Document ID: EPA-HQ-OPP-2007-1019-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-05-21T04:00Z

United States			Prevention, Pesticides	OPP-2005-0231			Environmental
Protection 		And Toxic Substances	March 2008

		Agency				(7508P)

			_________________________________________________________________

  SEQ CHAPTER \h \r 1 Reregistration Eligibility    Decision for 

Nicotine

List B

Case No. 2460 

  SEQ CHAPTER \h \r 1 

Reregistration Eligibility Decision (RED) Document 

For 

Nicotine 

Approved by:                                               .

	Steven Bradbury

	Director 

Special Review and 

  Reregistration Division

Date:           _____                                    .

  

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc193776629"  Table of
Contents	  PAGEREF _Toc193776629 \h  2  

  HYPERLINK \l "_Toc193776630"  Nicotine Reregistration Eligibility
Decision Team	  PAGEREF _Toc193776630 \h  3  

  HYPERLINK \l "_Toc193776631"  Glossary of Terms and Abbreviations	 
PAGEREF _Toc193776631 \h  4  

  HYPERLINK \l "_Toc193776632"  Abstract	  PAGEREF _Toc193776632 \h  6  

  HYPERLINK \l "_Toc193776634"  I.	INTRODUCTION	  PAGEREF _Toc193776634
\h  7  

  HYPERLINK \l "_Toc193776635"  II.	CHEMICAL OVERVIEW	  PAGEREF
_Toc193776635 \h  7  

  HYPERLINK \l "_Toc193776636"  A.	Chemical Identity	  PAGEREF
_Toc193776636 \h  7  

  HYPERLINK \l "_Toc193776637"  B.	Regulatory History	  PAGEREF
_Toc193776637 \h  8  

  HYPERLINK \l "_Toc193776638"  C.	Use Profile	  PAGEREF _Toc193776638
\h  9  

  HYPERLINK \l "_Toc193776639"  D.	Usage of Pesticide	  PAGEREF
_Toc193776639 \h  10  

  HYPERLINK \l "_Toc193776640"  E.	Tolerances	  PAGEREF _Toc193776640 \h
 10  

  HYPERLINK \l "_Toc193776641"  F.	Benefits	  PAGEREF _Toc193776641 \h 
10  

  HYPERLINK \l "_Toc193776642"  III.	SUMMARY OF NICOTINE RISK
ASSESSMENTS	  PAGEREF _Toc193776642 \h  10  

  HYPERLINK \l "_Toc193776643"  A.	Human Health Risk Assessment	 
PAGEREF _Toc193776643 \h  10  

  HYPERLINK \l "_Toc193776644"  B.	Toxicology	  PAGEREF _Toc193776644 \h
 11  

  HYPERLINK \l "_Toc193776645"  C.	Human Health Risk Characterization	 
PAGEREF _Toc193776645 \h  12  

  HYPERLINK \l "_Toc193776646"  IV.	RISK MANAGEMENT DECISION	  PAGEREF
_Toc193776646 \h  16  

  HYPERLINK \l "_Toc193776647"  A.	Risks of Concern	  PAGEREF
_Toc193776647 \h  16  

  HYPERLINK \l "_Toc193776648"  B.	Benefit Considerations	  PAGEREF
_Toc193776648 \h  19  

  HYPERLINK \l "_Toc193776649"  C.	Tolerances	  PAGEREF _Toc193776649 \h
 19  

  HYPERLINK \l "_Toc193776650"  D.	Data Gaps	  PAGEREF _Toc193776650 \h 
19  

  HYPERLINK \l "_Toc193776651"  V.	ACTIONS REQUIRED OF THE REGISTRANT	 
PAGEREF _Toc193776651 \h  20  

 Nicotine Reregistration Eligibility Decision Team

Office of Pesticide Programs

Biological and Economic Analysis Division

Colwell Cook, Arnet Jones			Biological Analysis Branch

John Faulkner, Tim Kiely			Economic Analysis Branch

Jenna Carter					Science Information and Analysis Branch

			

Environmental Fate and Effects Risk Assessment

Colleen Flaherty, Silvia C. Termes,		Environmental Risk Branch 3

Lucy Shanaman, Stephanie Syslo

Health Effects Risk Assessment

Bonnie Cropp-Kohlligian,			Reregistration Branch 4

Abdallah Khasawinah, Sue Hummel, Ray Kent

Registration Division

Dan Peacock					Insecticide/Rodenticide Branch

Risk Management

Jill Bloom, Tom Myers			Reregistration Branch 2

Glossary of Terms and Abbreviations  TC "Glossary of Terms and
Abbreviations" \f C \l "1"  

AGDCI	Agricultural Data Call-In

ai			Active Ingredient

aPAD			Acute Population Adjusted Dose

AR			Anticipated Residue

BCF			Bioconcentration Factor 

CFR			Code of Federal Regulations

cPAD			Chronic Population Adjusted Dose

CSF			Confidential Statement of Formula

CSFII			USDA Continuing Surveys for Food Intake by Individuals

DCI			Data Call-In

DEEM			Dietary Exposure Evaluation Model

DFR			Dislodgeable Foliar Residue

DWLOC		Drinking Water Level of Comparison.

