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 R equirement of an Immunotoxicity Study for Metaldeh yde . **PC Code:** 0 53001 **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 **T XR 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 Branch es V & VII Health Effects Division (7509P) EL ECTRONI C REVIEW PARTI CI PANTS HASPOC Members : Anna Lo wit, E lissa Reaves, E lizabeth Mendez, J. Rowland, J. Kough, J.

Chen, P resenter: L . TaylorPage 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. T he metaldeh yde risk assessment team r equested that HASPOC conduct an electronic review to specifically consider the need for an immunotoxicity study (870.7800) for metaldeh yde . **II. SUMMARY OF USE PROFILE, EXPOSURE, & HAZARD CONSIDERATIONS**  **: a.**  **Use Profile:** Metaldeh yde is a molluscicide used to control snails and slugs on a wide variet y of tree, fruit, and vegetable crops. Metaldehy de 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. T he Section 3 registration of metaldeh yde includes proposed uses on grass grown for seed, leaf petioles [Crop Subgroup 4B], wetland taro, field & sweet corn, mint, and soy beans, and for amendments to existing tolerances [crop subgroups 13 - 07A, B, & G]. There is potential for short - and intermediate - term occupational exposure to metaldeh yde during handling (mixing, loading , appl yi ng) liquid conce ntrates and appl yi ng 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 metaldeh yde are the liver, male reproductive organs, and nervou s sy stem. 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 an d atroph y 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 ( 9 0 mg/kg/day) in the dog chronic oral toxicity

stud y. 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 h ydrolysis to acetaldeh yde, which is rapidly absorbed. Metaldeh yde is also absorbed intact in the stomach and distributes widely throughout the body and readily

crosses th e blood - brain barrier. Since the PODs are based on neurotoxicity in the most sensitive species (dog), given the lack of evidence of an y effect on the immunePage 3 of 5

sy stem, the PODs are considered protective of any potential immunotoxicity . The nervous sy stem ef fects of metaldehy de are theorized to result from decreases in the concentrations of neurotransmitters in the brain, primaril y γ - aminobuty ric acid (GABA), serotonin (5 - HT), and norepinephrine (NE). In creases in the activit y of monoamine oxidase, an enzy me 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. Hy perthermia, 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 metaldeh yde guideline database. Parameter Findings Hematology

Indicators (WBC changes) None Clinical Chemistry Indicators (A/G Ratio) None Organ Weight Indicators (Spleen, Th ymus) None Histopathology

Indicators (Spleen, Th ymus, Lymph nodes) None Toxicity Profile (Target Organs) Liver, Male Reproductive Organs, Nervous s ys tem **Evidence for Immunotoxicity from SAR Chemicals** 
**– Retrospective Analysis**  None of the chemicals included in the retrospective anal ys is 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 d ietary exposure for all populations is based on clinical signs of neurotoxicity observed in all dogs of each se x 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 day s of dosing at the LOAEL of 150 mg/kg/day in the rat developmentalPage 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 th e dog chronic oral (diet) toxicity study . The POD for chronic dietary

exposure is based on death and atroph y 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 y oung following in utero (rats and rabbits) and pre - and post - natal exposure (rats) to metaldehy de. Developmenta l toxicity and reproductive toxicity were not observed. The FQPA safety factor was reduced to 1X. M etaldeh yde is classified as “Suggestive Evidence of Carcinogenicit y” based on benign liver tumors seen in both sexes of mice and in female rats. M utagenicity is not of concern . Q uantification of risk using a non - linear approach; i.e., RfD, for metaldeh yde will adequatel y account for all chronic toxicity , including carcinogenicity that could result from exposure to metaldeh yde. That conclusion is based on the following considerati ons: (1) the tumors found are commonly

seen in the mouse; (2) the liver tumors in both species were benign; (3) metaldehy de 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 lab oratory . The POD for short - term incidental oral and inhalation exposure s is based on clinical signs of neurotoxicity

at the LOAELof 90 mg/kg/day in the chronic oral toxicity study in the dog (NOAEL = 30 mg/kg/day) . T he 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 initiall y 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 (N OAEL = 10 mg/kg/day) . Atrophy of the testes and prostate was also observed in the subchronic dog stud y. Th ere was no hazard observed via the dermal route with lack of s ys temic toxicity following 21 day s of dermal exposure to rabbits. The endpoints of con cern were all assessed in this study , and there is no developmental or reproductive concern; therefore, quantification of dermal risk wa s not required. **I V**  **. RATIONALE**  **FOR THE WAIVER REQUEST:** The HASPOC recommends that a waiver can be granted for required immunotoxicity study for metaldeh yde, based on the following considerations:

 The toxicology

d atabase reveals no evidence of treatment - related effects on the immune sy stem suggesting that the immune sy stem is not the primary target organ.

 The known target organs of metaldehyde are the liver, male reproductive organs, and the nervous s ys tem.Page 5 of 5

The dog is the most sensitive species to the effects of metaldehy de; therefore, an immunotoxicity study i n 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 metaldeh yde hazard and exposure information, the HASPOC concludes that an immunotoxicity study is not required .