STUDY PROTOCOL FOR A COMPASSIONATE AQUACULTURE

INVESTIGATIONAL NEW ANIMAL DRUG (INAD) EXEMPTION

FOR SLICE® (EMAMECTIN BENZOATE)
(INAD #11-370)

Sponsor:

U.S. Fish and Wildlife Service, Division of Fish Hatcheries

______________________ ___________________
Sponsor Signature Date Approved

Manufacturer:

Intervet/Schering-Plough Animal Health

56 Livingston Avenue
Roseland, NJ 07068

Facility for Coordination of SLICE® (Emamectin Benzoate) INAD:

Aquatic Animal Drug Approval Partnership

4050 Bridger Canyon Road
Bozeman, Mt 59715

Proposed Starting Date May 1, 2010

Proposed Ending Date April 30, 2014

Study Director Mr. Jim Bowker

_________________________ ________________
Study Director Signature Date

Clinical Field Trial Location and Trial Number:

__________________________________________ _________________
Type or Print Facility Name Trial Number

Investigator______________________________________________________
Type or Print Name

__________________________________________ _________________
Investigator Signature Date
I. STUDY ID AND TITLE .................................................................................................................................. 1
II. SPONSOR..................................................................................................................................................... 1
III. INVESTIGATORS/FACILITIES .................................................................................................................... 2
IV. PROPOSED STARTING AND COMPLETION DATES: ......................................................................... 2
V. BACKGROUND/PURPOSE ........................................................................................................................ 2
VI. SPECIFIC OBJECTIVES ........................................................................................................................... 4
VII. MATERIALS ............................................................................................................................................... 5
VIII. EXPERIMENTAL UNIT ............................................................................................................................ 9
IX. ENTRANCE CRITERIA .............................................................................................................................. 9
X. TREATMENT GROUPS ............................................................................................................................ 11
XI. TREATMENT SCHEDULES .................................................................................................................... 11
XII. TREATMENT RESPONSE PARAMETERS .......................................................................................... 13
XIII. FORMS FOR DATA COLLECTION......................................................................................................... 14
XIV. RECORD KEEPING PROCEDURES ................................................................................................... 15
XV. DISPOSITION OF INVESTIGATIONAL ANIMALS .............................................................................. 15
XVI. DISPOSITION OF INVESTIGATIONAL DRUG ................................................................................... 15
XVII. DATA HANDLING, QUALITY CONTROL, MONITORING, ADMINISTRATIVE
RESPONSIBILITIES ......................................................................................................................................... 16
XVIII. PLANS FOR DATA ANALYSIS .......................................................................................................... 17
XIX. PROTOCOL AND PROTOCOL AMENDMENTS ................................................................................ 18
XX. PROTOCOL DEVIATIONS ..................................................................................................................... 18
LITERATURE CITED ........................................................................................................................................ 19
MATERIAL SAFETY DATA SHEET .............................................................................................................. 21
FORM SLICE-W: WORKSHEET ............................................................................................................... 21
FORM SLICE-1. REPORT ON RECEIPT OF DRUG ................................................................................................. 23
FORM SLICE-2A. CHEMICAL USE LOG .................................................................................................. 24
FORM SLICE-2B. CHEMICAL USE LOG .................................................................................................. 25
FORM SLICE-3: RESULTS REPORT FORM ......................................................................................... 26
FORM SLICE-3S: SUPPLEMENTAL INFORMATION ............................................................................. 31
STUDY PROTOCOL FOR A COMPASSIONATE AQUACULTURE INVESTIGATIONAL
NEW ANIMAL DRUG (INAD) EXEMPTION FOR SLICE® (EMAMECTIN BENZOATE)
UNDER INAD #11-370

I. STUDY ID AND TITLE

Clinical field trials to determine the efficacy SLICE® of (emamectin benzoate)

administered in feed to control mortality caused by external parasites in a variety of
freshwater fish species. INAD 11-370.

II. SPONSOR

Dr. David Erdahl, U.S. Fish and Wildlife Service, Branch Chief, Aquatic Animal Drug
Approval Partnership (AADAP) Program, 4050 Bridger Canyon Road, Bozeman, MT
59715; Phone: 406-994-9904; Fax: 406-582-0242; Email: [email protected]

Manufacturer: Intervet/Schering-Plough Animal Health

56 Livingston Avenue
Roseland, NJ 07068

Contact: Richard Endris; Phone: 862-245-5133

Study Director: Mr. Jim Bowker, U.S. Fish and Wildlife Service, Aquatic Animal Drug
Approval Partnership (AADAP) Program, 4050 Bridger Canyon
Road, Bozeman, MT 59715; Phone: 406-994-9910; Fax:
406-582-0242; Email: [email protected]

Principal Clinical Field Trial Coordinator: Bonnie Johnson, USFWS -

AADAP

INAD Study Monitors: See Appendix II for names and addresses.

1 Revised: 4/10
III. INVESTIGATORS/FACILITIES

See Appendix IIIa for names and addresses.

IV. PROPOSED STARTING AND COMPLETION DATES:

Proposed Starting Date: May 1, 2010

Proposed Completion Date: April 30, 2014

V. BACKGROUND/PURPOSE

External parasites form one of the largest groups of pathogenic organisms in cultured
aquatic species. Affected species include finfish (freshwater and marine) and
invertebrates. Environmental conditions such as temperature change and high organic
loading in culture systems due to intensive fertilization and feeding levels increase the
incidence and spread of many external parasites. Parasitic infections cause substantial
economic losses to aquaculturists if not controlled. Many culturists have learned that
some parasites can kill an entire population in a short time.

The organisms responsible for major parasitic infections on fish are, for the most part,
protozoan and metazoan. These organisms are highly opportunistic and generally
cause little pathology under normal conditions (e.g., in wildstock populations). However,
under intensive culture where large numbers of fish are present, many of these organisms
can cause serious disease problems.

Parasitic infections of fish, if not treated, can cause major losses and affect the restoration
and preservation of depleted stocks of fish cultured by the U.S. Fish and Wildlife Service
(USFWS). The extent of losses of fish from parasites depends upon the severity of the
primary cause of infection. Morbidity can vary from less than 10% to total loss of the
population (Post 1987).Historically, immersion treatments (static and flush) using a
variety of compounds have been used to control mortality caused by parasite infestations.
A number of the unapproved compounds (and/or concoctions) have been found to be
relatively effective.

In 1986, the U.S. Food and Drug Administration (FDA) approved a new animal drug
application (NADA) for the use of formalin to control external parasites (Icthyopthirius,
Chilodonella, Costia, Scyphidia, Epistylis, Trichodina, Cleidodiscus, Gyrodactylus, and
Dactylogyrus) on several fish species (salmonids, catfish, largemouth bass, and bluegill)
and to control fungal infections on the eggs of salmon, trout and esocids. This decision
by FDA was based on data that illustrated formalin was effective against those disease

2 Revised: 4/10
organisms and safe to use on those species allowed on the label. More recently, this
label claim was expanded to include “.....for use on all finfish”.

While formalin has proven to be an effective parasiticide, it is not an aquatic species

parasite control panacea, nor is it likely the drug-of-choice in all situations. As is the case
with the treatment of virtually all pathogens (in both terrestrial and aquatic species), it is
beneficial to have access to alternative treatment regimens to meet case-specific needs.
A single drug for the control of mortality caused by external parasites will simply will not
meet all needs of the aquaculture community. While an effective parasiticide, formalin
use is somewhat limited by species specific effectiveness and toxicity issues.
Furthermore, as formalin use as a parasiticide is an immersion treatment and formalin is
not the most environmentally friendly compound, there have been increasing concerns
over time (particularly at the individual State level) with regards to the discharge of
formalin-treated water from aquaculture facilities. It is unlikely that this concern over the
discharge of formalin in hatchery effluents will soon (if ever) reverse itself.

SLICE® is an in-feed treatment that was developed specifically for the control of sea lice
infestations in farmed salmon and trout. Control of sea lice (including Lepeophtheirus
salmonis, Caligus elongatus, C. rogercressyi, and C. teres) on farmed fish is essential as
lice feeding activity may result in mortalities, as well as susceptibility to a variety of other
pathogens. SLICE® has been extensively tested in trials to evaluate environmental
safety, efficacy, and tolerance in Atlantic salmon, Salmo salar, rainbow trout,
Oncorhynchus mykiss, and brown trout, Salmo trutta in the marine environment (Stone et
al., 1999; Stone et al., 2000a; Stone et al., 2000b; Stone et al., 2000c; Stone et al., 2002;
Roy et. al., 2000; and Armstrong et. al., 2000). Currently, SLICE® is approved for the
control of sea lice in salmonid species in the UK, Europe, Norway, and Chile.