EC			Emulsifiable Concentrate Formulation

EDWC			Estimated Drinking Water Concentration

EEC			Estimated Environmental Concentration

EPA			Environmental Protection Agency

EUP			End-Use Product

FDA			Food and Drug Administration

FIFRA			Federal Insecticide, Fungicide, and Rodenticide Act

FFDCA	Federal Food, Drug, and Cosmetic Act

FQPA			Food Quality Protection Act

FOB			Functional Observation Battery

G			Granular Formulation

GENEEC		Tier I Surface Water Computer Model

GLN			Guideline Number

HAFT			Highest Average Field Trial

IR			Index Reservoir

LC50			Median Lethal Concentration.  A statistically derived
concentration of a substance that can be expected to cause death in 50%
of test animals.  It is usually expressed as the weight of substance per
weight or volume of water, air or feed, e.g., mg/l, mg/kg or ppm.

LD50			Median Lethal Dose.  A statistically derived single dose that can
be expected to cause death in 50% of the test animals when administered
by the route indicated (oral, dermal, inhalation).  It is expressed as a
weight of substance per unit weight of animal, e.g., mg/kg.

LOC			Level of Concern

LOD			Limit of Detection 

LOAEL	Lowest Observed Adverse Effect Level

MATC			Maximum Acceptable Toxicant Concentration

µg/g			Micrograms Per Gram

µg/L			Micrograms Per Liter

mg/kg/day		Milligram Per Kilogram Per Day

mg/L			Milligrams Per Liter

MOE			Margin of Exposure 

MRID			Master Record Identification (number).  EPA's system of recording
and tracking studies submitted.

MUP			Manufacturing-Use Product

NA			Not Applicable

NAWQA		USGS National Water Quality Assessment

NPDES	National Pollutant Discharge Elimination System

NR			Not Required

NOAEC		No Observed Adverse Effect Concentration

NOAEL	No Observed Adverse Effect Level

OP			Organophosphate

OPP			EPA Office of Pesticide Programs

OPPTS		EPA Office of Prevention, Pesticides and Toxic Substances

PAD			Population Adjusted Dose

PCA			Percent Crop Area

PDP			USDA Pesticide Data Program

PHED			Pesticide Handler's Exposure Data 

PHI			Preharvest Interval

ppb			Parts Per Billion

PPE			Personal Protective Equipment

ppm			Parts Per Million

PRZM/EXAMS	Tier II Surface Water Computer Model  

Q1*			The Carcinogenic Potential of a Compound, Quantified by the EPA's
Cancer Risk Model

RAC			Raw Agriculture Commodity

RED			Reregistration Eligibility Decision

REI			Restricted Entry Interval

RfD			Reference Dose

RQ			Risk Quotient

SCI-GROW		Tier I Ground Water Computer Model

SAP			Science Advisory Panel

SF			Safety Factor

SLC			Single Layer Clothing

SLN			Special Local Need  (Registrations Under Section 24(c) of FIFRA)

TGAI			Technical Grade Active Ingredient

TRR			Total Radioactive Residue

USDA			United States Department of Agriculture

USGS			United States Geological Survey

UF			Uncertainty Factor

UV			Ultraviolet 

WPS			Worker Protection Standard

Abstract 

This document presents the Environmental Protection Agency’s (EPA’s
or the Agency’s) decision regarding the reregistration eligibility of
the registered uses of the active ingredient nicotine. The Agency
conducted human health and environmental fate and effects risk
assessments for nicotine non-food uses.  The registrant of the sole
remaining nicotine pesticide product requested the cancellation of its
registration on February 25, 2008, to be effective on December 31, 2013,
with existing stocks permitted to be sold by dealers and distributors
for one additional year.  The Agency has accepted this request in
concept, and it is subject to notice and public comment.  If public
comment provides no information that causes the Agency to reconsider,
the Agency may accept the cancellation request.

The assessment of risks for the pesticidal use of nicotine is unique in
that much of the supporting data is drawn from the open literature, as
opposed to studies conducted according to Agency guidelines, and the
data that are available are not entirely well-matched to anticipated
routes of exposure and use patterns for the nicotine pesticide. The lack
of more relevant data adds considerable uncertainty to the risk
assessment and would necessitate that the Agency call-in data from a
range of guideline studies.  Ultimately, the process the Agency
undertook to assess risks and formulate reregistration eligibility
decisions was overtaken by the registrant’s request for cancellation. 
The Agency is finalizing this reregistration eligibility decision as a
record of the database and methodologies that were used to assess
nicotine and the Agency’s preliminary conclusions about the risks
associated with its use.

The sole remaining nicotine registration, for which cancellation has
been requested, is a Restricted Use Pesticide used on greenhouse
ornamentals, including poinsettias, bedding plants, and chrysanthemums
to control whiteflies, aphids, and thrips. Nicotine has been known for
its pesticidal properties for centuries, and came into common use in the
U.S. about sixty years ago. Production and usage are now quite limited.

