Document ID: EPA-HQ-OPP-2002-0262-0064
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-11-16T05:00Z

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:	13 November 2007

SUBJECT:	Endosulfan. The Health Effects Division’s Addendum and Update
to the 2002 Risk Assessment.

DP Number:	D345935	MRID:  None

PC Code:	079401

	40 CFR:	180.182	Chemical Class:	Organochlorine insecticide

FROM:	Donald Wilbur, Chemist

		Elissa Reaves, PhD, Toxicologist

		Judy Facey, PhD, Toxicologist

		Alan Nielsen, Biologist 

		Shanna Recore, Industrial Hygienist

		Reregistration Branch II

Health Effects Division (7509P)

THRU:	Jack Arthur, Acting Branch Chief

		Reregistration Branch II

			and

		Jack Housenger, Associate Director	

Health Effects Division (7509P)

TO:		Tracy Perry, Chemical Review Manager

	        	Special Review Branch

	                        Special Review and Reregistration Division
(7508P)

This document updates the 2002 Health Effects Division (HED) Risk
Assessment (D. Locke, D250471, 05/30/2002) that was used to prepare the
2002 Reregistration Eligibility Decision (RED) document for endosulfan. 
This addendum focuses on the changes in HED’s risk assessment based on
the review of a recently submitted developmental neurotoxicity (DNT)
study.

I.  Executive Summary

The Agency completed the Reregistration Eligibility Decision (RED)
document for endosulfan in November 2002 based upon the HED risk
assessment completed in May 2002 (D. Locke, D250471, 05/30/2002).  Since
the completion of the RED in 2002, the Agency has received and reviewed
a developmental neurotoxicity study (DNT) (Gilmore et al, 2006; MRID
46968301) (D. Anderson and J. Facey, D327215, 03/15/2007).  Based on the
toxicological effects observed in the DNT, endpoints for risk assessment
were re-evaluated for endosulfan (E. Reaves, D338576, 04/02/2007). 
After reviewing the DNT and all other available data, HED has concluded
that:

The 10X FQPA safety factor could be reduced from 10X to 1X while still
being protective of children’s health.  

In order to effectively protect the most sensitive population (female
workers) from endosulfan, the DNT was deemed to be the most appropriate
study for short and intermediate term dermal exposure (LOAEL = 3.7
mg/kg/day).

All other endpoints established for endosulfan remain unchanged from the
2002 HED assessment.

An abbreviated summary of the changes that these conclusions have on the
HED risk assessment will be discussed in the following sections.  For
the full details of each exposure assessment, please refer to the
individual exposure assessment chapters listed in the reference section.

Based on the reduced FQPA safety factor of 10X to 1X and use of the same
input files as in the 2002 dietary assessment, the combined dietary
exposure to endosulfan residues (food and drinking water) does not
exceed the Agency’s level of concern (>100% of the PAD) for chronic or
acute exposures.

Potential areas of environmental justice concerns, to the extent
possible, were considered in this document, in accordance with U.S.
Executive Order 12898, "Federal Actions to Address Environmental Justice
in Minority Populations and Low-Income Populations,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).  Since
endosulfan has routinely been detected in arctic regions and the
Indigenous Peoples of the arctic region of the U.S. (Alaska) rely
heavily on subsistence diets (i.e. - fish) as their food source, it is
appropriate for the Agency to consider dietary risk and exposure to this
specific population subgroup from the worldwide use of endosulfan. 
Since no specific data are available for residues of endosulfan in/on
commodities consumed in subsistence diets, the Agency has concerns for
dietary exposure of indigenous populations to endosulfan based upon its
persistence and potential for bioaccumulation.

With the revised dermal endpoint and level of concern, many of the
occupational handler scenarios exceed HED’s level of concern even with
maximum personal protective equipment or engineering controls.  In
addition, for many of the occupational postapplication scenarios, the
restricted-entry interval (REI) would be several days longer than the
REIs established in the 2002 RED.

