Page 1 of 5 **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460 OFFICE OF**  **CHEMICAL SAFETY AND POLLUTION PREVENTION** 

**MEMORANDUM** March 15 , 201 2 TXR # 0052354 **SUBJECT: Acetamiprid**  **:** Summary of Hazard and Science Policy Co uncil ( 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 **T XR No.:**  0052354 **CAS No.:** 210880
- 92
- 5 **MRID No.:** N/A **40 CFR:** §180. 58 6 **FROM:** Kristin Rury , MPH

Executive Secretary , HASPOC Health Effects Division (7509 P ) **THROUGH:** Jess Rowland , Co
- Chair

Anna Lowit, Ph.D , Co
- Chair HASPOC Health Effects Division (7509P) **TO:** Elizabeth Holman , Chemist

Alan C. Lev y, Ph.D. , T oxicologist Suku Oonnithan , Biologist Christina Swartz, Chief Risk Assessment Branch II (RAB II ) Health Effects Division (HED; 7509P) MEETING ATTENDEES : HASPOC Members: Elissa Re aves, Jeff Evans, Jess Rowland, John Kough, Michael Metzger, PV Shah, Ray

Kent Presenter s : Christina Swartz , Suku Oonnithan , Michael Dohert y Other Attendees: Elizabeth Holman Michael Doherty , Kristin Rury , Julie Van Alstine.Page 2 of 5

I
. PURPOSE OF MEETING: R isk A ssessment B ranch II (RAB II) is preparing an acet amiprid 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 treatment s , and for use in food handling establishments
. Inaddition, ace t amiprid is registered for residential handler use as a mattress treatment, and as an outdoor perimeter treatment. In agricultural setting s , acetamiprid is applied using ground

- or aerial

- based broadcast spray

equipment. As a result of the registered use patterns, repeated exposures to aerosolized acet amiprid 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 sensit i ve endpoint for risk assessment while being protective of the offspring effects seen in the developmental toxicity study
. II. SUMMARY OF USE PROFILE & PREVIOUS RI SK ASSESSMENT S **:** 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 chloronicotiny l (neonicotinoid) class of insecticides. Acetamiprid is registered for use on agricultural crops an d 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. Formulati ons 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; howe ver, 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. Dohert y et al. D385260, D388794) and addressed potential risks associated with use on soy bean s 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 off spring effects [ decreased bod y weight and bod y weight gains in the offspring, decreased earl y pup survival on post

- natal day s (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 Qualit y Protection Act ( FQPA) Safet y Factor is needed (1X) for acetamiprid because there are no residual uncertaintie s for pre

- or post - natal toxicity
.Page 3 of 5

Inhalation MOEs from occupational activities range from 290 to 250,000 , with most of the value s bei n g greater than 3,000 [ Level of Concern (LOC) = 100 ]
. For residential uses, inhalation MOEs range from 3,600 for hand lers 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 i rritation and c orrosivity ; 2) v olatility ; 3) a erosol p article size; and 4) Acut e Toxicity Category and extrapolated MOE s (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 analy tical comparison was conducted of oral and inhalation experimental toxicology studies. In general, this analy sis showed that the degree to which oral PODs were protective of potential inhalation toxicity varied. In man y cases the oral POD was protective but in some cases the inhalatio n PODs were significantl y more sensitive. Currentl y, OPP us es 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 anal ys is. Inhalation exposure can be to vapors, droplets, and/or particles/dusts. The form of this exposure is determined b y a number of factors including physical

- chem ical properties, use pattern, and exposure scenario s . 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 = 2 22.7 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:** An y application scenario that leads to inhalation of droplets needs to be considered in the WOE anal ysis for an inhalation toxicolog y stud y waiver request. A ir

blast and aerial applications are more likel y to lead to higher occupational handler inhalation exp osure, particularly to droplets; and may also contribute to spray

drift. In the case of acetamiprid , the highest inhalation exposure s 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 NOAELfrom an oral toxicity study , and should be considered in the WOE analy sis 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 forPage 4 of 5 gr anting waiver requests (i.e., in the case of acetamiprid , higher than 1,000) . The 2009 anal ys is 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 inter mediate

- 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 highl y protective exposure estimate because it uses a conservative (high

- e nd) 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 L OC. However, for residential exposures, the MOEs are significantly

higher (inhalatio n 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 toxic ity (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 nonspeci fic toxicity was observed as decreases in bod y weight, body weight gain, food consumption and food efficiency . Generalized effects were also observed in the liver in the form of hepatocellular h yp ertrophy in both mice and rats and hepatocellular vacuolati on 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 oncogenicit y study , tremors in high dose females in the mouse subchronic study , and microconcretion s in the kidney papilla and mammary

hyperplasia in the rat chronic/oncogenicit y study. Decreased pup survival and neurological effects in rats are attributable to exposure to acet a miprid 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 ri sks 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 Ag ency

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
. Specificall y, 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

inhalationPage 5 of 5 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 s tudy 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 I**  **mplications** : Currently , HED has not ide ntified an y 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 uncertaint y 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 a ssociated with acetamiprid, the toxicity database showed consistent NOAEL s across studies and species. An inhalation study might provide additional information to inform the human health risk assessment by allowing HE D 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 uncertaint y 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
.