	UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM  

Date:		August 15, 2002

Subject:	Guidance: Waiver Criteria for Multiple-Exposure Inhalation
Toxicity Studies.

From:		Margaret J. Stasikowski, Director

Health Effects Division (7509C)

To:		Health Effects Division Staff

Attached is SOP 2002.01 - “HED Standard Operating Procedure:
“Guidance: Waiver Criteria for Multiple-Exposure Inhalation Toxicity
Studies”.

SOP provides guidance to HED staff members for determining when to grant
waivers for multiple exposure inhalation toxicity studies.

If you have any questions, please contact John Whalan (305-6511) or Jess
Rowland (308-2719). 

BACKGROUND

The only reliable way to characterize inhalation toxicity and to
quantify inhalation risk is through the use of inhalation toxicity
studies.  Chemicals tend to be more toxic by the inhalation route than
by the oral route due to rapid absorption and distribution, bypassing of
the liver’s metabolic protection (portal circulation), and potentially
serious portal-of-entry effects, such as irritation, edema, cellular
transformation, degeneration, and necrosis.  An inhalation risk
assessment that is based on oral data generally underestimates the
inhalation risk because it cannot account for these factors.

There are occasions when the requirement for inhalation toxicity studies
should be waived for ethical or scientific reasons.  The purpose of this
document is to provide guidance for  for waiving inhalation toxicity
studies when a pesticide active ingredient has a very low potential for
human inhalation hazard during handling or application.  This guidance
is based upon the following three waiver guidance documents, but has
been updated to reflect current regulatory concerns:

Penelope A. Fenner-Crisp.  Policy on Acute Inhalation Toxicity Data
Waivers.  Health Effects Division Memorandum to Anne E. Lindsay. 
December 8, 1991.  

Thomas C. Ellwanger.  Acute Toxicity Waiver Guidance Document. 
Registration Division Memorandum.  August 24, 1993.

John Whalan, Donald Cooper, Dennis Gibbons, John Ross, James Sanborn. 
Inhalation Exposure Waivers for Pesticides (A Guidance Document for
Pesticide Registrants).  Draft Joint NAFTA document. 1998.

The following scientists from the various Divisions of the Office of
Pesticide Progaram contributed to the preparation of this guidance.
Ayaad Assaad, Edwin Budd, William Burnam

Jeff Evans, Timothy Leighton, Jess Rowland, Steven Weiss, John Whalan,
Karen Whibty (HED), Karen Hicks (AD),  Roger Gardner (BPPD), John Redden
(RD), Mark Perry (SRRD)

B.	INTRODUCTION

This document provides guidance for determining when to grant waivers
for multiple exposure inhalation toxicity studies.  All waiver requests
are considered on a case-by-case basis, and the burden of proof lies
entirely with the registrant.  The process for granting waivers will
include consideration by a toxicologist, an exposure specialist, and the
Exposure Science Advisory Council for Exposure (ExpoSAC).  If no
significant inhalation hazard is identified during risk characterization
and risk assessment, HED may also initiate a waiver.  The following four
criteria may be used to justify a waiver:

Severe irritation and corrosivity

Low volatility

Large particle size

Inhalation Toxicity Category IV and an extrapolated Margin-of-Exposure
(MOE) 

Engineering solutions, such as closed systems and enclosed cabs are not
included in this guidance because it is difficult to verify the accuracy
of claims.  Any waiver request based on an engineering solution must be
definitively substantiated.

Waiver Criteria 1 and 3 (below) must be applied on a
chemical-by-chemical basis.  Any significant change in application
methodology, including recommended equipment, will require additional
waiver requests and data submission.

C. 	WAIVER CRITERIA

Criteria 1 - Severe Irritation and Corrosivity

An active ingredient which causes severe irritation or corrosion of the
skin or eye will also damage the sensitive respiratory mucosa if
inhaled.  Waivers should be granted for active ingredients which are
corrosive (pH <2 or >11.5) or severely irritating.

Waivers should not be granted for active ingredients which are slight to
moderate irritants.  Inhalation toxicity studies of irritants can
quantify the sensitivity of this route and characterize portal-of-entry
effects.  This information is essential in an inhalation risk
assessment.  

Criteria 2 - Low Volatility

Waivers will be considered for non-volatile active ingredients which are
not aerosolized (i.e. generated as mists, fogs, dust, smoke, fumes),
heated, evaporated, or otherwise made inhalable as a gas or vapor. 
Non-volatile active ingredients are defined as having vapor pressures <1
x 10-5 kPa (7.5 x 10-5 mmHg) for indoor uses, and  <1 x 10-4 kPa (7.5 x
10-4 mmHg) for outdoor uses at 20-30(C.   Waiver candidates based on
volatility may include, but are not limited to: Viscous liquids (under
conditions of use), waxes, resins, lotions, and caulks. Waivers for
formulated products such as animal dips, shampoos, pour-ons, slow
release collars, ear tags, and tree injections will be considered by the
appropriate division.