II.  2007 Hazard Assessment

Table 1 below highlights the studies and endpoints used in the
Agency’s 2002 endosulfan risk assessment and the current 2007
addendum.  The Agency has re-evaluated the toxicological endpoints for
endosulfan (E. Reaves, D338576, 04/02/2007) based upon recently
submitted data. This memo outlines the rationale and characterization
for endpoint selection for the endosulfan risk assessment following the
review of a developmental neurotoxicity study (D. Anderson and J. Facey,
D327215, 03/15/2007).

		DNT- (Gilmore et al., 2006; MRID 46968301)

The Agency recently received and reviewed a developmental neurotoxicity
study with endosulfan in wistar rats in December 2006 (D. Anderson and
J. Facey, D327215, 03/15/2007).  The study findings were presented to
the Developmental Neurotoxicity Committee (DNT) on January 10, 2007. 
Based on the review of the study by the DNT Committee, the Committee
concluded that there was no NOAEL (No Observed Adverse Effect Level) for
pups.  The LOAEL (Lowest Observed Adverse Effect Level) of 3.74
mg/kg/day was the lowest dose tested (LDT), based on decreased pup
weight [PND 11] and weight gain [PND 4-11], with delayed preputial
separation in males receiving the maximum dose tested (MDT).  For dams,
the NOAEL is 3.74 mg/kg/day.  The LOAEL for dams is 10.8 mg/kg/day,
based on decreased body weight, food consumption and food efficiency.
This study is acceptable/guideline.

		FQPA Safety Factor

The FQPA factor for endosulfan has changed over the past few years
mainly due to database uncertainties.  In November 1998, the FQPA
Committee recommended a 3X factor due to the lack of a developmental
neurotoxicity study.  The 5/30/2002 risk assessment, however, retained
the 10x FQPA factor due to database uncertainties.  These database
uncertainties included: 1) lack of subchronic and developmental
neurotoxicity studies; 2) concerns for effects on sperm parameters
reported in the literature; 3) the lack of evaluation of sperm
parameters in guideline studies; 4) testicular lesions observed in the
chronic rat study; and 5) increased pituitary and uterine weight in the
two-generation reproduction study.  Since the 5/30/2002 evaluation, a
subchronic neurotoxicity study and a developmental neurotoxicity study
have been submitted and reviewed by the Agency.  Therefore, the FQPA
factor was again re-evaluated and is discussed in the endosulfan
endpoint memo (E. Reaves, D338576, 04/02/2007).  This endpoint memo
describes the residual uncertainties from the 5/30/2002 risk assessment
and outlines how recent neurotoxicity data and published literature
demonstrate that the uncertainties associated with the previous FQPA
evaluation have been addressed.  Therefore, it was recommended that the
FQPA factor be reduced (i.e., 1X) since there were no residual
uncertainties for pre and/or post-natal toxicity.

		Dermal Exposure (Short-& Intermediate Term)

Previously, two available 21-day dermal toxicity rat studies were the
basis of quantifying dermal risk.  The dermal NOAEL was 12 mg/kg/day
with a LOAEL of 48 mg/kg/day based on mortality.  However, the results
of the recently submitted DNT shows concern for offspring toxicity
(decreased pre-weaning body weight) which is not evaluated in the 21-day
dermal study (conducted in adult animals only).  Additionally, the DNT
was examined to address the concern for changes in the uterine and
pituitary weights that were seen in adults at the highest dose only (6.2
mg/kg/day) in the two-generation reproduction study.  The use of an
offspring endpoint from the DNT study (LOAEL = 3.7 mg/kg/day) is the
most appropriate endpoint in order to be protective of the most
sensitive population (female workers).  This decision is supported by
the pup weight decrements being observed only during lactation (i.e.,
the pup body weights were not affected at birth AND the pups recovered
after post-weaning (PND 22)) and therefore are likely due to nursing. 
Furthermore, the 2-generation reproduction study (MRID 00148264) noted a
similar effect (decrease litter weight) during the lactation to weaning
period in both matings in the F0 generation, which was significant at
the high dose (6.18 mg/kg) level in the first mating and at the mid
(1.23 mg/kg) and high dose (6.18 mg/kg) levels in the second mating. 
Since a NOAEL was not established in the DNT, a LOAEL to NOAEL factor is
necessary for the dermal assessment.  Based on the degree of pup weight
loss in the DNT and pup weight loss in the 2-generation reproduction
study, a 3X is most appropriate.  The dermal absorption factor of 45%
remains consistent with the 2002 assessment.