The active component of SLICE® is emamectin benzoate. Emamectin is an avermectin

developed initially for food crop use and is derived synthetically from avermectins which
are produced by fermentation of the soil organism Streptomyces avermitilis. When
emamectin benzoate is fed to fish it is absorbed from the gut and distributed to a variety of
tissues. When sea lice (or other parasites) feed on the skin, mucus, blood, and muscle
of the host fish, emamectin is taken up into the tissues of the louse. It then binds to ion
channels of nerve cells and disrupts transmission of nerve impulses which results in
paralysis and death of the parasite. Furthermore, emamectin benzoate is excreted
slowly by the fish or metabolized to inactive compounds, resulting an extended period of
protection from lice, long after medicated feed treatment has been completed (Stone et
al., 2000c). This extended period of protection may extend up to 9 weeks
post-treatment, thus making SLICE® a very attractive candidate for long-term parasite
control.

3 Revised: 4/10
Although SLICE® has been used most extensively for the control of sea lice in the marine
environment, SLICE® has also been shown to be effective (and safe) when used to
control sea lice on fish transferred from salt water and held in freshwater. It has also
been shown to be effective (and safe) when used to treat naive smolts that are being
maintained in freshwater immediately prior to transfer to saltwater. The “extended
period of protection” provided by SLICE® affords the highly susceptible smolt stage a
better chance of surviving the many rigors associated with transfer to salt water (Stone et
al., 2002).

In addition, more recently SLICE® has been used to effectively control mortality caused by
freshwater parasites in salmonid species (Hakalahti et al., 2004 and Duston and Cusak,
2002). SLICE® has been found to be very effective for the treatment of Argulus coregoni
in rainbow trout, as well as for the treatment of Salmincola edwardsii in brook trout.
Interestingly, the observed efficacy of SLICE® against these A. coregoni and S. edwardsii
included the “extended period of protection” previously documented with respect to the
use of SLICE® against sea lice.
It is anticipated that SLICE® may be similarly effective for the treatment of other
freshwater copepods including Actheres ambloplitis, Ergasilus, and Lernaea. The
addition of SLICE® for the control or external parasites in freshwater fish to aquaculture’s
approved medicine chest would be a value-added tool to help optimize overall fish health
and population fitness.

The purpose of this compassionate INAD for emamectin benzoate (SLICE®) administered
in feed is to develop clinical field trial data that will be used to determine the efficacy and
appropriate treatment regimes for emamectin benzoate (SLICE®) medicated feed to
control mortality caused by external parasites in a variety of freshwater fish species.
These data will be used to support a new animal drug application (NADA) for emamectin
benzoate (SLICE®) medicated feed.

The USFWS anticipates that it may take several year to complete all technical section
data for a NADA for emamectin benzoate (SLICE®) medicated feed. The USFWS is
aware that opportunities for emamectin benzoate (SLICE®) medicated feed therapy are
unpredictable. There is no way of knowing in advance if, when, or where opportunities for
pivotal studies will be encountered. The USFWS believes it is likely that data from 3-5
treatment seasons will be required in order to adequately assess the efficacy of
emamectin benzoate (SLICE®) medicated feed treatment, and to generate sufficient data
to support a NADA.

VI. SPECIFIC OBJECTIVES

The two major objectives of this study protocol are as follows:

4 Revised: 4/10
 1. Collect scientific data necessary to establish the efficacy of SLICE®
(emamectin benzoate) administered in feed to control mortality caused by
external parasites in a variety of freshwater fish species.

2. Provide the opportunity for fishery biologists to legally use SLICE®

(emamectin benzoate) medicated feed to control mortality caused by
external parasites in a variety of freshwater fish species during the period of
time necessary for collection of efficacy, safety, and residue data required
for an NADA for SLICE® (emamectin benzoate) medicated feed use in
fish. Specifically, SLICE® (emamectin benzoate) medicated feed will be
used in a variety of environmental conditions, at a wide range of
temperatures, and in a variety of cultured fish species to maintain healthy
stocks of fish during the period of time necessary for collection of data that
will be used to support an NADA for the use SLICE® (emamectin benzoate)
medicated feed.

VII. MATERIALS

A. Test and control articles:

1. Drug Identity

a. Active ingredient

Common Name: Emamectin benzoate

Product Name: SLICE® Premix (Emamectin benzoate, 0.2%

Aquaculture premix)

Chemical Name: 4"-deoxy-4"-epi-methylamino-avermectin

benzoate

CAS Number: 137512-74-4

Appearance: white to grey powder

Odor: slight to none

b. Strength and dosage form

5 Revised: 4/10
 Emamectin benzoate is the active component of SLICE®.
Emamectin is an avermectin developed initially for food crop use.
Emamectin is derived synthetically from avermectins, which are
produced by fermentation of the soil organism Streptomyces
avermitilis. SLICE® Aquaculture Premix consists of 0.2%
emamectin benzoate in an inert carrier, consisting of GM-free
cornstarch, maltodextrin, antioxidant, and solvent. The premix has
been formulated specifically for incorporation of emamectin
benzoate onto fish feeds.

c. Manufacturer, source of supply

Intervet/Schering-Plough Animal Health

56 Livingston Avenue
Roseland, NJ 07068

Contact Person: Richard Endris

Phone: 862-245-5133
Fax: 862-245-3654

2. Verification of drug integrity/strength:

The Manufacturer, Intervet/Schering-Plough Animal Health, will provide the

analytical data necessary to establish the purity of each lot of SLICE® (emamectin
benzoate) premix supplied. The lot number and date of manufacture for each
batch of SLICE® (emamectin benzoate) premix will be placed on the label of each
container. The form "Report on Receipt of Drug - Guide for Reporting
Investigational New Animal Drug Shipments for Poikilothermic Food Animals"
(Form SLICE-1) will clearly identify the lot number and date of manufacture of
SLICE® (emamectin benzoate) shipments (i.e., premix or medicated feed). If the
integrity of the SLICE® (emamectin benzoate) is compromised (i.e., by spilling or
contamination of the stock container or feed bags) the event will be carefully
recorded, dated, and signed in the Chemical Use Log (Form SLICE-2a and/or
Form SLICE-2b). The Study Monitor assigned to the Investigator involved will be
immediately notified.

Based on discussions with Investigators concerning planned feed rate and kg of

fish to be medicated, commercial fish feed manufacturers shall prepare feed with

6 Revised: 4/10
dosages of SLICE® (emamectin benzoate) premix to assure the target dose of 50
ug emamectin benzoatel/kg fish/day is being achieved.

The Investigator may also prepare his/her own drug-treated feed by top-coating
feed on-hand (or specially ordered feed) with SLICE® (emamectin benzoate)
premix. Target dosage must be 50 ug emamectin benzoatel/kg fish/day. If the
Investigator chooses this option, they are encouraged (but not required) to have a
sample of the top-coated feed assayed for emamectin benzoate concentration by
a certified, analytical testing laboratory. Results of drug-treated feed assays
should be appended to Form SLICE-3.

3. Storage Conditions

SLICE® (emamectin benzoate) will be stored in the original container supplied by

the Manufacturer with the appropriate investigational label attached. The
container will be stored in dry conditions at temperatures between 2 and 30oC.
Unopened SLICE® premix stored in this manner has a shelf life of 24 months.
The storage unit for SLICE® premix must be labeled to indicate that it contains
hazardous material and that "NO Food or Drink is to be Stored in this unit".
SLICE® medicated feed should be stored at temperatures and for periods of time
not to exceed limits set by the feed manufacturer. Medicated feed should be
ordered only as needed and not stored for possible future use.

4. Handling Procedures

Each Study Monitor and Investigator will be required to have a current copy of the
Material Safety Data Sheet (MSDS) for SLICE® (emamectin benzoate; see
Appendix IV). Each person involved with the study and each person who may be
present during the use of SLICE® (emamectin benzoate) medicated feed shall be
required to read the MSDS. Safety precautions as outlined in the MSDS will be
followed at all times when working with SLICE® (emamectin benzoate).

5. Investigational labeling

Copies of the labels to be attached to each container of SLICE® (emamectin

benzoate) and all bags of SLICE® (emamectin benzoate) medicated feed are
provided in Appendix V. It is the responsibility of the Investigator to ensure proper
labeling of all containers of SLICE® (emamectin benzoate) premix and medicated
feed.

7 Revised: 4/10
 6. Accountability

Intervet/Schering-Plough Animal Health will be the sole supplier of SLICE®

(emamectin benzoate) to all Investigators under INAD 11-370.

1. USFWS and Non-USFWS Facilities

Immediately upon receiving an order/shipment of SLICE® (emamectin

benzoate), the Investigator will complete Form SLICE-1 “Report on Receipt
of Drug - Guide for Reporting Investigational New Animal Drug Shipments
for Poikilothermic Food Animals". The investigator will archive the original
in the facilities INAD file, and send a copy to his/her Study Monitor. Both
the Investigator and the Study Monitor are required to sign Form SLICE-1.
The Study Monitor will then forward a copy to the Clinical field Trial
Coordinator at the Aquatic Animal Drug Approval Partnership Office. The
Clinical Field Trial Coordinator will archive one copy, and send two copies of
Form SLICE-1 to FDA. Arrangements should be made between
Investigators and Study Monitors to insure completed Form SLICE-1s are
received by the Clinical field Trial Coordinator in a timely manner.