Using the limited available data, EPA has assessed the human health
risks for the remaining nicotine registration and has concluded that
risks for workers both during and after application, and for consumers
of plants from treated greenhouses and members of the public who might
be exposed to nicotine residues in treated greenhouses, are potentially
of concern.  Nicotine is not used on any food and feed crops so dietary
risks have not been assessed.  Because nicotine is used in greenhouses
only, drinking water and ecological risks were not assessed for this use
pattern, although the Agency did assess the ecological risks associated
with another nicotine product used outdoors to repel vertebrate pests of
ornamentals which has since been cancelled.  The ecological risk
assessment and an assessment of episodic ingestion of the nicotine
repellant product are posted to the nicotine docket, as are the
technical documents supporting the human health risk assessment for the
nicotine greenhouse use.

INTRODUCTION

	  SEQ CHAPTER \h \r 1 The Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) was amended in 1988 to accelerate the
reregistration of products with active ingredients registered prior to
November 1, 1984.  The amended Act calls for the development and
submission of data to support the reregistration of an active
ingredient, as well as a review of all data submitted to EPA. 
Reregistration involves a thorough review of the scientific database
underlying a pesticide's registration.  The purpose of the Agency's
review is to reassess the potential risks arising from the currently
registered uses of a pesticide, to determine the need for additional
data on health and environmental effects, and to determine whether or
not the pesticide meets the "no unreasonable adverse effects" standard
of FIFRA.  

	This document presents EPA's human health risk assessment.  It consists
of five sections. Section I (this section) contains the regulatory
framework for reregistration and tolerance reassessment.  Section II
provides a description of the chemical and a profile of the use and
usage of the chemical.  Section III summarizes the human health risk
assessment for pesticidal nicotine. Section IV presents the Agency's
risk management decision. Section V addresses the obligations of the
registrant pursuant to this RED, including mitigation measures the
Agency believes need to be implemented during the phase-out period.  The
documents that support this RED and characterize the risks associated
with nicotine products that recently have been cancelled are available
in the public docket maintained electronically by the Federal
government.  All these documents can be accessed via the edocket website
at   HYPERLINK "http://www.regulations.gov"  www.regulations.gov  under
docket identification number EPA-HQ-OPP-2007-1019.

CHEMICAL OVERVIEW

Chemical Identity

Empirical Formula	C10H14N2

Molecular Structure

  

Common Name:  		Nicotine

Chemical Name:  		3-(1-methylpyrrolidin-2-yl)pyridine; S-enantiomer

Synonyms:  	Pyridine, 3-[(2S)-1-methyl-2-pyrrolidinyl]-; Pyridine,
3-(1-methyl-2-pyrrolidinyl)-, (S)-; L-Nicotine; Pyridine,
(S)-3-(1-methyl-2-pyrrolidinyl); 1-Methyl-2-(3-pyridyl) pyrrolidine;
Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S);
(S)-3-(1-Methyl-2-pyrrolidinyl)pyridine; (-)-Nicotine

OPP Chemical Code: 		056702

CAS Number:	54-11-5

Molecular Weight, g.mol-1:  	162.234 

Chemical Family: 		Pyridine alkaloid

Technical Registrant: 		None registered 

Special Local Need:  		None 

Regulatory History

Nicotine, derived from the tobacco plant, has been used as a pesticide
since at least the 15th century.  Its use in the United States began
expanding in the 1940s and 50s.  By the 1990s, nicotine use dropped as
new insecticides were registered (and continue to be registered) for the
same crop/pest combinations. The last food use registrations of nicotine
were cancelled in January 1994, and the tolerances associated with the
last remaining food uses were revoked effective December 2005.

When the Agency began the reregistration process for nicotine, there
were three active pesticide registrations containing the active
ingredient.  Early in the process, the registrant of two of these
products indicated that it would request cancellation for one of them,
EPA Registration Number 4-340, Bonide Tobacco Dust.  As a result, the
Agency did not initiate risk assessments for the corresponding use
pattern.

In September 2007, Bonide formally requested the voluntary cancellation
of its Tobacco Dust registration (EPA Registration Number 4-340) and
also for its other nicotine registration (EPA Registration Number 4-465,
Bonide Rabbit & Dog Chaser).  Both of these products were registered for
use outdoors, the first to control insect pests of ornamentals, and the
second as a rabbit and dog repellant for ornamentals including turf. 
When Bonide indicated its intention to cancel the second of these two
registrations, the Agency stopped work on aspects of the risk
assessments corresponding to the applicable use pattern.  The Agency has
developed an environmental fate and ecological risk assessment document
and a summary characterization of the risks from episodic ingestion of
the Rabbit & Dog Chaser product.  Although these documents do not figure
in the Agency’s conclusions about the remaining nicotine product, they
are posted to the electronic docket as part of the record for the
nicotine pesticides.  Potential risk concerns are identified in both the
human health and ecological risk analyses for the outdoor use patterns.