		Inhalation Exposure (Short-& Intermediate Term)

No changes have been made to the inhalation endpoint and assessment
since the 2002 risk assessment.

		Published Literature

A 2007 literature study concerning autism spectrum disorder and
pesticide applications in southern California (Roberts et al., 2007)
also was reviewed by HED (C. Christensen, D342660, 10/18/07).  Although
this study attempts to correlate pesticide application with the
development of autism spectrum disorder, the study failed to provide
data that is useful in the quantification of risk to endosulfan.

Table 1.  Comparison of Toxicological Data for Endosulfan

Exposure Scenario	EPA 2002	EPA 2007

Acute Dietary

(general population including infants and children)

	PoD, UF	NOAEL = 1.5 mg/kg/day

UF = 100

FQPA = 10x	NOAEL = 1.5 mg/kg/day

UF = 100

FQPA = 1x

	Level of Concern for Risk Assessment with UFs	aRfD = 0.015 mg/kg/day

aPAD = 0.0015 mg/kg/day	aRfD = 0.015 mg/kg/day

aPAD = 0.015 mg/kg/day 

	Critical Study and

Endpoints	Acute Neurotoxicity-rats

LOAEL= 3 mg/kg/day; based on increased incidence of convulsions seen in
female rats within 8 hours after dosing.	Acute Neurotoxicity-rats

LOAEL= 3 mg/kg/day; based on increased incidence of convulsions seen in
female rats within 8 hours after dosing.

	Reference	MRID 44403101	MRID 44403101

Chronic Dietary

(all populations)

	PoD, UF	NOAEL = 0.6 mg/kg/day

UF = 100

FQPA = 10x	NOAEL = 0.6 mg/kg/day

UF = 100

FQPA = 1x

	Level of Concern for Risk Assessment with UFs	cRfD = 0.006 mg/kg/day

cPAD = 0.0006 mg/kg/day	cRfD = 0.006 mg/kg/day

cPAD = 0.006 mg/kg/day

	Critical Study and

Endpoints	Chronic/Cancer rats-

LOAEL = 2.9 mg/kg/day, based on reduced body weight gain, increased
incidences of marked progressive glomerulonephrosis & blood vessel
aneurysms in male rats.	Chronic/Cancer rats-

LOAEL = 2.9 mg/kg/day, based on reduced body weight gain, increased
incidences of marked progressive glomerulonephrosis & blood vessel
aneurysms in male rats.

	Reference	MRID 41099502	MRID 41099502

Dermal

Short (1-30 days)

and

Intermediate-term

(1-6 mos)

	PoD, UF	NOAEL = 12 mg/kg/day

45% absorption	NOAEL not established.

45% dermal absorption

	Level of Concern (LOC) and Margins of Exposure (MOE)	Occupational LOC

MOE = 100	Occupational LOC

MOE = 300

	Critical Study and

Endpoints	21-Day Dermal-Rat

LOAEL= 27 mg/kg/day, based on mortality in females	DNT- rat:

LOAEL = 3.74 mg/kg/day, based on decreased pup weight.

UF = 100

NOAEL to LOAEL UF = 3x

	Reference	MRID 00146841/00147744

MRID 00146841	MRID 46968301

Dermal

Long-term (> 6 months)	PoD, UF	NOAEL = 12 mg/kg/day

45% absorption	Long-term dermal exposure is not expected for endosulfan.

