 Aggregate Exposure/Risk Characterization.................................................................. 28

7.1 Acute Aggregate Risk................................................................................................... 28

7.2 Short- and Intermediate Term Aggregate Risk ........................................................ 28

7.4 Chronic Aggregate Risk .............................................................................................. 30

8.0 Cumulative Exposure/Risk Characterization ............................................................... 30

9.0 Occupational Exposure/Risk Characterization ............................................................ 31

9.1 Short-/Intermediate-Term Handler Risk................................................................... 31

9.2 Short-/Intermediate-Term Post-Application Risk .................................................... 32

9.2.2 Inhalation Post-application Risk............................................................................. 33

10.0 References......................................................................................................................... 33

Appendix A. Toxicology Profile and Executive Summaries .................................................. 34

A.1 Toxicology Data Requirements................................................................................... 34

A.2 Toxicity Profiles............................................................................................................ 35

A.3 Hazard Identification and Endpoint Selection .......................................................... 40

A.4 Executive Summaries................................................................................................... 42

Appendix B. Metabolism Summary Table ............................................................................... 56

Appendix C. Physical/Chemical Properties............................................................................. 57

Appendix D. Review of Human Research................................................................................ 58

Appendix E. Email message from Melanie Biscoe (EFED) to W. Donovan (HED), 15-JUL2014............................................................................................................................................... 59
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1.0 Executive Summary

Background: 

Metaldehyde [2,4,6,8-tetramethyl-1,3,5,7-tetraoxyacyclooctane] is used to control slugs and 

snails on a wide variety of tree, fruit and vegetable crops. Metaldehyde is formulated as granules 

(G), pelleted (P/T) baits, emulsifiable concentrate (EC), flowable concentrate (FlC), and readyto-use liquid (RTU/L) formulations. Formulated products generally contain 0.13-25% active 

ingredient.

The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure 

data and conduct dietary, occupational, residential, and aggregate exposure assessments, as 

needed, to estimate the risk to human health that will result from the proposed Section 3 

registration uses of the active ingredient (ai), metaldehyde, for proposed uses on vegetable, 

legume, edible podded [subgroup 6A], pea and bean, succulent shelled [subgroup 6B], vegetable, 

foliage of legume, except soybean [subgroup 7A], clover forage and hay, and ginseng; and for 

amendments to existing tolerances [tomato and crop group 10].

Previous to this risk assessment, the next most recent human-health risk assessment for 

metaldehyde was the risk assessment to support a variety of new crop uses of metaldehyde 

completed on June 20, 2013 (M. Lloyd, et al.; D404859). 

Hazard Assessment: 

The toxicological database for metaldehyde is considered complete for characterization of 

potential developmental, reproductive, carcinogenetic, mutagenic, neurotoxic, and immunotoxic 

effects. Based on a WOE approach considering all the available metaldehyde hazard and 

exposure information, the Hazard and Science Policy Council (HASPOC) concluded that the 

acute neurotoxicity study, a 28-day inhalation toxicity study, and an immunotoxicity study may 

be waived for metaldehyde (TXR Nos. 0056524 and 0056825).

The toxicity profile of metaldehyde shows that the principal toxic effects are clinical signs of 

neurotoxicity, and changes in the liver and testes/prostate following repeated oral dosing. The 

dog is the most sensitive species for the neurotoxic effects. The nervous system effects observed 

in the subchronic and chronic oral toxicity studies include: ataxia; tremor; twitching; salivation;

emesis; rapid respiration in dogs and maternal rats; and limb paralysis, spinal cord necrosis, and 

hemorrhage in maternal rats.

Developmental toxicity was not observed in the rat or rabbit developmental toxicity studies, and 

maternal toxicity was not observed in the rabbit. In the rat, maternal toxicity was observed, as 

evidenced by clinical signs (ataxia, tremors, and twitching) at the highest dose tested. In the rat 

reproductive toxicity study, mortality and clinical signs (limb paralysis, spinal cord necrosis and 

hemorrhage) were observed in the maternal animals, and the effects on the offspring consisted of 

decreased pup body weight and body weight gains. Reproductive toxicity was not observed. 
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The Food Quality Protection Act (FQPA) safety factor was reduced to 1X for the relevant 

lifestages because the toxicity database is adequate to assess safety for infants and children and 

the exposure assessment will not underestimate children’s exposure. 

The carcinogenicity of metaldehyde has been evaluated by HED and is classified as “suggestive 

evidence of carcinogenicity”. Metaldehyde is not mutagenic. HED has determined that 

quantification of risk using a non-linear approach (i.e., the RfD) is appropriate and will 

adequately account for all chronic toxicity, including carcinogenicity, that could result from 

exposure to metaldehyde. 

Food Residue Profile: 

Adequate residue chemistry data have been provided for the requested new uses of metaldehyde. 

Field trials are of adequate number and geographic representation. Data analyses employed 

validated analytical methods and are supported by appropriate storage stability data. No 

processed commodities are associated with the new uses proposed in the current petition. The 

Agency waived livestock metabolism and feeding studies because metaldehyde is expected to be 

rapidly metabolized in mammalian systems with subsequent incorporation of degradates into 

naturally occurring components. Thus, all uses of metaldehyde are classified under 40 CFR 

§180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in livestock 

commodities. Limited rotational crop field trial data demonstrated that residues are not expected 

in crops planted 30-days after metaldehyde is applied to soil; therefore, 

30-day plant back intervals (PBIs) are appropriate for unregistered crops in rotation to primary 

crops. Registered crops may be planted back at any time.

Exposure Profile and Risk Estimates: 

Occupational exposures are expected from the proposed use of metaldehyde. The occupational 

handler assessment of the proposed uses was completed assuming the maximum label 

application rate. Based on the proposed use patterns, there is potential for short- and 

intermediate-term occupational exposure to metaldehyde during mixing, loading, applying, and 

other handling tasks. As no dermal hazard was identified, only inhalation exposure was 

quantitatively assessed. Chronic exposure is not expected for the proposed agricultural uses. 

The level of concern (LOC) for occupational inhalation exposures is for margins of exposure 

(MOEs) <100 (i.e., MOEs ≥ 100 are not of concern to HED). For the proposed uses, all 

occupational short- and intermediate-term handler (with standard work clothing and no 

respiratory protection) MOEs were >100. The proposed metaldehyde label includes a personalprotective equipment (PPE) requirement that applicators and other handlers wear long-sleeved 

shirts, long pants, chemical-resistant gloves, shoes plus socks, and protective eyewear. Because 

no dermal point of departure was selected, occupational post-application exposures are addressed 

qualitatively.

Non-occupational (residential) exposures are not expected from the proposed uses of 

metaldehyde. However, residential exposure is expected based on existing uses of metaldehyde. 

The residential exposure assessment completed as part of HED’s 2013 risk assessment is up-to-
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date. There were no risk estimates of concern identified for the residential handler or the postapplication assessment (i.e., MOEs were >100). 

Aggregate Risk Estimates:

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. The acute and 

chronic aggregate risk assessments takes into account exposure estimates from dietary 

consumption of metaldehyde (food and drinking water). The acute dietary exposure estimates 

are not of concern to HED (<100% aPAD) at the 95th exposure percentile for the general U.S. 

population and all other population subgroups. The chronic dietary exposure estimates are not of 

concern to HED (<100% cPAD) for the general U.S. population and all population subgroups.

The short- and intermediate-term aggregate risk assessment combines residential handler 

inhalation exposure (adult only) and oral post-application exposures (children) with average food 

and water exposures. The risks estimated for adults and children are not of concern (i.e., MOEs 

are > 100). 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. Please refer to Appendix D for a 

discussion of the human study data used in this risk assessment. 

2.0 HED Recommendations

Pending resolution of the deficiencies outlined below and submission of a revised Section F as 

specified in Section 2.2.3, there are no other residue chemistry, occupational, or toxicological

data deficiencies that would preclude the establishment of permanent tolerances for residues of 

metaldehyde as outlined in Table 2.2.2. 

2.1 Data Deficiencies

There are no data deficiencies in the toxicology database.

Additionally, there are no data deficiencies in the occupational/residential exposure or residue 

chemistry databases.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The GC/MS method (EN-CAS Method No. ENC-3/99, Revision 1) is acceptable for tolerance 

enforcement of metaldehyde residues in plants. For this method, residues in homogenized plant 

matrices (except citrus and mint oil) are extracted with dichloromethane (DCM) containing 

sodium sulfate, filtered, concentrated, and analyzed by GC/MS using the m/z 89 and 45 ions for 

quantitation and confirmation, respectively. For citrus and mint oil, the residue extraction step is 

slightly modified; thus, residues in citrus oil are dissolved in methanol (MeOH), diluted with 
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hexane and partitioned with water. Residues in the resulting MeOH:water fraction are then 

partitioned into DCM, concentrated, and analyzed by GC/MS. Mint oil samples are diluted with 

hexane and partitioned with 5% acetic acid and then DCM, prior to GC/MS analysis. For wheat 

grain, rape seed, and other oily matrices an additional cleanup step consisting of a 

hexane/methanol partition is also used. The level of quantitation (LOQ) for metaldehyde in/on 

plant commodities is 0.05 ppm.

2.2.2 Recommended Tolerances

The recommended tolerances for metaldehyde were derived by 1) use of the OECD MRL 

calculation procedures for crops with measurable residue levels, 2) use of the LOQ for crops 

where residues in the field trials were not measurable (ginseng), and 3) direct translation where 

appropriate (subgroup 8-10A and group 10-10). 

Tables 2.2.2a and 2.2.2b summarize the registrant’s proposed tolerances and the Agency’s 

tolerance recommendations. The tolerance expression for metaldehyde [40 CFR §180.523(a)] 

appropriately reads as follows:

Tolerances are established for residues of the molluscicide metaldehyde, including its 

metabolites and degradates, in or on the commodities listed in the following table. 

Compliance with the specified tolerance levels is to be determined by measuring only 

metaldehyde, 2,4,6,8-tetramethyl-1,3,5,7-tetroxocane, in or on the commodity.

Table 2.2.2a Tolerance Summary for Metaldehyde, §180.523(a).

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Vegetable, legume, edible 

podded, subgroup 6A

0.80 0.80 Based on OECD calculator result 

using edible podded bean dataset

Pea and bean, succulent 

shelled, subgroup 6B

0.20 0.20 Based on OECD calculator result 

using succulent shelled pea and bean 

datasets. 

Vegetable, foliage of 

legume, except soybean, 

subgroup 7A

1.50 1.50 Based on OECD calculator result 

using edible podded bean foliage 

dataset

Tomato subgroup 8-10A 0.24 0.24 Translated from tomato

Fruit, citrus, group 10-10 0.26 0.26 Translated from fruit, citrus, group 

10

Ginseng 0.05 0.05 LOQ based tolerance level

Further, the tolerance expression in 40 CFR §180.523(c) reads as follows: 

“Tolerances with a regional registration as defined in §180.1(l) are established for 

residues of the molluscicide metaldehyde, including its metabolites and degradates, in or 

on the commodities listed below. Compliance with the tolerance level specified below is 

to be determined by measuring only metaldehyde, 2,4,6,8-tetramethyl-1,3,5,7-

tetroxocane, in or on the commodity.
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Table 2.2.2b Tolerance Summary for Metaldehyde, §180.523(c).

Commodity Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Clover, forage 0.5 0.60 Pacific Northwest

Clover, hay 0.5 0.60 Pacific Northwest

Note to RD: Upon establishment of the recommended subgroup 8-10A and group 10-10 

tolerances, the existing tomato and group 10 tolerance listings should be deleted.

2.2.3 Revisions to Petitioned-For Tolerances

HED recommends tolerances of 0.60 ppm for clover hay and forage because of the determination 

that only three independent clover trials were conducted instead of the four trials assumed by the 

petitioner. Use of the OECD tolerance calculation procedures with three residue values each for 

clover hay and forage results in recommended tolerances of 0.60 ppm for both commodities. 

The petitioner should submit a revised Section F to reflect this change. 

2.2.4 International Harmonization

As there are no CODEX or Canadian MRLs established for metaldehyde, no international 

harmonization issues are expected to arise from establishment of the recommended tolerances.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The proposed labels should contain the following restriction:

A 30-day plant back interval (PBI) is appropriate for all rotational crops. Labeled crops may be 

replanted immediately. 

All other metaldehyde labels should be amended in registration review to contain the 

aforementioned restriction.

2.3.2 Recommendations from Occupational/Residential Assessment

There are no recommendations for the assessment of occupational/residential exposures at this 

time. As quantification of dermal risk is not required for metaldehyde, no dislodgeable foliar 

residue (DFR) or turf transferable residue (TTR) studies are required at this time. If future hazard 

database changes result in the identification of a dermal endpoint, HED will reassess the need for 

these data. 

3.0 Introduction

3.1 Chemical Identity
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TABLE 3.1. Nomenclature of Metaldehyde.

Compound Chemical Structure

Common name Metaldehyde

Company experimental names Not applicable

IUPAC name r-2,c-4,c-6,c-8-tetramethyl-1,3,5,7-tetroxocane (or)

2,4,6,8-tetramethyl-1,3,5,7-tetraoxacyclo-octane

CAS name 2,4,6,8-tetramethyl-1,3,5,7-tetroxocane

CAS # 108-62-3 (tetramer) and 9002-91-9 (homopolymer)

End-use products/EP 7.5% G (Durham Metaldehyde Granules; EPA Reg No. 5481-103); 

4% P/T (Deadline MPs Mini-Pellets; EPA Reg. No. 5481-511); and 

4% RTU/L (Deadline Force II; EPA Reg. No. 8119-6)

3.2 Physical/Chemical Characteristics

The physical/chemical properties of metaldehyde are summarized in Appendix C. Metaldehyde 

has a vapor pressure of 6.6 ± 0.3 Pa at 25 °C. Metaldehyde is expected to be mobile and 

moderately persistent in the environment. Metaldehyde degrades aerobically with a reported 

half-life of 67 days, anaerobically with a reported half-life of 222 days, and is stable to abiotic 

degradation (hydrolysis and photolysis). 

3.3 Pesticide Use Pattern

Table 3.3 contains a summary of the proposed uses for metaldehyde. The personal protective 

equipment proposed for the new uses direct mixers, loaders, applicators and other handlers to 

wear chemical resistant gloves in addition to baseline clothing (i.e., long sleeved shirt, long 

pants, and shoes with socks). This is identical to existing PPE requirements on currently 

registered metaldehyde labels.

O

O

O

O

H C3CH3

CH3H C3
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Table 3.3. Summary of Directions for Use of Metaldehyde Granular Formulation

Application 

Timing, 

Type, and 

Equip.

Formulatio

n [EPA 

Reg. No.]

Applica

tion 

Rate (lb 

ai/A)

Max. No. 

Application 

per Season

Max. 

Seasonal 

Application 

Rate (lb 

ai/A)

PHI (days) Use Directions and 

Limitations

Vegetable, legume, edible podded (Subgroup 6A)

Broadcast 

(ground & 

handheld 

equipment)

71096-13 1.0 3 3 Pre-bloom RTI = 7 days

Pea and Bean, succulent shelled (Subgroup 6B)

Broadcast 

(ground & 

handheld 

equipment)

71096-13 1.0 3 3 Pre-bloom RTI = 7 days

Vegetable, foliage of legume, except soybean (Subgroup 7A)

Broadcast 

(ground & 

handheld 

equipment)

71096-13 1.0 3 3 1 RTI = 7 days

Clover, forage*

Broadcast 

(ground & 

handheld 

equipment)

71096-13 0.8 2 1.6 30 RTI = 10 days

Clover, hay*

Broadcast 

(ground & 

handheld 

equipment)

71096-13 0.8 2 1.6 30 RTI = 10 days

Ginseng

Broadcast 

(ground & 

handheld 

equipment)

71096-13 1.0 6 6 21 RTI = 21 days

* For use in the following states: Oregon, Idaho, and Washington

The use directions are adequate to allow evaluation of the residue data relative to the proposed 

uses. The proposed maximum application rates are supported by the submitted field trial data. 