All Investigators are also responsible for maintaining an accurate inventory

of SLICE® (emamectin benzoate) on-hand. A Chemical Use Log (Forms
SLICE-2a and SLICE-2b) will be supplied to each Investigator. Each time
SLICE® (emamectin benzoate) is used, it must be recorded by the
Investigator on Form SLICE-2a and/or Form SLICE-2b.

7. Preparation Procedures

SLICE® (emamectin benzoate) will be supplied to Investigators either as SLICE®

premix or as SLICE® medicated feed. Neither product should be adulterated in
any manner prior to use. If Investigators are using SLICE® premix to make their
own SLICE® medicated feed, SLICE® premix should be top-coated on feed.
Top-coating procedures should include “finishing” with 0.5% vegetable oil.

B. Items Needed for Treatment, Data Collection, Etc.:

Sampling techniques and diagnostic equipment will most likely be provided by trained fish
health biologists serving as Study Monitors or their designee(s). Equipment and
supplies needed would include items to sample fish and identify parasites.

When the Study Protocol has been approved and treatments are scheduled, the
Investigator at each facility covered by the SLICE® (emamectin benzoate) INAD will need
to complete several forms. These forms are described in Section XIII (p 11). Copies of
these forms are attached to this Study Protocol.

8 Revised: 4/10
VIII. EXPERIMENTAL UNIT

The experimental unit in these clinical field trials will consist of contained or isolated
groups of fish. This will generally be a groups of fish contained in tanks, raceways, or
ponds. However, the experimental unit in clinical field trials may also be individual
animals. If individual animals are considered to be the experimental unit, treatment
response parameters for each animal must be evaluated separately.

IX. ENTRANCE CRITERIA

A. Facilities/Investigators

The proposed facility and the Investigator must be listed in Appendix IIIa of the
Study Protocol before SLICE® (emamectin benzoate) medicated feed can be
ordered and dispensed under this INAD. Last minute deviations can be
requested by the Sponsor, Study Director, or by an Investigator in case
emergency use-pattern needs should arise (See Section XX).

B. The characteristics of the study animals (species, number, etc.) is presented

in Appendix VIb.

C. Environmental conditions

Environmental conditions will be variable and include a broad spectrum of

water temperatures and water quality parameters. Environmental conditions
will be reported on Form SLICE-3.

D. Ability of Investigator to fulfill all the requirements of the Study Protocol

See Appendix IIIb for example of knowledge required of hatchery managers

(i.e., Investigators).

E. Pathogen/disease considerations

1. Parasites should be presumptively identified by procedures described in

Section 3 of the "Blue Book" (Procedures for the Detection and
Identification of Certain Fish Pathogens, Third Edition, Fish Health
Section/American Fisheries Society, 1985). Other methods described
elsewhere in peer-reviewed references, or as mutually determined by
the local fish health biologist, in consultation with the Study Monitor, also
may be used. (Note: Diagnostic methods other than those in the
Third Edition of the "Blue Book" should be described on a

9 Revised: 4/10
 separate sheet attached to Form 3 “Diagnosis and Treatment
Record”).

2. There should be increased mortality rates among fish in two or more

similar rearing units for three or more consecutive days. (Note:
Station history and the experience of the investigator, monitor, or the
fish health biologist may over-ride this criterion to halt potentially
explosive disease outbreaks. In such cases, however, careful
diagnostic surveillance should be carried out in all rearing units
proposed for treatment and controlled tests should be carried out if at all
possible.)

3. Typical disease signs should be detectable in at least a few fish and the
causative parasite must be identified.

4. Since the efficacy of SLICE® (emamectin benzoate) medicated feed

therapy for the control of a external parasites is being tested,
investigators must be prepared to make no changes in the fish cultural
procedures or environmental conditions and apply no other treatments
once a decision has been made to conduct SLICE® (emamectin
benzoate) medicated feed therapy. Complicating bacterial or other
parasitic diseases should be carefully documented. If necessary, these
infections can be treated once SLICE® (emamectin benzoate)
medicated feed response (efficacy) data has been collected. However,
it may take as long as 10 days after the completion of SLICE®
(emamectin benzoate) medicated feed therapy to determine differences
between test and control groups and to complete post-treatment
evaluations.

Prior to initiating each treatment event, the Investigator must first complete
Form SLICE-W. “Worksheet for Designing Individual Field Trials” that pertains to
each specific treatment event. The worksheet should be filled out, signed, and
sent by Fax to the Study Monitor. The Study Monitor will review the planned
treatment (worksheet), sign it, and forward (Fax) the paperwork to the AADAP
Office. The AADAP Office will then review the worksheet, assign the approved
treatment a Study Number, and then notify both the Investigator and the Study
Monitor of the assigned number and approval to proceed. In most cases, this
entire process should be able to be accomplished within a single working day.
After initiation of the field trial, the Investigator should also record the assigned
study number on Form SLICE-2a (and/or Form SLICE-2b) and SLICE-3, as well as
on any additional correspondence regarding that specific treatment event. If for
some reason the Investigator is unable to reach his/her Study Monitor with regards
to worksheet approval, and infection/disease/treatment need is rapidly escalating,
the Investigator should contact the AADAP Office for a study number and
permission to proceed.

10 Revised: 4/10
X. TREATMENT GROUPS

A. A treatment group or experimental unit may be an entire tank, pond,

raceway, or group of fish, or it may be individual animals.

B. Separately confined, untreated control fish will not be required in

supplementary field studies conducted to determine the effectiveness of SLICE®
(emamectin benzoate) medicated feed treatment. Fish from a group or lot will first
be examined to determine if treatment with SLICE® (emamectin benzoate) is
required. When treatment is underway or has been completed, fish from the
same group will be examined to determine the effect of treatment on the
parameters used to initially sanction the treatment. Evaluation will in all cases
consist of determining fish mortality, although in most cases degree or severity of
parasite infestation will also be quantified.

Although untreated control groups are not a required element of treatment under
this INAD exemption and are at the discretion of the Investigator, they are strongly
encouraged whenever circumstances permit. Control groups are extremely
important to not only document response to treatment, but also to validate
potential adverse reactions in treated animals. Use of control groups will ensure
that results of efficacy studies provide useful information that will support an
NADA.
It is important that all fish are treated in a similar fashion. If fish are physically
moved into separate test groups or different rearing units, caution should be used
so that handling and rearing conditions are as similar as possible. Control fish
should be kept under conditions as similar as possible to treated fish for valid
comparison. Although not required, replicate treatment groups are strongly
encouraged in both treated and control groups. Assignment to control and
treatment groups should be random and designed to avoid bias.

Blinded studies can reduce bias in data collection. Whenever possible,

investigators should consider methods by which treatment response observations
are recorded by individuals who are unaware which fish have been treated and
which fish are controls.

XI. TREATMENT SCHEDULES

A. Route of administration

SLICE® (emamectin benzoate) will be administered only as a medicated feed

treatment.

11 Revised: 4/10
B. Dose to be administered

SLICE® (emamectin benzoate) will be administered at a dosage of 50 ug/kg of

fish biomass/day.

C. Dosing interval and repetition

SLICE® (emamectin benzoate) will be administered as a single treatment

regime, with no repetition of treatment.

D. Duration of treatment

SLICE® (emamectin benzoate) medicated feed will be fed for 7 consecutive

days.

E. Drug preparation and administration procedures

SLICE® (emamectin benzoate) premix will typically be incorporated into

standard diets by an established feed manufacturer. However, in certain
situations, SLICE® (emamectin benzoate) premix may be top-coated on
feed by investigators. Standard personal protective equipment such as
gloves, lab coats or aprons, eye protection, etc. should be worn at all times
when preparing or administering SLICE® (emamectin benzoate) medicated
feed. Medicated feed for each individual lot of fish should be accurately
weighed prior to treatment. Fish should be fed in such a manner as to
ensure optimal consumption of SLICE® (emamectin benzoate) medicated
feed (see Feeding Regime below).

F. Feeding Regime

During the course of therapy fish may be fed only treated feed, or a
combination of treated and untreated feed. The actual feeding regime used
will be left to the discretion of the investigator, and will be dictated by the
feeding behavior of the fish to be treated and level of premix incorporated in
the feed. In most cases it is anticipated that use of only treated feed will work
best. However, in some cases, treated feed followed by untreated feed may
be determined to be the optimal feeding regime. In still other cases, a small
amount of untreated feed followed by a “full course” of treated feed may be
utilized. In all cases, the daily feeding regime should be designed to
maximize consumption of the treated feed to result in the intended dosage of
50 ug emamectin benzoate per kg body weight.

Specify on source data sheets how fish were fed (e.g. % treated feed vs %
untreated feed, by hand, using automatic feeders, utilizing demand feeders),

12 Revised: 4/10
 amount of feed offered (% body weight), and whether feed was well accepted
or poorly utilized.

G. Permissible concomitant therapy

Since efficacy data are being collected during the INAD process, there should
be little or no concomitant therapy. Preferably, there should be no other
therapy during a period extending from 2 weeks prior to treatment to 2 weeks
after treatment. Investigators must be prepared to make no changes in fish
cultural procedures or environmental conditions, and apply no other drug
therapy once a decision has been made to conduct SLICE® (emamectin
benzoate) medicated feed treatment. However, if concomitant therapy is
required in order to protect valuable fish stocks, it should be fully documented
and the efficacy data from the SLICE® (emamectin benzoate) medicated feed
treatment involved should be appropriately labeled.

