Notes from the November 6, 2013 Imazalil Cancer Risk Concern Meeting with EPA and Janssen PMF

Imazalil Cancer Risk Meeting with Registrant 

Janssen PMF

Wednesday, November 6th at 3-4pm (Eastern Time)

Location: Potomac Yards South, Room PYS 9261

Purpose of Meeting:

The upcoming meeting is intended as an opportunity for the EPA science divisions to ask registrant 

Janssen PMF questions relating to potential cancer risks from imazalil. 

EPA Attendees:

HED: Jaime D’Agostino, Dennis McNeilly, Karlyn Middleton, Christina Swartz, Jess Rowland, 

Charles Wood (calling in)

PRD: Kevin Costello, Meg Hathaway (Chemical Review Manager), Tom Myers

RD: Tony Kish

Registrants (Calling In):

Janssen PMF Bill Goodwine; Dr. Vince Picirillo (Toxicologist)

Agenda:

I. Introductions

II. Upcoming regulatory milestones

a. December 2013 = Docket opening & Preliminary Work Plan (PWP) publication

b. February 2014 = Close of public comment period on Imazalil PWP

c. May 2014 = Final Work Plan (FWP) publishes 

III. Discussion of EPA science team questions and available MoA data

a. HED discussion of options for registrant to move forward on addressing imazalil cancer 

risk concerns

b. Other concerns?

IV. Questions from the Registrants

V. Conclusion (Next Steps/Repetition of Action Items)
Meeting Summary:

On November 6, 2013, staff from HED, PRD, and RD held a teleconference with representatives from 

Janssen PMP, a technical registrant for imazalil and imazalil sulfate. Imazalil and imazalil sulfate are 

imidazole systemic fungicides used for a wide range of applications such as postharvest citrus 

treatments, equipment sterilization in poultry hatcheries, seed treatments, and greenhouse foggers.

Registrants provided EPA with an overview of available and proposed cancer-related studies on imazalil 

and addressed questions from HED regarding various data gaps. The discussion focused on the type of 

data EPA would need to establish a mitogenic Mode of Action (MoA). Janssen PMP is interested in 

establishing a MoA in anticipation of submitting a cancer reclassification package for imazalil. EPA 

provided clarification on submission details for a cancer reclassification petition. The registrant agreed 

to respond to questions from HED after reviewing data available from their imazalil study archives.

While a cancer reclassification is not necessary for registration review to proceed, Janssen PMF is 

interested in submitting their cancer reclassification petition before EPA’s registration review process 

for imazalil is complete.

Discussion Topics:

(EPA Concerns in Black; Meeting Outcomes in Red)

The registrant plans to request a re-classification of Imazalil in the near future. However, the Agency 

currently believes that there is not enough data to support the proposed MoA for liver or thyroid tumors 

in either species. Instead, the Agency recommends the following options to address the tumors 

observed in each species:

 Liver tumors in male mice. Previously, the registrant conducted a 4-day study with imazalil at 

1200 ppm which showed an increased BrdU labeling index in the liver indicative of an early 

mitogenic burst. This study was conducted at a dose higher than those that caused tumors (200 

ppm) and is not useful to support a mitogenic MoA. The Agency suggests conducting a cellular 

proliferation study in mice with doses at and below the dose (200 ppm) that induced liver 

tumors. The results of this proposed study when taken together with the existing data in mice 

may provide the appropriate data for evaluating a potential MoA for liver tumors in mice.

 MEETING RESULTS: Registrant responds that they have a completed study that will address 

EPA’s concerns. They plan to submit this study along with the cancer reclassification petition 

package.

 Thyroid tumors in male rats. A previous study in rats (MRID 45160101) was conducted 

investigating thyroid hormones (T4 and TSH) following treatment with Imazalil. The study was 

conducted at doses both below (1200 ppm) and above (3200 ppm) the dose that induced 

tumors (2400 ppm). The data is suggestive of hormone changes but the data is not robust for 

reaching a decision on thyroid hormone perturbation. Consequently, the Agency recommends 

conducting a new study using doses at and below the dose that induced tumors; the treatment 

period should be for 90 days with thyroid hormone (T4 and TSH) measurements at appropriate 

time periods. 

 MEETING RESULTS: Registrant responds that they need to review their old studies and will get 

back to EPA on this topic. Also, EPA’s Jess Rowland agreed to look through the thyroid MOA data 
EPA has in-house to see if any received submissions were short-term studies (e.g., 28 days vs. 

the 90-day study EPA was recommending) and inform Janssen of his findings. After both parties 

report back to each other, a meeting/teleconference may be needed.

 Liver tumors in male rats. The cellular proliferation study recently reviewed by the Agency was 

not supportive of the mitogenic MoA proposed by the registrant. The study was conducted at 

the appropriate time points and with the appropriate doses; however, there was no evidence of 

cellular proliferation. Since the study was conducted adequately, repeating the study is not 

likely to provide different results. Therefore, the Agency proposes a peer review of the original 

slides to confirm the diagnosis of the observed tumors (e.g, the adenomas).

 MEETING RESULTS: EPA informs the registrants that this item will not be of concern if 

acceptable studies are submitted for items A and B. After the registrant addresses the liver 

(mouse) and thyroid (rat) tumor issues, a meeting may be needed to confirm this possible 

outcome.