Refer to section 2.3 for recommended modifications to the proposed labels.

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new and expanded 

uses of metaldehyde. Humans may be exposed to metaldehyde in food and drinking water, since 

metaldehyde may be applied directly to growing crops and application may result in 

metaldehyde reaching surface and ground water sources of drinking water. In an occupational 
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setting, applicators may be exposed while handling the pesticide prior to application, as well as 

during application. There is a potential for post-application exposure for workers re-entering 

treated fields. Because there is no dermal hazard identified for metaldehyde, occupational 

handler inhalation exposures are assessed quantitatively; post-application exposures resulting 

from metaldehyde applications (dermal and inhalation) are assessed qualitatively. 

While the request doesn’t include any residential uses of metaldehyde, residential exposure is 

possible. Humans may be exposed to metaldehyde in residential settings, since it may be applied 

around lawns/ornamental plants in residences and public areas. Because there is no dermal 

hazard identified for metaldehyde, a quantitative handler and post-application dermal exposure

assessment has not been conducted. Residential handler inhalation exposures and postapplication incidental oral exposure were assessed quantitatively in 2013 and provide and up-todate non-occupational exposure assessment. 

Therefore, this risk assessment addresses both the existing and proposed residential uses of 

metaldehyde. This risk assessment considers all of the aforementioned exposure pathways.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas post-application are 

evaluated. Further considerations are currently in development as OPP has committed resources 

and expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis
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The toxicology database on metaldehyde is sufficient for assessing the toxicity and 

characterizing the hazard of the chemical. The toxicology studies for metaldehyde are 

summarized in Table A.1 in Appendix A. The database includes the following studies.

 Acute/lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, and 

dermal sensitization)

 Subchronic: 21-day dermal toxicity (rabbit), 90-day oral toxicity (dog)

 Developmental toxicity: rat and rabbit developmental toxicity studies

 Reproduction: 2-generation reproduction study (rat)

 Chronic: combined oral chronic toxicity/carcinogenicity (rat), carcinogenicity (mouse), 

chronic oral toxicity (dog)

 Neurotoxicity: subchronic neurotoxicity (rat)

 Other: mutagenicity battery, metabolism

The studies available for consideration of metaldehyde toxicity provide a comprehensive 

database, with routes of administration that are consistent with potential exposure scenarios. 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Metaldehyde is rapidly absorbed, distributed, and metabolized in the rat, with most of the 

administered dose (78-98%) being recovered as 14CO2 in expired air within 24 hours for male 

rats and within 48 hours in female rats. Metaldehyde is readily absorbed into the bloodstream 

from the gastrointestinal tract, distributed widely throughout the body, and readily crosses the 

blood-brain barrier. Recovery in urine/feces is low (2.5-5.1%), and the sexes differ slightly. In 

addition, the half-life of metaldehyde was longer in females (8.8 hours) than in males (3.4 

hours). More 14C was found in nervous tissues, fat, liver, and reproductive organs than in other 

tissues. 

4.2.1 Dermal Absorption

No dermal absorption studies are available. Quantification of dermal risk is not required, based 

on lack of toxicity in the rabbit dermal toxicity study at the limit dose, and the lack of pertinent 

effects in other toxicity studies not measured in the dermal toxicity study. Therefore, a dermal 

absorption factor is not required.

4.3 Toxicological Effects

The principal toxic effects of metaldehyde are clinical signs of neurotoxicity, and changes in the 

liver and testes/prostate following repeated oral dosing. The dog is the most sensitive species for 

the neurotoxic effects. The nervous system effects observed in the subchronic and chronic oral 

toxicity studies include: ataxia; tremor; twitching; salivation; emesis; rapid respiration in dogs 

and maternal rats; and limb paralysis, spinal cord necrosis, and hemorrhage in maternal rats. The 

liver effects include increased liver weight, increased incidence of liver lesions (hepatocellular 

necrosis, hepatocellular hypertrophy and inflammation), and an increased incidence of 
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hepatocellular adenomas1in female rats and in both sexes of mice. In dogs, atrophy of the testes 

and prostate was observed following subchronic and chronic exposure. Toxicity was not 

observed in a rabbit 21-day dermal toxicity study at the limit dose. Acute lethality studies show 

that metaldehyde is not acutely toxic by the dermal and inhalation routes of exposure but is 

moderately toxic via the oral route. Metaldehyde is moderately irritating to the eyes and

minimally irritating to the skin.

Developmental toxicity was not observed in the rat or rabbit developmental toxicity studies, and 

maternal toxicity was not observed in the rabbit. In the rat, maternal toxicity was observed, as 

evidenced by clinical signs (ataxia, tremors, and twitching) at the highest dose tested. In the rat 

reproductive toxicity study, mortality and clinical signs (limb paralysis, spinal cord necrosis and 

hemorrhage) were observed in the maternal animals, and the effects on the offspring consisted of 

decreased pup body weight and body weight gains. Reproductive toxicity was not observed. 

In the rat, clinical signs of neurotoxicity occur only at dose levels in excess of 100 mg/kg/day 

following repeat oral exposure. In the 90-day neurotoxicity study, bilateral hindlimb paralysis 

was observed in one female rat at the highest dose tested. No acute neurotoxicity study on 

metaldehyde is available. However, the Hazard and Science Policy Council (HASPOC) 

determined that the acute neurotoxicity study is not required since dogs appear to be the most 

sensitive species for neurotoxicity, and the acute neurotoxicity study in rats will not provide a 

point of departure or a more sensitive endpoint than those currently used in the overall risk 

assessment, which are based on the dog. 

Chronic feeding studies in rats and mice indicated that metaldehyde produced liver effects 

characterized by liver hypertrophy and liver tumors. HED has classified metaldehyde as 

“suggestive evidence of carcinogenicity”. Metaldehyde is not mutagenic. Although the mouse 

study showed that metaldehyde was associated with a common tumor in both sexes (liver 

tumors, adenomas), and the rat study showed that metaldehyde was associated with liver 

adenomas in the female, HED has determined that quantification of risk using a non-linear 

approach; i.e., RfD, for metaldehyde will adequately account for all chronic toxicity, including 

carcinogenicity, that could result from exposure to metaldehyde. That conclusion is based on the 

following considerations: (1) the tumors found are commonly seen in the mouse; (2) the liver 

tumors (adenomas) in both species were benign; (3) metaldehyde is not mutagenic; (4) no 

carcinogenic response was seen in the male rat; (5) incidence of adenomas at the high-dose in the 

female rat was within the historical control range of the testing lab.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

HED recommends that the 10X FQPA Safety Factor (for the protection of infants and children) 

be reduced to 1X. An FQPA Safety Factor of 1X is appropriate for the following reasons:

 

1 The classification is driven by adenomas although one carcinoma was observed at the highest dose tested. The 

statistic for combined adenomas/carcinomas is statistically significant; however, no dose response was noted when 

carcinomas were evaluated alone.
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The toxicity database is complete and adequate to assess safety for infants and children. There is 

no evidence of increased qualitative or quantitative susceptibility in the developmental rat and 

rabbit studies or in the rat 2-generation reproduction study. These studies have clearly defined 

NOAEL/LOAELs. There is a subchronic neurotoxicity study on metaldehyde with a clearly 

defined NOAEL/LOAEL. Both the acute neurotoxicity study and the developmental 

neurotoxicity study have been waived. The exposure assessment will not underestimate 

children’s exposure to metaldehyde. Further details may be found in the following sections.

4.4.1 Completeness of the Toxicology Database

The toxicology database for metaldehyde is complete and adequate to address the proposed uses 

and to revisit the existing residential uses. Acceptable rat and rabbit developmental toxicity 

studies, a rat 2-generation reproduction study, a subchronic neurotoxicity study in rats, are 

available. The HED’s Hazard and Science Policy Council (HASPOC) determined that the acute 

neurotoxicity (ACN) study, the immunotoxicity study, and the inhalation toxicity study can be 

waived2. 

4.4.2 Evidence of Neurotoxicity

There is a concern for neurotoxicity resulting from exposure to metaldehyde, based on (1) 

clinical signs [ataxia, twitching, tremors, prostration, paresis of hind legs] in female rats in the 

developmental toxicity study; (2) hindlimb paralysis, necrosis and hemorrhage in the spinal cord 

and vertebra luxation in F0 dams during lactation period in the two-generation reproduction 

study; (3) bilateral hindlimb paralysis observed initially on day 10 in one high-dose female 

sacrificed on day 22 due to poor condition in the 90-day subchronic neurotoxicity study in rats;

no neuropathology was evident; (4) clinical signs [ataxia, tremors, twitching, salivation] in the 

chronic dog study, which occurred within the first week of exposure and persisted through week 

19; other signs included lateral position, reduced mobility, convulsions, and vocalization in one 

female, and agitation in another. It should be noted that most of the neurotoxic signs seen in rats 

occurred at dose levels above 100 mg/kg. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased susceptibility following in utero exposure to metaldehyde in 

either the rat or rabbit developmental toxicity study, and there is no evidence of increased 

susceptibility following in utero and/or pre-/post-natal exposure in the 2-generation reproduction 

study in rats. 

Metaldehyde has been evaluated for potential developmental effects in the rat and rabbit (gavage 

administration). Maternal toxicity in rats included mortality, clinical signs of toxicity (ataxia, 

tremors, twitching, and rapid respiration) on days 7 and 8, and decreased body-weight gain and 

food consumption during dosing. Maternal toxicity was not observed in rabbits. No 

developmental effects were observed in the rat or rabbit. Mortality, clinical signs (hindlimb 

paralysis in F0 females), gross/histopathological lesions in females (spinal cord necrosis and 

hemorrhage, vertebra luxation in F0 females), and increased liver weight in both sexes were 

 

2 K. Rury; February 21, 2013; TXR# 0056524
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observed in the rat 2-generation reproduction study at the same dose levels where decreased pup 

body weight and pup body-weight gain were observed in both sexes/both generations.

4.4.4 Residual Uncertainty in the Exposure Database

For all dietary risk assessments, the established and recommended tolerances were used and 

100% crop treated was assumed. Modeling was used to derive estimated drinking water 

concentrations. The occupational and residential exposure assessment was conducted such that 

exposures and risks will not be underestimated. The aggregate exposure and risk estimates 

presented in this assessment are conservative and will not underestimate actual exposure and risk 

expected based on the current and proposed use patterns.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of 

departure for various exposure scenarios is presented in Appendix A.

An acute dietary endpoint for all populations was selected from the chronic oral toxicity study in 

the dog with a NOAEL of 30 mg/kg/day for clinical signs. At the LOAEL of 90 mg/kg/day, 

clinical signs of neurotoxicity were observed in all dogs of each sex on the first day of dosing at 

this dose level. This endpoint is protective of the mortality and clinical signs seen in the maternal 

rats following 1-2 days of dosing at the LOAEL of 150 mg/kg/day in the rat developmental 

toxicity study (NOAEL 75 mkd). The dog is the more sensitive species for the neurotoxicity 

observed, and this endpoint is consistent with endpoints for all the other exposure assessments,

which are based on the dog chronic oral (diet) toxicity study. A 100X uncertainty factor was 

applied to account for inter- and intra-species variability resulting in an acute reference dose 

(aRfD) of 0.30 mg/kg/day. Since the FQPA factor is reduced to 1X, the aRfD is equivalent to 

the acute population adjusted dose (aPAD).

No developmental endpoint attributable to a single exposure was identified for females 13+ from 

the available oral toxicity database.

The chronic dietary endpoint was selected from the chronic oral toxicity study in the dog with a 

study NOAEL of 10 mg/kg/day. At the study LOAEL of 30 mg/kg/day, death and atrophy of the 

testes and prostate were observed. A 100X uncertainty factor was applied to account for interand intra-species variability resulting in a chronic reference dose (cRfD) of 0.10 mg/kg/day. 

Since the FQPA factor is reduced to 1X, the cRfD is equivalent to the chronic population 

adjusted dose (cPAD).

The short-term incidental oral and inhalation endpoints for risk assessment were selected from 

the same chronic oral toxicity study in the dog described above, using the same NOAEL as used 

for acute dietary assessment (30 mg/kg/day). At the LOAEL of 90 mg/kg/day, clinical signs of 

neurotoxicity were observed on the first day of exposure in all dogs and throughout the first 

week of exposure.
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The intermediate-term incidental oral and inhalation endpoints for risk assessment were selected 

from the chronic oral toxicity study in the dog with a NOAEL of 10 mg/kg/day. At the study 

LOAEL of 30 mg/kg/day, death and atrophy of the testes and prostate were observed. Atrophy of 

the testes and prostate was also observed in the subchronic dog study.

There was no hazard observed via the dermal route with lack of systemic toxicity following 21 

days of dermal exposure to rabbits. The endpoints of concern were all assessed in this study, and 

there is no developmental or reproductive concern; therefore, quantification of dermal risk is not 

required.

4.5.3 Cancer Classification and Risk Assessment Recommendation

The CARC classified metaldehyde as “Suggestive Evidence of Carcinogenicity” based on benign 

liver tumors seen in both sexes of mice and in female rats. Metaldehyde is not mutagenic.

Although the mouse study showed that metaldehyde was associated with a common tumor in 

both sexes (liver tumors, adenomas), and the rat study showed that metaldehyde was associated 

with liver adenomas in the female, HED has determined that quantification of risk using a nonlinear approach; i.e., RfD, for metaldehyde will adequately account for all chronic toxicity, 

including carcinogenicity, that could result from exposure to metaldehyde. That conclusion is 

based on the following considerations: (1) the tumors found are commonly seen in the mouse; 

(2) the liver tumors in both species were benign; (3) metaldehyde is not mutagenic; (4) no 

carcinogenic response was seen in the male rat; (5) incidence of adenomas in the female rat was 

within the historical control range of the testing lab.

A summary of both carcinogenicity studies is presented in Appendix A.

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Metaldehyde for Use in Dietary and 

Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD,

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute 

Dietary (All 

Populations)

NOAEL = 

30 

mg/kg/day

UFA 10x

UFH 10x

FQPA SF = 1x

aRfD = 0.30 

mg/kg/day

aPAD = 0.30 

mg/kg/day

Chronic dog oral toxicity study

LOAEL = 90 mg/kg/day, based on

clinical signs (ataxia, tremor, salivation, 

twitching) seen on day 1 of dosing (both 

sexes).

Chronic 

Dietary (All 

Populations)

NOAEL = 

10 

mg/kg/day

UFA 10x

UFH 10x

FQPA SF = 1x

cRfD = 0.10 

mg/kg/day

cPAD = 0.10 

mg/kg/day

Chronic dog oral toxicity study

LOAEL = 30 mg/kg/day, based on death 

and atrophy of the testes and prostate

Incidental 

Oral ShortTerm (1-30 

days)

NOAEL = 

30 

mg/kg/day

UFA 10x

UFH 10x

FQPA SF = 1x

Residential

LOC for 

MOE < 100

Chronic dog oral toxicity study

LOAEL = 90 mg/kg/day, based on

clinical signs (ataxia, tremor, salivation, 

twitching) seen on day 1 of dosing (both 

sexes).
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Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Metaldehyde for Use in Dietary and 

Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD,

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Incidental 

Oral 

IntermediateTerm (1-6 

months)

NOAEL = 

10 

mg/kg/day

UFA 10x

UFH 10x

FQPA SF = 1x

Residential

LOC for 

MOE < 100

Chronic dog oral toxicity study

LOAEL = 30 mg/kg/day, based on death

and atrophy of the testes and prostate

Dermal (All 

durations)

No hazard observed via the dermal route, based on the lack of systemic effects following repeat 

dermal exposure of rabbits. The endpoints of concern were all assessed in this study, and there is 

no developmental or reproductive concern.

