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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

February 20, 2013 

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

Meeting of January 17, 2013: Revisit of 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: NA Case No.: N/A

TXR No.: 0056556 CAS No.: 135410-20-7

MRID No.: N/A 40 CFR: §180.578

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

Christina Swartz, Chief 

Risk Assessment Branch II (RABII)

Health Effects Division (HED; 7509P) 

MEETING ATTENDEES: 

HASPOC Members: Anna Lowit, Elissa Reaves, Jess Rowland, John Kough, Jonathan Chen, 

Julie Van Alstine, Kristin Rury, Michael Metzger, PV Shah, Ray Kent

Presenters: Elizabeth Holman

Other Attendees: Ayaad Assad, Angela Howard, Christina Swartz, Christopher Schlosser, 

Jessica Kidwell, Jolene Trujillo, Kelly Lowe, Kelly O’Rourke, Matthew Lloyd, Myron Ottley, 

Nancy Dodd (phone), Scott Miller
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I. PURPOSE OF MEETING:

Risk Assessment Branch II (RAB II) prepared an acetamiprid risk assessment for several new 

agricultural uses in 2012 and acetamiprid is currently undergoing Registration Review. 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 

concluded based on a WOE approach that a 28-day inhalation toxicity study was required to 

reduce uncertainty associated with the use of an oral point of departure (POD) for assessing risk 

via the inhalation route based on low margins of exposure (MOEs) (i.e, MOEs < 300) for some 

seed treatment uses and the toxicological profile of acetamiprid.

Since that HASPOC meeting, the registrant has provided additional information and requested 

HED reevaluate the need for the 28-day inhalation study. Therefore, the HASPOC met on 

January 17, 2013 to reevaluate the need for an acetamiprid 28-day inhalation study based on the 

information provided by the registrant. 

II. SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENTS:

Acetamiprid is a selective insecticide used 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, with a subclass designation as a nitromethylene neonicotinoid. 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 wettable powder (WP), dry flowable (DF), 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. In agricultural 

settings, acetamiprid is applied using ground- or aerial-based broadcast spray equipment. In 

residential settings, acetamiprid is applied using handheld equipment. 

In the most recent acetamiprid risk assessment (E. Holman, D394322, 04/19/2012) an oral point 

of departure (POD) of 10 mg/kg/day was used to assess risk via short- and intermediate-term 

inhalation exposure. The POD was based on 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 seen at the lowest observed adverse effect level (LOAEL) of 

45 mg/kg/day in the developmental neurotoxicity . 

Inhalation MOEs from occupational activities range from 260 to 250,000 with baseline attire (no 

respirator). However, with the additional mitigation of a respirator for mixing/loading the WP 

for aerial application, all occupational handler inhalation MOEs range from 1300 to 250,000

(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.
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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 mixing/loading the WP formulation of acetamiprid for aerial 

treatment to tree nuts.

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 
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exposure durations. At the March 15, 2012 meeting, the HASPOC noted that the highest

exposure estimate (MOE = 290) assumed the use of a respirator when treating canola and 

mustard seed with a WP formulation of acetamiprid. However, this WP formulation of 

acetamiprid is not registered for use on canola and mustard seeds. Treating canola and 

mustard seeds with the liquid (EC) formulation does not result in risks of concern 

(MOE=32,000). With the addition of a respirator for mixing/loading WP acetamiprid for 

aerial application, all occupational handler MOEs are > 1300. This is one type of 

mitigation the registrant could elect to put in place, although reducing the application rate 

to higher acreage crops may also achieve MOEs >1000. In addition, for residential 

exposures, the MOEs are significantly higher (inhalation MOEs range from 3,600 to 

560,000).

4. Toxicity: Acetamiprid and its metabolites have relatively low acute toxicity via 

inhalation (Toxicity Category III) and dermal (Toxicity Category III) routes of exposure 

in the rat and there is no evidence of dermal sensitization or eye irritation. Acetamiprid 

showed somewhat higher toxicity (Toxicity Category II) via the oral route. Acute 

toxicity testing of the WP, WSP, and RTU formulations resulted in Toxicity 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. 

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), but was 

not required for thiamethoxam (K. Rury, TXR#0056482, 12/17/2012). 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 PODs for that chemical. Note that 

the toxicological profile for thiacloprid is quite different from that of the other 

neonicotinoid insecticides.

IV. HASPOC RECOMMENDATIONS:

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

proposed addition of a respirator for mixing/loading WP acetamiprid for aerial application, or 

other appropriate mitigation, the HASPOC recommends that a subchronic inhalation toxicity 
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study is not required for acetamiprid at this time. This determination considered all of the 

available hazard and exposure information for acetamiprid, including: (1) registrant’s agreement 

on risk mitigation on the use of the WP label for mixing/loading; and 2) the WP formulation not 

used as seed treatment and 3) the use of an oral POD that results in MOEs greater than 1300 for 

all occupational and residential exposures. However, if the exposure profile for acetamiprid 

changes, the HASPOC will reevaluate the need for a subchronic inhalation toxicity study.