XII. TREATMENT RESPONSE PARAMETERS

The collection and reporting of source data begins with the decision to treat valuable fish
based on hatchery records or other pertinent species information indicating treatment is
warranted. Daily morbidity and mortality records, case history records, as well as any
extenuating or mitigating circumstances that may affect treatment response need to be
documented. All pertinent treatment response parameters should be reported on Form
SLICE-3. Treatment response parameters that should be addressed include the
following:

1. Primary Parameters

Morbidity and mortality data, coupled with case history and analyses of
parasite load, usually indicate when SLICE® (emamectin benzoate) medicated
feed treatment is needed. This source data must be collected for at least
5 days before treatment, during treatment, and for up to at least 10 days
after the treatment period has ended. Collection of this data is critically
important in all cases. Gill, skin, fin, mucous or other tissue from groups of
representative fish should be evaluated using appropriate methodology to
determine parasite presence and load (i.e., parasite density).

2. Secondary Parameters

Secondary parameters may also include general observations on fish behavior

and response to routine culture/handling activities. This would include such
responses as feeding activity, feed consumption, apparent level of stress,
negative fish behavior, etc.

13 Revised: 4/10
 3. Adverse Reactions

Any adverse reaction to treatment should be reported immediately to the Study

Monitor, who will in turn notify the Study Director. Such responses might
include extremely negative responses/behavior by the fish or hazards to the
applicator. Although SLICE® (emamectin benzoate) medicated feed has been
used fairly extensively with beneficial effect in fish culture, and is currently
approved in the UK, Ireland, Norway, Chile, and Canada, it is possible adverse
reactions may occur under certain environmental conditions or with respect to
specific species/strains of fish. Carefully observe all treated fish for any signs
of any adverse reaction to treatment. The Investigator should carefully
document all observations of adverse reactions. If any signs of drug toxicity
are detected, they should also be documented and immediately reported to the
Study Monitor, who will in turn notify the Study Director.

Note: Investigators are strongly encouraged to record observations/comments

with respect to all phases of treatment. This may include a description
of events before, during, and post-treatment. All extenuating or
mitigating treatment circumstances need to be described in detail.
Such information is imperative so that accurate study/data analysis
can be performed.

XIII. FORMS FOR DATA COLLECTION

When the Study Protocol has been approved and treatments are scheduled, the
Investigator at each facility covered by the SLICE® (emamectin benzoate) medicated feed
INAD will need to complete the following forms:

Form SLICE-W. Worksheet for Designing Individual Field Trials under INAD
11-370

Form SLICE-1. Report on Receipt of Drug - Guide for Reporting

Investigational New Animal Drug Shipments for
Poikilothermic Food Animals

Form SLICE-2a. Chemical Use Log for Clinical Field Trials Using SLICE®
(emamectin benzoate) Medicated Feed under INAD 11-370 -
SLICE® Premix

Form SLICE-2b. Chemical Use Log for Clinical Field Trials Using SLICE®
(emamectin benzoate) Medicated Feed under INAD 11-370 -
SLICE® Medicated Feed

14 Revised: 4/10
 Form SLICE-3. Results Report Form for use of SLICE® (emamectin
benzoate) under INAD 11-370

Copies of these forms are attached to this Study Protocol.

XIV. RECORD KEEPING PROCEDURES

The data should be recorded in permanent ink (preferably black). The data should be
recorded on the official data record forms at the time the observations are made. The
raw data should be original, i.e., they should be the first recording of the observations,
rather than a transcription of original observations to another data sheet. Each original
data sheet should be legibly signed and dated by the person making the observation and
recording the entry. If more than one person makes and records the observations,
entries should be properly attributed to each person. The data should be accurate and
legible. If a mistake is made, it should be crossed out using a single strike-through and
the correct data should be recorded next to it. Each change to the raw data should be
initialed and dated by the person making the change, and a statement should be provided
explaining why the change was made. If the data sheet needs to be copied, all data
should be transferred, including the properly noted changes. The original record should
be retained and submitted with the revised copy, along with a memo explaining the
reason for the copying.

XV. DISPOSITION OF INVESTIGATIONAL ANIMALS

Animals that die during treatment should be disposed of by burial or incineration. All
fish treated with SLICE® (emamectin benzoate) medicated feed must be maintained in
culture facilities for a minimum of 60 days following completion of therapy before
stocking/release or harvest.

No withdrawal period will be required for fish that will not be catchable for 60 or more days
after release or are illegal for harvest during that 60 day period. No withdrawal period
shall be required for dead fish that will be buried or rendered into non-edible products.

The Investigator must verify compliance with requirements regarding the disposition of all
treated fish on Form SLICE-3.

XVI. DISPOSITION OF INVESTIGATIONAL DRUG

SLICE® (emamectin benzoate) medicated feed will be used only in the manner and by the
individuals specified in the Study Protocol. If any unused or out-dated SLICE®
(emamectin benzoate) medicated feed remains at the end of the study period,
Investigators should contact Study Monitors for instructions regarding drug disposal.

15 Revised: 4/10
The investigational drug may not be redistributed to others not specified in the Study
Protocol.

XVII. DATA HANDLING, QUALITY CONTROL, MONITORING, ADMINISTRATIVE

RESPONSIBILITIES

A. Drug distribution

See Section VII.A.6. Accountability (page 6) for information and details.

B. Study Monitors

Study Monitors are generally fish health professionals with experience in

diagnosing and treating fish diseases, and the ability to monitor overall fish health
with respect to ongoing fish culture practices. A study monitor should be
assigned to each facility that is authorized to treat fish with SLICE® (emamectin
benzoate) medicated feed. A list of Study Monitors, along with addresses and
phone numbers, can be found in Appendix II. Study Monitors are responsible for
supervision of the trials, adherence of the Investigator to the Study Protocol, and
inspection of the site.

C. Special equipment and materials

Most of the equipment and materials required for this study (with the exception of
the SLICE® (emamectin benzoate) medicated feed itself) are already available at
each participating fish hatchery. The use of various drugs, chemicals, and
therapeutants to meet management and/or production goals is a common
occurrence at most fish hatcheries. Fish hatchery managers (i.e., Investigators)
are well trained and well equipped to handle these situations (see Appendix IIIb).
If any additional equipment or materials are required, they will be provided by the
Study Monitors (See Section VII.B. Items needed for sample collection,
observations, etc., page 6).

D. Administrator of the drug

SLICE® (emamectin benzoate) medicated feed will be administered directly by the

assigned Investigator (fish hatchery manager) or under the Investigator's direct
supervision (see Appendix IIIa for names). SLICE® (emamectin benzoate)
medicated feed will be maintained in a secure location, and only the Investigator or
persons under his/her direct supervision will have access.

E. Drug accountability records

16 Revised: 4/10
 See Section VII.A.6. Accountability (page 6) for details and Forms SLICE-W,
SLICE-1, SLICE-2a, SLICE-2b, and SLICE-3 (page 11) for actual forms to be used
in the study.

F. Recording observations

The Investigator or a person under his/her direct supervision will be responsible for
implementing the Study Protocol, making observations, collecting samples, and
recording data during the clinical field trials. After the data have been collected
and recorded on the forms, the Investigator will send the data to the Study
Monitors who will review the information and ensure that all required data is
provided. The Study Monitors will in turn send the data to the Study Director.
The Study Director will analyze and summarize the data and prepare an annual
report that will be submitted to the FDA.

G. Data storage

The Investigator is responsible for complete and accurate data collection. The
Investigator is also responsible for archiving a complete set of all original data. A
copy of Form SLICE-1 should be sent immediately to the Study Monitor, who will in
turn forward a copy to the Study Director. A copy of Form SLICE-2 should be sent
to Study Monitors with the corresponding Form SLICE-3 (if no further treatments
are necessary/planned), or at the end of the calendar year. A copy of Form
SLICE-3 should be sent to the Study Monitor after completion of the entire
treatment period, which includes the post-treatment observation period. Study
Monitors should carefully check each set of data for accuracy and completeness.
If there are any discrepancies in the data, the Study Monitor should contact the
Investigator immediately to rectify the problem. After review, Study Monitors
should forward all data to the Study Director. As stated above, a complete set of
raw data should be archived by the Investigator. All data should be stored in a
secure place. Another complete data set (copies) will be archived by the Study
Director.

XVIII. PLANS FOR DATA ANALYSIS

Data analysis will be completed by the Study Director located at the Bozeman National
INAD Office. Data from the treatment year will be summarized through tabulation and
appropriate statistical analysis. An annual report will be prepared and submitted to the
FDA. This submission will probably include a request for an extension of the INAD
based on the data collected during that year. When sufficient data are collected, the
entire INAD data set will be summarized in a final report for submission to support a full
NADA.

