Document ID: EPA-HQ-OPP-2010-0920-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-12-22T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

November 10, 2010			

SUBJECT:	Prodiamine: Human Health Risk Scoping Document in Support of
Registration Review 

PC Code:  110201	DP Barcode:  380297

Decision No.:  437638	Registration No.: NA

Petition No.:  None	Regulatory Action: Registration Review

Assessment Type: Scoping Document	Reregistration Case No.: NA

TXR No.:  None	CAS No.: 29091-21-2

MRID No.:  None	40 CFR: NA

FROM:		Becky Daiss, Biologist

	Risk Assessment Branch 4

	Health Effects Division (7509P)

		Office of Pesticide Programs

THROUGH:	Susan Hummel, Senior Scientist

		Risk Assessment Branch 4

		Health Effects Division (7509P)

		Office of Pesticide Programs

TO:		Barbara Brisco, Chemical Review Manager

Pesticide Re-evaluation Division

		Risk Management and Implementation Branch IV

Executive Summary

Attached is Health Effects Division’s (HED) human health risk
assessment status update for prodiamine as part of the Registration
Review process.  Prodiamine is a selective, preemergent herbicide used
for control of many grasses and broadleaf weeds.  It is available in
multiple formulations and applied using a variety of application
methods.  An analysis of available toxicity studies and an assessment of
occupational and residential exposure were conducted for prodiamine in
December, 1991 in support of a registration decision document issued in
February, 1992.  

 	The 1991 HED occupational and residential exposure assessment risk
assessment was conducted in support of a new chemical registration
decision for prodiamine.  That assessment concluded that residential and
worker risks were not of concern for the proposed new uses.  A dietary
exposure risk assessment was not conducted at that time because
prodiamine was not registered for use on food commodities.        

HED’s problem formulation conclusions are as follows.  1) Existing
State and Local Needs (SLN) uses on irrigation drainage ditches need to
be reviewed to determine if the uses constitute a food use.  If so,
tolerances may be needed on fish, shellfish, irrigated crops and exposed
livestock, and a dietary and drinking water exposure assessment needs to
be conducted.  2) An updated drinking water exposure assessment is
required. 3) Existing Section 3 labels for registered products provide
for use of prodiamine on residential lawns.  Therefore a quantitative
residential exposure assessment is needed.  3) An updated occupational
exposure assessment is needed.  4) An aggregate risk assessment may be
required pending reevaluation of potential dietary and residential
exposures.  5) Data evaluation records (DERs) for available toxicity
studies need to be reevaluated and updated based on current policies and
procedures.  5) A comprehensive, integrated review of submitted
toxicological studies is required for the purpose of selecting
appropriate endpoints for risk assessment.  6) A subchronic inhalation
toxicity study is required based on the registered uses and application
methods.  7) An immunotoxicity study is required under 40 CFR Part 158
as a part of the new data requirements for registration of a pesticide
(food and non-food uses).  

Introduction

HED has evaluated the existing human health risk assessments for
prodiamine to determine whether sufficient data are available and
whether a new human health risk assessment is needed to support
Registration Review.  HED has considered the most recent risk
assessments for prodiamine, updates to its toxicity, exposure and usage
databases, and current Agency science policies and risk assessment
methods.  

Use Profile 

Prodiamine is a selective 2,6-dinitroaniline herbicide used for
pre-emergence control of many grasses and broadleaf weeds in non-crop
areas such as rights-of-ways, conifer and hardwood seedling nurseries,
established perennial and wildflower plantings, established turf sites,
residential and institutional lawns, commercial sod farms, golf courses,
railways, and landscape ornamentals.  There are also State and Local
Needs (SLN) registrations in CA and AZ for use on irrigation drainage
ditches, spreading grounds, channels, canals, and levees in wastewater
treatment facilities for pre-emergent control of shallow germinating
annual grasses.  These applications can be made only when the ditch is
not in use.  The mode of action of prodiamine is to inhibit root growth
by blocking plant cell division steps needed for chromosome separation
and cell wall formation.  Registered prodiamine products are applied by
foliar spray, broadcast, band treatment by sprayer, aircraft, or low
pressure ground equipment and spot treatment by spreader.  Residential
exposures to prodiamine can occur as a result of homeowner application
or by entering previously treated areas (e.g., residential lawns, parks,
golf courses). 

