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 6 th 

## 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 Attendee s:

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 s cience team questions and available MoA data

a. HED discussion of options for registrant to move forward on addressing imazalil cancer
risk concerns
b. Other c oncerns?

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 wid e 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

a nd 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 r eclassification 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. Whil e 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 Con cerns 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 e ither 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 ag reed to look through the thyroid MOA dataEPA 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 othe r, 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 regi strant addresses the liver (mouse) and thyroid (rat) tumor issues, a meeting may be needed to confirm this possible

outcome.