                    UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C. 20460

                             OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



MEMORANDUM

March 15, 2012
TXR # 0052354

SUBJECT:	Acetamiprid:  Summary of Hazard and Science Policy Council (HASPOC) Meeting of March 15, 2012:  Recommendation on the need for a 28-day inhalation study. 

PC Code:  099050
DP Barcode:  N/A
Decision No.:  N/A
Registration No.:  N/A
Petition No.:  N/A
Regulatory Action:  N/A
Risk Assessment Type:  Single Chemical/ Aggregate
Case No.:  7620
TXR No.:  0052354
CAS No.:  210880-92-5
MRID No.:  N/A
40 CFR:  §180.586
	
FROM:	Kristin Rury, MPH
		Executive Secretary, HASPOC
		Health Effects Division (7509P)

THROUGH:	Jess Rowland, Co-Chair
      Anna Lowit, Ph.D, Co-Chair
            HASPOC
		Health Effects Division (7509P)

TO:		Elizabeth Holman, Chemist
      Alan C. Levy, Ph.D., Toxicologist
		Suku Oonnithan, Biologist
		Christina Swartz, Chief 
      Risk Assessment Branch II (RABII)
            Health Effects Division (HED; 7509P)          
	
MEETING ATTENDEES:  

HASPOC Members:  Elissa Reaves, Jeff Evans, Jess Rowland, John Kough, Michael Metzger, PV Shah, Ray Kent
Presenters:  Christina Swartz, Suku Oonnithan, Michael Doherty

Other Attendees:  Elizabeth Holman Michael Doherty, Kristin Rury, Julie Van Alstine.

I.  PURPOSE OF MEETING:

Risk Assessment Branch II (RAB II) is preparing an acetamiprid risk assessment for several Interregional Research Project 4 (IR-4) uses and beginning the re-evaluation of all existing acetamiprid uses for registration review.  Acetamiprid is a member of the neonicotinoid class of insecticides.  It is registered for use on a variety of agricultural crops and ornamental plants, as seed and crack and crevice treatments, and for use in food handling establishments.  In addition, acetamiprid is registered for residential handler use as a mattress treatment, and as an outdoor perimeter treatment.  In agricultural settings, acetamiprid is applied using ground- or aerial-based broadcast spray equipment.  As a result of the registered use patterns, repeated exposures to aerosolized acetamiprid may occur.  The toxicity database does not contain a repeated exposure inhalation toxicity study; therefore, an oral study has been used to assess risks via the inhalation route of exposure for both residential and occupational handlers.  The Hazard Science Policy Council (HASPOC) met on March 15, 2012 to discuss the need for a 28-day rat inhalation study to support registered and proposed uses of acetamiprid.  The HASPOC discussed both the exposure estimates using the point of departure (POD) from the developmental neurotoxicity study and the potential mitigation options available to reduce handler exposure.  The HASPOC also discussed whether an additional inhalation study would provide a more sensitive endpoint for risk assessment while being protective of the offspring effects seen in the developmental toxicity study.    

II.  SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENTS:

Acetamiprid is a selective insecticide intended for use to control various sucking/chewing insect pests that feed upon fruit and vegetable crops.  It is a member of the chloronicotinyl (neonicotinoid) class of insecticides.  Acetamiprid is registered for use on agricultural crops and ornamental plants, as seed treatments, and for use in food handling establishments.  In addition, acetamiprid is registered for residential uses as crack and crevice and mattress treatments, and as outdoor termiticide and perimeter treatments.  Formulations include dry flowable (DF), wettable powder (WP), water-soluble packet (WSP), emulsifiable concentrate (EC), and ready-to-use liquid (RTU).  Occupational handlers are expected to be exposed to acetamiprid for short- and intermediate-term durations; however, residential handlers are expected to be exposed for short-term durations only.  