	Level of Concern (LOC) and absorption rate	Occupational LOC

MOE = 100

Critical Study and

Endpoints	21-Day Dermal-Rat

LOAEL= 27 mg/kg/day, based on mortality in females

Reference	MRID 00146841/00147744

MRID 00146841

	Inhalation

Short (1-30 days) and Intermediate

term

(1 – 6 months)	PoD, UF	NOAEL = 0.2

(0.001 mg/L)	NOAEL = 0.2

(0.001 mg/L)

	Level of Concern (LOC) and absorption rate	MOE = 100

100% absorption	MOE = 100

100% absorption

	Critical Study and

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LOAEL= 0.002 mg/L, based on ↓ body weight gains, ↓ leukocyte counts
(M), and ↑ creatinine values (F); 0.4 mg/kg/day	21-Day inhalation
–rats

LOAEL= 0.002 mg/L, based on ↓ body weight gains, ↓ leukocyte counts
(M), and ↑ creatinine values (F); 0.4 mg/kg/day

	Reference	MRID 00147183

MRID 41667501	MRID 00147183

MRID 41667501

Inhalation

Long-term (> 6 months)	PoD, UF	None Established	Long-term inhalation
exposure is not expected for endosulfan.

	Level of Concern (LOC) and absorption rate

	Critical Study and

Endpoints

	Reference

Cancer	Classification	Group E- Evidence of non-carcinogenicity for
humans	Group E- Evidence of non-carcinogenicity for humans

	Statistical Analysis	Q1* not calculated	Q1* not calculated

III.  2007 Dietary Assessment

Acute and chronic dietary risk assessments were conducted using the
Dietary Exposure Evaluation Model (DEEM™)  Program which used food
consumption data from the U.S. Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1989-1992) in 2002
(S. Kinard, D281201, 02/28/2002) in support of the Reregistration
Eligibility Decision (RED).  At that time, drinking water exposure was
not directly incorporated into the dietary evaluation; rather, estimated
environmental concentrations (EECs) were compared with drinking water
levels of concerns (DWLOCs).  The acute and chronic population adjusted
doses (PAD) at that time were calculated using an FQPA Safety Factor of
10x due to toxicological database uncertainties, including the absence
of a developmental neurotoxicity study (DNT).  In 2006, a DNT study
(Gilmore et al, 2006) was submitted and reviewed by the Agency (D.
Anderson and J. Facey, D327215, 03/15/2007).  Based on a 01/10/2007 DNT
Committee meeting and subsequent follow-up (E. Reaves, D338576,
04/02/2007) HED concluded that based upon these submitted data, the FQPA
Safety Factor could be reduced from 10x to 1x while still being
protective of children’s health.  

To update the RED, new acute and chronic dietary exposure assessments
(food only, drinking water only, and food plus drinking water) were
conducted (D. Wilbur, D336646, 03/14/2007) using the Dietary Exposure
Evaluation Model software with the Food Commodity Intake Database
(DEEM-FCID™, Version 2.03), which incorporates consumption data from
USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII),
1994-1996 and 1998.  The same input files (PDP monitoring data, FDA
data,  % crop treated data, and drinking water exposure data) from the
2002 dietary assessment were used in this new analysis, while
incorporating the FQPA Safety Factor change from 10x to 1x.  The
combined dietary exposure (food and drinking water) does not exceed the
Agency’s level of concern (>100% of the PAD) for chronic or acute
exposures. 

	Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in this document, in accordance with U.S.
Executive Order 12898, "Federal Actions to Address Environmental Justice
in Minority Populations and Low-Income Populations,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant, and when data are available.  Further considerations are
currently in development as OPP has committed resources and expertise to
the development of specialized software and models that consider
exposure based on traditional dietary patterns among specific subgroups.

Endosulfan is a volatile and persistent organochlorine pesticide that
can migrate over long distances through various environmental media such
as air, water, and sediment. Recent studies suggest that endosulfan
continues to recycle in the global system while slowly migrating and
redepositing via wet deposition in the northern Hemisphere. The
occurrence of endosulfan in remote regions such as the arctic is well
documented.  Therefore, since the Indigenous Peoples of the arctic
region of the U.S. (Alaska) rely heavily on subsistence diets (i.e.
fish) as their food source, it is appropriate for the Agency to consider
dietary risk and exposure to this specific population subgroup from the
worldwide use of endosulfan. Based upon its octanol-water coefficient
(log Kow = 3.5 to 4.5), endosulfan shows appreciable lipophilicity and,
therefore, a potential to bioaccumulate in fatty tissues.  Since
subsistence diets often consist of fish and other traditional
subsistence food harvests (e.g., polar bear, walrus, caribou, moose),
exposure to tissues into which endosulfan has bioaccumulated is
possible. 

