Attachment 3.pdf

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: August 30, 2018

SUBJECT: Sodium Nitrite: Residue Data Requirements for the Use of Sodium Nitrite to Control Feral Swine: OCSPP 860.1480 Meat/Milk/Poultry/Eggs.

PC Code: 076204 DP Number: D447956 Decision No.: 542698 Registration No.: 56228-EUP-42 Petition No.: NA Regulatory Action: Protocol Review Risk Assessment Type: N/A Case No.: N/A TXR No.: N/A CAS No.: 7632-00-0 MRID No.: N/A 40 CFR: N/A

FROM: Janet Camp, Chemist Thurston Morton, Senior Chemist Risk Assessment Branch IV (RAB IV) Health Effects Division (HED; 7509P)

THROUGH: Donald Wilbur, Branch Chief

RAB IV

HED (7509P)

TO: Deanna Colby Gene Benbow Invertebrate & Vertebrate Branch III Registration Division (7509P)

Executive Summary

The United States Department of Agriculture Animal and Plant Health Inspection Service (USDA APHIS) requested input on a modified study design outline for a sodium nitrite based toxicant for the control of feral swine. The toxicant is designated a non-food use product by the Agency. In this case, the pest species (feral swine) also serves as the potential food source, and the intended dose of toxicant is lethal to pigs. Therefore, OCSPP 860.1480 Meat/Milk Poultry Eggs study guidelines are not completely compatible with this type of pest and application and a modified study design was proposed to determine residues in the tissues of feral swine that

Attachment 3, 12639521Q0024

Sodium nitrite Protocol Review DP Number: D447956 consume the sodium nitrite bait and are subsequently processed for human food. APHIS made the request to deviate from the guideline requirement of 28 days based on the intended use pattern of the toxicant in field applications and its effect on feral swine. RAB IV conferred with HED ChemSAC on this decision. The following was the conclusion of the ChemSAC at their August 15, 2018 meeting.

1. Potential Study Design to Address Food Use Residue Data Requirements for the Use of Sodium Nitrite to Control Feral Swine: OCSPP 860.1480 Meat/Milk/Poultry/Eggs (J.

Camp)

ChemSAC Issue

A sodium nitrite (NaNO2) based toxicant for the control of feral swine is designated a non-food use product. However, the OCSPP 860.1480 Meat/Milk/Poultry/Eggs study guidelines are not completely compatible with this type of pest and application. In this case, the pest species (feral swine) is also the potential food source, and thus the intended dose of toxicant is lethal to pigs. A modified study design is proposed to determine residues in the tissues of feral swine that consume the sodium nitrite bait and are subsequently processed for human food. APHIS requested input on the assumptions and study design outline below.

Question

Is the proposed sampling regime appropriate?

Background

The sole end use product, HOGGONE®, contains 10% sodium nitrite micro-encapsulated with a single coating of a confidential food grade polymer commonly used by the food industry. USDA APHIS previously requested an experimental use permit (EUP) for sodium nitrite. The resulting field study in Texas was proposed for December 2017 through March 2018 and in Alabama from May 2018 to August 2018. USDA APHIS operations personnel are the only permitted handlers of the bait. Enclosed bait stations are located on private property which the USDA has been granted permission from the land owner for the EUP study.

Below are the submitted assumptions pertinent to the proposed study design to address food use residue data requirements for the use of sodium nitrite to control feral swine, as well as the study design rationale proposed by APHIS.

Assumptions Pertinent to Study Design

1) The concern for nitrite residues in meat is based on the possibility that sub-lethal or lethally dosed pigs may be harvested for consumption by hunting or trapping.

2) The study design measures tissue residues during the period(s) of time that pigs may be harvested for processing.

3) A reasonable person would not harvest for food a pig that appeared visibly distressed or collect a pig found dead. Pigs typically die within 2-3 hours after feeding on toxic bait.

4) The likely scenario for harvesting a pig is after it has ingested a sub-lethal or lethal dose of the toxic bait and before onset of obvious symptoms, or after pigs are nearly recovered from receiving a sub-lethal dose.

5) The study design outline specifies dosing domestic pigs with the active ingredient, sodium nitrite, via oral gavage. Oral gavage may speed onset of symptoms and death. An alternative is to allow fasted pigs to feed on encapsulated sodium nitrite mixed into bait.

6) The tissues for collection and analysis include muscle, fat, and liver pending consultation with

EPA.

7) Nitrite is the analyte of concern in tissues. The target LOQ will be decided pending consultation with EPA.

Study Design Rationale

1) The low sodium nitrite dose level was selected to reflect a sublethal dose (80 mg/kg) most likely to ensure survival. Cowled et al. (2008) reported the minimum lethal dose (MLD) of sodium nitrite delivered to pigs by gavage was 90 mg/kg. Texas Parks and Wildlife (TPW) (TPW, 2011) reported an MLD for sodium nitrite of 113 mg/kg when delivered by oral gavage, and an LD50 of 133 mg/kg. Both Cowled et al. and TPW reported an LD99 of ~ 400 mg/kg for pigs. The dose levels for this study were selected to cover sub-lethal bait consumption and consumption of multiple doses. Some feral swine may consume more than two lethal doses.

However, these animals may die more quickly, thus impacting the proposed sampling time. The average time to death for a pig receiving 400 mg/kg sodium nitrite is 2 - 3 hours.