17 Revised: 4/10
XIX. PROTOCOL AND PROTOCOL AMENDMENTS

A signed copy of the Study Protocol must be retained by each Investigator. At any time
before the study begins, desired changes in the Study Protocol should be brought to the
attention of the Study Director. The desired changes will be fully described in the form of
an amendment along with the reason for the change. The amendment will be signed by
the Sponsor (or its representative)and forwarder to the FDA for review. Copies of the
signed amendment will be attached to each copy of the Study Protocol. Investigators
will be liable for non-compliance violation if drugs are used without a Study
Protocol or in a manner different than specified in the Study Protocol, if forms are
not filed on time, or if the study data are not properly collected, maintained, and
reported. The Study Monitor is responsible for ensuring that all INAD procedures are
being followed as defined by the Study Protocol.

XX. PROTOCOL DEVIATIONS

Deviations from the established Study Protocol occasionally cannot be avoided. If

deviations occur, the Study Monitor should be notified immediately. Protocol
deviations should be fully documented and should be accompanied by a written
explanation of what happened, why, and what steps were taken to mitigate the
deviation. Deviation statements should be signed and dated. These statements
should be forwarded to the Study Monitor along with Form SLICE-3, and ultimately be
submitted to the Study Director.

18 Revised: 4/10
 LITERATURE CITED

Armstrong, R., D. MacPhee, T. Katz, and R. Endris. 2000. A field efficacy evaluation
of emamectin benzoate for the control of sea lice in Atlantic salmon. Canadian
Veterinary Journal. 41: 607-612.

Dunston, J. and R.R. Cusak. 2002. Emamcetin benzoate: an effective in-feed

treatment against the gill parasite Salmincola edwardsii on brook trout.
Aquaculture. 207: 1-9.

Hakalahti, T, Y. Lankinen, and E.T. Valtonen. 2004. Efficacy of emamectin

benzoate in the control of Argulus coregoni (Crustacea:Branchiura) on rainbow
trout Oncorhynchus myskiss. Diseases of Organisms. 60: 187-204.

Roy, W.J., I.H. Sutherland, H.D.M. Roger, and K.J. Varma. 2000. Tolerance of
Atlantic salmon, Salmo salar L., and rainbow trout, Oncorhynchus mykiss
(Walbaum), to emamectin benzoate, a new orally administered treatment for
sea lice. Aquaculture. 184: 19-29.

Stone, J., I.H. Sutherland, C. Sommerville, R.H. Richards, and K.J. Varma. 1999.
The efficacy of emamectin benzoate as an oral treatment of sea lice,
Lepeophtheirus salmonis (Kroyer), infestations in Atlantic salmon, Slamo salar
L. Journal of Fish Diseases. 22: 261-270.

Stone, J., I.H. Sutherland, C. Sommerville, R.H. Richards, and K.J. Varma. 2000a.
Field trials to evaluate the efficacy of emamectin benzoate as an oral
treatmentof sea lice, Lepeophtheirus salmonis (Kroyer), and Caligus
elongatus Nordman, infestations in Atlantic salmon, Salmo salar L.
Aquaculture. 186: 205-219.

Stone, J., I.H. Sutherland, C. Sommerville, R.H. Richards, and K.J. Varma. 2000b.
Commercial trials using ememectin benzoate to control Lepeophtheirus
salmonis (Kroyer), and Caligus elongatus Nordman, infestations in Atlantic
salmon, Salmo salar L. Diseases of Aquatic Organisms. 41: 141-149.

Stone, J., I.H. Sutherland, C. Sommerville, R.H. Richards, and R.G. Endris. 2000c.
The duration of efficacy following oral treatment with emamectin benzoate
against infestations of sea lice, Lepeophtheirus salmonis (Kroyer) in Atlantic
salmon, Salmo salar L. Journal of Fish Diseases. 23:185-192.

Stone, J., W.J. Roy, I.H. Sutherland, H.W. Ferguson, C. Sommerville, R.H. Richard,
and R.G. Endris. 2002. Safety and efficacy of emamectin benzoate
Form SLICE-3 Results Report Form Revised: 4/10
 administered in feed to Atlantic salmon, Salmo salar L., smolts is freshwater, as
a preventative treatment against infestations of sea lice, Lepeophtheirus
salmonis (Kroyer). Aquaculture. 210: 21-34.

Form SLICE-3 Results Report Form Revised: 4/10

 Version: 1.0
Revision date: 06.12.2013

SAFETY DATA SHEET

1 PRODUCT AND COMPANY IDENTIFICATION

Product name: SLICE (Emamectin Benzoate 0.2% SDS No: P00000023015

Aquaculture Premix)

Synonyms, Trade Names:

SLICE Premix, SP000125

Manufacturer: Telephone: 908-423-1000 (General Information

Merck Only)
One Merck Drive P.O. Box 100 Fax: 908-735-1496
Whitehouse Station, NJ, USA 08889-0100

Contact Person: EHS Data Steward Emergency telephone: 1-908-423-6000

e-mail: [email protected] (24/7/365) English Only

Intended Use: Finished veterinary product: Antiparasitic

2 HAZARDS IDENTIFICATION

Emergency Overview:

Appearance:
Color: White, Gray
Form : Powder

Signal words CAUTION!

Potential Health Effects:

General Finished veterinary product: Toxic if swallowed. Harmful if inhaled. Do not
breathe dust or vapor. Do not eat, drink or smoke when using the product.
Wash thoroughly after handling. Avoid release to the environment.

Inhalation: Harmful if inhaled.

skin: No data available.

eye: No data available.

Ingestion: Toxic if swallowed.

OSHA Regulatory Status This product is hazardous according to OSHA 29CFR 1910.1200.

Environment: Very toxic to aquatic life with long lasting effects.

OTHER INFORMATION No additional information

North American SDS 1/9

 Version: 1.0
Revision date: 06.12.2013

3 COMPOSITION / INFORMATION ON INGREDIENTS

General information: The formulations for these products are proprietary information. Only
hazardous ingredients in concentrations of 1% or greater and/or carcinogenic
ingredients in concentrations of 0.1% or greater are listed in the composition
table. Active ingredients in any concentration are listed.

Hazardous Component(s):
Chemical name CAS-No. Concentration
Propylene Glycol 57-55-6 2.50%
Emamectin benzoate 137512-74-4 0.20%
* All concentrations are percent by weight unless ingredient is a gas. Gas concentrations are in percent by volume.

4 FIRST AID MEASURES

Inhalation: Move into fresh air and keep at rest. For breathing difficulties, oxygen may be
necessary. Get medical attention. If breathing stops, provide artificial
respiration.

Skin contact: Wash skin thoroughly with soap and water. Get medical attention if irritation
persists after washing. Remove contaminated clothing and shoes. Wash
contaminated clothing before reuse. Destroy or thoroughly clean contaminated
shoes.

Eye contact: Immediately flush with plenty of water for at least 15 minutes. If easy to do,
remove contact lenses. Get medical attention.

Ingestion: Do not induce vomiting unless directed to do so by medical personnel. Never

give liquid to an unconscious person. Get medical attention.

Notes to the physician:

Hazards: See Sections 2 and 11.
Treatment: Treat supportively and symptomatically.

5 FIRE-FIGHTING MEASURES

Extinguishing media: Water spray, fog, CO2, dry chemical, or alcohol resistant foam.

Unsuitable extinguishing None known.

media:

Unusual Fire & Explosion Emits toxic fumes under fire conditions.
Hazards:

Special Fire Fighting Self-contained breathing apparatus and full protective clothing must be worn in
Procedures: case of fire.

Protective Measures: Prevent runoff from fire control or dilution from entering streams, sewers, or
drinking water supply.

6 ACCIDENTAL RELEASE MEASURES

Personal precautions: Use personal protective equipment. Immediately contact emergency personnel.
Keep unnecessary personnel away. Follow all fire fighting procedures.

North American SDS SLICE (Emamectin Benzoate 0.2% Aquaculture Premix) 2/9
 Version: 1.0
Revision date: 06.12.2013

Environmental precautions: Do not release into the environment.

Spill Cleanup Methods: Use a vacuum cleaner. If not possible, moisten dust with water before it is
collected with shovel, broom or the like. Collect in containers and seal securely.
For waste disposal, see section 13 of the MSDS. Prevent runoff from entering
drains, sewers, or streams.

7 HANDLING AND STORAGE

Handling: Do not breathe dust. Avoid contact with eyes, skin, and clothing. Wash
thoroughly after handling.

Storage: Keep container tightly closed in a cool, well-ventilated place.

8 EXPOSURE CONTROLS / PERSONAL PROTECTION

Exposure limits:
Chemical name Type Exposure Limit values Source

Starch TWA 10 mg/m3 US. ACGIH Threshold Limit Values

(2009)
Starch - Respirable fraction. PEL 5 mg/m3 US. OSHA Table Z-1 Limits for Air
Contaminants (29 CFR 1910.1000) (02
2006)
Starch - Total dust. PEL 15 mg/m3 US. OSHA Table Z-1 Limits for Air
Contaminants (29 CFR 1910.1000) (02
2006)
Propylene Glycol - Aerosol. TWA 10 mg/m3 US. Workplace Environmental Exposure
Level (WEEL) Guides (2009)
Emamectin benzoate TWA 15 ug/m3 (OEB 3)a. Merck
Wipe 150 ug/100 cm2 Merck
Limit

OEB (Occupational Exposure Band) is an internal Merck control band.

a. A skin notation has been assigned to this compound because cutaneous exposure may contribute significantly to the overall exposure and
produce systemic effects.