Inhalation 

Short- Term 

(1-30 days)

NOAEL = 

30

mg/kg/day

UFA 10x

UFH 10x

FQPA SF = 1x

Residential 

LOC for 

MOE < 100

Chronic dog oral toxicity study

LOAEL = 90 mg/kg/day, based on

clinical signs (ataxia, tremor, salivation, 

twitching) seen on day 1 of dosing (both 

sexes).

Inhalation 

IntermediateTerm (1-6 

months)

NOAEL = 

10 

mg/kg/day

UFA 10x

UFH 10x

FQPA SF = 1x

Residential 

LOC for 

MOE < 100

Chronic dog oral toxicity study

LOAEL = 30 mg/kg/day, based on death

and atrophy of the testes and prostate

Cancer (oral, 

inhalation)

Classification: Suggestive Evidence of Carcinogenicity; EPA has determined that quantification 

of risk using a non-linear approach (i.e., RfD) will adequately account for all chronic toxicity, 

including carcinogenicity.

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 4.5.4.2 Summary of Toxicological Doses and Endpoints for Metaldehyde 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 ShortTerm (1-30 

days) No hazard observed via the dermal route, based on the lack of systemic effects following repeat 

dermal exposure of rabbits. The endpoints of concern were all assessed in this study, and there 

is no developmental or reproductive concern.

Dermal 

IntermediateTerm (1-6 

months)

Inhalation 

Short-Term (1-

30 days)

oral 

NOAEL= 

30

Inhalation 

hazard 

assumed to 

be equivalent 

to oral hazard

UFA=10x

UFH=10x Occupational 

LOC for MOE = 

100

Chronic dog oral toxicity study

LOAEL = 90 mg/kg/day for clinical signs 

seen beginning the first week of dosing.
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Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Metaldehyde 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

Inhalation 

Intermediateterm (1-6 

months)

oral 

NOAEL = 

10 

mg/kg/day

Inhalation 

hazard 

assumed to 

be equivalent 

to oral hazard

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

Chronic oral toxicity study – dog

LOAEL = 30 mg/kg/day based on deaths 

and testes/prostate atrophy

Cancer (oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenic Potential”. EPA has determined that 

quantification of risk using a non-linear approach (i.e., RfD) will adequately account for all 

chronic toxicity, including carcinogenicity. 

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). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.
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5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

No new metabolism studies were submitted in support of this petition. The residue of concern in 

plants consists only of metaldehyde. Livestock metabolism studies have been waived.

5.1.2 Summary of Environmental Degradation

Metaldehyde is expected to be mobile and moderately persistent in the environment. 

Metaldehyde degrades aerobically with a reported half-life of 67 days, anaerobically with a 

reported half-life of 222 days, and is stable to abiotic degradation (hydrolysis and photolysis). 

There were no toxic residues of concern identified for the metaldehyde transformation products, 

so transformation products were not included in the EFED drinking water assessment. 

5.1.3 Comparison of Metabolic Pathways

The major residue found in plant metabolism studies on lettuce and sugar beets was the parent 

compound, metaldehyde. There were considerable non-extractable residues in sugar beet root 

and tops that were not further characterized. The Confined Rotational Crop study was waived 

since the metabolism in secondary crops is likely to be similar to the primary crops. 

Livestock metabolism studies have been waived because metaldehyde is expected to be rapidly 

metabolized in mammalian systems with subsequent incorporation of degradates into naturally 

occurring components. This conclusion is supported by the extensive metabolism observed in rat 

metabolism studies. 

Metaldehyde is rapidly absorbed, distributed, and metabolized in the rat. Between 78-98% of the 

administered dose was recovered in expired air within 24 hours as 14CO2 in the rat metabolism 

study. 

There was extensive metabolism of metaldehyde in both plants and animals. 

5.1.4 Residues of Concern Summary and Rationale

The qualitative nature of metaldehyde residues in plants is understood based on lettuce and sugar 

beet metabolism studies. The HED Metabolism Committee (7/2/96) concluded that the regulated 

residue of concern in plants is parent metaldehyde. This conclusion was confirmed in the 

Metaldehyde Reregistration Eligibility Decision (RED) document (D327385, M. Lloyd et. al.,

April 3, 2006).

The residue of concern for drinking water exposure assessment is metaldehyde. 
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Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk 

Assessment and Tolerance Expression

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants

Primary Crop Metaldehyde Metaldehyde

Rotational Crop Metaldehyde Metaldehyde

Livestock Not Applicable Not Applicable

Drinking Water Metaldehyde Not Applicable

5.2 Food Residue Profile

D418047, A. Doh, 10-JUL-2014

Adequate residue chemistry data have been provided for metaldehyde. Field trials are of 

adequate number and geographic representation. Data analyses employed validated analytical 

methods and are supported by appropriate storage stability data. No processed commodities are 

associated with the new uses proposed in the current petition. The Agency waived livestock 

metabolism and feeding studies; thus, all uses of metaldehyde are classified under 40 CFR 

§180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in livestock 

commodities. Limited rotational crop field trials demonstrate that residues are not expected in 

crops planted 30-days after metaldehyde is applied to soil; therefore, 30-day plant back intervals 

(PBIs) are appropriate for unregistered crops in rotation to primary crops. Registered crops may 

be planted back at any time.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the 

Environmental Fate and Effects Division (EFED) in a memo (D404861, J. Hetrick and M. 

Biscoe, 7/17/13) and supplemented by updated calculations3. In addition to point estimates for 

deterministic assessments, a full distribution of water values was provided for a probabilistic 

assessment. 

There are no monitoring data currently available for metaldehyde in drinking water. Estimated 

drinking water concentrations (EDWCs) were generated using computer modeling procedures. 

The highest EDWCs resulted from the special mollusk eradication use on turf, and these values 

were used in the present dietary analysis. Surface water estimates were determined using the 

PRZM-EXAMS model and ground water estimates were determined using the PRZM-GW 

model. These latter values were recommended for use in the human-health dietary risk 

assessment as they were the highest values obtained. Additional information concerning the 

water models is available at the EPA web site4. 

 

3 Email message from Melanie Biscoe (EFED) to W. Donovan (HED), 15-JUL-2014. See Appendix E.

4 http://www.epa.gov/pesticides/science/models_pg.htm#aquatic
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Maximum application rates for metaldehyde as a high-end estimate of exposure in drinking 

water were modeled based on the proposed labels. Chemical specific and generic model input 

values were chosen in accordance with current EFED input parameter guidance (USEPA, 2009). 

The maximum surface and ground water EDWCs for use in the human-health risk assessment for 

metaldehyde are shown in Table 5.3. 

Table 5.3. Maximum Tier II estimated drinking water concentrations (EDWCs) in parts per 

billion (μg/L) resulting from 6 applications of 2 lb a.i./acre of metaldehyde to turf with a 

reapplication interval of 14 days.

Drinking water source 

(model)

1-in-10 year 30-year simulation

Acute Chronic Acute Chronic

Surface water (PRZMEXAMS)1 205 136 - 83

Ground water (PRZMGW)2

- - 1880 915

1D404861, J. Hetrick and M. Biscoe, 7/17/13.

2See Appendix E.

5.4 Dietary Risk Assessment

D420705, A. Doh, 28-JUL-2014

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments 

were conducted using the Dietary Exposure Evaluation Model with the Food Commodity Intake 

Database (DEEM-FCID) Version 3.18. This software incorporates 2003-2008 food consumption 

data from the U.S. Department of Agriculture’s National Health and Nutrition Examination 

Survey, What We Eat in America, (NHANES/WWEIA). For all dietary risk assessments, the 

established and recommended tolerances were used and 100% crop treated was assumed. 

Processing studies for tomatoes and oranges indicate that metaldehyde residues do not 

concentrate in processed commodities derived from these crops. Exaggerated rates studies in 

corn and soybean showed no detectable grain or seed residues at rates of 5x and 10x, 

respectively. Therefore, no processing factors were used in the analyses except for those 

processed commodities for which no processing studies are typically conducted (tomato, dried; 

tomato, juice; cranberry, juice; and high fructose corn syrup), for which default factors were 

used.

5.4.2 Acute Dietary Risk Assessment

An unrefined acute dietary assessment was conducted using tolerance-level residues, 100% crop 

treated assumptions, and modeled water numbers. The full distribution of modeled drinking 

water estimates was included in the acute analysis. Processing factors were assumed to be 1.0 

for all commodities except for tomato, dried; tomato, juice; cranberry, juice; and high fructose 

corn syrup; for these commodities, DEEM default processing factors were used. At the 95th

percentile of exposure, the estimated risk from food and water sources is ≤55% of the acute 

population adjusted dose (aPAD) for the U.S. population and all subpopulations. For food only 
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exposures, the estimated risk is ≤11% of the aPAD for the U.S. population and all population 

subgroups. Comparison of food and drinking water results to the food only results demonstrates

that water is the primary contributor to risk. Results are shown in Tables 5.4.5a and 5.4.5b.

5.4.3 Chronic Dietary Risk Assessment

An unrefined chronic dietary assessment was conducted using tolerance-level residues, 100% 

crop treated assumptions, and modeled water numbers. Drinking water was included in the 

analysis as a point estimate (915 ppb). Processing factors were assumed to be 1.0 for all 

commodities except for tomato, dried; tomato, juice; cranberry, juice; and high fructose corn 

syrup; for these commodities, DEEM default processing factors were used. The estimated risk

from food and water sources is ≤51% of the chronic population adjusted dose (cPAD) for the 

U.S. population and all subpopulations. For food only exposures, the estimated risk is ≤8.1% of 

the cPAD for the U.S. population and all population subgroups. Comparison of food and 

drinking water results to the food only results demonstrates that water is the primary contributor 

to risk. Results are shown in Tables 5.4.5a and 5.4.5b.

5.4.4 Cancer Dietary Risk Assessment

EPA has determined that quantification of risk using a non-linear approach (i.e., RfD) will 

adequately account for all chronic toxicity, including carcinogenicity.

5.4.5 Summary Table

Table 5.4.5a Summary of Dietary (Food and Drinking Water) Exposure and Risk for Metaldehyde.

1

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.053956 18 0.016151 22

N/A N/A

All Infants (< 1 year old) 0.165402 55 0.051359 51

Children 1-2 years old 0.090370 30 0.035775 36

Children 3-5 years old 0.072701 24 0.029568 30

Children 6-12 years old 0.051399 17 0.020479 21

Youth 13-19 years old 0.041418 14 0.016263 16

Adults 20-49 years old 0.053415 18 0.021418 21

Adults 50-99 years old 0.051142 17 0.021529 22

Females 13-49 years old 0.054209 18 0.021545 22

1Highest exposure identified in bold.
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Table 5.4.5b. Summary of Dietary (Food only) Exposure and Risk for Metaldehyde.

1

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.011030 3.7 0.002854 2.9

N/A N/A

All Infants (< 1 year old) 0.007663 2.6 0.001957 2.0

Children 1-2 years old 0.033819 11.3 0.008137 8.1

Children 3-5 years old 0.022429 7.5 0.006282 6.3

Children 6-12 years old 0.014674 4.9 0.003686 3.7

Youth 13-19 years old 0.009390 3.1 0.002291 2.3

Adults 20-49 years old 0.009133 3.0 0.002302 2.3

Adults 50-99 years old 0.009830 3.3 0.002632 2.6

Females 13-49 years old 0.010292 3.4 0.002499 2.5

1Highest exposure identified in bold.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed non-occupational (residential) uses associated with the current action. The 

most recent HED residential exposure assessment5is up to date and reflects

HED’s 2012 Residential SOPs6along with policy changes for body weight assumptions. There 

is no revision to the residential exposure assessment, and therefore only the residential 

contribution to the aggregate is presented in this risk assessment document. For additional details 

on the residential exposure assessment, please see HED’s 2013 occupational and residential 

exposure memo, D408747.

6.1 Residential Handler Exposure

At this time, no chemical-specific data for metaldehyde are available to assess residential 

exposure, and there are no new scenarios to address since the 2013 risk assessment. Since there 

is no toxicity from the dermal route of exposure, the residential handler assessment only includes 

the inhalation route of exposure. The 2013 assessment evaluated a number of residential 

exposure scenarios based on turf and ornamental uses with a variety of different equipment 

types. Residential handler risk estimates for all scenarios were not of concern (i.e., MOEs are 

≥100). The highest exposure residential handler scenario was “hand dispersal of metaldehyde 

 

5 Available: Metaldehyde Occupational and Residential Exposure Assessment memo (D408747)

6 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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granules for residential gardens”; the MOE for that scenario was 75,000 (with an LOC of 100). 

Most other residential handler scenarios had MOEs >100,000.

6.2 Post-Application Exposure

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with metaldehyde. As no dermal hazard was 

identified, only incidental oral exposure for children was quantitatively assessed. Since 

metaldehyde is moderately persistent in the environment, intermediate-term exposure is also 

possible for incidental soil ingestion exposure. These post-application exposures were evaluated 

in the 2013 ORE memo (D408747) and are up-to-date. All residential post-application risk 

estimates for metaldehyde were found to be “not of concern” (MOEs > LOC) for all exposure 

scenarios and lifestages. For liquid sprays on turf, short-term residential incidental oral risk 

estimates ranged from 2,000 to 890,000. For granular products applied to turf, short-term risk

estimates for the hand to mouth, object to mouth, and incidental soil ingestion ranged from 

20,000 to 890,000 and were not of concern to HED.

6.4 Residential Risk Estimates for Use in Aggregate Assessment

Based on the 2013 ORE memo, there are residential contributions to the metaldehyde aggregate 

risk assessment. Residential exposure from granular applications to ornamentals/home gardens 

via hand dispersal) is used in the adult (for both male and females) aggregate assessment.

The residential exposure for use in the short-/intermediate-term aggregate assessment for 

children 1 to <2 years old is short-term hand-to-mouth (incidental oral) exposure from contacting 

treated turf. Because of the long environmental half-life of metaldehyde, there is also an 

intermediate-term residential aggregate assessment. The residential exposure for use in the 

children 1 to <2 years old intermediate-term aggregate assessment is (incidental oral) exposure 

from ingesting treated soil.

See Table 6.4.1 for additional information.
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Table 6.4.1 Residential Exposures for Use In the Metaldehyde Aggregate Assessment.1

Lifestage

Residential Handler Residential Post-application 

Dose (mg/kg/day)2 MOE3 Dose (mg/kg/day)4 MOE5

Dermal Inhalation Total Dermal Inhalation Total Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Short-Term

Adult Male N/A 0.0004 0.0004 N/A 75,000 75,000 N/A N/A N/A N/A N/A N/A N/A N/A

Adult Female N/A 0.0004 0.0004 N/A 75,000 75,000 N/A N/A N/A N/A N/A N/A N/A N/A

Child N/A N/A N/A 0.0152 0.0152 N/A N/A 2,000 2,000

Intermediate-Term

Child N/A N/A N/A 0.00003 0.00003 330,000 330,000

1 Highlighted risk estimates should contribute to the residential exposure portion of the aggregate assessment; 

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed. Total = dermal (N/A) + inhalation.