Chemical Identity

 

Common name	Prodiamine

IUPAC name	5-dipropylamino-α,α,α-trifluoro-4,6-dinitro-o-toluidine

CAS #	29091-21-2

	

Hazard Identification/Toxicology

The toxicity data base for prodiamine is substantially complete.  The
available toxicity studies have been reviewed, data evaluation records
(DERs) have been generated, and NOAELs and LOAELs have been identified
for individual studies.  The available studies and results are
summarized in a 1991 HED Peer Review Committee document.  However, a
hazard profile summarizing salient toxicity findings (e.g., primary
target organ effects, developmental and reproduction toxicity etc.) has
not been completed.  Neither has a comprehensive, coordinated review of
the available toxicity data for the purposes of identifying points of
departure (PODs) for use in risk assessment been conducted.  Prodiamine
exhibits low acute toxicity via inhalation, dermal (Toxicity Category
III) and oral (Category IV) routes of exposure.  Based on the most
recent cancer evaluation of prodiamine, conducted by the HED
Carcinogenicity Peer Review Committee in 1991 (6/10/91), prodiamine was
classified as a Group C carcinogen.  The Committee further recommended
use of the reference dose (RfD) approach for quantitation of human risk.
 Acute and subchronic neurotoxity studies were required as part of the
conditional registration of prodiamine in 1992.  These studies,
submitted by the registrant in 1994, have been reviewed by HED and
determined to be acceptable.  

Data Requirements

A subchronic inhalation toxicity study is required based on the
registered uses and application methods (i.e., ground and aerial
broadcast and hand held spray).  An immunotoxicity study is required as
a part of new data requirements in the 40 CFR Part 158 for conventional
pesticide registration.  Because the immune system is highly complex,
studies not specifically conducted to assess immunotoxic endpoints are
inadequate to characterize a pesticide’s potential immunotoxicity. 
While data from hematology, lymphoid organ weights, and histopathology
in routine chronic or subchronic toxicity studies may offer useful
information on potential immunotoxic effects, these endpoints alone are
insufficient to predict immunotoxicity.  In the absence of required
studies, EPA may use a database uncertainty factor of up to 10X.  Once
all of the newly required toxicity data have been received and reviewed,
the Prodiamine Registration Review Team recommends that the points of
departure and safety factors be reexamined and a new risk assessment
done, if necessary.  

Conclusions

The toxicity data base for prodiamine is substantially complete. 
However, DERs for the available toxicity studies need to be reevaluated
and updated based on current HED/OPP policies and procedures.  In
addition, a comprehensive evaluation of the available toxicity data is
needed for the purpose of selecting points of departure (PODs) based on
current endpoint selection criteria for all potential routes of exposure
for registered uses of prodiamine.  A subchronic inhalation study is
required based on uses and application methods.  An immunotoxicity study
is required under the updated 40 CFR Part 158 requirements. Required
study summaries and rationales are provided in Appendix A.

Dietary Exposures

There were no registered food uses of prodiamine in 1992 when the
assessment for the registration decision document was conducted. 
Therefore, a dietary exposure assessment was not required.  However, SLN
registrations issued between 2005 and 2008 provide for use of prodiamine
on irrigation ditches.  These SLN registrations need to be evaluated to
determine whether this use may be considered a food use under current
criteria.  If so, tolerances are needed on fish, shellfish, irrigated
crops and livestock exposed to treated water and a dietary and drinking
water exposure assessment is needed.  A quantitative drinking water
assessment has not been conducted for prodiamine.  A drinking water
assessment will need to be completed as part of the human health dietary
risk assessment.  Tier I Estimated Drinking Water Concentrations (EDWCs)
for human health assessments will be estimated using EFED’s aquatic
models FIRST for surface water and SCI-GROW  for ground water.  If
needed, Tier II EDWCs in surface water will be estimated using PRZM and
EXAMS models. 

Data Requirements

If existing uses in irrigation ditches are determined to constitute a
food use, the registrant would need to submit all of the studies
required by the Agency to determine the levels of pesticide residues in
water, fish, and irrigated crops when products are applied directly to
water.  The data are used in dietary risk assessment and to establish
tolerances in treated/exposed commodities for enforcement purposes.

Conclusions

Existing State and Local Needs (SLN) uses on irrigation drainage ditches
need to be reviewed to determine if the uses constitute a food use.  If
so, tolerances are needed on water, fish, shellfish, irrigated crops,
and livestock exposed to treated water and a dietary and drinking water
exposure assessment is needed.  If not, a dietary exposure assessment is
not required.   An updated quantitative drinking water assessment is
required for Reregistration Review.

Residential Exposure

A residential exposure assessment was conducted for prodiamine in
December, 1991.  That assessment concluded that since prodiamine does
not have quantifiable carcinogenic risk and does not involve repeated or
chronic exposure, exposure and risk to residents/bystanders is assumed
to be negligible.  Therefore, a quantitative residential exposure
assessment was not conducted at that time.  HED policies, standard
operating procedures, and exposure assessment methodologies have changed
significantly since the residential exposure assessment was conducted in
1991.  In addition, a number of registrations for use of prodiamine on
turf have been accepted in recent years.  Consequently, a new
quantitative assessment of residential exposure and risk from currently
registered uses of prodiamine is required.  