Protective Measures: Observe occupational exposure limits and minimize the risk of inhalation of
dust. Minimize open handling. Containment technologies suitable for controlling
compounds are required to control at source and to prevent migration of the
compound to uncontrolled areas (e.g., open-face containment devices).

Respiratory Protection: Use an appropriate approved air-purifying respirator equipped with HEPA
cartridges/canisters where there is the potential for exceeding established
occupational exposure limits or occupational exposure bands. Powered air filter
respirator. Use a positive pressure, air-supplied, pressure demand tight fitting
respirator (e.g., SCBA or airline equipped with emergency escape bottle) where
there is a potential for uncontrolled releases in excess of the respirator's
capabilities, where exposure levels are unknown or where air-purifying
respirators may not provide adequate protection.

Hand protection: Chemical resistant gloves. Consider double gloving.

Eye protection: Wear safety glasses with side shields (or goggles). If the work environment or
activity involves dusty conditions, mists or aerosols, wear the appropriate
goggles. Wear a faceshield or other full face protection if there is a potential for
direct contact to the face with dusts, mists, or aerosols.

North American SDS SLICE (Emamectin Benzoate 0.2% Aquaculture Premix) 3/9
 Version: 1.0
Revision date: 06.12.2013

Skin and Body Protection: Additional body garments should be used based upon the task being performed
(e.g., sleevelets, apron, gauntlets, disposable suits) to avoid exposed skin
surfaces. Use appropriate degowning techniques to remove potentially
contaminated clothing.

Hygiene measures: Wash skin thoroughly with soap and water.

9 PHYSICAL AND CHEMICAL PROPERTIES

Information on basic physical and chemical properties

Appearance:
Physical State: Solid
Form: Powder
Color: White, Gray
Solubility(ies):
Solubility in Water: Soluble

10 STABILITY AND REACTIVITY

Stability: Stable

Possibility of hazardous Stable

reactions:

Conditions to avoid: Excessive heat. Moisture.

Incompatible materials: No data available.

Hazardous decomposition Thermal decomposition or combustion may liberate carbon oxides and other
products: toxic gases or vapors.

11 TOXICOLOGICAL INFORMATION

General information: The information presented below pertains to the individual ingredients, and not
to the mixture(s) or final formulations.

North American SDS SLICE (Emamectin Benzoate 0.2% Aquaculture Premix) 4/9
 Version: 1.0
Revision date: 06.12.2013

Specified substance(s):

Acute Toxicity (Oral);

Name Test results
Propylene Glycol LD50 (Rat): > 20 g/kg
Emamectin benzoate LD50 (Rat): 76 - 88 mg/kg Toxic if swallowed.
(Mouse): 21 - 31 mg/kg Toxic if swallowed.

Acute Toxicity (Dermal):

Name Test results
Propylene Glycol LD50 (Rat): > 20 g/kg
Emamectin benzoate LOEL - Lowest Observable Effect Level (Rabbit): 500 mg/kg Harmful in contact with
skin.

Acute Toxicity (Inhalation):

Name Test results
Propylene Glycol LC50 (Rat, 8 h): 4.1 mg/l No mortality observed.
Emamectin benzoate LC50 (Rat, 4 h): > 1.049 mg/l Harmful if inhaled.

Repeated dose toxicity:

Name Test results
Propylene Glycol In rare cases, repeated excessive exposure may cause: central nervous system effects.
Emamectin benzoate NOAEL (Rat, Oral, 14 Weeks, daily): 0.5 - 1.0 mg/kg NOEL (Rat, Oral, 14 Weeks,
daily): (Target Organ(s): central nervous system, Peripheral nervous system) In repeat-
dose toxicity studies in rats serious or significant adverse effects were observed in the
following organs: nervous system , May cause nervous system damage. Data
referenced is based on the benzoate salt. Data referenced is based on the
hydrochloride salt.
NOAEL (Rat, Oral, 53 Weeks, daily): 1.0 mg/kg NOEL (Rat, Oral, 53 Weeks, daily):
(Target Organ(s): central nervous system, Peripheral nervous system) In repeat-dose
toxicity studies in rats serious or significant adverse effects were observed in the
following organs: nervous system , May cause nervous system damage. Data
referenced is based on the benzoate salt. Data referenced is based on the
hydrochloride salt.
NOAEL (Dog, Oral, 14 Weeks, daily): 0.25 mg/kg NOEL (Dog, Oral, 14 Weeks, daily):
(Target Organ(s): central nervous system, Peripheral nervous system, skeletal muscle)
May cause nervous system damage. May cause muscle damage. Data referenced is
based on the benzoate salt. Data referenced is based on the hydrochloride salt.
NOAEL (Mouse, Oral, 79 Weeks, daily): 2.5 mg/kg NOEL (Mouse, Oral, 79 Weeks,
daily): (Target Organ(s): central nervous system, Peripheral nervous system) May
cause nervous system damage. Data referenced is based on the benzoate salt. Data
referenced is based on the hydrochloride salt.
NOAEL (Rat, Oral, 105 Weeks, daily): 0.25 mg/kg NOEL (Rat, Oral, 105 Weeks, daily):
(Target Organ(s): central nervous system, Peripheral nervous system, liver, bladder)
May cause nervous system damage. May cause liver damage. May cause bladder
damage. Data referenced is based on the benzoate salt. Data referenced is based on
the hydrochloride salt.

Inhalation: Harmful if inhaled.

Ingestion: Toxic if swallowed.

Skin corrosion/irritation: No data available.

Serious eye damage/eye No data available.

irritation:

North American SDS SLICE (Emamectin Benzoate 0.2% Aquaculture Premix) 5/9
 Version: 1.0
Revision date: 06.12.2013

Respiratory sensitizer/Skin No data available for finished product. Active veterinary ingredient: Not a skin
sensitizer: sensitizer.

Carcinogenicity: No data available for finished product. Active veterinary ingredient: No

evidence of carcinogenicity in rats and mice. Not listed as carcinogen by
OSHA, NTP or IARC.

Mutagenesis: No data available for finished product.

Reproductive toxicity: No data available for finished product. Active veterinary ingredient: Adverse
developmental and reproduction effects were observed in rats. Adverse
neonatal and fetal effects were observed in rats. Fetotoxicity was observed in
rats. Tremors, hindlimb extension, reduced body weight gain were observed in
rat pups; neuronal degeneration of brain or spinal cord in F0 rats. No
teratogenicity observed in rats or rabbits at low doses. In rats at the highest
dose group (8 mg/kg/day), there was increased number of fetuses with
supernumerary ribs and an increased incidence of delayed ossification.

Other Effects: No additional information

12 ECOLOGICAL INFORMATION

General information: The information presented below pertains to the individual ingredients, and not
to the mixture(s) or final formulations.

Ecotoxicity:

Product:

Chronic Toxicity(Fish): No data available.

North American SDS SLICE (Emamectin Benzoate 0.2% Aquaculture Premix) 6/9
 Version: 1.0
Revision date: 06.12.2013

Specified substance(s):

Acute toxicity(Fish):
Name Test results
Propylene Glycol LC50 (Rainbow Trout (Oncorhynchus mykiss), 96 h): 44 - 51.6 g/l
Emamectin benzoate LC50 (Rainbow Trout (Oncorhynchus mykiss), 96 h): 0.174 mg/l
LC50 (Bluegill (Lepomis macrochirus), 96 h): 0.180 mg/l
LC50 (Sheepshead minnow (Cyprinodon variegatus), 96 h): 1.34 mg/l

Acute toxicity(Aquatic invertebrates):

Name Test results
Propylene Glycol EC 50 (Water flea (Daphnia magna), 48 h): 4.85 - 34 g/l
Emamectin benzoate EC 50 (Water flea (Daphnia magna), 48 h): 0.00099 mg/l
EC 50 (Mysid (Americamysis bahia), 48 h): 0.000043 mg/l

Chronic Toxicity(Aquatic invertebrates):

Name Test results
Propylene Glycol No data available.
Emamectin benzoate Maximum acceptable toxicant concentration (MATC) (Water flea (Daphnia magna)):
0.12 ug/l

Acute toxicity(Aquatic plants):

Name Test results
Propylene Glycol EC 50 (Green algae (Pseudokirchneriella subcapitata)): 19 g/l (growth inhibition)
Emamectin benzoate No data available.

Persistence and degradability: No data available for finished product. Active veterinary ingredient: Expected to
biodegrade.

Bioaccumulative potential: No data available for finished product. Active veterinary ingredient: Not
expected to bioaccumulate.

Mobility: No data available for finished product. Active veterinary ingredient: Expected to
be immobile in soil.

13 DISPOSAL CONSIDERATIONS

Disposal Methods: Disposal must be in accordance with applicable national, state/provincial,

and/or local regulations.