3 Residential Handler MOE = the MOEs associated with the highest doses identified. Total = 1 ÷ (1/Inhalation MOE).

4 Residential Post-application Dose = the highest post-application dose for each applicable lifestage of all scenarios assessed . Total = incidental oral exposure.

5 Residential Post-application MOE = the MOEs associated with the highest doses identified. Total = 1 ÷ (1/Incidental oral MOE). 

Child 1 to <2 years - HTM contact with treated turf (ST); soil ingestion [because of long environmental half life] (IT).
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6.5 Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for metaldehyde at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and low vapor pressure (6.6 ± 0.3 Pa at 25 °C) at 

ambient temperatures. However, volatilization of pesticides may be a source of post-application 

inhalation exposure to individuals nearby pesticide applications. The Agency sought expert 

advice and input on issues related to volatilization of pesticides from its Federal Insecticide, 

Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and 

received the SAP’s final report on March 2, 20107. The Agency is in the process of evaluating 

the SAP report and may, as appropriate, develop policies and procedures to identify the need for

and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's 

risk assessments. If new policies or procedures are developed, the Agency may revisit the need 

for a quantitative post-application inhalation exposure assessment for metaldehyde.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for handlers (i.e., residential 

applicators). Risks were not of concern for residential handlers. This exposure scenario is 

representative of a worse case inhalation exposure and should be considered protective of other

post-application inhalation exposure scenarios.

6.6 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for metaldehyde. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information8). The 

Agency has completed its evaluation of the new database submitted by the Spray Drift Task 

Force, a membership of U.S. pesticide registrants, and is developing a policy on how to 

appropriately apply the data and the AgDRIFT computer model to its risk assessments for 

pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in 

place, the Agency may impose further refinements in spray drift management practices to reduce 

off-target drift with specific products with significant risk estimates associated with drift.

It is noted that the 1 lb ai/acre application rate for turf was modeled to estimate post-application 

residential (incidental oral) exposure of children. As this rate is comparable to the agricultural 

application rates, this turf scenario is considered protective of any exposure from spray drift from 

agricultural metaldehyde applications.

 

7 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

8 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When 

aggregating exposures and risks from various sources, HED considers both the route and 

duration of exposure.

No endpoint was identified for dermal exposure, so dermal exposures need not be quantified in

the metaldehyde aggregate assessment. Therefore, for the residential contribution to the 

aggregate assessment, the adult contribution is from the inhalation route of exposure and the 

child contribution is from the incidental oral route of exposure. Only food and water are

generally aggregated for acute (one-day) exposures to metaldehyde. For short- and intermediateterm aggregate exposure to metaldehyde, contributions from food, water, and residential 

incidental oral exposures are aggregated. Chronic exposures to metaldehyde are expected for 

food and water only. 

7.1 Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure estimates from dietary 

consumption of metaldehyde (food and drinking water). While HED does calculate an acute 

granular ingestion scenario for pelletized pesticides, it is not appropriate to aggregate because it 

represents episodic and sporadic ingestion, not a typical one day exposure pattern. Further, these 

products contain a bittering agent which makes ingestion of metaldehyde formulations generally 

not palatable to children. The acute dietary exposure estimates are not of concern to HED 

(<100% aPAD) at the 95th exposure percentile for the general U.S. population and all other 

population subgroups (see Table 5.4.5a). The dietary exposure assessment utilized tolerancelevel residues, 100% CT information for all crops, default processing factors, and a ground water 

EDWC generated by the PRZM-GW Model. 

7.2 Short- and Intermediate Term Aggregate Risk

The short- and intermediate-term aggregate risks combine duration appropriate residential 

handler (adult only) and/or post application exposures with average food and water exposures. 

The residential contribution to the short- and intermediate-term aggregate risk assessments are 

summarized below in Table 7.2.1. 
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Table 7.2.1. Short- and Intermediate-Term Residential Exposure Values and Sources 

Used in the Metaldehyde Aggregate Risk Assessment

Population

Handler Exposure 

(mg/kg/day)

Postapplication 

Exposure

(mg/kg/day)

Residential 

Exposure

(mg/kg/day)1

Short-Term

Adult Male

0.0004

Source: Table 6.13

Garden/tree, granule, 

hand dispersal

N/A; no dermal 

endpoint 0.0004

Adult Female

0.0004

Source: Table 6.1

Garden/tree, granule, 

hand dispersal

N/A; no dermal 

endpoint 0.0004

Child N/A; only adults are 

assessed as handlers3

0.0152

Source: Table 5.2.14

Hand-to-Mouth from 

Treated Turf

0.0152

Intermediate-Term

Adult Male

N/A; intermediate 

term exposure not 

expected

N/A; no dermal 

endpoint N/A

Adult Female

N/A; intermediate 

term exposure not 

expected

N/A; no dermal 

endpoint N/A

Child N/A; only adults are 

assessed as handlers

0.000034

Source: Table 5.25

Incidental Soil 

Ingestion

0.000034

1 Residential exposure is the representative residential contribution to the aggregate assessment 

2 N/A is not applicable

3,4,5- Lloyd, et al, D404859; Metaldehyde; Human Health Risk Assessment for Proposed Uses on Grass Grown for Seed, Leaf 

Petioles [Crop Subgroup 4B], Wetland Taro, Field & Sweet Corn, Mint, and Soybeans, and for Amendments to Existing 

Tolerances [Crop Subgroups 13-07A, B, & G]. 

Short- and intermediate-term aggregate margins of exposure for adults and children are not of 

concern (i.e., MOEs are > 100). Short- and intermediate-term estimated aggregate exposures and 

risks are shown in Table 7.2.2, below. 
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Table 7.2.2. Short-Term and Intermediate-Term Aggregate Risks

Population

NOAEL

mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure

mg/kg/day

Residential 

Exposure3

mg/kg/day

Aggregate MOE

(food and

residential)4

Short-Term Scenario

Adult Male 30 100 0.3 0.021529 0.0004 1,400

Adult Female 30 100 0.3 0.021545 0.0004 1,400

Child 30 100 0.3 0.035775 0.0152 590

Intermediate-Term Scenario

Adult Male N/A

Adult Female N/A

Child 10 100 0.1 0.035775 0.000034 280

1 The LOC of 100 is based on the standard inter- and intra-species uncertainty factors.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 30/100 = 0.3 mg/kg/day (ST).

NOAEL/LOC = 10/100 = 0.1 mg/kg/day (IT).

3 Residential Exposure values taken from Table 7.2.1.Average food & water exposure taken from Table 

5.4.5a.

4 Aggregate MOE = [Incidental Oral NOAEL [ST=30; IT=10] ÷ (Avg Food & Water Exposure + 

Residential Exposure)]

7.4 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from 

dietary consumption of metaldehyde (food and drinking water). The chronic dietary risk

estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all 

population subgroups (see Table 5.4.5). The dietary exposure assessment utilized tolerance-level 

residues for all commodities, 100% crop treated, default processing factors, and a chronic ground

water EDWC generated by the PRZM-GW model.

8.0 Cumulative Exposure/Risk Characterization

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

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to metaldehyde and any other substances and metaldehyde does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that metaldehyde has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 
Metaldehyde Human Health Risk Assessment DP No. D417506

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mechanism determinations and procedures for cumulating effects from substances found to have 

a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

HED completed an occupational exposure assessment in an HED memorandum dated 06/12/13

(M. Lloyd; D408747). That 2013 HED occupational assessment considers crops with use 

patterns identical to the proposed uses (legumes 6A/6B, 7A, clover, and ginseng) and uses up to 

date exposure methodologies and exposure assumptions. Therefore, no stand-alone occupational 

and residential exposure disciplinary chapter was completed. This risk assessment presents the 

risk estimates from the proposed crops/crop groups, which are identical to the occupational 

assessment HED completed in 2013 for “leaf petiole/mint/taro/13-07A.” For the proposed use 

sites, there is a potential for short- and intermediate-term occupational exposure to metaldehyde 

during mixing, loading, applying, and other handling tasks. Chronic exposure is not expected for 

the proposed agricultural uses. 

9.1 Short-/Intermediate-Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment (inhalation only) developed for occupational handlers 

is based on the following scenarios: 

 Mix/Load - granular formulations for legumes 6A/6B, 7A, clover and ginseng

 Applicator – granular formulations (ground equipment & hand dispersal)

 Load/Apply – granular formulations (belly grinder/rotary spreader equipment)

The occupational and residential exposure assessment (D408747) provides more detail on the 

assumptions used in the occupational assessment, specifically, details about the relevant 

application rates, the unit exposures, and assumptions about the area treated. As no dermal 

hazard was identified, only inhalation exposure was quantitatively assessed. 

Based on the proposed use, short- and intermediate-term exposures are expected for the 

following reasons: (1) the product can be applied multiple times per year (2) the product can be 

applied to multiple application sites and (3) there may be a large agribusiness and/or commercial 

applicators who may apply a product over a period of weeks or months.

All occupational handler scenarios are not of concern (i.e., inhalation MOEs are > 100) with 

baseline clothing (no respiratory protection) for both the short- and intermediate-term exposure 
Metaldehyde Human Health Risk Assessment DP No. D417506

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durations. While no quantification of dermal risk was appropriate based on the available toxicity 

information, it is relevant to note that the proposed product labels include chemical-resistant 

gloves.

Table 6.1.1. Occupational Handler Short-/Intermediate-Term Non-Cancer Exposure and Risk Estimates for 

Metaldehyde.

Exposure 

Scenario

Crop or 

Target

Dermal Unit 

Exposure (μg/lb ai)1

Inhalation Unit 

Exposure (μg/lb ai)1 Maximum

Application 

Rate2

Area 

Treated or 

Amount 

Handled 

Daily3

Inhalation

Mitigation Level Mitigation Level Dose 

(mg/kg/day)4 MOE5

Mixer/Loader

M/L Granular 

Product for 

Ground 

Application

legumes 

6A/6B, 7A, 

clover, and 

ginseng

N/A 1.7 1 80 0.0017 18,000 (ST)

5,900 (IT)

Applicator

Applicator –

Tractor Drawn 

spreader

legumes 

6A/6B, 7A, 

clover, and 

ginseng

N/A 1.2

1 80 0.0012

25,000 (ST)

8,300 (IT)

Applicator – Hand 

Dispersal

Field crops N/A 470

1 1 0.006

5,100 (ST)

1,700 (IT)

Loader/Applicator

Belly Grinder Dispersal to 

field crop rows

N/A 62 1 1 0.000775 39,000 (ST)

13,000 (IT)

Rotary Spreader Dispersal to 

field crop rows

N/A 10 1 5 0.000625 48,000 (ST)

16,000 (IT)

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, no 

respiratory protection

2 Based on registered or proposed label (Reg. No. 71096-13).

3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or 

Amount Handled Daily (A or gal/day) ÷ BW (80 kg).

5 Inhalation MOE = Inhalation NOAEL (mg/kg/day) (30 ST/ 10 IT) ÷ Inhalation Dose (mg/kg/day).

9.2 Short-/Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. No dermal toxicity is seen for metaldehyde and, 

therefore, no post-application dermal exposures and risks have been quantitatively assessed in 

this document. The potential for occupational post-application inhalation exposures is discussed 

below.
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9.2.2 Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for metaldehyde at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV) and the low vapor pressure 6.6 ± 0.3 Pa at 25 °C). 

However, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and resuspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory 

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 20109. The 

Agency is in the process of evaluating the SAP report as well as available post-application 

inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and 

procedures, to identify the need for and, subsequently, the way to incorporate occupational postapplication 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 metaldehyde.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers, and all risks were below the level of concern (i.e., MOEs ≥ 100). Handler exposure 

resulting from application of pesticides outdoors is likely to result in higher exposure than postapplication exposure. Therefore, it is expected that these handler inhalation exposure estimates 

would be protective of most occupational post-application inhalation exposure scenarios.

10.0 References

Previous Risk Assessments:

M. Lloyd, et al, “Metaldehyde; Human Health Risk Assessment for Proposed Uses on Grass

Grown for Seed, Leaf Petioles [Crop Subgroup 4B], Wetland Taro, Field & Sweet

Corn, Mint, and Soybeans, and for Amendments to Existing Tolerances [Crop 

Subgroups 13-07A, B, & G].” D404859, 06/20/2013.

M. Lloyd, et al, “Metaldehyde: HED Chapter of the Reregistration Eligibility Decision 

Document (RED).” PC Code: 053001; DP Barcode: DP327385, 04/03/06.

HASPOC Memo: K. Rury; February 21, 2013; TXR# 0056524.

HASPOC Memo: K. Rury; November 12, 2013; TXR# 0056825.

Chemistry Memo: A. Doh; 10-JUL-2014; D418047

Drinking Water Memo: J. Hetrick and M. Biscoe, 17-JUL-2013; D404861.

Dietary Memo: A. Doh; 28-JUL-2014; D420705.

Occupational & Residential Exposure Memo: M. Lloyd; 06/12/13; D408747

 

9 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for metaldehyde are in Table 1. Use of the new guideline numbers 

does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation..............................................

870.2600 Dermal Sensitization .....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

no

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21-Day Dermal..............................................................

870.3250 90-Day Dermal..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

CR

yes

yes

yes

yes

-

yesA

870.3700a Developmental Toxicity (rodent) ..................................

870.3700b Developmental Toxicity (nonrodent) ............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse) ...................................................

870.4300 Chronic/Oncogenicity ...................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5385 Mutagenicity—Structural Chromosomal Aberrations...

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen) ..........................................

870.6200a Acute Neurotoxicity Screening Battery (rat).................

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

CR

-

-

yesA

yesA

-

B

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

CR

yes

yes

-

yesC

AWaived by HASPOC (TXR# 0056524); B EPA concluded there was no need for DNT (TXR# 0055119, June 10, 2009); 

CWaived by HASPOC (TXR# 0056825). 
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A.2 Toxicity Profiles

Table A.2.1 - Acute Toxicity Profile – Metaldehyde

Guideline 

No.

Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral [Sprague-Dawley rat] LD50 = 283 mg/kg II

870.1200 Acute dermal [CFY rat] 00131434 LD50 = >5000 mg/kg III

870.1300 Acute inhalation [SpragueDawley rat]00131429 LC50 = 13.5 mg/L/4 hrs IV

870.2400 Acute eye irritation [rabbit] 42068801 mild irritant III

870.2500 Acute dermal irritation [rabbit] 00131971 not an irritant IV

870.2600 Skin sensitization [guinea pig] N/A [N/A ] [N/A ]

Table 2 - Subchronic, Chronic and Other Toxicity Profile – Metaldehyde

Guideline No./ 

Study Type

MRID No. (year)

Classification /Doses

Results

870.3100

90-Day oral 

toxicity (mouse)

43297701 (1990)

mouse [range-finding study] 0, 100, 

300, 1000, 3000, and 10000 ppm

[19, 54, 178, 560, and 1918 

mg/kg/day (males); 24, 70, 235, 742, 

and 2296 mg/kg/day (females)]

NOAEL = 300 ppm [54/70 mg/kg/day]

LOAEL = 1000 ppm [178/235 mg/kg/day], based on 

increased liver weight and increased incidence of 

liver lesions [hepatocellular necrosis, hepatocellular 

hypertrophy, inflammation, and anisokaryosis in both 

sexes.