Conclusions

A quantitative residential exposure assessment is required. 

Aggregate Exposure

An aggregate risk assessment integrates the assessments conducted for
dietary/drinking water and residential exposure.  Since dietary and
residential exposures were not assessed in previous risk assessments
conducted for prodiamine, an aggregate assessment was not required. 
However, an aggregate assessment may be needed in an updated risk
assessment depending on the results of EPA’s reevaluation of the need
for dietary and/or drinking water assessments.

 

Conclusions

An aggregate exposure assessment may be required based on a reevaluation
of dietary, drinking water, and residential exposures. 

Occupational Exposure 

An occupational exposure assessment addressing both cancer and
non-cancer risks was conducted for prodiamine in December, 1991. 
Scenarios assessed were mixing, loading and applying a 65% a.i. wettable
granular formulation to turf and landscape areas with groundboom or
handwand equipment.  The assessment was conducted using surrogate
exposure data for cyproconazole.  PODs for both dermal and inhalation
exposure were selected by the Occupational and Residential Exposure
Branch from a chronic feeding study in rats.  Dermal and inhalation
absorption were assumed to be 100%.  Estimated MOEs were 1600 for the
mixer/loader and 13000 for applicators.  

Conclusions

An new occupational risk assessment is needed for the Registration
Review of prodiamine in light of significant changes to standard
exposure protocols, assumptions and algorithms and to incorporate
updated dermal and inhalation PODs identified as part of an updated
hazard identification assessment.  

Incident Report

An updated incident report was recently conducted.  Based on the low
frequency of incident cases, there does not appear to be a concern at
this time that would warrant further investigation. The Agency will
continue to monitor the incident information and if a concern is
triggered, additional analysis will be included in the risk assessment.

Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other

ingredients) “may have an effect in humans that is similar to an
effect produced by a

naturally occurring estrogen, or other such endocrine effects as the
Administrator may

designate.”   Following recommendations of its Endocrine Disruptor and
Testing Advisory

Committee (EDSTAC), EPA determined that there was a scientific basis for
including, as

part of the program, the androgen and thyroid hormone systems, in
addition to the estrogen

hormone system.  EPA also adopted EDSTAC’s recommendation that the
Program include

evaluations of potential effects in wildlife. For pesticide chemicals,
EPA will use FIFRA

and, to the extent that effects in wildlife may help determine whether a
substance may have

an effect in humans, FFDCA authority to require the wildlife
evaluations. As the science

develops and resources allow, screening of additional hormone systems
may be added to the

Endocrine Disruptor Screening Program (EDSP).  When additional
appropriate screening and/or testing protocols being considered under
the Agency’s EDSP have been developed, prodiamine may be subjected to
further screening and/or testing to better characterize effects related
to endocrine disruption.

Cumulative

EPA does not have, at this time, available data to determine whether
prodiamine has a common mechanism of toxicity with other substances. 
EPA has not made a common mechanism of toxicity finding for prodiamine
and any other substances and, prodiamine does not appear to produce a
toxic metabolite produced by other substances which have tolerances in
the U. S.  Therefore, EPA has not assumed that prodiamine has a common
mechanism of toxicity with other substances.  

Human Studies

The occupational exposure assessment relied in part on data from a study
in which adult human subjects were intentionally exposed to the
surrogate pesticide cyproconazole.  This study has not been reviewed as
required under EPA’s Rule for the protection of Human Subjects of
Research (40 CFR Part 26).  However, any future occupational and/or
residential assessments conduct for prodiamine will be based on data
contained in HEDs generic pesticide exposure databases such as the
Pesticide Handlers Exposure Database (PHED), the Agricultural Reentry
Task Force (ARTF) Database and the Outdoor Residential Exposure Task
Force (ORETF) Database.  EPA has reviewed all the studies supporting
these multi-pesticide generic exposure databases, and has found no clear
and convincing evidence that the conduct of any of them was either
fundamentally unethical or significantly deficient relative to the
ethical standards prevailing at the time the research was conducted. 
All applicable requirements of EPA’s Rule for the Protection of Human
Subjects of Research (40 CFR Part 26) have been satisfied, and there is
no regulatory barrier to continued reliance on these studies.  

Conclusions/Future Actions Needed

The actions needed in the future Registration Review for prodiamine are
listed below.

Hazard Identification and Endpoint Selection

The available prodiamine toxicity studies need to be re-evaluated for
purposes of hazard identification and endpoint selection.  PODs for all
routes of exposure need to be identified for use in risk assessment.  An
immunotoxicity study is required in accordance with the revised 40 CFR
Part 158 Toxicology Data Requirements.  A subchronic inhalation toxicity
study is required based on the registered uses and application methods
(i.e., ground and aerial broadcast and hand held spray).  