Measures for Avoidance and Incineration is the most effective method of disposal in most instances. Do not
Recovery: allow runoff to sewer, waterway or ground. Operations that involve the
crushing or shredding of waste materials or returned goods should take into
account recommended exposure limits where they exist.

14 TRANSPORT INFORMATION

DOT
Not regulated.

North American SDS SLICE (Emamectin Benzoate 0.2% Aquaculture Premix) 7/9
 Version: 1.0
Revision date: 06.12.2013

IMDG - International Maritime Dangerous Goods Code

UN number UN3077
Proper Shipping Name ENVIRONMENTALLY HAZARDOUS SUBSTANCE,
SOLID, N.O.S.(Emamectin benzoate)
Class 9
Packing group III
Label(s) 9
Subsidiary risk label
Marine Pollutant / Envir. Hazardous, Labels Only
EmS No. F-A; S-F

IATA - International Air Transport Association

UN number UN3077
Proper Shipping Name ENVIRONMENTALLY HAZARDOUS SUBSTANCE,
SOLID, N.O.S.(Emamectin benzoate)
Class 9
Packing group III
Label(s) 9MI
Subsidiary risk label

15 REGULATORY INFORMATION

US Regulations
● CERCLA Hazardous Substance List (40 CFR 302.4):
None

● Clean Water Act Section 311 Hazardous Substances (40 CFR 117.3):
None

● Clean Air Act (CAA) Section 112(r) Accidental Release Prevention (40 CFR 68.130):
None

SARA Title III

● Section 302 Extremely Hazardous Substance (40 CFR 355, Appendix A):
None

● Section 313 Toxic Release Inventory (40 CFR 372):

None present or none present in regulated quantities.

State Regulations
● California Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65):
Butylated hydroxyanisole Hazard Designation: Carcinogenic.

● Massachusetts Right-To-Know List:

Starch Listed
Butylated hydroxyanisole Listed

● New Jersey Right-To-Know List:

Propylene Glycol Listed

● Pennsylvania Right-To-Know List:

Starch Listed
Propylene Glycol Listed

16 OTHER INFORMATION

North American SDS SLICE (Emamectin Benzoate 0.2% Aquaculture Premix) 8/9
 Version: 1.0
Revision date: 06.12.2013

OTHER INFORMATION This SDS is written to provide health and safety information
for individuals who will be handling the final product
formulation during research, manufacturing, and
distribution. For health and safety information for individual
ingredients used during manufacturing, refer to the
appropriate SDS for each ingredient. Refer to the package
insert or product label for handling guidance for the
consumer.

NFPA Hazard ID

0 Flammability
Health
2 0
Reactivity
Special hazard.

Hazard rating: 0 - Minimal; 1 - Slight; 2 - Moderate; 3 - Serious; 4 - Severe

Revision Information: Not relevant.

Issue Date: 06.12.2013
Disclaimer: This information is provided without warranty. The information is believed to be
correct. This information should be used to make an independent determination of
the methods to safeguard workers and the environment.

North American SDS SLICE (Emamectin Benzoate 0.2% Aquaculture Premix) 9/9
Form SLICE-W: Worksheet for Designing Individual Field Trials Under SLICE® (Emamectin
Benzoate) INAD 11-370

INSTRUCTIONS
1. Investigator must fill out Form SLICE-W for each trial conducted under this INAD before actual use of
SLICE® (emamectin benzoate) medicated feed. The Investigator is responsible for accurate completion of
Form SLICE-W.
2. Investigator should keep the original on file, and fax a copy to the Study Monitor for review.
3. After review, the Study Monitor will fax a copy to the AADAP Office for assignment of the Study Number.
4. The AADAP Office will review the worksheet, and then fax the assigned trial Study Number to both the
Investigator and Study Monitor, at which time the trial may be initiated.
5. Note: Both Investigator and Study Monitor should sign and date Form SLICE-W.

SITE INFORMATION
Facility
Address

Investigator
Reporting Individual (if not Investigator
Phone Fax

FISH CULTURE AND DRUG TREATMENT INFORMATION
Fish parasite to be treated
Fish species/stock to be treated
Number of fish per rearing unit (i.e., tank, raceway, or pond)
Number of rearing units Number of untreated (i.e., control)
to be treated rearing units
Average number of fish Estimated total weight of treated
per pound fish (lbs)
Intended SLICE® (emamectin benzoate) dosage 50 ug per kg per day
Feed rate (% body weight to be fed per day)
Planned duration of treatment (days) 7
Estimated amount of medicated feed needed for proposed treatment (lbs or kg)
Anticipated date treatment will be initiated

Form SLICE-3 Results Report Form Revised: 4/10

STUDY DESIGN: Describe in detail the purpose of the clinical trial. Study design must be carefully
focused and lend itself to rigorous evaluation. If more space is required to describe study details, title additional
page(s) “Study Design” and attach them to this Worksheet.

Study designed by; __________________________________________________________

DISPOSITION OF TREATED FISH (Human Food Safety Considerations):

Investigator should initial here to indicate awareness that fish disposition must be in compliance
with the FDA-mandated withdrawal time of 60 days as described in the Study Protocol.

USE AND DISPOSITION OF EMAMECTIN BENZOATE (SLICE®) MEDICATED FEED

(Environmental Safety Considerations):

Investigator should initial here to indicate awareness that SLICE® (emamectin benzoate)
medicated feed usage and disposition must be in compliance with requirements described in the
Study Protocol.

WORKER SAFETY CONSIDERATIONS:

Investigator should initial here to indicate that all personnel handling SLICE® (emamectin
benzoate) medicated feed have read the Material Safety Data Sheet for SLICE® (emamectin
benzoate) premix and have been provided personal protective equipment, in good working
condition, as described in the Study Protocol.

Date Prepared: _______________ Investigator: __________________________________

Date Reviewed: _______________ Study Monitor: _________________________________

Form SLICE-3 Results Report Form Revised: 4/10

FORM SLICE-1. Report on Receipt of Drug - Guide for Reporting Investigational New Animal
Drug Shipments for Poikilothermic Food Animals

INSTRUCTIONS
1. Investigator must fill out Form SLICE-1 immediately upon receipt of SLICE® (emamectin benzoate) pre-
mix or SLICE® (emamectin benzoate) medicated feed.
2. Investigator should keep the original on file, and send one copy to the Study Monitor for review.
3. Within 10 days of receipt, the Study Monitor should send a copy to the AADAP Office.
4. Note: Both Investigator and Study Monitor should sign and date Form SLICE-1.

The sponsor, U.S. Fish and Wildlife Service, submits a notice of claimed investigational exemption for the
shipment or delivery of a new animal drug under the provisions of Section 512 of the Federal Food, Drug,
and Cosmetics Act.
Name of Drug SLICE® INAD Number 11-370
(Emamectin
benzoate)
Proposed Use of Drug Treatment of external parasites that occur in a variety of freshwater fish
species.
Date of CVM Authorization Letter To be Determined
Source of Drug Western Chemical Inc.
Date of Drug Receipt Amount of Drug Received
Drug Lot Number Trial Number
Name of Investigator
Address of Investigator
Location of Trial
Pivotal Study Yes Non-pivotal Study (yes/no) -----
Approximate Number of Treated Approximate Number of
Animals Control Animals
Number of Animals Used Previously1
Study Protocol Number 11-370
Approximate dates of trial (start/end)
Species, Size, and Type of Animals
Maximum daily dose and duration 50 ug emamectin benzoate / kg fish / day for 7 days
Methods(s) of Administration Medicated-feed
Withdrawal Period 60 days - all species
1
To be filled out by the AADAP Office

Date Prepared: ________________ Investigator: _______________________________________

Date Reviewed: ________________ Study Monitor: _____________________________________

Date Reviewed: ________________ Sponsor: __________________________________________

Form SLICE-3 Results Report Form Revised: 4/10

Form SLICE-2a. Chemical Use Log for Clinical Field Trials Using SLICE® (emamectin benzoate) Medicated Feed Under
INAD #11-370 - SLICE® Premix

INSTRUCTIONS
1. Initiate Form 2a immediately upon receipt of SLICE® (emamectin benzoate) premix.
2. Each lot number of SLICE® (emamectin benzoate) premix may be used for multiple treatment regimes.
3. A signed copy of Form 2a should be sent to the Study Monitor at the end of the Study Year.
4. Original Form 2a should be archived at the investigating facility.

Qty on Hand from

previous page (ml) __________________ Facility _______________________________________ Reporting individual___________________________________________
SLICE®
SLICE® SLICE® SLICE® SLICE®
Date Amount Date Study Premix
Premix Premix Premix Premix Inventory by
Received Received Used Number Used for
Lot Number Shipped1 Disposal On-Hand (initials)
(g) Teatment
(g) (g) (g)
(g)

1
Unused SLICE® Premix that is shipped to another facility participating in SLICE® INAD #11-370 (Note: SLICE® Premix can only be shipped to another facility with prior
authorization by the AADAP Office).
2
Unused SLICE® Premix that is disposed of by burial or in a landfill.