Non-guideline

28-Day oral 

toxicity (rat)

44237704 (1989)

acceptable/non-guideline

0, 2500, 5000, 10000, 20000 ppm 

[m/f]-[0, 197/233, 382/454, 761/875 

1545 (males only) mg/kg/day]

Systemic NOAEL not established

Systemic LOAEL = 2500 ppm [200 mg/kg/day], based 

on increased absolute and relative liver weights at all 

dose levels in both sexes

Mortality, hindlimb paralysis [females at 10000 ppm; 

both sexes at 20000 ppm]; fracture/luxation of 

vertebra, hemorrhage of spinal cord

870.3150

Subchronic oral 

toxicity in 

nonrodents (dog)

MRID 00131432 (1980)

acceptable/guideline

0, 20, 60, 90 mg/kg/day 

[26 weeks]

NOAEL = 20 mg/kg/day

LOAEL = 60 mg/kg/day based on diffuse or focal 

atrophy of the testes and prostate; at HDT, follicular 

hyperplasia of mesenteric lymph node in both sexes

870.3200

21/28-Day dermal 

toxicity (rabbit)

42063401 (1991)

acceptable/guideline

0, 100, 300, 1000 mg/kg/day

NOAEL = 1000 mg/kg/day [highest dose tested]

LOAEL = no effects observed

870.3465

90-Day inhalation 

toxicity (rat)

HASPOC determined that an inhalation toxicity study was not required, based on MOEs that 

were >1000
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Table 2 - Subchronic, Chronic and Other Toxicity Profile – Metaldehyde

Guideline No./ 

Study Type

MRID No. (year)

Classification /Doses

Results

870.3700a

Prenatal 

developmental in 

rodent (rat)

41656001 (1990)

acceptable/guideline

0, 25, 75, 150 mg/kg/day

gestation days 6-15

Maternal NOAEL = 75 mg/kg/day ]

LOAEL = 150 mg/kg/day, based on mortality, clinical 

signs of toxicity [ataxia, tremors, twitching, rapid 

respiration] on days 7 and 8, and decreased bodyweight gain during dosing, and decreased food 

consumption during dosing.

Developmental NOAEL = 150 mg/kg/day [HDT]

LOAEL = no effects.

870.3700b

Prenatal 

developmental in 

nonrodent (rabbit)

41590501 (1990)

acceptable/guideline

0, 10, 40, 80 mg/kg/day

gestation days 6-18

Maternal toxicity NOAEL = 80 mg/kg/day [HDT]

Maternal toxicity LOAEL = no effects observed.

Developmental toxicity NOAEL = 80 mg/kg/day 

[HDT]

Developmental toxicity LOAEL = no effects.

870.3800

Reproduction and 

fertility effects 

(rats)

MRID 42823101 (1993)

acceptable/guideline 

0, 50, 1000, 2000 ppm

males: F0 0, 3.4, 69.37, 138.36; F1 0, 

3.23, 64.93, 133.53 mg/kg/day

females: F0 0, 4.16, 80.81, 160.42; 

F1 0, 4.03, 80.51, 164.15 mg/kg/day

Parental toxicity NOAEL = 1000 ppm [males 65 

mg/kg/day; females 81 mg/kg/day]

Parental toxicity LOAEL = 2000 ppm [males 133 

mg/kg/day; females 160 mg/kg/day], based on 

mortality, clinical signs (hindlimb paralysis in F0 

females) on lactation days 16-18, 

gross/histopatholigical lesions in females (spinal cord 

necrosis and hemorrhage, vertebra luxation in F0 

females), and increased liver weight in both sexes.

Reproductive NOAEL =2000 ppm [males 133 

mg/kg/day; females 160 mg/kg/day], the highest dose 

tested.

Offspring NOAEL = 1000 ppm [males 65 mg/kg/day; 

females 81 mg/kg/day]; Offspring LOAEL = 2000 

ppm [males 133 mg/kg/day; females 160 mg/kg/day], 

based on decreased pup body weight and body-weight 

gain in both sexes/both generations.

870.4100a

Chronic toxicity 

rodents (SD rat)

MRID 42203601 (1992)

acceptable/guideline

0, 50, 1000, 5000 ppm

M 0, 2, 44, 244 mg/kg/day

F 0, 3, 60, 314 mg/kg/day

NOAEL = 50 ppm [males 2 mg/kg/day; females 3 

mg/kg/day] A

LOAEL = 1000 ppm [males 44 mg/kg/day; females 60 

mg/kg/day], based on increased incidence of 

hepatocellular hypertrophy (both sexes) and increased 

cholesterol (females), and decreased body-weight gain 

in females. [see under 870.4200 below]

870.4100b

Chronic toxicity 

nonrodent (dogs)

MRID 46378401 (2003)

acceptable/guideline

0, 10, 30, 90 mg/kg/day

Overall NOAEL = 10 mg/kg/day

LOAEL = 30 mg/kg/day, based on deaths and atrophy 

of testes/prostate

NOAEL = 30 mg/kg/day

LOAEL = 90 mg/kg/day, based on clinical signs of 

neurotoxicity in all dogs on the first day of exposure 

and throughout the first week.
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Table 2 - Subchronic, Chronic and Other Toxicity Profile – Metaldehyde

Guideline No./ 

Study Type

MRID No. (year)

Classification /Doses

Results

870.4200

Carcinogenicity 

rats

MRID 42203601 (1992)

acceptable/guideline

0, 50, 1000, 5000 ppm

M 0, 2, 44, 244 mg/kg/day

F 0, 3, 60, 314 mg/kg/day

NOAEL = 50 ppm [2 mg/kg/day; females 3 

mg/kg/day] A

LOAEL = 1000 ppm [males 44 mg/kg/day; females 60 

mg/kg/day], based on increased incidence of 

hepatocellular hypertrophy (both sexes) and increased 

cholesterol (females), and decreased body-weight gain 

in females.

evidence of carcinogenicity: females displayed a 

treatment-related increase in hepatocellular 

adenomas and adenomas and carcinomas 

combined [positive trend at 5000 ppm] at the highdose level [adenomas 6/60, 10%] compared to both 

control groups [0/60 and 1/60]; carcinomas 1/60, 

1.7% compared to both controls [0/60 and 1/60]; 

and combined 7/60, 11.7% compared to both 

controls [0/60 and 2/60]; the incidence was within 

the historical control range [adenomas 0%-10%; 

carcinomas 0%; combined 0%-10%]. 

870.4300

Carcinogenicity 

mice

42737201 (1993)

acceptable/guideline when combined 

with MRID 44625101

2 control groups 25, 100, 300 ppm

M 4.0, 15.9, 48.9 mg/kg/day

F 4.8, 19.7, 59.8 mg/kg/day

NOAEL = 100 ppm [males 15.9/females 19.7 

mg/kg/day]A

LOAEL = 300 ppm [males 48.9/females 59.8 

mg/kg/day based on increased incidence of 

hepatocellular hypertrophy in both sexes.

Dose levels not adequate to assess carcinogenicity 

potential;

slight increase in hepatocellular adenomas in both 

sexes compared to both control groups

870.4300

Carcinogenicity 

mice

MRID 44625101 (1998)

Acceptable/guideline when 

combined with MRID 42737201

2 control groups, 1000 ppm

increased liver weight, increase in incidence of 

hepatocellular hypertrophy (both sexes), single 

cell/focal/multifocal necrosis (males), and an increase 

in the incidence of hepatocellular adenomas in both 

sexes

Gene Mutation -

Ames assay

870.5265

MRID 41553205 (1978)

unacceptable

1.28, 6.4, 32, 160 ease in incidence 

of hepatocellular hy

does not provide sufficient evidence of a negative 

response in strains TA98, TA100, TA1535, TA1537, 

TA1538 with and without metabolic activation; no 

MTD; poor performance of some strains

Gene Mutation -

Ames assay

870.5100

MRID 48666101 (2011)

tested up to limit dose (5000 

μg/plate);insoluble at ≥2500 μg/plate 

+/-S9.

Acceptable/guideline

No evidence of cytotoxicity; no appreciable increases 

in mean number of revertants/plate in any strain in 

either trial (+/-S9). The positive controls induced the 

appropriate response in all strains in the presence and 

absence of S9-activation. There was no evidence of 

induced mutant colonies over background.
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Table 2 - Subchronic, Chronic and Other Toxicity Profile – Metaldehyde

Guideline No./ 

Study Type

MRID No. (year)

Classification /Doses

Results

Gene Mutation -

mouse lymphoma 

L5178Y (TK+/-) 

cell line

870.5300

MRID 41553206 (1986)

unacceptable

no conclusions can be drawn; doses “not completely 

dissolved in the selected solvent (culture medium); all 

concentrations precipitated. Additionally, exposure 

time (2 hours) was shorter than the standard exposure 

time for this test system (4 hours).

Gene Mutation -

mouse lymphoma 

L5178Y (TK+/-) 

cell line

870.5300

MRID 48721401 (2011)

tested up to solubility limit (≥ 600

μg/mL +/-S9)

Acceptable/guideline

No evidence of induced mutant colonies over 

background.

Gene Mutation -

mouse lymphoma 

L5178Y (TK+/-) 

cell line

870.5300

MRID 42044007 (1986; revised 

1991)

clarification of MRID 41553206

unacceptable

w/S9 -

w/out S9 -

No evidence for inducing forward gene mutation at 

TK locus in mouse lymphoma (L5178Y) cell 

with/without S9 activation up to precipitating 

concentrations (100-

mutation at TK locus in mouse lymphoma (L5178Y) 

cell with/with standard exposure time for this test 

system (4 hours).

Chromosomal 

aberrations in 

CHO cells

870.5375

MRID 00163832 (1986)

unacceptable

w/S9 -

w/out S9 -20, 50, 100, 200 

No evidence for inducing chromosome aberrations in 

CHO cells up to a precipitating concentration (200 

μg/mL -S9). With S9, no evidence up to the highest 

in CHO cells up to a precipitat

Chromosome 

Aberration Assay

870.5385

MRID 48788201 (2012)

0, 62.5, 125, and 250 mg/kg (M) or 

0, 31.25, 62.5, and 125 mg/kg (F)

Acceptable/guideline

No evidence of cytogenicity in this in vivo rat bone 

marrow chromosome aberration assay.

Micronucleus 

assay

870.5395

MRID 42044006 (1990)

unacceptable

25, 50, 100 mg/kg

Highest dose tested (100 mg/kg); MTD not reached

870.6200a

Acute 

neurotoxicity 

screening battery

HASPOC (TXR# 0056524) determined that a rat ACN was not required, based on the fact 

that neurotoxicity effects observed in the rat occur only at high dose levels; the dog is the 

more sensitive species for neurotoxic effects and points of departure based on the dog study 

are protective of any neurotoxicity at higher dose levels.

870.6200b

Subchronic 

neurotoxicity 

screening battery

MRID 46223401 (2003)

Unacceptable (did not demonstrate 

ability to detect neurotoxic effects) 

/guideline

0 [basal diet], 100, 500, and 2500 

ppm (equivalent to 0, 8, 39, 185 

mg/kg bw/day) 

NOAEL = 100 ppm [8 mg/kg/day]

LOAEL = 500 ppm [39 mg/kg/day], based on 

increased motor activity in females. At the HDT [185 

mg/kg], bilateral hindlimb paralysis [one female] and 

decreased body-weight gains in females during the 

first week of the study.
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Table 2 - Subchronic, Chronic and Other Toxicity Profile – Metaldehyde

Guideline No./ 

Study Type

MRID No. (year)

Classification /Doses

Results

870.6300

Developmental 

neurotoxicity

DNT Workgroup (2009) determined that DNT was not required, based on a weight-ofevidence: (1) no evidence of ↑ susceptibility following in utero exposures to rats/rabbits or 

following pre-/postnatal exposure in rat reproduction study; (2) no treatment-related effects on 

any reproductive parameters; offspring effects were ↓ pup body weight/gain only at ≥133 mkd; 

(3) most of the neurotoxic signs; e.g., limb paralysis, ataxia, and tremors, were seen in adult 

rats at dose levels of 150 mkd to 185 mkd; (4) pharmacokinetic profile indicates a short halflife with primary metabolite being its degradation/metabolism to acetaldehyde, an endogenous 

chemical; (5) based on offspring LOAEL of 133 mkd, in order to elicit effects in the offspring, 

the DNT would need to be tested at high doses (>100 mkd), which would not yield lower POD 

than those currently used for overall risk assessment.

870.7485

Metabolism and 

pharmacokinetics 

(Sprague-Dawley 

rat)

MRID 42300901 (1992)

single gavage dose 10 or 100 mg/kg

repeated dose 10 mg/kg/day for 14 

days, then single dose 14C [10 

mg/kg] 

Classification: acceptable/guideline

rapidly absorbed, distributed, metabolized; most 

recovered in expired air [78%-98% of administered 

dose] within 24 hours [48 hr high-dose females] as 

14CO2; recovery in urine/feces low [2.5%-5.1%] ; 

sexes differ slightly; peak blood levels [males 1-2 hrs; 

females 2-4 hrs] and excretion faster in males [T1/2

males 3.4 hrs.; females 8.8 hrs.]; recovery greater 

following low-dose than high-dose and repeat 

exposure; concentration of total 14C in blood at peak 

similar for sexes but concentration of intact 

metaldehyde was >50% higher in females than in 

males at peak, first and second blood half-lives; 14C in 

tissues/carcass after 7 days similar for all groups [7%-

11% of administered dose]; high concentrations 14C 

recovered in nervous tissue, fat, liver, female

reproductive organs; 2 major peaks [plasma] were 

metaldehyde and acetaldehyde

870.7600

Dermal 

penetration

no study available no study available.

870.7800

Immunotoxicity

HASPOC (TXR# 0056825) determined that an immunotoxicity study was not required, 

based on a WOE approach considering all the available metaldehyde hazard and exposure 

information.

Special studies 

(CD-1 mouse)

MRID 44810901 (1999)

retrospective analysis of cell 

proliferation/apoptosis [liver tissue]

males - correlation between cell proliferation, liver 

weight increase, and an increased incidence of liver 

necrosis and/or hypertrophy at 1000 ppm and 3000 

ppm]; clear evidence of cell proliferation and 

hepatotoxicity not evident at lower doses; females -

suggestive evidence of a similar correlation at 1000 

ppm and 3000 ppm; however, lack of a dose-response 

and extreme variability of data renders findings 

equivocal for proposed mode of carcinogenic action 

[liver tumors]; no data on whether proliferative 

response sustained.

A

Regarding the lower NOAELs observed in both the rat and mouse long-term studies, discussion was included in the endpoint 

selection section of the RED. For the chronic dietary scenario, it was noted that the chronic toxicity/carcinogenicity study in rats 

provided a lower NOAEL (2 mg/kg). However, the endpoint of concern [liver effects (hepatocellular hypertrophy)] was seen at 44 

mg/kg (LOAEL); the effects were considered an adaptive effect and not appropriate for selection of the chronic dietary endpoint. 