 

After a public comment period on the cancellation requests in which no
comments were submitted, the Agency issued a cancellation order for both
Bonide registrations.  The cancellations became effective March 5, 2008.
 Bonide has not manufactured its Tobacco Dust product for three or four
years; there are no existing stocks in its possession.  In accordance
with its request, Bonide was granted 24 months after the effective date
of cancellation to distribute or sell its existing stocks of the Rabbit
& Dog Chaser product.

At present, Fuller Corporation has requested the voluntary cancellation
of the sole active registration for nicotine, its Fulex Nicotine
Fumigator (EPA Registration Number 1327-41).  The Agency determined
early in the reregistration process that ecological and drinking water
assessments were not needed for this product, because of its limited
usage and because it is used indoors only.  The Agency did conduct a
human health risk assessment for the Fulex product.  While the
assessment is characterized by a great deal of uncertainty, EPA has
identified potential risks; these are discussed in this document and
detailed in the supporting documents. Fuller Corporation requested the
cancellation of its registration on February 25, 2008, to be effective
on December 31, 2013, with existing stocks permitted to be sold by
dealers and distributors for one additional year.  

 

Nicotine has not been registered for use on food crops or crops
contributing to livestock diet for many years.  Tolerances for residues
of nicotine on or in cucumber, lettuce, and tomato at 40 CFR180.167
expired as of December 4, 2005.  Citations for the expired tolerances
will be removed from the Code of Federal Regulations through the
rule-making process. 

Use Profile

The following information is based on the currently registered uses of
nicotine.

Type of Pesticide:	Insecticide

Use Sites:  	Ornamental plants in greenhouses only, especially
poinsettias, and including annual bedding plants and chrysanthemums. 
Should not be used on violets.

Target Pests:		Adult thrips, whiteflies, and aphids.

Formulation Type:  	Smoke generating canisters (12 and 24 oz., 12/pkg.),
13.4% ai

Method and Rates 	Nicotine and inerts are packaged in metal cans with
sparklers

of Application: 	included.  Sparkler is lit and inserted into canister;
smoke escapes from canister.  A 12 oz. can treats 20,000 cubic ft. 
After the fumigation is completed, typically the next morning after a
late day application, the greenhouse is vented.  Ventilation
requirements are specified by the WPS.  Passive ventilation is
accomplished by opening greenhouse vents for approximately 2 hours;
active ventilation is accomplished by opening vents and running venting
fans for about 1 hour.  Vents may be opened and fans started manually or
remotely.

Timing:  		Multiple applications may be needed, typically up to three
times

and Application 	per season, at three to 12-day intervals.  For plant
production

Parameters:	facilities, the product is used mostly at the end of the
growing cycle before shipping to retail outlets.  Use declines from
mid-June to mid-September, and peaks again with poinsettia finishing.

Use Classification:	This product is designated a Restricted Use
Pesticide due to very high acute inhalation, oral, dermal, and eye
toxicity to humans.

Usage of Pesticide

Since there is only one nicotine product, volume of production is CBI.

Tolerances

Tolerances for residues of nicotine in or on cucumbers, lettuce, and
tomatoes are listed at 40 CFR 180.167, and expired effective December 4,
2005.  Citations for the expired tolerances will be removed from the
Code of Federal Regulations through the rule-making process.

Benefits

In contrast to some other treatments, there are no reports of nicotine
resistance in whitefly populations.  The smoke provides full coverage
for overhead hanging baskets, under benches, in dense plant canopies,
etc.  Smoke does not discolor blooms as liquid applications might. Using
a smoke formulation, rather than a manual spray operation, can reduce
the possibility of heat stress in handlers as applications typically are
made at night, when greenhouse temperatures are lowest.

SUMMARY OF NICOTINE RISK ASSESSMENTS

Human Health Risk Assessment 

The Agency’s findings on the human health risks associated with the
use of the sole remaining nicotine registration are detailed in the
docket in the document, "Nicotine and derivatives:  PC Code:  056702,"
with attachments, dated March XX, 2008.  The risk assessment summarized
below forms the basis of this RED.



Toxicology

While nicotine itself has been the subject of extensive research,
guideline studies appropriate to its pesticidal use are lacking.  For
the most part, this assessment relies on endpoints derived from
published data in the open literature.  The Agency searched a wide
variety of databases to identify potentially relevant toxicity
literature, including Science Direct, PubMed, ToxNet, ToxLine, a report
of the Surgeon General, and records from the International Programme on
Chemical Safety.

The utility of the open literature for hazard characterization in this
risk assessment is very limited.  Ideally, pesticide risk assessments
rely on studies that approximate the potential exposure routes.  For the
purposes of this risk assessment, the potential routes of exposure are
inhalation, dermal, and to a lesser extend oral; the Agency is able to
relate exposures in oral studies to other exposure routes with the use
of generally accepted assumptions.  Unfortunately, the open literature
includes only a few studies in which nicotine was administered orally or
by inhalation.  These studies were considered by the Agency for this
assessment.  Very few of the open literature studies employed the dermal
route, and these studies were qualitative and did not provide a
quantitative measure of the degree of toxicity.  All studies surveyed by
the Agency were used collectively to characterize the toxicity of
nicotine, but only studies with the appropriate routes of exposure were
used in endpoint selection for this risk assessment.