The most recent risk assessment for acetamiprid was completed on 11/30/2011 (Memo, M. Doherty et al. D385260, D388794) and addressed potential risks associated with use on soybeans and in food/feed handling establishments.  In the absence of a route-specific inhalation toxicity study, the inhalation risk assessment was based on the POD and the endpoint from an oral toxicity study.  The endpoint for risk assessment was offspring effects [decreased body weight and body weight gains in the offspring, decreased early pup survival on post-natal days (PND) 0-1, and decreased startle response on PND 20/60 in males] in the developmental neurotoxicity study observed at the LOAEL of 45 mg/kg/day.  The POD to assess short- and intermediate-term inhalation exposures to acetamiprid was the NOAEL of 10 mg/kg/day.  No Food Quality Protection Act (FQPA) Safety Factor is needed (1X) for acetamiprid because there are no residual uncertainties for pre- or post-natal toxicity.   

Inhalation MOEs from occupational activities range from 290 to 250,000, with most of the values being greater than 3,000 [Level of Concern (LOC) = 100].  For residential uses, inhalation MOEs range from 3,600 for handlers applying an outdoor perimeter treatment to 560,000 for adults, post-application, following indoor crack and crevice treatment.

III. STUDY WAIVER REQUESTS

Inhalation Study

Previously, the Office of Pesticide Programs (OPP) used a set of criteria to determine whether or not an inhalation study could be waived.  These criteria considered the scientific information available for the chemical, including its: (1) degree of irritation and corrosivity; 2) volatility; 3) aerosol particle size; and 4) Acute Toxicity Category and extrapolated MOEs (e.g., MOEs 10 times higher than the target).  In 2009, OPP developed an issue paper on risk assessment approaches for semi-volatile pesticides.  As part of that issue paper, an analytical comparison was conducted of oral and inhalation experimental toxicology studies.  In general, this analysis showed that the degree to which oral PODs were protective of potential inhalation toxicity varied.  In many cases the oral POD was protective but in some cases the inhalation PODs were significantly more sensitive.  Currently, OPP uses a weight of the evidence (WOE) approach that builds upon OPP's experience using the criteria listed above conclusions from the 2009 SAP.  As approaches for route to route extrapolation continue to evolve and improve, OPP may incorporate additional considerations into the WOE analysis.   

Inhalation exposure can be to vapors, droplets, and/or particles/dusts.  The form of this exposure is determined by a number of factors including physical-chemical properties, use pattern, and exposure scenarios.  This interim WOE approach considers:

   1. Physical-chemical properties:  Vapor pressure and Henry's law constant are key considerations with respect to the volatilization after sprays have settled.  Acetamiprid (MW = 222.7 g/mol) has a low vapor pressure (1 x10[-8] mm Hg at 25°C) and an estimated Henry's law constant of 6.9 x 10[-8] atm-cu m/mole at 25°C.  However, low vapor pressure and/or Henry's law constant does not preclude exposure to aerosolized droplets or particles/dusts.  

   2. Use pattern & exposure scenarios:  Any application scenario that leads to inhalation of droplets needs to be considered in the WOE analysis for an inhalation toxicology study waiver request.  Airblast and aerial applications are more likely to lead to higher occupational handler inhalation exposure, particularly to droplets; and may also contribute to spray drift.  In the case of acetamiprid, the highest inhalation exposures were associated with mixer/applicator seed treatment activities with canola and mustard seed with the use of a respirator (MOE = 290).
 
   3. Margins of Exposure (MOEs): The MOE estimates for inhalation scenarios were calculated using the NOAEL from an oral toxicity study, and should be considered in the WOE analysis for an inhalation toxicology study waiver.  In the past, OPP has used MOEs of approximately 10 times higher than the level of concern as a benchmark for granting waiver requests (i.e., in the case of acetamiprid, higher than 1,000).  The 2009 analysis suggests this approach is appropriate for most pesticides, but not all.  Under the interim WOE approach, MOEs from 10-100 times greater than the level of concern will be considered in combination with other factors discussed here.  All worker exposures are assessed as short-and intermediate-term based on label-prescribed uses and expected exposure durations.  The HASPOC notes that the highest exposure estimate (MOE = 290) assumes the use of a respirator when treating canola and mustard seed with a WP formulation of acetamiprid.  However, this is considered a highly protective exposure estimate because it uses a conservative (high-end) amount of seed treated.  Despite the use of a respirator, the MOEs for occupational handlers do not meet the waiver criterion for MOEs ranging from 10-100 times the LOC.   However, for residential exposures, the MOEs are significantly higher (inhalation MOEs range from 3,600 to 560,000), and meet the waiver criterion. 