In addition, the lower NOAEL seen in the rat study might be influenced by dose selection. Although the mouse study was not 
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discussed, a similar conclusion is appropriate; i.e., the endpoint of concern in the mouse study [increased incidence of hepatocellular

hypertrophy in both sexes] was seen at 48 mg/kg/day (LOAEL); the lower NOAEL (16/20 mkd) in the mouse study might be 

influenced by dose selection; and the effects might also be considered adaptive and not appropriate for selection of the dietary 

endpoint.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - All populations

Study Selected: Chronic oral toxicity study - dog

MRID No.: 46378401 

Executive Summary: See Appendix A, Guideline [§ 870.3100] 

Dose and Endpoint for Risk Assessment: NOAEL = 30 mg/kg/day based on clinical signs 

(ataxia, tremors, salivation, twitching) seen on day 1 of dosing in both sexes at LOAEL = 90 

mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: Since the signs of neurotoxicity were 

observed on the first day of dosing, the study is appropriate for an acute assessment. The dog is 

the most sensitive species for the neurotoxic effects observed, and neurotoxicity is the most 

sensitive endpoint in the toxicity database. The dose and endpoint are appropriate for all 

populations. No endpoint appropriate for females 13+ was identified in the database. Although 

maternal deaths occurred following 1-2 exposures in the rat and rabbit developmental toxicity 

studies, the deaths occurred at dose levels ≥100 mg/kg/day. The dose and endpoint selected from 

the chronic dog study are protective of these findings and of potential acute toxicity for all 

populations. 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.2 Chronic Reference Dose (cRfD) `

Study Selected: Chronic oral toxicity study - dog

MRID No.: 46378401 

Executive Summary: See Appendix A, Guideline [§ 870.3100] 

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on death and atrophy 

of the testes and prostate seen on at LOAEL = 30 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint provides the 

most sensitive NOAEL available from a study of appropriate duration and exposure (oral). 

Atrophy of the testes and prostate were observed in the dog subchronic oral toxicity study also at 

a dose of 60 mg/kg/day (NOAEL = 20 mg/kg/day). 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.3 Incidental Oral Exposure (Short- Term)

Study Selected: Chronic oral toxicity study - dog

MRID No.: 46378401 

Executive Summary: See Appendix A, Guideline [§ 870.3100] 

Dose and Endpoint for Risk Assessment: NOAEL = 30 mg/kg/day based on clinical signs 

(ataxia, tremors, salivation, twitching) seen on day 1 of dosing in both sexes at LOAEL = 90 

mg/kg/day.
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Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for the shortterm assessment since the signs of neurotoxicity were observed on the first day of dosing and 

throughout the first week of exposure. The dog is the most sensitive species for the neurotoxic 

effects observed, and neurotoxicity is the most sensitive endpoint in the toxicity database. The 

dose and endpoint are protective of effects observed in postnatal animals (population of concern) 

in the reproduction toxicity study (decreased pup body weight/gain).

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.4 Incidental Oral Exposure (Intermediate-Term)

Study Selected: Chronic oral toxicity study - dog

MRID No.: 46378401 

Executive Summary: See Appendix A, Guideline [§ 870.3100] 

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on death and atrophy 

of the testes and prostate seen on at LOAEL = 30 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint provides the 

most sensitive NOAEL available from a study of appropriate duration and exposure (oral). 

Atrophy of the testes and prostate were observed in the dog subchronic oral toxicity study also at 

a dose of 60 mg/kg/day (NOAEL = 20 mg/kg/day). 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)

The repeated [21-day] dermal toxicity study was considered for these exposure scenarios because 

the route of exposure is appropriate. Although no effects were observed, the limit dose was 

tested, no clinical signs were observed, the target organs [liver and testes] were evaluated, and 

there is no reproductive toxicity concern. Since no hazard was identified, no risk from dermal 

exposure is expected.

A.3.6 Inhalation Exposure (Short -Term) 

Study Selected: Chronic oral toxicity study - dog

MRID No.: 46378401 

Executive Summary: See Appendix A, Guideline [§ 870.3100] 

Dose and Endpoint for Risk Assessment: NOAEL = 30 mg/kg/day based on clinical signs 

(ataxia, tremors, salivation, twitching) seen on day 1 of dosing in both sexes at LOAEL = 90 

mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for the shortterm assessment since the signs of neurotoxicity were observed on the first day of dosing and 

throughout the first week of exposure. The dog is the most sensitive species for the neurotoxic 

effects observed, and neurotoxicity is the most sensitive endpoint in the toxicity database. The 

dose and endpoint are protective of effects observed in postnatal animals (population of concern) 

in the reproduction toxicity study (decreased pup body weight/gain). 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.7 Inhalation Exposure (Intermediate- and Long-Term) 

Study Selected: Chronic oral toxicity study - dog

MRID No.: 46378401 
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Executive Summary: See Appendix A, Guideline [§ 870.3100] 

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on death and atrophy 

of the testes and prostate seen on at LOAEL = 30 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint provides the 

most sensitive NOAEL available from a study of appropriate duration and exposure (oral). 

Atrophy of the testes and prostate were observed in the dog subchronic oral toxicity study also at 

a dose of 60 mg/kg/day (NOAEL = 20 mg/kg/day). 

Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity - Rat

In a subchronic oral toxicity study (MRID 44237704), metaldehyde (99.0% a.i.) was fed to 10 

Sprague-Dawley CD rats/sex/dose at dietary concentrations of 0, 2,500, 5,000, 10,000, or 20,000 

ppm (equivalent to approximately 0, 200, 400, 800, or 1550 mg/kg/day) for 28 consecutive days. 

The study was to be used as a range-finding study for a chronic oncogenicity and a 2-generation 

study that were scheduled to be conducted.

Mortality, either as spontaneous death or moribund sacrifice, occurred in 6/10 10,000-ppm females 

and 10/10 20,000-ppm females, and in 4/10 20,000-ppm males. In decedent animals, hind limb 

paralysis was the predominant effect observed prior to death, although tonic convulsions, 

excessive vocalization, gasping, and hyperactivity were also observed in one high-dose female. 

Increases (10-28%) in blood urea nitrogen concentrations in all treated females were observed, 

with significance (p<0.05 or 0.01) at the 2,500- and 10,000-ppm levels. Slight decreases (6-8%, 

p<0.05) in erythrocytes were observed in the 10,000-ppm males.

Treatment-related increases (p<0.01) in absolute (up to 67%) and relative (up to 69%) liver weights 

were observed in both sexes and all test groups. Furthermore, histopathological examination 

revealed hepatocellular hypertrophy in both sexes at all test levels. 

Findings upon gross necropsy were limited to animals that died or were sacrificed during the study 

and included fracture/luxation of the vertebra, hemorrhage of the spinal cord, abnormal coloration 

of various organs, hydronephrosis and/or hemorrhage of the kidneys, and dilatation/distention 

and/or hemorrhage of the urinary bladder. The urinary tract abnormalities were presumably 

secondary to urine stasis resulting from paralysis. Similarly, microscopic examination revealed 

luxation of the vertebra; hemorrhaging of the vertebra and spinal cord; spinal cord compression, 

vacuolization, and malacia; hydronephrosis; and general congestion and/or hemorrhaging of 

various organs, including the thymic region, lungs, kidneys, and urinary bladder. 

The systemic LOAEL is 2,500 ppm (equivalent to approximately 200 mg/kg/day) based on 

increased absolute and relative liver weights in all dose groups and hepatocellular 

hypertrophy at all dose levels in both sexes. The systemic NOAEL was not established. 
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This 28-day oral (dietary) study is classified acceptable (Non Guideline) as it is not a required 

guideline study. It is acceptable for the purposes for which it was intended [range-finding study]. 

870.3150 90-Day Oral Toxicity - Dog

In a 26-week oral toxicity study (MRID 00131432); beagle dogs were administered 0, 20, 60 or 

90 mg/kg/day metaldehyde in the diet. All animals survived the 26-week period and no clinical 

signs of toxicity were observed. No effects were observed for food consumption, body weight, 

drinking water intake, hematology, clinical chemistry, ophthalmology, or organ weights. Diffuse 

or focal atrophy of the prostate and testes were observed in the 60 and 90 mg/kg/day groups. 

There were increases in follicular hyperplasia of the mesenteric lymph node in the 90 mg/kg/day 

group. Animals in the 90 mg/kg/group had slight increases in periportal infiltration of 

lymphocytes, histiocytes and eosinophilic granulocytes in the liver and very slight hydropic 

swelling in focal areas of the liver, which are probably of no toxicological significance. 

The NOEL/LEL were determined to be 20 mg/kg/day / 60 mg/kg/day, based on diffuse or focal 

atrophy of the testes and prostate. The study is core-minimum and satisfies the requirements for 

a Guideline Series 83-1(b) chronic toxicity study in dogs.

870.3200 21/28-Day Dermal Toxicity – Rat

In a 21-day dermal toxicity study (MRID 42063401), 5 New Zealand White rabbits/sex/group 

were administered metaldehyde [99.0%] via dermal application [dry powder covered with a 

gauze patch moistened with Milli-Q® filtered water; once a day for 6 hours, 5 days/week] for 22 

days at concentrations of 0, 100, 300, and 1000 mg/kg/day.

Treatment had no adverse effect on survival, clinical signs, mean body weight, body-weight 

gain, food consumption, hematology, clinical chemistry, organ weights, or gross and microscopic 

pathology. There was no dose-related increase in the incidence or severity of signs of dermal 

toxicity.

The NOAEL for systemic and dermal toxicity is 1000 mg/kg/day, the highest dose tested

This guideline 21-day dermal toxicity study is classified ACCEPTABLE, and it satisfies the

guideline requirement [§82-2; 870.3200] for a 21-day dermal toxicity study. Although fewer 

rabbits/sex/group were utilized than specified in the Guideline, this does not by itself diminish 

the finding of no effect at the limit dose. 

870.3465 90-Day Inhalation – Rat

Study waived by HASPOC (TXR# 0056524, dated 2/21/13)

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study - Rat

In a developmental toxicity study [MRID 41656001], female Sprague-Dawley Crl:CD(SD)BR 

rats [25/group] were administered metaldehyde [99%] via gavage at dose levels of 0 [Mazola® 
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corn oil], 25 mg/kg/day, 75 mg/kg/day, and 150 mg/kg/day from gestation day 6 through 

gestation day 15. 

There were six deaths [all pregnant; high-dose level only], which occurred between gestation 

days 7 and 8. Clinical signs attributed to treatment were observed at the high-dose level in those 

dams that died and included ataxia [all six], rapid respiration [5 dams], twitching [4 dams], 

tremors [3 dams], prostration [1 dam], abdominal breathing [1 dam], hyperactivity [1 dam], 

paresis of the hind legs [1 dam], pallor [2 dams], perioral encrustation [3 dams], and perinasal 

encrustation [2 dams]. Decreased body weight [96% of control] was observed at the high-dose 

level only on gestation day [GD] 9. Body-weight gain was significantly decreased [74% of 

control] initially [GD 6-9] and throughout the dosing period at the high-dose level. Although 

dams at the mid-dose level displayed only a slightly lower body-weight gain during the dosing 

period [91% of control] compared to the control, based on their pre-dose body-weight gain 

[115% of control], the decrease is considered treatment-related. A compensatory weight gain was 

noted during the post-dosing period at the high-dose level. Corrected body-weight gain at the 

high-dose level was slightly [94% of control] lower than the control value. Food consumption 

was decreased at the high-dose level during the dosing period and increased significantly during 

the post-dosing period at the mid- and high-dose levels. 

Treatment-related necropsy findings in the dams dying on test included thinning of the stomach 

wall [1 dam], ulceration of the glandular [2 dams] and nonglandular [2 dams] portion of the 

stomach, red/brown lungs [6 dams], dilated renal pelvis [2 dams], and hydronephrosis [1 dam]. 

Additionally, perioral encrustation [6 dams], perinasal encrustation [5 dams], and paravertebral 

hemorrhage [1 dam] were observed in those dying on test. There were no adverse effects 

observed on maternal liver weight or gravid uterine weight.

There were no abortions, and the pregnancy rate was comparable among the groups. The 

numbers of corpora lutea, implantation, live fetuses, and resorptions [both total and per dam], as 

well as pre- and post-implantation losses were comparable among the groups. There was one 

dead fetus [high dose]. Fetal body weights and the sex ratio were comparable among the groups. 

There were no statistically-significant or dose-related differences in the incidence of fetal 

malformations or variations [external, visceral, and skeletal].

The maternal toxicity NOAEL is 75 mg/kg/day, and the maternal toxicity LOAEL is 150 

mg/kg/day, based on mortality, clinical signs of toxicity [ataxia, tremors, twitching, rapid 

respiration], decreased body-weight gain during dosing, and decreased food consumption 

during dosing. The NOAEL for developmental toxicity is 150 mg/kg/day, the highest dose 

tested. 

This guideline developmental toxicity study is classified Acceptable, and it satisfies the guideline 

[OPPTS 870.3700; §83-3(a)] for a developmental toxicity study in the rodent. 

870.3700b Prenatal Developmental Toxicity Study - Rabbit

In a developmental toxicity study [MRID 41590501], female New Zealand white rabbits 

[16/group] were administered metaldehyde [99%] via gavage at dose levels of 0 [Mazola® corn 
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oil], 10 mg/kg/day, 40 mg/kg/day, and 80 mg/kg/day from gestation day 6 through gestation day 

18. 

There were no treatment-related deaths or clinical signs of toxicity. Body-weight gains were 

extremely variable, and there was no dose-response. All groups, including the control, displayed 

negative corrected body-weight gains but there was no dose-response. Food consumption was 

decreased at all dose levels during the dosing period compared to the control, but there was no 

dose-response.

Necropsy findings were comparable among the groups. There were no adverse effects observed 

on maternal liver weight or gravid uterine weight.

There were no abortions, and the pregnancy rate was not adversely affected by treatment. The 

numbers of corpora lutea, implantation, live fetuses, resorptions [both total and per dam], and 

dead fetuses, as well as pre- and post-implantation losses were comparable among the groups. 

Fetal body weights and the sex ratio were comparable among the groups. There were no 

statistically-significant or dose-related differences in the incidence of external or visceral 

malformations, but a slightly higher incidence of skeletal malformations [5 fetuses in 3 litters] 

was observed at the high-dose level compared to the control and lower dose groups [1 

fetus/group]. This latter finding is considered attributable to the greater number of fetus 

examined at the high-dose level [140 fetuses in 16 litters] compared to the other groups [112 

fetuses/12 litters; 104 fetuses/13 litters; and 107 fetuses/13 litters in the control, low- and middose groups, respectively]. External, visceral, and skeletal variations were comparable among the 

groups.

The maternal toxicity NOAEL is 80 mg/kg/day, the highest dose tested. The NOAEL for 

developmental toxicity is 80 mg/kg/day, the highest dose tested. 

This guideline developmental toxicity study is classified Acceptable, and it satisfies the guideline 

[OPPTS 870.3700; §83-3(b)] for a developmental toxicity study in the rodent. NOTE: Although 

no maternal or developmental effects were observed, the dose levels are considered adequate 

based on effects observed in the range-finding study. All does [5/group] in the 200, 350 and 500 

mg/kg/day groups died [following 1 or 2 doses] or were sacrificed moribund [gestation days 8-

12], and one doe at 100 mg/kg/day died. A repeat study at higher dose levels would not provide 

useful data. This is supported by the results in the rat. The maternal NOAEL in the rat 

developmental toxicity study is 75 mg/kg/day, based on mortality, clinical signs of toxicity 

[ataxia, tremors, twitching, rapid respiration], decreased body-weight gain during dosing, and 

decreased food consumption during dosing at the LOAEL of 150 mg/kg/day. The NOAEL for 

developmental toxicity is 150 mg/kg/day, the highest dose tested.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects - Rat

In a 2-generation reproduction study [MRID 42823101], 28 male/28 female F0 CD®

rats/sex/group were administered metaldehyde [>99% a.i.] via the diet for 10 weeks prior to 

mating and through gestation and lactation of one litter at dose levels of 0 ppm, 50 ppm, 1000 
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ppm, and 2000 ppm [F0 males: 0, 3.4, 69.37, and 138.36mg/kg/day; F0 females: 0, 4.16, 80.81, 

and 160.42 mg/kg/day; F1 males: 0, 3.23, 64.93, and 133.53 mg/kg/day; F1 females: 0, 4.03, 

80.51, and 164.15 mg/kg/day]. Rats were mated, one male with one female. The resulting F1 

litters were weaned at day 28 post partum. The F1 generation [28 rats/sex/group] was 

administered the test material at the same dose levels as F0 animals and mated in a similar 

manner, avoiding sibling matings. The resulting F2 litters were weaned at day 28 post partum.