As specific residue data in/on commodities consumed in subsistence diets
are not available for endosulfan, risk estimates for these population
subgroups have not been evaluated by HED.  However, based upon the
chemical and toxicity profile of endosulfan, the Agency has concerns for
dietary exposure of indigenous populations to endosulfan.

IV.  2007 Occupational Assessment

Endosulfan currently is formulated into liquid concentrate and wettable
powder end-use products.  It is registered for occupational-use on
terrestrial food and feed crops, indoor food crops, and terrestrial
non-food crops.  There currently are no end-use products registered for
use at residential sites.  Application equipment for occupational use
includes fixed-wing aircraft, chemigation (potatoes only), groundboom
sprayer, airblast sprayer, handgun sprayer, low-pressure handwand
sprayer, high-pressure handwand sprayer, and dip treatment. 

The updated occupational assessment for endosulfan indicates short- and
intermediate-term risk for mixers, loaders, and applicators for the
majority of crop scenarios, even with maximum personal protective
equipment or engineering controls.  In addition, postapplication risks
are such that the majority of reentry intervals (REIs) would need to be
extended by several days.  [See Tables 9-18 for mixer/loader/applicator
risks and Tables 24-27 for postapplication risks in the revised
occupational assessment, S. Recore, D339509, 05/03/2007.]  

Please note that while the revised occupational assessment presents risk
estimates for grapes, pecans, spinach, succulent beans, and succulent
peas, these crops are no longer allowed on endosulfan labels with the
implementation of the 2002 RED mitigation. HED clarifies that where two
rates are presented for a crop (i.e., “label” rate and
“proposed” rate), the “proposed” rate reflects the rates
required in the 2002 RED. 

V.  References

1.   DP Barcode:	D272431	

      Subject:		Endosulfan: HED Risk Assessment for the Endosulfan 				
Reregistration Eligibility Decision (RED) Document.

      From:		D. Locke	

      To:			R. Dumas     

      Dated:		01/31/2001	      

2.   DP Barcode:	D250471	

      Subject:		Endosulfan: Reevaluation of the HED Risk Assessment for
the 				Endosulfan Reregistration Eligibility Decision (RED) Document.

      From:		D. Locke

      To:			R. McNally     

      Dated:		05/30/2002	      

3.   DP Barcode:	D327215

      Subject:		A Developmental Neurotoxicity Study with Technical Grade
				Endosulfan in Wistar Rats. Project Number: 201563

      From:		D. Anderson and J. Facey

      Dated:		03/15/2007

      MRID(s):		46968301

4.   DP Barcode:	D338576

      Subject:		Endosulfan.  Hazard Characterization and Endpoint
Selection 				Reflecting Receipt of a Developmental Neurotoxicity Study
and 				Subchronic Neurotoxicity Study.

      From:		E. Reaves

      To:			T. Perry

      Dated:		04/02/2007

5.   DP Barcode:	D281201

      Subject:		Endosulfan. Anticipated Residues, and Revised Acute and
Chronic 			Dietary Exposure Analysis.

      From:		S. Kinard

      To:			D. Locke

      Dated:		02/28/2002

6.   DP Barcode:	D336646

      Subject:		Acute and Chronic (Food and Drinking Water) Dietary
Exposure 				Assessment to update the 2002 Reregistration Eligibility
Decision

      From:		D. Wilbur

      To:			T. Perry

      Dated:		03/14/2007

7.   DP Barcode:	D339509

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Endosulfan: Occupational and Residential Exposure Assessment 				for the
Reregistration Eligibility Decision Document.

      From:		S. Recore

      To:			T. Perry

      Dated:		05/03/2007

8.   DP Barcode:	D342660

      Subject:		A Review of “Maternal Residence near Agricultural
Pesticide 				Applications and Autism Spectrum Disorders among Children
in 				the California Central Valley” Roberts et al., 2007 [EHP, 115;
10:  				1482-1489]  (Endosulfan (PC code 079401) and Dicofol (PC code 	
		010501)

      From:		C. Christensen

      To:			T. Perry

      Dated:		10/18/2007

 PAGE   

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

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