Nicotine is acutely toxic (Category I) by all routes of exposure (oral,
dermal, and inhalation).  The LD50 of nicotine is 50 mg/kg for rats and
3 mg/kg for mice.  A dose of 40–60 mg can be a lethal dosage for adult
human beings and doses as low as 1-4 mg can be associated with toxic
effects in some individuals.  Nicotine is an agonist at nicotinic
receptors in the peripheral and central nervous system 

The Agency selected a subchronic oral rat toxicity study conducted with
nicotine hydrogen tartrate (Yuen et al. 1995) as a basis for the
episodic oral, dermal, and inhalation toxicity endpoints.  In this
study, nicotine was administered to pregnant and non-pregnant female
rats in the drinking water for 10 days at doses equivalent to 1.25 and
2.5 mg/kg/day.  The animals exhibited mild fatty change, mild focal
necrosis and mild dark cell change, with effects on the mitochondria, in
a dose proportional manner.  Effects at the lower dose were not
statistically significant, so the NOAEL was identified as 1.25
mg/kg/day; the LOAEL was identified as 2.5 mg/kg/day.  The NOAEL from
this study was selected for the assessment of short- and
intermediate-term human health risks associated with the current
nicotine use pattern.

According to the International Programme on Chemical Safety and other
authorities, nicotine is neither an initiator nor a promoter of tumors
in rodents.

The Agency determined that the appropriate margin of exposure for human
health effects is 1000—10X for inter-species extrapolation, 10X for
intra-species variability, and 10X for database uncertainty (10X).

Human Health Risk Characterization

Occupational Risk

Workers can be exposed to nicotine from the Fulex product through
application and by post-application activities in treated areas.  The
occupational handlers of nicotine are the certified applicators (and
those under their direct supervision) who apply nicotine and re-enter a
greenhouse to operate ventilation equipment and clean-up canisters after
deployment.  Post-application workers include those who water, pack,
prepare for shipment, or otherwise handle treated plants.

No nature of the residue data are available for the unique
smoke-generator application method of nicotine, which appears to alter
the physical state of the active ingredient and may result in the
generation of nicotine reaction products and degradates.  All potential
combustion products and degradates of nicotine from the Fulex product
are accounted for in the occupational exposure assessments and the
Agency has assumed that they are toxicologically equivalent to the
parent.  

Occupational risk is measured by a Margin of Exposure (MOE) which
determines how close the occupational exposure comes to the selected No
Observed Adverse Effect Level (NOAEL).  For nicotine, risks of concern
are those that fall below the MOE of 1000.  For workers entering a site
to perform post-application tasks with a potential for dermal exposure,
Restricted Entry Intervals may be calculated to determine the minimum
length of time required before workers or others are allowed to reenter
(in this case, at an interval when the MOE approaches 1000).  For
post-application inhalation exposures, there is no one time period of
restricted entry after nicotine application, but the ventilation
criteria of the Worker Protection Standard must be satisfied before
post-application activities can resume.

Dietary and Drinking Water Risk

There are no registered food uses for nicotine, and it is used in
greenhouses only. Dietary and drinking water exposures are not expected
and were not assessed.

Residential Risk

The sole currently registered nicotine product is a Restricted Use
Pesticide that must be applied by a properly certified applicator or
subordinate and is used only in greenhouses.  The Agency believes that
it is unlikely that the product is used in private greenhouses, but the
current label does not prohibit such use.

Risk to Consumers of Plants Treated with Nicotine

Based on the potential post-application risk to greenhouse workers who
handle plants from greenhouses treated with nicotine (discussed later in
this document), the Agency believes there also is a potential for risk
to consumers who enter a greenhouse soon after treatment with nicotine
to purchase plants.  The current label does not prohibit retail sales of
treated plants for a set interval after nicotine application. 

Aggregate Risk

Exposures contributing to aggregate risk are dietary, drinking water,
and residential/ consumer exposures.  Dietary and drinking water
exposures for the current nicotine use pattern are not likely.  Thus,
only risks to residents and retail consumers have been assessed.

Exposure estimates for occupational handlers

Handler exposures to nicotine are expected to be short- or
intermediate-term in length; since the endpoint for either exposure
category is the same, only one set of values is reported.

The extent of a handler’s dermal exposure to nicotine from the Fulex
product is assumed to be small relative to the potential inhalation
exposure.  A dermal exposure assessment for handlers was not performed. 
Inhalation exposure estimates in this risk assessment are based on
maximum theoretical air concentration calculations and default
assumptions.  

  

Duration of exposure is directly proportionate to the number of
canisters of the Fulex product that must be deployed and retrieved after
application by the handler.  The exposure assessment is based on
exposure times of 30 minutes to represent small greenhouses and 60
minutes to represent large greenhouses.  