No treatment-related clinical signs of toxicity or mortality were observed in F0 males at any time 

point or in F0 females during the pre-mating and mating periods or during gestation. However, at 

2000 ppm, three F0 dams were sacrificed moribund during the lactation period [lactation days 

16-18; days 110, 110, 113 on test] due to bilateral hindlimb paralysis. No treatment-related 

clinical signs of toxicity or mortality were observed in F1 males at any time point or in F1

females during the pre-mating and mating periods. However, during gestation/lactation, three F1

dams [2000 ppm] were found dead [days 95, 101, and 125]. The 2000 ppm F1 dam that was 

found dead on day 95 displayed ataxia, labored breathing, cold extremities, and pallor on day 94. 

An additional 2000 ppm F1 female [nongravid] displayed prostration, tremors, abdominal 

breathing, and rapid respiration on day 102 but survived until terminal sacrifice [day 134]. The 

author stated that the relationship of these latter signs to treatment was unclear. The cause of 

death of two of the F1 females was not determined [third female due to septic emboli to various 

organs]. None of the other deaths [ F0 male and 2 F0 females at 50 ppm, 2 F1 females at 50 ppm, 

and one F1 male at 1000 ppm] was considered treatment-related. No additional treatment-related 

clinical signs were noted. 

F0 parental animals Body weights for the treatment groups were similar to control throughout 

the study for both sexes. During the pre-mating dosing period, there were no consistent adverse 

effects on body-weight gain in either sex. Body-weight gains of the F0 high-dose males were 

decreased initially [weeks 0-1 (91% of control)] and during weeks 5-6 (89% of control) and 

weeks 8-9 (75% of control). During weeks 2-3, there was an apparent dose-related increase in 

body-weight gain in males at the mid- (112% of control) and high-dose (114% of control) levels. 

F0 females displayed a decrease in body-weight gain [66% of control] during weeks 2- 3 at the 

high-dose level, although statistical significance was not attained, and the standard deviation 

exceeded the group mean. Food consumption was not affected in either sex. 

There were no consistent, treatment-related, adverse effects on body weights or body-weight 

gains of the F1 parental animals during the pre-mating dosing period, although both sexes at the 

high dose displayed a smaller body-weight gain during weeks 9-10 [males 83%; females 65% of 

control] than control. Food consumption was comparable among the groups [both sexes] 

throughout the study. 

At sacrifice, necrosis and hemorrhage in the spinal cord and vertebra luxation were observed in 

the three high-dose F0 dams that displayed hindlimb paralysis. An additional F0 dam at 2000 

ppm displayed spinal cord lesions microscopically.

At necropsy, no treatment-related adverse effects were observed in F1 animals at any dose level. 
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At 2000 ppm, F1 males displayed increased relative liver weights [15%] and F1 females 

displayed increased absolute [12%] and relative [11%] liver weights. These organ-weight 

changes were not accompanied by histopathological lesions and may be attributed to adaptation 

to the test material. NOTE: Liver weights were not determined for F0 animals.

F0 Generation. No apparent adverse effect was observed on fertility, and the mating and 

gestation indices were comparable among the groups. Pre-coital intervals were not reported. The 

duration of gestation was comparable among the groups. The number of live pups was 

comparable among the groups. The number of pups born dead/dying by day 1 was not affected 

by treatment. Litter size was slightly lower at the high-dose level [Day 0 (13.6), Day 4 precull 

(13.3), Day 21 (7.5)] compared to the control [Day 0 (13.7), Day 4 precull (13.5), Day 21 (7.8)] 

and other dose groups [Day 0 (14.0 and 13.8), Day 4 precull (13.7 and 13.8), Day 21 (7.7 and 

7.9) for low-and mid-dose groups, respectively] throughout the weaning period. The live birth 

index and the viability index were comparable among the groups, but the lactation index was 

slightly lowered [89%] at the high-dose level compared to the control [99%] and other dose 

groups [99%]. At the high-dose level, a slightly lower pup body weight was observed on 

lactation days 7 [males 96%/females 95% of control] and 21 [95% of control], although 

statistical significance was not attained for either timepoint. Body-weight gains were slightly 

lower for both sexes at the high-dose level [94%-95% of control] compared to the control 

throughout lactation. The sex ratio was comparable among the groups. F1 Generation. No 

apparent, treatment-related, adverse effect was observed on fertility, and the mating and 

gestation indices were comparable among the groups. Pre-coital intervals were not reported. The 

duration of gestation was comparable among the groups. The high-dose group had the fewest 

females [22] with live born pups [27 control and 23 each at the low- and mid-dose levels]. The 

number of live pups was comparable among the groups. The number of pups born dead/dying by 

day 1 was not affected by treatment. Litter size was comparable among the groups, and the live 

birth index, viability index, and the lactation index were comparable among the groups. At the 

high-dose level, a slightly lower pup body weight was observed on lactation days 1 [males 

93%/females 93% of control], 7 [females 95% of control], and 21 [males 93%/females 92% of 

control], although statistical significance was attained only at the day 21 time point. Body-weight 

gains were slightly lower for both sexes at the high-dose level [91%-93% of control] compared 

to the control throughout lactation. The sex ratio was comparable among the groups. 

The NOAEL for parental toxicity is 1000 ppm [males 65 mg/kg/day; females 81 mg/kg/day) 

and the parental LOAEL is 2000 ppm [males 133 mg/kg/day; females 160 mg/kg/day], 

based on mortality (F0 and F1 females), clinical signs (hindlimb paralysis in F0 females), 

and histopathology (spinal cord necrosis and hemorrhage, and vertebra luxation in F0 

females and increased liver weight in both sexes [F1]. 

The NOAEL for reproductive toxicity is 2000 ppm [males 133 mg/kg/day; females 160 

mg/kg/day], the highest dose tested.

The NOAEL for offspring toxicity is 1000 ppm [males 65 mg/kg/day; females 81 

mg/kg/day) and the LOAEL for offspring toxicity is 2000 ppm [males 133 mg/kg/day; 

females 160 mg/kg/day], based on decreased pup body weight/body-weight gain [F1 and F2 

pups].
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This 2-generation reproduction study is classified Acceptable/Guideline. This study satisfies the 

guideline requirement (OPPTS 870.3800; §83-4) for a 2-generation reproduction study. The 

original DER set the reproductive toxicity LOEL at 2000 ppm, based on decreased pup body 

weight and weight gain in both sexes, which is not a reproductive toxicity endpoint but an 

offspring endpoint. Reproductive toxicity was not observed in this study, based on the 

parameters examined. It is to be noted that several parameters in the current protocol that 

measure reproductive effects, such as age of vaginal opening and preputial separation; 

anogenital distance for F2 pups; implantations sites; estrous cycle length and periodicity (F1 

weanlings); and sperm measures, were not evaluated. These are included in the new protocol, 

which was not in effect at the time of the study.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

See below under 870.4200

870.4100b Chronic Toxicity - Dog

In a chronic oral toxicity study (MRID 46378401), metaldehyde (98.3% a.i.; batch # 30202) was 

administered once daily for 52 consecutive weeks to groups of 4 male and 4 female Beagle dogs 

at dose levels of 10, 30, and 90 mg/kg/day. The amount of test material given was adjusted to 

each dog’s actual body weight weekly.

There were three deaths [one each sex at 30 mg/kg/day and one female at 90 mg/kg/day], which 

occurred between weeks 37 and 46. Treatment-related clinical signs were observed from week 

one on at the high dose and included ataxia, emesis, tremor, twitching, and salivation. The 

incidence and severity of these clinical signs lessened with time from week 19, although 1 or 2 

animals continued to display salivation throughout the study. One high-dose female displayed 

lateral position early in the study, reduced motility during most of the study, and convulsion and 

vocalization during week 46. Agitation was displayed by one high-dose female during weeks 6-9 

and 24-52. Body weight was slightly lower in the treated dogs [males ↓7%-17%; females ↓6%-

19%] throughout most of the study, although a dose-response was not always evident. At study 

termination, male body weights were ↓16%, ↓12%, and ↓17% and female body weights were 

↓4%, ↓10%, and ↓19% with increasing dose. During the first week on test, males displayed 

decreased body-weight gains at all dose levels, although the decrease was inversely related to 

dose [↓53%, ↓34%, and ↓26% with increasing dose]. Only the mid-dose females displayed a 

decrease in body-weight gain initially [↓64%]. During the 0-13 week interval, males at all dose 

levels [↓25%, ↓17%, and ↓43% with increasing dose] and females at the mid- [63%] and high-

[79%] dose levels displayed decreased body-weight gains compared to the controls. Food 

consumption was not adversely affected. Food efficiency values were not provided. 

No lesions of the eyes or optic region were found, and there were no differences in the urinalysis 

parameters monitored in either sex. During the 13-week assessment, one high-dose dog of each 

sex did not react to the noise test, but no effects were noted in either sex at the 26- and 52-week 

assessments. Increases in hemoglobin, RBC, and hematocrit were observed in both sexes at the 

high-dose level at week 13, but only in females at week 26. Alkaline phosphatase was increased 
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throughout the study in both sexes at the high-dose level, with the magnitude of the response 

from control increasing with time [both sexes]. High-dose females displayed an increase in 

gamma-GT throughout the study, but other liver enzyme activities [AST, ALT] were not affected 

by treatment. Triglycerides were increased in the high-dose females throughout the study 

compared to the control values. 

At the high-dose level in both sexes, liver weight was increased significantly compared to the 

control values. There was a dose-related decrease in absolute prostate weight [↓18%, ↓29%, and 

↓32% with increasing dose], a decrease in testes weight at the low- and high-dose level, and an 

increase in absolute and relative lung weight in high-dose males. Increased brain weight (↑5%)

was observed in females at the high-dose level compared to the control. There were no apparent 

microscopic lesions in the liver, but atrophy and/or degeneration was observed in the testes and 

prostate.

The lowest-observed-adverse-effect level (LOAEL) for metaldehyde in the dog is 30 

mg/kg/day, based on death and atrophy of the testes and prostate. The NOAEL is 10 

mg/kg/day.

The LOAEL for clinical signs of neurotoxicity is 90 mg/kg/day, based on ataxia, emesis, 

tremor, twitching, and salivation that occurred in all dogs of both sexes during days 1-7. 

The NOAEL for clinical signs of neurotoxicity is 30 mg/kg/day.

This chronic oral toxicity study in the dog is Acceptable/Guideline, and it satisfies the guideline 

requirement for a chronic oral toxicity study [OPPTS 870.4100); OECD 452] in the dog.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study - rat

In a chronic toxicity/carcinogenicity study [MRID 42203601], 60 Sprague-Dawley CD® 

rats/sex/dose were administered metaldehyde [99 %] via the diet at concentrations of 0 ppm and 

0 ppm (2 control groups), 50 ppm [males 2 mg/kg/day; females 3 mg/kg/day], 1000 ppm [males 

44 mg/kg/day; females 60 mg/kg/day], 5000 ppm [males 224 mg/kg/day; females 314 

mg/kg/day] for 104 weeks.

There was no adverse effect of treatment on survival of either sex, although females at the mid-

[60%] and high- [58%] dose levels displayed a slightly greater mortality than the control groups 

[50% and 48%]. There were no apparent treatment-related clinical signs of toxicity. There was a 

slight reduction in body weight [↓5%] throughout most of the study in both sexes at the highdose level compared to the control groups. During the first week, females in all treated groups 

displayed a dose-related [statistically-significant at all dose levels] decrease in body-weight gain 

compared to the 2 control groups [86%/94%, 69%/75%, and 60%/66% of control with increasing 

dose]. During the same time-frame, males displayed a similar dose-related decrease in bodyweight gain, which was statistically significant at the mid- [87% of control] and high- [78% of 

control] dose level compared to one of the control groups. Food consumption was decreased at 

the high-dose level in both sexes during the first few weeks of the study, which suggests a 

palatability problem. 
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There were no apparent, treatment-related, effects on the ophthalmological or hematological 

parameters monitored in either sex. Mid- and high-dose females displayed a statisticallysignificant, dose-related, increase in cholesterol levels throughout most of the study. Globulin 

values were elevated in the high-dose females throughout most of the study [weeks 26, 52, and 

78] and in mid-dose females only at week 78. There were no treatment-related alterations in the 

liver enzymes monitored. There was a dose-related increase in urine volume in females [37%, 

40%, and 54% with increasing dose] at week 77 only. 

Increased liver weight [males ↑11%-18%; females ↑21%-32%] was observed in both sexes at the 

high-dose level, although the values in males did not attain statistical significance. Females at all 

dose levels displayed an increase in ovarian weight, but there was no dose-response, and the 

standard deviation of the low- and high-dose female groups exceeded the means.

In the liver, there was a dose-related increase in hepatocellular hypertrophy in both sexes, which 

was statistically-significant at the mid-dose level in males and at the high-dose level in both 

sexes. There was a statistically-significant increase in hepatocellular adenomas in high-dose 

females [10%] compared to the control and other dose groups. The majority of the liver 

adenomas were observed at the terminal sacrifice, and the incidence is within the historical 

control incidence of the testing facility [0%-10%]. One hepatocellular carcinoma was observed 

in one of the control groups and in one high-dose female. The combined incidence [adenomas 

and carcinomas] of liver tumors in the high-dose females [11.7%] is slightly outside the 

historical control incidence of the testing facility [0%-10%]. Males did not display an increase in 

liver tumors. 

The systemic toxicity NOAEL is 50 ppm [males 2 mg/kg/day; females 3 mg/kg/day], based 

on hepatocellular hypertrophy and increased cholesterol in both sexes and decreased bodyweight gain in females at the systemic LOAEL of 1000 ppm [males 44 mg/kg/day; females 

60 mg/kg/day]. 

This guideline chronic toxicity/carcinogenicity study is classified ACCEPTABLE, and it 

satisfies the guideline [OPPTS 870.4300; §83-5] for a chronic toxicity/ carcinogenicity study in 

the rat.

870.4200b Carcinogenicity (feeding) - Mouse

In a carcinogenicity study [MRID 42737201], 60 CD-1 mice/sex/dose were administered 

metaldehyde [>99%; Lot # 5448] via the diet at concentrations of 0 ppm [2 control groups], 25 

ppm [males 4.0 mg/kg/day; females 4.8 mg/kg/day], 100 ppm [males 15.9 mg/kg/day; females 

19.7 mg/kg/day], and 300 ppm [males 48.9 mg/kg/day; females 59.8 mg/kg/day] for 18 months.

There were no treatment-related effects on survival or clinical signs in either sex, and body 

weights, body-weight gains, and food consumption were comparable among the groups for both 

sexes.

The hematologic parameters monitored were comparable among the groups [both sexes]. 

Clinical chemistry and urinalysis parameters were not monitored. 
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At necropsy, there were no gross lesions attributed to treatment in either sex. With the exception 

of liver weights in males, which displayed a dose-related increase (although statistical 

significance was not attained), organ weights were comparable among the groups [both sexes]. 