Investigator: __________________________________________ Study Monitor: _________________________________________________

Signature and Date Signature and Date

Form SLICE-3 Results Report Form Revised: 4/10

Form SLICE-2a. Chemical Use Log for Clinical Field Trials Using SLICE® (emamectin benzoate) Medicated Feed Under
INAD #11-370 - SLICE® Medicated Feed

INSTRUCTIONS
1. Initiate Form 2b immediately upon receipt of SLICE® (emamectin benzoate) medicated feed.
2. Each lot number of SLICE® (emamectin benzoate) medicated feed should be used for a single treatment regime.
3. A signed copy of Form 2b should be sent to the Study Monitor at the end of the study, or at the end of the Study Year.
4. Original Form 2b should be archived at the investigating facility.

Qty on Hand from

previous page (ml) __________________ Facility _______________________________________ Reporting individual___________________________________________
SLICE®
SLICE® SLICE® SLICE® SLICE®
Date Amount Date Study Medicataed
Medicataed Medicataed Medicataed Medicataed Inventory by
Received Received Used Number Used for
Lot Number Shipped1 Disposal On-Hand (initials)
(g) Teatment
(g) (g) (g)
(g)

1
Unused SLICE® medicataed feed that is shipped to another facility participating in SLICE® INAD #11-370 (Note: SLICE® medicataed feed can only be shipped to another
facility with prior authorization by the AADAP Office).
2
Unused SLICE® medicataed feed that is disposed of by burial or in a landfill.

Investigator: __________________________________________ Study Monitor: _________________________________________________

Signature and Date Signature and Date

Form SLICE-3 Results Report Form Revised: 4/10

STUDY NUMBER ___________________________________ Page 1 of 4

Form SLICE-3: Results Report Form for Clinical Field Trials Using SLICE®
(emamectin benzoate) Medicated Feed Under INAD 11-370

INSTRUCTIONS
1. Investigator must fill out Form SLICE-3 no later than 10 days after completion of treatment. Study Number
must be recorded on all pages of Form SLICE-3. Attach lab reports and other information.
2. If SLICE® (emamectin benzoate) was not used under the assigned Study Number, fill out only the Site
Information portion on this page, and skip to the end of page 4 and fill out only the “Negative Report”
section.
3. Investigator should keep the original on file, and send a copy to the Study Monitor. Within 10 days of
receipt, the Study Monitor should send a copy to the AADAP Office for inclusion in the permanent file.
4. Note: Both Investigator and Study Monitor should sign and date Form SLICE-3.

SITE INFORMATION
Facility
Reporting Individual

FISH CULTURE AND DRUG TREATMENT INFORMATION

SLICE® (emamectin Medicated feed
benzoate) lot number manufacture/preparation date
Treatment dosage 50 ug/kg bw/day Treatment duration 7 days
Fish species treated Fish parasite treated
Number of rearing units Number of fish per treated
treated rearing unit
ID of all treated rearing units (e.g. Tank 5, Pond 6B)
Total number of fish treated
Number of control units Number of fish per control unit
Number of fish per pound Average fish length (in)
Preparation of medicated feed (i.e. top-coated at
your facility or prepared by feed manufacturer)
Feed type (manufacturer, moist vs dry, particle size)
Feed rate (% BW fed per day)
Date treatment initiated Date treatment completed

Form SLICE-3 Results Report Form Revised: 4/10

STUDY NUMBER ___________________________________ Page 2 of 4
Daily Mortality Record

INSTRUCTIONS
1. Investigator must fill out the Daily Mortality Record as completely as possible.
2. Prior to initiation of the trial, fill out Rearing Unit ID, whether a rearing unit is Treated or Control, and the
number of fish in each rearing unit.
3. Water temperature and individual tank mortality should be recorded on a daily basis.
4. Use additional copies of this form if more than 6 rearing units are involved in the trial.

FACILITY
Rearing Unit ID
Treated or Control
Number of Fish
Water Daily
Day Date Temp Mortality Mortality Mortality Mortality Mortality Mortality Observer
(Fo) Initials
5
Pre-Treatment

4
Period

3
2
1
1
2
3
Treatment

4
5
6
7
1
2
3
Post-Treatment Period

4
5
6
7
8
9
10

Form SLICE-3 Results Report Form Revised: 4/10

STUDY NUMBER ___________________________________ Page 3 of 4

Daily Mortality Record (Supplemental Post-treatment Period Data)

INSTRUCTIONS
1. Investigator should fill out the Daily Mortality Record (Supplemental Post-treatment Period Data) only if
data is collected for more than 10 days post-treatment.
2. Use additional copies of this form if more than 6 rearing units are involved in the trial.

FACILITY
Rearing Unit ID
Treated or Control
Number of Shrimp
Water Daily
Day Date Temp Mortality Mortality Mortality Mortality Mortality Mortality Observer
(Fo) Initials
11
12
13
14
15
16
17
Post - Treatment Period

18
19
20
21
22
23
24
25
26
27
28

WATER QUALITY PARAMETERS

Ave pre-treatment temp (oF) Dissolved Oxygen (mg/L)
Ave treatment temp (oF) pH
Ave post-treatment temp (oF) Hardness - CaCO3 (mg/L)

Form SLICE-3 Results Report Form Revised: 4/10

STUDY NUMBER ___________________________________ Page 4 of 4

RESULTS: Describe in detail treatment results. Was treatment successful? If treatment did not appear to
be successful, explain why not? Describe general fish behavior, including feeding behavior. Were there any
mitigating environmental conditions that may have impacted treatment results? Were there any deviations from
the Study Protocol?

PATHOLOGY REPORT: Attach pathology report to this form. Report should include: 1) a description of
how the pathogen(s) was identified; 2) disease identification records that confirm the presence of the pathogen;
and 3) the name and title of the individual performing the diagnosis.

Pathology Report included: ________ pre-treatment ________ post-treatment

TOXICITY OBSERVATIONS: (Report any apparent drug toxicity including a description of unusual fish
behavior. )

OBSERVED WITHDRAWAL PERIOD OF TREATED FISH:

Observed withdrawal period:

_____ Investigator should initial here to indicate compliance with established withdrawal period

_____ 60 days

Estimated number of days between last treatment and first availability of fish for human consumption
(ensure this time period meets the withdrawal period). ______________

DISPOSITION OF SLICE® (EMAMECTIN BENZOATE) MEDICATED FEED

Use and disposition of all SLICE® (emamectin benzoate) medicated feed followed Study
Protocol guidelines and has been clearly identified on Form SLICE-2b (Investigator should
initial)

NEGATIVE REPORT: SLICE® (emamectin benzoate) medicated feed was not used at this
facility under this Study Number during the reporting period (Investigator should initial for
negative reports as soon as the Study Number is known to be no longer needed or valid

Date Prepared: __________________ Investigator: ______________________________________

Date Reviewed: __________________ Study Monitor: ____________________________________

STUDY NUMBER ___________________________________ Page 1 of 2
Form SLICE-3s: Supplemental Information Documenting Level of Parasite Infestation
Pre-Treatment and Post-Treatment

INSTRUCTIONS
1. Investigator should fill-out one copy of Form SLICE-3s for each rearing unit treated.
2. Be sure to include STUDY NUMBER in upper left-hand corner of this form.
3. Data on Pre-treatment level of infestation should be collected within 5 days prior to the initiation of treatment.
4. Data on Post-treatment level of infestation should be collected at least once.
5. Note: Each sampling (i.e., pre- and post-treatment) should include data from a minimum of 10 fish, and completed Form
SLICE-3s’s should be appended to Form SLICE-3.
Rearing Unit ID: ______________
Pre-treatment Post-treatment1
Date Fish Number of Date Days Fish Number of
Number Parasites Post-treatment Number Parasites
1 1
2 2
3 3
4 4
5 5
6 6
7 7
8 8
9 9
10 10
11 11
12 12
13 13
14 14
15 15
16 16
17 17
18 18
19 19
20 20
21 21
22 22
23 23
24 24
25 25
26 26
27 27
28 28
29 29
30 30

1
Additional copies of table for post-treatment infestation level are available on page 2 of this form
Form SLICE-3 Results Report Form Revised: 4/10
STUDY NUMBER ___________________________________ Page 2 of 2

Form SLICE-3s: Supplemental Information Documenting Level of Parasite Infestation

Additional Documentation of Level of Parasite Infestation Post-Treatment

Note: If data on post-treatment level of parasite infestation is only collected once, please simply
write “N/A” in the box

Rearing Unit ID: ______________

Post-treatment Post-treatment
Days Fish Number of Days Fish Number of
Date Date
Post-treatment Number Parasites Post-treatment Number Parasites
1 1
2 2
3 3
4 4
5 5
6 6
7 7
8 8
9 9
10 10
11 11
12 12
13 13
14 14
15 15
16 16
17 17
18 18
19 19
20 20
21 21
22 22
23 23
24 24
25 25
26 26
27 27
28 28
29 29
30 30

Form SLICE-3s: Supplemental Information Documenting Level of Parasite Infestation

Form SLICE-3 Results Report Form Revised: 4/10