Page 1 of 5

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

 OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

Date: November 12, 2013

SUBJECT: Metaldehyde: Summary of Hazard and Science Policy Council (HASPOC): 

Recommendations on the Requirement of an Immunotoxicity Study for 

Metaldehyde. 

PC Code: 053001 DP Barcode: N/A

Decision No.: N/A Registration No.: N/A

Petition No.: N/A Regulatory Action: N/A

Risk Assessment Type: Section 3 Case No.: N/A

TXR No.: 0056825 CAS No.: 108-62-3

MRID No.: N/A 40 CFR: §180.535

FROM: Kristin Rury, MPH

Executive Secretary, HASPOC

Health Effects Division (7509P)

THROUGH: Jess Rowland, Co-Chair, HASPOC

Anna Lowit, Ph.D., Co-Chair, HASPOC

Health Effects Division (7509P)

TO: Linda Taylor, Ph.D.

Michael Metzger, Branch Chief

Risk Assessment Branches V & VII

Health Effects Division (7509P)

ELECTRONIC REVIEW PARTICIPANTS

HASPOC Members: Anna Lowit, Elissa Reaves, Elizabeth Mendez, J. Rowland, J. Kough, J. 

Chen, 

Presenter: L. Taylor
Page 2 of 5

I. PURPOSE OF REVIEW:

In accordance with the revised 2007 40 CFR Part 158 Toxicology Data Requirements, an 

immunotoxicity study is required for food and non-food use pesticides. Previously, the HED 

Hazard and Science Policy Council (HASPOC) reviewed the metaldehyde toxicity database and 

concluded that an acute neurotoxicity study was not required but that the subchronic inhalation 

study was required (TXR# 0056524). HASPOC did not address the need for an immunotoxicity

study at that time. The metaldehyde risk assessment team requested that HASPOC conduct an 

electronic review to specifically consider the need for an immunotoxicity study (870.7800) for 

metaldehyde. 

II. SUMMARY OF USE PROFILE, EXPOSURE, & HAZARD CONSIDERATIONS:

a. Use Profile:

Metaldehyde is a molluscicide used to control snails and slugs on a wide variety of tree, fruit, 

and vegetable crops. Metaldehyde is formulated as granules (G); pelleted (P/T) baits; and

emulsifiable concentrate (EC), flowable concentrate (FlC), and ready-to-use liquid (RTU/L) 

formulations. Formulated products generally contain 0.13-25% active ingredient.

The Section 3 registration of metaldehyde includes 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].

There is potential for short- and intermediate-term occupational exposure to metaldehyde during 

handling (mixing, loading, applying) liquid concentrates and applying granules. Based on the 

use pattern, long-term exposures (greater than 6 months) are not anticipated. 

b. Toxicity Profile: 

The major target organs following repeated oral exposure to metaldehyde are the liver, male 

reproductive organs, and nervous system. The point of departure (POD) selected for acute 

dietary and short-term incidental oral exposure assessment, was based on clinical signs (ataxia, 

tremor, salivation, twitching) seen on day 1 of dosing in both sexes at the lowest observed 

adverse effect level (LOAEL) in the chronic dog toxicity study (no observed adverse effect level; 

NOAEL = 30 mg/kg/day). The POD selected to estimate chronic dietary and intermediate-term 

incidental oral exposure assessment, is based on death and atrophy of the testes and prostate seen 

at the LOAEL of 30 mg/kg/day in the chronic dog toxicity study (NOAEL = 10 mg/kg/day).

The POD selected for short-term inhalation exposure assessment was based on clinical signs 

beginning during the first week of exposure at the LOAEL (90 mg/kg/day) in the dog chronic 

oral toxicity study. The POD (10 mg/kg/day) selected to estimate intermediate-term inhalation 

exposure risks is based on mortality, and atrophy of the testes and prostate at the LOAEL (30 

mg/kg/day) in the dog chronic oral toxicity study.