Non-neoplastic lesions: The incidence [overall: high-dose males 62% vs 30%-33% control; highdose females: 30% vs 7%-15% control] and severity of hepatocellular hypertrophy were 

increased in both sexes at the high-dose level compared to the control groups. The majority of 

the mice with hepatocellular hypertrophy were diagnosed at terminal sacrifice.

Neoplastic lesions: There was no statistically-significant increase in the incidence of liver tumors 

in either sex, although the high-dose males displayed a slight increase [15 adenomas and 3 

carcinomas] compared to both control groups [8 adenomas/1 carcinoma and 8 

adenomas/3carcinomas].

The systemic toxicity NOAEL is 100 ppm [15.9 mg/kg/day (males); 19.7 mg/kg/day (females)], 

based on a significantly increased incidence of hepatocellular hypertrophy in both sexes at the 

LOAEL of 300 ppm [48.9 mg/kg/day (males); 59.8 mg/kg/day (females)]. No other 

toxicological effects were observed in either sex. The incidence of tumors was comparable 

among the groups [both sexes].

This guideline carcinogenicity study is classified ACCEPTABLE/Guideline. However, the dose 

levels were not considered adequate for assessing the carcinogenic potential of metaldehyde, and 

a supplementary study was performed [MRID 44625101; separate DER]. In the 90-day mouse 

study [not submitted to the Agency] performed to determine dose levels to be used in the current 

study, mortality was said to have been observed at 3000 ppm and 10000 ppm and dose-related 

increases in liver weight and hepatic lesions were reported in both sexes at ≥300 ppm. The 

supplemental carcinogenicity study [MRID 44625101] was performed using one dose level of 

metaldehyde [1000 ppm]. At 1000 ppm, there was a treatment-related increase in the incidence 

of hepatocellular adenomas in both sexes when compared to controls. Dosing was considered 

adequate based on the increased incidence of liver lesions [liver single cell/focal/multifocal 

necrosis (males) and hepatocellular eosinophilic cell foci (females)] in both sexes, in addition to 

hepatocellular hypertrophy (both sexes), which was the only treatment-related finding in the 

current study at 300 ppm. When all the information, including the 90-day study (MRID 

43297701), are considered together, MRID 42737201 and MRID 44625101 satisfy the guideline 

requirement [OPPTS 870.4200; §83-2] for a carcinogenicity study in the mouse.

In a carcinogenicity study [MRID 44625101], metaldehyde was administered to 60 Crl:CD-1®-

(ICR)BR mice/sex/dose via the diet at dose levels of 0, 0, and 1000 ppm [equivalent to 0, 0, 135 

mg/kg bw/day (males)/163 mg/kg bw/day (females)] for at least 78 weeks. 

There were no compound-related effects on mortality, clinical signs, body weight, food 

consumption, or hematology in either sex. With the exception of the liver, organ weights were 

comparable to those of the control groups for both sexes. Liver weights were increased 

significantly in both sexes at 1000 ppm compared to both of their respective control groups. 

Gross and histologic pathology findings were comparable among the groups for both sexes, with 
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the exception of the liver. Hepatocellular hypertrophy was observed in both sexes at 1000 ppm. 

Males at 1000 ppm displayed single cell necrosis, focal or multifocal necrosis, pigment 

accumulation, and sinusoidal. Females at 1000 ppm displayed a small increase in the incidence 

of hepatocellular eosinophilic cell foci. There was a significant increase in the incidence of 

hepatocellular adenomas in both sexes [males: 4 and 5 vs 14; females: 1 and 0 vs 5], with the 

males displaying the greater effect. Males also displayed a slight increase in hepatocellular 

carcinomas [2 and 2 vs 4] compared to both control groups. 

Under the conditions of this study, at the only dose of metaldehyde tested [1000 ppm; 135 

(males)/163 (females) mg/kg/day)], increased liver weight (both sexes), hepatocellular 

hypertrophy (both sexes), liver single cell/focal/multifocal necrosis (males), liver pigment 

accumulation (males), sinusoidal histiocytosis (males), hepatocellular eosinophilic cell foci 

(females), and hepatocellular adenomas (both sexes) were observed. The NOAEL is not 

established in the current study. However, based on a previous mouse carcinogenicity study in 

the same strain of mouse [MRID 42737201], in which an increased incidence of hepatocellular 

hypertrophy was observed in both sexes at the highest dose tested [300 ppm; 48.9 (males)/59.8 

(females) mg/kg/day], the NOAEL is 100 ppm [15.9 (males)/19.7 (females) mg/kg/day], with the 

LOAEL based on an increased incidence of hepatocellular hypertrophy in both sexes.

At the dose tested in the current study, there was a treatment related increase in the incidence of 

hepatocellular adenomas in both sexes when compared to the controls. Dosing was considered 

adequate based on the increased incidence of liver lesions [liver single cell/focal/multifocal 

necrosis (males) and hepatocellular eosinophilic cell foci (females)] in both sexes, in addition to 

the hepatocellular hypertrophy observed in the previous study at 300 ppm.

This carcinogenicity study in the mouse is Acceptable/non-guideline. It is non-guideline since 

only one dose level was tested. The study was performed as a supplement to a previous 18-

month mouse carcinogenicity study [MRID 42737201] and should be considered along with the 

previous study. Together, the two studies satisfy the guideline requirement for a carcinogenicity 

study [OPPTS 870.4200; OECD 451] in mice. 

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, reverse gene 

mutation assay in bacteria

MRID 48666101 (2011)

Classification: acceptable/guideline

Salmonella typhimurium strains TA98, TA100, TA102, TA1535, and 

TA1537; concentrations of 0, 3, 10, 33, 100, 333, 1000, 2500, or 5000 

μg/plate (+/- S9-activation); insoluble at ≥2500 μg/plate +/-S9. 

No evidence of induced mutant colonies over background.

Cytogenetics

Guideline 870.5300, in vitro

mutagenicity (mammalian forward 

gene mutation) 

MRID 48721401 (2011)

Classification: acceptable/guideline

Tested up to solubility limit (≥ 600 μg/mL +/-S9); failed to induce either 

a cytotoxic or a mutagenic effect. There was no evidence of induced 

mutant colonies over background.
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Guideline 870.5385, in vivo

cytogenetic mutagenicity assay

MRID 48788201 (2012)

Classification: acceptable/guideline

in vivo rat bone marrow chromosome aberration test at doses of 0, 62.5, 

125, and 250 mg/kg (M) or 0, 31.25, 62.5, and 125 mg/kg (F); no 

evidence of cytogenicity in this whole animal chromosome aberration 

assay.

Other Genotoxicity

Guideline 870.5395, micronucleus 

assay

MRID 42044006 (1990)

Classification; Unacceptable/guideline

highest dose tested (100 mg/kg); MTD not reached

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

Study was waived by HASPOC (TXR# 0056524; dated 2/21/13).

870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (MRID 46223401), metaldehyde (98.3% a.i., batch # 31509) 

was administered via the diet to 10 Sprague-Dawley Crl:CD® (SD) IGS BR rats/sex/group at dose 

levels of 0 [basal diet], 100, 500, and 2500 ppm (equivalent to 0, 8, 39, 185 mg/kg bw/day) for 90 

consecutive days. Clinical signs, body-weight development, food and water consumption were 

monitored during the study, and ophthalmoscopic examination of the control and high-dose rats 

was performed pre-test and during final week of the study. Neurobehavioral assessment (functional 

observational battery and motor activity testing) was performed in all rats/sex/group prior to the 

start of dosing and during weeks 2, 4, 8, and 12. At study termination, 5 animals/sex/group were 

euthanized and perfused with gluteraldehyde: paraformaldehyde via the heart, following initial 

whole-body perfusion with heparinzed saline, for neuropathological examination. Of the perfused 

animals, all control and high-dose rats were subjected to histopathological evaluation of brain and 

peripheral nervous system tissues.One high-dose female was sacrificed [day 22] due to poor 

condition [bilateral hindlimb paralysis], which was observed initially on day 10. There were no 

other treatment-related deaths. Body weights and body-weight gains of the males were comparable 

among the groups throughout the study. Females at the mid- and high-dose levels displayed 

slightly lower body weights [↓5%-6%] throughout the study. Body-weight gains of the mid-dose 

females [80% of control; not statistically significant] and high-dose females [↓30%; statistically 

significant] were lower during the first week and remained lower than control throughout the study, 

although statistical significance was not attained and a dose-response was not always apparent. 

Food consumption was comparable among the male groups but lower than control in the high-dose 

females throughout the study. Food efficiency was comparable among the groups for both sexes.

No ocular effects were observed in either sex.

Differences in motor activity parameters were observed sporadically, but there was no consistent 

dose response, some standard deviations were greater than the means, and statistical significance

was rarely attained. Differences in grip strength and startle reflex values were observed 
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sporadically also, but there was no consistent dose response and statistical significance was rarely 

attained.

At termination, no macroscopic abnormalities were reported for either sex. No treatment-related 

changes were observed in brain weight for either sex, and no treatment-related histopathological 

alterations were reported in either sex. 

NOTE: The positive control data [February-April, 2003] bring into question the capability the 

testing facility had to adequately assess neurotoxicity at the time the metaldehyde study was 

performed [February-October, 2002]. Additionally, the available positive control data do not 

provide adequate evidence of the ability of the testing facility to identify a neurotoxic compound. 

Since the trimethyltin [1 mg/kg] animals did not survive to study termination, no FOB assessment 

was performed on these animals [no motor activity, grip strength, startle reflex]. Neuropathology 

was demonstrated following trimethyltin exposure, however. The only neuropathological findings 

in the acrylamide-treated animals [15 mg/kg] were contraction vacuoles in the sciatic and/or tibial 

nerves, mainly in females. No axonal degeneration was observed. Findings in the acrylamide 

females were not observed in the acrylamide males, and a sex difference following acrylamide 

exposure is not expected. Individuals performing the various assessments were not identified in 

either the metaldehyde study or the positive control study, and methodology and apparatus 

descriptions are not adequate. Further, a more definitive explanation/presentation of the data, 

especially the motor activity data are required. 

Provisionally, the LOAEL for neurotoxicity can be set at 500 ppm [39 mg/kg/day], based on 

increased motor activity in females. The NOAEL can be set at 100 ppm [8 mg/kg/day]. At 

the highest dose tested [2500 ppm (185 mg/kg)], bilateral hindlimb paralysis was observed in 

one female, and females displayed decreased body-weight gains during the first week of the 

study.

The study is classified as Unacceptable (guideline), and it does not satisfy the guideline 

requirement for a subchronic neurotoxicity study in rats (870.6200b). The study is classified 

Unacceptable since the results suggest little neurotoxicity following exposure to metaldehyde; 

more importantly, the positive control data submitted do not demonstrate proficiency of the testing 

facility to detect alterations in the neurotoxicity parameters monitored.

A.4.8 Metabolism

870.7485 Metabolism - Rat

In a metabolism study in rats (MRID 42300901),the absorption, distribution, metabolism and 

excretion of metaldehyde were studied in groups of male and female Sprague-Dawley rats 

administered a single oral gavage dose of 10 or 100 mg/kg 14C-metaldehyde or following 

repeated oral dosing of 10 mg/kg non-labeled metaldehyde for 14 days followed by a single dose 

of labeled metaldehyde on day 15. In addition, the pharmacokinetics of metaldehyde was

evaluated in rats receiving a single oral dose of 10 mg/kg labeled metaldehyde.

Metaldehyde was rapidly absorbed, distributed, and metabolized in rats for all dosing regimens. 

The 7-day recoveries were >94% for all groups. Most of the radioactivity was recovered in 
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expired air (78-98% of administered dose) within 24 hours (48 hours for high-dose females), the 

majority of which was reported to be 14CO2. Recovery in urine and feces was low for all dosing 

groups (2.5-5.1%). Slight sex-, dose-, and regimen-related effects on metaldehyde excretion were 

found. The recovery of administered radioactivity was greater in low-dose animals than in highdose and repeated dose animals. The pharmacokinetics study showed that males reached peak 

blood levels and excreted radioactivity faster than females. The concentration of total 

radioactivity in the blood at peak levels was similar for both sexes, but the concentration of intact 

metaldehyde was >50% higher in females than in males at peak, first and second blood halflives.

Recovered radioactivity in tissues/carcass after 7 days was similar for all dose groups (7-11% of 

administered dose). High concentrations of radioactivity were recovered in nervous tissue, fat, 

liver, and reproductive organs. Tissue examination of low-dose animals showed that radioactive 

residues (percent of administered dose) were highest in the carcass at peak, first and second 

blood half-lives. At second blood half-life, percent dose in the liver exceeded that of any other 

tissue (except carcass) in both males and females. No clinical signs of toxicity were observed.

Classified acceptable for a metabolism study under Guideline series 85-1.
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Appendix B. Metabolism Summary Table

Table B.1 - Tabular Summary of Metabolites and Degradates

Chemical 

Name Commodity

Percent TRR (PPM) 1

Structure

Matrices -

Major 

Residue2 

(>10%TRR)

Matrices -

Minor 

Residue2

(<10%TRR)

Parent:

Metaldehyde

Lettuce 95.3

Sugar beet -

root

35

Sugar beet -

top

33

Rat *

Degradate:

NonExtractable 

Residues

Lettuce <5

N/A

Sugar beet -

root

43.4

Sugar beet -

top

43.2

Rat ND 2.5-5.1

CO2 Rat 78-98

Lettuce; 43923301; 13.8 lb ai/A; 10x; single directed application; 28 days.

Sugar beets; 43923302; 13.76 lb ai/A; 10x; single directed application; 48 days.

Rat: 42300901; single gavage dose 10 or 100 mg/kg, repeated dose 10 mg/kg/day for 14 days, 

then single dose 14C [10 mg/kg], Sprague-Dawley, 1 day depuration

* = metaldehyde and acetaldehyde detected in plasma; no quantification available at this time.

ND = not detectable

Note 1: Confined Rotational Crop study waiver granted by CHEMSAC on 12/9/04.

Note 2: Livestock metabolism and feeding studies (ruminant & poultry) waiver granted 

Metaldehyde: 3/11/97)

O

O

O

O

H C3CH3

CH3H C3
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Appendix C. Physical/Chemical Properties

TABLE C.1. Physicochemical Properties of Metaldehyde

Parameter Value Reference

Melting point/range 246°C Metaldehyde RED, PC 

Chapter

pH Not applicable due to the low solubility of 

metaldehyde in water. N/A

Density 1.27 g/cm3

Metaldehyde RED, PC 

Chapter

Water solubility (20°C) 0.222 g/L at 20°C

Solvent solubility 

(g/L at 20.3-22.4°C)

5.21 x 10-2 in hexane

0.53 in toluene

1.56 in tetrahydrofuran

1.73 in methanol

Vapor pressure 6.6 ± 0.3 Pa at 25°C

Dissociation constant (pKa) 3.5 Pa (m3/mol) (Henry’s Law Constant)

Octanol/water partition 

coefficient, Kow

1.33 (log Kow = 0.12) at 20°C
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Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review 

pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website10. 

 

10 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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Appendix E. Exerpt from email message from Melanie Biscoe (EFED) to W. Donovan 

(HED), 15-JUL-2014.

Metaldehyde ground water 

modeling comparison

30-year simulation 

(metaldehyde applied first 6 years only)

Acute 

(Peak)

ug/L

Chronic 

(Post-Breakthrough Average)

ug/L

2013 Drinking Water 

Assessment

PRZM-GW v. 1.0

1,740

(WI Sands)

635

(WI Sands)

Initial Scenarios

PRZM-GW v. 1.07

1,880

(FL Citrus)

915

(NC Coastal) Revised Scenarios distributed 

March 2014