Inhalation dose estimates are based on theoretical air concentration of
nicotine in a greenhouse when applied according to label directions, an
exposure time of 30 or 60 minutes (small and large greenhouses; see
above), a standard adult breathing rate of one cubic meter per hour and
the default adult body weight of 70 kg (about 150 lbs).  The dose is
adjusted for the levels of protection provided by the different types of
respiratory protection, and the Agency has estimated risks for
individuals using different types of respiratory protection.

Risk estimates and discussion

Risk estimates based on the above-mentioned variables and default values
are captured in Table 1. An MOE of 1000 or above is considered
protective of human health in this context.  MOEs in boldface represent
risks potentially of concern.

Table 1.  Short-Term Occupational Handler Inhalation Risk Estimates

Respirator type	Exposure time

(per day)	Inhalation Dose (mg/kg/day)	Inhalation MOE 

Baseline

No Respirator	30 minutes	0.57	2

	60 minutes	1.14	1

PF10 Respirator

Half-face organic-vapor-removing respirator providing 90% protection	30
minutes	0.057	22

	60 minutes	0.114	11

	<1 min.	0.00125	1000

PF50 Full-face organic-vapor-removing respirator providing 98%
protection	30 minutes	0.01	125

	60 minutes	0.02	63

	~3 min.	0.00125	1000

PF10,000 Self-contained breathing apparatus (SCBA) providing 99.99%
protection	60 minutes	0.0001	12500

The product label requires that handlers wear PPE including a respirator
with either an organic vapor cartridge with a prefilter approved for
pesticides or a canister approved for pesticides. The label does not
specify half-face or full-face respirators.  

Risk estimates based on the limited available data and maximum
theoretical air concentration exceed levels of concern for handlers in
small and large greenhouses, with exposure times of 30 and 60 minutes,
respectively, and wearing half- or full-face respirators with the
specifications detailed in the table above.  Actual exposure times for
Fulex applicators probably are shorter than 30 and 60 minutes, and more
than the one or three minutes for which MOEs also are calculated. 

This method of estimating risk assumes that the handler is exposed to
the maximum possible concentration of nicotine in the greenhouse, when
it is reasonable to assume that application activities are complete
before the cans have released their entire nicotine contents into the
greenhouse air.  Thus, actual exposures are likely to be less than the
inhalation doses shown in Table 1. 

Occupational post-application exposure estimates

There is potential for both dermal and inhalation post-application
exposures to workers, as some residues will settle on the greenhouse
surfaces and plant leaves, and some will remain suspended in the air or
subsequently become re-suspended.

Dermal exposures were estimated using transfer coefficients tasks
representing different levels of exposure, according to the document
“Science Advisory Council for Exposure: Agricultural Reentry Task
Force Ornamental Plants Transfer Coefficients, April 2002.” These
coefficients, representing the rate of transfer of residues from
surfaces to skin, vary for different tasks depending on the amount of
contact between the worker and the surfaces.  Tasks can be designated as
low or high exposure depending on the amount of contact.

Table 2.  Post-application dermal transfer coefficients for greenhouse
ornamentals

Transfer Coefficients (cm2/hr)	Example activities

175 (“low exposure”)	greenhouse hand pinching ornamentals; nurseries
activities

400	moving plants from greenhouse to trucks, reorganizing gallon pots or
containers

5100 (“high exposure”)	hand-harvesting cut flowers

The exposure assessment is also based on a number of other assumptions:

Exposure was assessed at an application rate of 2.178 lb ai/A, based on
a 10-foot greenhouse ceiling height and application information from the
product label, converted to pounds of ai per acre.

Estimates were based on an 8-hour work day, and a body weight of 70 kg,
and absorption of 100% of the nicotine on skin.

The Agency assumed that the fraction of residue retained on foliage
which is available for transfer to skin is 20% on the day of
application, and dissipates at the rate of 10% a day per standard values
established by HED’s Science Advisory Council for Exposure. 

Table 3.  Nicotine post-application dermal risk estimates for greenhouse
workers

Days after treatment	Dermal Dose (mg/kg/day)	Dermal MOE

	Low exposure activity	High exposure activity	Low exposure activity	High
exposure activity

0	0.0976	2.844	13	<1

3 	0.0712	2.075	18	<1

40	0.00144	0.042	868	30

To estimate inhalation exposure for workers engaged in post-application
activities, the Agency calculated air concentrations expected when
treated greenhouses are ventilated as required by the WPS.  The WPS
allows a number of different ways that a greenhouse may be properly
ventilated before workers can re-enter.  For this assessment, the Agency
assumed a ventilation operation that results in 10 air changes.  The
Agency assumed an 8-hour workday, and standard body weight and breathing
rate.  Estimated according to these parameters, the post-application
inhalation risk estimate for greenhouse workers is an MOE of 3049. 
Post-application worker inhalation is not a risk of concern for nicotine
used in the greenhouse.