2) The most relevant sampling periods represent times when pigs would be likely to be harvested, before onset of symptoms at 1.5 hours, and cessation of symptoms for sub-lethally dosed pigs at 10 hours. Snow (unpublished data) reported onset of incoordination at ~ 1.6 hours in pigs receiving sodium nitrite at 400 mg/kg. The time to death is typically 2 -3 hours after feeding on toxic bait. See graph below. Cowled et al. (2008) showed that pigs receiving sub-lethal doses of 90 mg/kg sodium nitrite recovered at approximately 600 ± 187 minutes (~10 hours) post-dose. Time to onset of symptoms and death are accelerated with increasing dose.

Cowled et al. (2008) reported onset of symptoms within 0.9 hours with death at ~2.15 hours, and Snow (unpublished data) reported onset of symptoms at < 0.5 hours and death at < 0.66 hours.

Thus, pigs consuming multiple lethal doses of sodium nitrite mixed in bait die quickly and closer to bait stations, and therefore are less likely to be harvested than pigs consuming ≤ 400 mg/kg.

3) The analytical phase of the study will measure one analyte, nitrite. Dietary nitrite is metabolized to nitric oxide which is unstable (ATSDR 2017). The bioavailability of nitric oxide is 2-6 seconds. Nitric oxide may be converted to nitrate, which in turn may be converted to nitrite. Given the difficulty in distinguishing endogenous from exogenous sources of nitrite, the control animal tissues will serve as a baseline of endogenous nitrite and possible dietary exogenous sources unrelated to treatment.

Proposed Solution

The proposed protocol submitted by Aphis is outlined below.

In-Life Phase

The proposed treatment groups and sampling times are shown below. APHIS proposed to conduct a dosing study administering a single dose of NaNO2 via oral gavage to each domestic pig (~20 kg). Tissue sampling time periods will conform to the guidelines with samples collected within 24 hours of dosing. The rationale for the tissue sampling time points and doses is provided above.

Treatment Groups Dose Administered to

Pigs by Gavage (mg/kg)

Number of Pigs per Treatment Group

Tissue Sampling Time

Points (hours post-gavage)

Control 0 4 1.5 Sub-lethal - NaNO2 80 4 1.5 Sub-lethal - NaNO2 80 4 10

Lethal - NaNO2 400 4 1.5

Analytical Phase

Muscle, fat, and liver tissue samples will be analyzed for the presence of nitrite. The target nitrite LOQ is to be determined.

Deviation from Guideline

Deviation from the guideline requirement of 28 days is requested based on the intended use pattern of the toxicant in field applications and its effect to feral swine. Currently, baiting with the toxicant would not extend beyond 2 days. In addition, sodium nitrite is being proposed as a toxicant for use against feral swine, therefore animals would succumb to the effects of sodium nitrite much sooner than 28 days if applied at expected doses that would occur during field application. The current guideline requirement is designed to measure pesticide residues in food items that have been treated with a pesticide and then are used as a source of food for domestic animals that may be harvested for human consumption, which is not the intended use of sodium nitrite for feral swine. For these reasons, APHIS is proposing one dose of sodium nitrite administered to each pig and then tissue would be collected for residue analysis at 1.5 or 10 hours depending on the treatment group.

ChemSAC Recommendations

Overall, the ChemSAC concurs with the general study outline in terms of number of animals, dose levels, tissues for collection and analysis (muscle, fat, and liver), and tissue sampling time points. Additionally, the ChemSAC came to the following conclusions regarding the proposed protocol:

1. Dosing via gavage is necessary based on the short time intervals and precise dose levels proposed for this study.

2. The analytical method should analyze both nitrite and nitrate.

References

ATSDR. 2017. Toxicological profile for nitrate and nitrite. 278 pages.

https://www.atsdr.cdc.gov/toxprofiles/tp204.pdf

Cowled, B.D., P. Elsworth, and S.J. Lapidge. 2008. Additional toxins for feral pig (Sus scrofa) control: identifying and testing Achilles’ heels. Wildlife Research 35, 651-662.

https://www.publish.csiro.au/wr/wr07072.

Snow, N.P., J.A. Foster, E.H. VanNatta, K.E. Horak, S.T. Humphrys, L.D. Staples, D.G. Hewitt, and K.C. VerCauteren. 2017. Potential secondary poisoning risks to non-targets from a sodium nitrite toxic bait for invasive wild pigs. Pest. Manag. Sci, 74: 181-188.

https://onlinelibrary.wiley.com/doi/abs/10.1002/ps.4692.

TPW. 2011. Effects of Sodium Nitrite on Feral Swine and Non-Targets, TX Dept. of Ag. Project Number FH-1-05. 8 pages.

EPA Office of Pesticide Programs Statement on Lethal Endpoints in Product Efficacy Studies of Toxicants

EPA Registration Division conducted a protocol review (June 26, 2019) of an APHIS National Wildlife Research Center study protocol to test product efficacy of a toxicant rodenticide product. In this EPA review, EPA explained their position on lethal endpoints in efficacy studies to support product registrations of toxicants (Please see comment box). The protocol review was conducted by Gene Benbow and Paul De Salvo, EPA Office of Pesticide Programs, Registration Division, Invertebrate – Vertebrate Branch 3.