                 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

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 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 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. 

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.  