Dietary Exposure and Risk

A dietary exposure assessment is needed if existing uses of prodiamine
in irrigation ditches are determined to constitute a food use.  An
updated quantitative drinking water assessment is required for
Reregistration Review.

Residential Exposure and Risk

A residential risk assessment needs to be conducted in accordance with
current policies and SOPs.  

Aggregate Exposure and Risk

An aggregate exposure assessment may be needed based on updated dietary
and/or residential exposure assessments.    

Occupational Exposure and Risk

The existing occupational exposure assessment needs to be reevaluated
and revised based on an updated toxicity assessment and current refined
exposure assumptions and algorithms. 

Incident Report

The Agency will continue to monitor the incident information and if a
concern is triggered, additional analysis will be included in the risk
assessment. 

Data Requirements

Toxicology

- 	28 Day Inhalation Toxicity Study (GLN 870.3465)

- 	Immunotoxicity study (GLN 870.7800)  

Residue Chemistry

The following data will be required if existing uses of prodiamine are
determined to include products registered for use on food commodities.  
   

  

- 	860.1300 - Nature of the Residue--Plants, Livestock 

-	860.1380 - Storage Stability Data  

-	  HYPERLINK
"http://www.regulations.gov/fdmspublic/ContentViewer?objectId=0900006480
9bc3a4&disposition=attachment&contentType=pdf"  860.1400 - Water, Fish,
Irrigated Crops  

-	  HYPERLINK
"http://www.regulations.gov/fdmspublic/ContentViewer?objectId=0900006480
9bc3bc&disposition=attachment&contentType=pdf"  860.1480 -
Meat/Milk/Poultry/Eggs  

-	  HYPERLINK
"http://www.regulations.gov/fdmspublic/ContentViewer?objectId=0900006480
9bc3bf&disposition=attachment&contentType=pdf"  860.1500 - Crop Field
Trials  

-	  HYPERLINK
"http://www.regulations.gov/fdmspublic/ContentViewer?objectId=0900006480
9bc3c0&disposition=attachment&contentType=pdf"  860.1520 - Processed
Food/Feed (August 1996)  

-	  HYPERLINK
"http://www.regulations.gov/fdmspublic/ContentViewer?objectId=0900006480
9bc3f2&disposition=attachment&contentType=pdf"  860.1850 - Confined
Accumulation in Rotational Crops  

-	  HYPERLINK
"http://www.regulations.gov/fdmspublic/ContentViewer?objectId=0900006480
9bc3f3&disposition=attachment&contentType=pdf"  860.1900 - Field
Accumulation in Rotational Crops   

References

Exposure Assessment for New Chemical, Prodiamine, Using Surrogate Data.
A. Mehta (12/17/91, D169921) 

Peer Review of Prodiamine. J. Chen (3/28/91)  

Registration of Prodiamine. A. Lindsay (2/7/92)	

Prodiamine: Review of Human Incidents.  Karlyn Middleton, Shanna Recore,
and Khin Oo (D380376, 8/20/10)

Appendix A

Guideline Number:  870.3465

Study Title:   28-Day Inhalation - Rat 

Rationale for Requiring the Data

This study is required under the updated data requirements at 40 CFR
158.500 because prodiamine is applied as a high volume, high pressure
spray so there is a likelihood of significant repeated exposure to
applicators.  As discussed in the footnotes at 40 CFR 158.500, a
non-guideline 21- or 28-day study is sufficient in situations such as
this where intermediate-term rather than chronic exposure is expected. 
A 21- or 28-day study would be considerably less costly for the
registrant to conduct.

Practical Utility of the Data

How will the data be used?  

The 28-inhalation toxicity study would allow EPA to properly
characterize the hazard and risks to occupational workers associated
with applying prodiamine as an aerosol.    

How could the data impact the Agency’s future decision-making?

In the absence of inhalation toxicity data, EPA would have to estimate
inhalation risks using oral toxicity studies and relying on the
assumption that absorption and toxicity of prodiamine are the same via
the oral and inhalation routes of exposure.  Receiving the inhalation
data would allow the Agency to refine its estimates of inhalation risks,
to ensure that those risks are not overestimated or underestimated.  

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies not specifically conducted to assess immunotoxic
endpoints are inadequate to characterize a pesticide’s potential
immunotoxicity.  While data from hematology, lymphoid organ weights, and
histopathology in routine chronic or subchronic toxicity studies may
offer useful information on potential immunotoxic effects, these
endpoints alone are insufficient to predict immunotoxicity.  

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the immune
system from pesticide exposure. Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios and are
considered a primary data source for reliable reference dose
calculation. For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive, and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO)
based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

 	

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