RISK MANAGEMENT DECISION

Rather than develop data to better characterize actual risks, the
registrant has requested the cancellation of the sole active nicotine
registration, with cancellation effective on December 31, 2013, and
existing stocks permitted to be sold by dealers and distributors for one
additional year.  The Agency intends to grant that request unless public
comment warrants reconsideration. 

The Agency believes that a phase-out is warranted in light of the
extremely low volume of nicotine pesticide use, the niche benefits
associated with the greenhouse use, and implementation of interim
labeling to reduce the potential for exposure and reduce risk during the
phase-out period.  The registrant has committed to submit, for Agency
approval and within three months of the date of this RED, revised
labeling to address our mutual understanding of risks of concern.  This
labeling will prohibit 1) the use of nicotine on plants grown for cut
flowers, 2) nicotine use in non-commercial greenhouses, and 3) the
retail sale of treated plants within 24 hours after nicotine
application.  The Agency believes that these measures are sufficient to
address the exposures to individuals at risk--greenhouse workers who
hand-cut flowers, those who spend time in private greenhouses, and
people, including children who come into contact with treated plants via
retail sale.  

If comments received during the comment period on the notice of receipt
of request for voluntary cancellation warrant a reconsideration of the
request or the Agency’s risk management decision, there are a number
of data requirements that would attach to the continued registration of
the existing Fulex product, or any new uses. These data gaps, as well as
the risks, benefits, and interim labeling requirements are discussed
below.

Risks of Concern

The Agency has assessed the risks associated with the use of the sole
remaining nicotine registration.  The certainty of the conclusions drawn
from these assessments is limited by a lack of critical data, including
guideline study-generated data that address the toxicology of nicotine
itself when test animals are exposed via routes of exposure relevant to
the use pattern.  The fate of nicotine upon deployment from the
smoke-generating canister and how residues in the greenhouse dissipate
over time are not known and not supported by empirical data.

Using the limited available data and protective assumptions, the Agency
has identified potential risks of concern in several areas:  residents
exposed to nicotine from its use in private greenhouses, people who
purchase and handle treated plants from retail establishments,
occupational handlers, and workers who are exposed during
post-application activities.  Because nicotine is not used on food or
feed crops, and is only applied in greenhouses, dietary risks and risks
to wildlife are not expected nor assessed.

The Agency believes that the risks of concern identified for mitigation
in this RED (and described below) generally tend toward overestimation
because of the use of conservative assumptions.  The use of these
assumptions, mainly for estimating exposures, adds uncertainty to the
calculated risk estimates; nevertheless, we believe that the risk
estimates indicate that risk mitigation is warranted.  The registrant
elected not to develop the data that would be needed to conduct a more
certain assessment of the risks and chose to request a voluntary
phase-out instead.  The Agency has determined that the 5-year phase-out
requested by the registrant is acceptable, as long as the risk
mitigation detailed in this RED is implemented in the interim before
cancellation becomes effective.     

  

Handler Risks

In the context of the limited data available for assessment, the Agency
has identified risk estimates above levels of concern for occupational
handlers of the nicotine product, but a definitive assessment of handler
risks is precluded by the lack of conclusive information about
applicator exposures, including the time spent deploying canisters and
how much nicotine from the canisters is in the air that applicators
breathe.

The duration of handler exposure during deployment of the canisters
probably varies quite a bit in actuality, but the 30 and 60 minutes
defaults used in this assessment likely are substantial overestimates
that result in overestimates of risk.  The registrant has submitted a
self-directed study of these potential exposure times that, while not
meeting Agency standards, suggests that handler exposure durations are
much shorter.

The methodology the Agency employed for estimating concentrations of
nicotine in greenhouse air in the absence of empirical data also tends
to lead to an overestimation of handler exposures, since the entire
contents of the Fulex canister are not instantaneously released as the
handler lights the sparkler.  The applicator is instructed to move away
from the container as soon as it is lit and to repeat with each
successive canister while moving toward the greenhouse exit, so
applicator exposure to nicotine released from the container right after
ignition should be minimized. 

Because of the uncertainties in the assessment that indicate risks to
handlers above levels of concern, and the tendency of  the methodologies
used by the Agency in the absence of empirical data, the Agency believes
that actual handler risk is likely to be considerably lower than the
risk estimates.  The current label requirements for PPE, including the
requirement that a handler must wear a respirator with either an organic
vapor cartridge and a prefilter approved for pesticides, or a canister
approved for pesticides, remain in effect, but no additional protective
measures are deemed necessary.

Mitigation of Post-application Risks for Occupational Workers

In the absence of chemical-specific information, estimates of worker
post-application dermal exposures have been based on important
assumptions that tend to result in overestimates of exposure.  For
example, it is assumed that all the nicotine from the Fulex containers
is released and comes to rest on greenhouse surfaces, and on the day of
application, 20% of that amount is available on foliage for contact with
skin.  The rate of dissipation of nicotine in the greenhouse after
application and the dermal absorption rate are based on standard
assumptions rather than the particular characteristics of nicotine; the
Agency uses conservative assumptions in order to avoid underestimating
real risk.  