Criteria 3 - Large Aerosol Particle Size

An inhalable particle is capable of entering the respiratory tract via
the nose and/or mouth.  A respirable particle evades capture in the
upper respiratory tract and reaches the lungs.  The larger the particle,
the less likely it is to be inhalable or respirable.  Waivers will be
considered for active ingredients that do not pose a significant
inhalation hazard because the particles are too large to be inhaled. 

Large particles have the potential to do considerable local damage if
they are absorbed because of the volume of material they contain.  Table
1 demonstrates that with each 10-fold increase in particle diameter,
there is a 1000-fold increase in particle volume.  Compared to a 0.1 μm
particle, a 100 μm particle has 1000-times the diameter and a
billion-times the volume.

	Table 1.  A Comparison of Aerosol Particle Diameters and Volumes	

Particle Diameter (μm)	

 Diameter Δ	

Particle Volume 

(μm3)a	

Volume Δ



0.1	

–	

0.000524	

–



1.0	

10	

0.524	

1000



10	

100	

524	

1,000,000



100	

1000	

523,599	

1,000,000,000



 

An aerosol for a product formulation or application method can be
considered essentially non-inhalable provided (99% of the particles are
>100 μm in diameter.  Although aerosols that meet this criteria are
candidates for waivers, it is the responsibility of the registrant to
provide data on aerosol size distribution.  Waiver candidates based on
large particle size include, but are not limited to:

Microencapsulated formulations which are not readily fractured,
dissolved, time-released, leaky, or small enough to be respirable during
mixing/loading or application.  Evidence of capsule durability must be
provided.

Granular products placed in or on the soil, and baits applied by hand or
during seed planting.  Although granular products are inherently
non-inhalable, they may pose a significant inhalation hazard if
attrition occurs.  Attrition is the breaking down of a material into
smaller particles as can occur during shipping, handling, pouring, and
application.  A product susceptible to attrition is said to be friable. 
A friable product may pose a significant inhalation hazard if it
produces a measurable quantity of dust when poured or scattered.

A registrant requesting a waiver on the basis of particle size must
demonstrate that their product contains large, non-inhalable particles
which are resistant to attrition.  This can be accomplished by using the
latest version of the American Society of Testing Materials (ASTM) Test
Method 35.22–Pesticide Formulations and Application Systems Method for
the Determination of Inhalable Particles of Granular Products.  This
test method is not available from the EPA, but can be purchased from
ASTM (100 Barr Harbor Drive, West Conshohocken, Pennsylvania, USA
19428-2959; or http://www.astm.org/).

Criteria 4 - Toxicity Category IV and An Extrapolated MOE 

Inhalation waivers are not granted for active ingredients based solely
on low oral toxicity because:

Toxicity via the inhalation route tends to be more severe than by other
routes.

Inhaled chemicals by-pass the metabolic protection of the liver (portal
circulation).

Oral data cannot be used to predict respiratory portal-of-entry effects
(e.g. irritation, edema, cellular transformation, degeneration, and
necrosis).

The use of route extrapolation in a risk assessment minimizes the true
inhalation risk (see example below).

The application rate is usually higher for pesticides with low oral
toxicity, so there is a potential for high inhalation exposure.

Nevertheless, a waiver may be granted for an active ingredient that is
Toxicity Category IV for inhalation provided an extrapolated inhalation
MOE (based on an oral NOAEL) exceeds a target MOE of 1000 or greater. 
The target MOE may include the conventional UF of 100; an additional UF
of 10-100 to account for unknown pharmacokinetic and pharmacodynamic
differences between the oral and inhalation routes in animals and
humans, and respiratory portal-of-entry effects; and any other
additional assigned UF (e.g. for use of a LOAEL).  

	Example:  Route-Specific MOE v Route-Extrapolated MOE

`„Ð

f

g

ˆÿž	˜

ˆÿž	˜

ˆÿž	˜

ˆÿž	˜

 0.013 mg/kg/day

Route-Specific MOE:

 

Route-Extrapolated MOE:

 

Comparison: Route-Extrapolated MOE v Route-Specific MOE:  

 

If the extrapolated inhalation MOE had been based on an oral endpoint
instead of an inhalation endpoint, the true inhalation risk would
probably be under-stated by more than 600%.  This is because the oral
endpoint would neither reflect the impact of an inhaled chemical
by-passing the metabolic protection of the liver, nor consider the
extent of respiratory portal-of entry effects.

HED SOP2002.01									August 15, 2002

GUIDANCE: WAIVER CRITERIA FOR MULTIPLE-EXPOSURE INHALATION TOXICITY
STUDIES
________________________________________________________________________
__

 PAGE  7 