In the stomach, metaldehyde undergoes acid hydrolysis to acetaldehyde, which is rapidly 

absorbed. Metaldehyde is also absorbed intact in the stomach and distributes widely throughout 

the body and readily crosses the blood-brain barrier. Since the PODs are based on neurotoxicity

in the most sensitive species (dog), given the lack of evidence of any effect on the immune 
Page 3 of 5

system, the PODs are considered protective of any potential immunotoxicity. The nervous 

system effects of metaldehyde are theorized to result from decreases in the concentrations of 

neurotransmitters in the brain, primarily γ-aminobutyric acid (GABA), serotonin (5-HT), and 

norepinephrine (NE). Increases in the activity of monoamine oxidase, an enzyme involved in the 

metabolism of 5-HT and NE, may be partly responsible for the decreased levels of these 

transmitters. Reduced concentrations of GABA result in dis-inhibition of neuronal excitation, 

which causes seizure activity. Decreases in 5-HT and NE concentrations may also contribute to 

seizure activity because of a lowering of the seizure threshold. Hyperthermia, a common 

presentation of metaldehyde toxicosis, may be secondary to severe muscle tremors.

III. STUDY WAIVER REQUEST

a. Immunotoxicity Study

Indicators for Potential Immunotoxicity – Metaldehyde

There are no signs of immunotoxicity following subchronic or chronic dosing in multiple species 

in the metaldehyde guideline database. 

Parameter Findings

Hematology Indicators

(WBC changes) None

Clinical Chemistry

Indicators

(A/G Ratio)

None

Organ Weight Indicators

(Spleen, Thymus) None

Histopathology Indicators

(Spleen, Thymus,

Lymph nodes)

None

Toxicity Profile

(Target Organs) Liver, Male Reproductive Organs, Nervous system

Evidence for Immunotoxicity from SAR Chemicals – Retrospective Analysis

None of the chemicals included in the retrospective analysis of immunotoxicity studies is related 

to metaldehyde.

Risk Assessment Consideration

An acute POD for females 13-49 was not selected because no appropriate endpoint attributable 

to a single exposure was identified from oral toxicity studies. The POD for acute dietary

exposure for all populations is based on clinical signs of neurotoxicity observed in all dogs of 

each sex on the first day of dosing in the chronic oral toxicity study in the dog (NOAEL = 30 

mg/kg/day). 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 
Page 4 of 5

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

observed following repeat oral exposures, and this endpoint is consistent with endpoints for all 

other exposure assessments, which are based on the dog chronic oral (diet) toxicity study. The 

POD for chronic dietary exposure is based on death and atrophy of the testes and prostate at the 

LOAEL of 30 mg/kg/day in the chronic oral toxicity study in the dog (NOAEL = 10 mg/kg/day). 

There is no concern for increased quantitative or qualitative susceptibility of the young following 

in utero (rats and rabbits) and pre-and post-natal exposure (rats) to metaldehyde. Developmental 

toxicity and reproductive toxicity were not observed. The FQPA safety factor was reduced to 1X. 

Metaldehyde is classified as “Suggestive Evidence of Carcinogenicity” based on benign liver 

tumors seen in both sexes of mice and in female rats. Mutagenicity is not of concern.

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 in both species were benign; (3) metaldehyde 

is not mutagenic; (4) no carcinogenic response was seen in the male rat; and (5) incidence of 

adenomas in the female rat was within the historical control range of the testing laboratory. 

The POD for short-term incidental oral and inhalation exposures is based on clinical signs of 

neurotoxicity at the LOAEL of 90 mg/kg/day in the chronic oral toxicity study in the dog

(NOAEL = 30 mg/kg/day). The clinical signs of neurotoxicity were observed on the first day of 

exposure in all dogs at this dose level and throughout the first week of exposure. The clinical 

signs occurred initially and only at the high dose level and are considered appropriate for the 

short-term exposure duration.

The POD for intermediate-term incidental oral and inhalation exposure is based on death and 

atrophy of the testes and prostate at the LOAEL of 30 mg/kg/day in the chronic oral toxicity

study in the dog (NOAEL = 10 mg/kg/day). 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 was 

not required.

IV. RATIONALE FOR THE WAIVER REQUEST:

The HASPOC recommends that a waiver can be granted for required immunotoxicity study for

metaldehyde, based on the following considerations:

 The toxicology database reveals no evidence of treatment-related effects on the immune 

system suggesting that the immune system is not the primary target organ.

 The known target organs of metaldehyde are the liver, male reproductive organs, and the 

nervous system.
Page 5 of 5

The dog is the most sensitive species to the effects of metaldehyde; therefore, an immunotoxicity

study in rats would not provide a more sensitive endpoint or a point of departure for risk 

assessment. 

IV. HASPOC CONCLUSIONS:

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

information, the HASPOC concludes that an immunotoxicity study is not required.