Given these considerable uncertainties and the tendency of exposure to
be overestimated, the Agency believes that the MOEs calculated for
greenhouse tasks of different intensity and different intervals after
application are probably too low, but that hand-harvesting of cut
flowers, while not a major use site for nicotine, has the highest
potential for exposure relative to other greenhouse tasks.  While the
magnitude of risk for all the post-application activities is likely to
be less than estimated, the Agency believes it is prudent to eliminate
the highest exposure scenario for nicotine-treated plants during the
phase-out period.  In the interim before cancellation, labels of the
Fulex product will be amended to prohibit the use of nicotine on plants
grown for cut flowers.

Mitigation of Residential/Consumer Risks

The Agency believes that it is unlikely that nicotine is used in
non-commercial greenhouses.  To the extent that it may be, owners of
private greenhouses and those that enter such greenhouses (including
children) after nicotine has been applied by a Certified Applicator
would not necessarily have an understanding of precautions that should
be taken to limit exposure.  Prohibiting nicotine use in non-commercial
greenhouses will eliminate risks to people who own private greenhouses,
live in close proximity to such greenhouses, or spend time in them.

The Agency has based its concern about people who shop for and handle
treated plants on the risk estimates for greenhouse workers engaging in
post-application tasks.  Risks to the workers are probably overestimated
based on the factors discussed in Section 2 above.  In addition, worker
risk estimates are based on an 8-hour workday, which likely exceeds the
amount of time a consumer would spend in contact with treated plants.

People who enter treated greenhouses after application (and after the
ventilation criteria have been met) and people who handle or come in
contact with treated plants both in retail greenhouses and once they
have been purchased may include consumers themselves and the children
who accompany them, help with planting, and play around such plants
placed in residential gardens.  The differential risks to children from
exposure to nicotine residues have not been quantified, but it seems
prudent to limit their exposure.  While the rate of dissipation of
nicotine residues in treated greenhouses and on treated plants is not
known, it is assumed that residues will decline over time, and may
impart be removed from foliage and other surfaces during daily watering.
It is anticipated that closing treated greenhouses to consumers and
keeping treated plants out of retail sale for a short period of time is
not only prudent but will not cause an undue burden to businesses.
Potential risks to consumers of treated plants and children who might
also be exposed to treated plants will be reduced by prohibiting the
retail sale of treated plants within 24 hours after nicotine
application. 

Benefit Considerations

The use of the nicotine product is very limited, but several growers and
applicators have contacted the Agency to show support for the product,
which they indicate is easier to use than the alternatives; takes less
time to apply and reduces the amount of time an applicator needs to
spend in hot protective clothing; and provides ready coverage of plants
in harder-to reach places, such as overhead hanging baskets and pots
under greenhouse benches.

The registrant has noted that certain strains of whitefly are developing
resistance to pesticides. Nicotine is effective against this
“Q-biotype” whitefly, but the Agency believes that there are a
number of pesticidal alternatives to nicotine that are also effective
and do not promote resistance.

Tolerances

The tolerances for nicotine have been reassessed, and revocation of
these tolerances (for residues in cucumber, lettuce, and tomato) was
announced in a Federal Register notice on July 23, 2004 (69 FR 43924,  
HYPERLINK
"http://www.epa.gov/fedrgstr/EPA-PEST/2004/July/Day-23/p16718.htm" 
http://www.epa.gov/fedrgstr/EPA-PEST/2004/July/Day-23/p16718.htm ) after
termination of the last food uses of nicotine.  Per that notice, the
tolerance revocations became effective on December 4, 2005.  Citations
for the expired tolerances will be removed from the Code of Federal
Regulations through the rule-making process.  

Data Gaps   TC \l1 "10.0	Data Needs and Label Recommendations   TC \l2
"10.1	Toxicology 			

The database for nicotine is incomplete.  Data that would be needed to
refine the Agency’s understanding of the risks associated with the use
of nicotine include:

830 series	Special study; fate of nicotine released from
smoke-generating canisters

870.1100	Acute Oral Toxicity

870.1200	Acute Dermal Toxicity

870.1300	Acute Inhalation Toxicity

870.2400	Primary Eye Irritation

870.2500	acute dermal irritation - rabbit

870.2600 	skin sensitization

870.3200	21-day dermal toxicity study in rats

870.3465	90-day inhalation study (duration reduced to 21 days)

870.3700a	Prenatal developmental - rodent

870.3800	Reproduction and fertility effects

870.6200a 	acute neurotoxicity screening battery

870.3700a 	prenatal developmental – rodent

870.3700b 	prenatal developmental – non-rodent

For outdoor uses--environmental fate and effects data (including acute
and chronic toxicity data for terrestrial and aquatic wildlife, and data
on effects to aquatic plants and honeybees).

ACTIONS REQUIRED OF THE REGISTRANT

The registrant has agreed to interim labeling as noted above and will
submit revised labeling within 90 days of publication of this RED.

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