   4. Toxicity:  Acetamiprid and its metabolites have relatively low (Category III or IV) acute toxicity via inhalation and dermal routes of exposure in the rat and there is no evidence of dermal sensitization or eye irritation.  Acetamiprid showed somewhat higher toxicity (Category II) via the oral route.  Acute toxicity testing of the WP, WSP, and RTU formulations resulted in Category III or IV designations for all routes of exposure.  Overall, the toxicology data showed that in all species tested, generalized nonspecific toxicity was observed as decreases in body weight, body weight gain, food consumption and food efficiency.  Generalized effects were also observed in the liver in the form of hepatocellular hypertrophy in both mice and rats and hepatocellular vacuolation in the rat.  These effects are considered to be adaptive.  Other effects observed in the oral studies include amyloidosis of multiple organs in the mouse oncogenicity study, tremors in high dose females in the mouse subchronic study, and microconcretions in the kidney papilla and mammary hyperplasia in the rat chronic/oncogenicity study.  Decreased pup survival and neurological effects in rats are attributable to exposure to acetamiprid and these effects serve as the basis for acute risk assessments.  An oral POD of 10 mg/kg/day based on offspring effects (decreased survival, body weight and body weight gains and decreased startle response) observed at 45 mg/kg/day in a developmental neurotoxicity study is used for assessing short and intermediate term risks via inhalation exposure resulting from occupational and residential uses.  For evaluating long-term exposure, risks are evaluated based on body weight effects and liver effects (hepatocellular vacuolation).  Based on the completeness of the database, the observed effects, and the endpoints used for risk assessment, the FQPA Safety Factor has been reduced to 1X.  Acetamiprid has been classified as not likely to be carcinogenic to humans.

When considering the need for an inhalation toxicity study, the Agency will evaluate other pesticides which share the same MOA and/or are in the same class.  These pesticides can provide important information with respect to potential inhalation toxicity.  Specifically, if other similar pesticides show inhalation toxicity studies to be more sensitive, an inhalation toxicity study may be required regardless of MOE, depending on the exposure profile.  Acetamiprid is a member of the neonicitinoid class of insecticides, which also includes the following insecticides:  clothianadin, imidacloprid, dinotefuran, thiamethoxam, and thiacloprid.  HASPOC recently concluded that a 28-day inhalation study was required for clothianadin (J. VanAlstine, TXR#0055320, 03/23/2012).  Inhalation studies are available for imidacloprid, dinotefuran and thiacloprid.  No effects were noted in the inhalation studies for imidacloprid and dinotefuran at the highest concentration tested, and thus these studies were not used for PODs in the risk assessment.  However, the thiacloprid inhalation study is the basis of inhalation risk assessment PODs for that chemical.  Note that the toxicological profile for thaicloprid is quite different from that of the other neonicotinoid insecticides.  
 
   5. Risk Assessment Implications:  Currently, HED has not identified any risks of concern for occupational handlers exposed via the inhalation route; however, risk estimates are approaching HED's level of concern for some scenarios that include maximum PPE mitigation (respirator).  Given the low MOEs, a route-specific inhalation toxicity study will reduce uncertainty associated with the use of an oral POD and provide a more refined, accurate estimate of the MOEs.  Despite an inhalation study's inability to address the concerns for developmental toxicity associated with acetamiprid, the toxicity database showed consistent NOAELs across studies and species.  An inhalation study might provide additional information to inform the human health risk assessment by allowing HED to select a route-specific endpoint and dose that would still be protective of offspring effects.    
IV.  HASPOC RECOMMENDATIONS:

The HASPOC concluded based on a WOE approach that a 28-day inhalation toxicity study is required at this time to reduce uncertainty associated with the use of an oral POD for assessing risk via the inhalation route.  This determination considered all of the available hazard and exposure information for acetamiprid, including: (1) the use of an oral POD that results in MOEs as low as approximately 300 for risk via the inhalation route resulting from occupational exposures; and (2) the toxicological profile of acetamiprid.




