 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

MEMORANDUM

Date:		20-FEB-2009 

SUBJECT:		Tribufos.  Revised Human Health Assessment Scoping Document in
Support of 				Registration Review.  

PC Code:  074801	DP Barcode:  D361529

Decision No.: 401604	Registration No.:  NA

Petition No.: NA	Regulatory Action: Registration Review Scoping

Risk Assessment Type: NA	Case No.: 2145

TXR No.: NA	CAS No.: 78-48-8

MRID No.: NA	40 CFR: 180.272

Ver.Apr.08

FROM:		William H. Donovan, Ph.D., Chemist	

			John Doherty, Ph.D., Toxicologist

			Risk Assessment Branch V

			Health Effects Division (7509P)

			Office of Pesticide Programs

			

			AND

			Shalu Shelat, ORE Assessor

			Risk Assessment Branch VI

			Health Effects Division (7509P)

			Office of Pesticide Programs

THROUGH:	Jack Arthur, Branch Chief

			Danette Drew, Senior Scientist

			Risk Assessment Branch V

			Health Effects Division (7509P)

			Office of Pesticide Programs

TO:		Molly Clayton, CRM

			Reregistration Branch 3 (RB3)

			Special Review and Reregistration Division (7508P)

			Office of Pesticide Programs

Executive Summary

The Health Effects Division Tribufos Risk Assessment team has evaluated
the most recent human health assessments and database for the
insecticide tribufos to determine the scope of work necessary to support
the established tolerances.  The risk assessment used to support the
interim Reregistration Eligibility Decision (IRED), conducted in June,
2000, was the primary source for this evaluation.  That assessment
identified three outstanding toxicity studies necessary to complete the
toxicity database for tribufos: 1) acute neurotoxicity study in the rat,
2) subchronic neurotoxicity study in the rat, and 3) developmental
neurotoxicity study in the rat.  These studies were subsequently
submitted, reviewed and found to be acceptable.  However, in accordance
with current data requirements, two toxicity studies are required to
complete the toxicity database for tribufos: a Comparative
Cholinesterase Assay (CCA) and an immunotoxicity study.  

The residue chemistry database is complete; however, in the registration
review process, the dietary burden to ruminants should be reevaluated to
account for the recently reduced estimate of the contribution of cotton
gin byproducts to ruminant diets (Table 1 Feedstuffs, June 2008).  In
addition, the dietary exposure analysis should be updated to include
current anticipated residue levels, current percent crop treated
information and updated estimates of drinking water concentrations.  An
updated occupational exposure assessment, which shows risk levels of
concern for several scenarios, is provided in this document. 
Consequently, in order to refine worker risk levels, a biomonitoring
study or a similar study that provides exposure data that can be used to
refine occupational handler and post-application risk estimates, is
needed.  HED will conduct a revised human health risk assessment when
all of the required toxicity and worker exposure studies are submitted
and reviewed.

1.  Introduction

Tribufos [S,S,S-tributyl phosphorotrithioate] is an emulsifiable
concentrate (EC) cotton defoliant registered for use as a total
defoliant and as a bottom defoliant to reduce or prevent losses from
boll rot organisms, and also as a mix with the last insecticide
application to accelerate the aging of cotton leaves.  

As with other organophosphates, the principal toxic effects induced by
tribufos are related to its cholinesterase-inhibiting activity. It
produces the associated clinical signs, such as tremors, unsteady gait,
decreased activity, salivation, and disturbed balance in rats and
rabbits, and decreased cholinesterase activity (plasma, brain) in rats
and rabbits following acute, subchronic, and chronic oral exposure.  No
risks of concern were identified in previous dietary risk assessments.

Tolerances are established in 40 CFR §180.272 for cotton and livestock
commodities.  The residue of concern in plants and livestock consists of
parent tribufos (Metabolism Committee Issues Memo, C. Eiden, 4/27/1995 &
Metabolism Decision Memo, C. Eiden, 6/7/1995).  

Tribufos-containing products currently registered include: 1) Def 6
Emulsifiable Defoliant (EPA Reg. No. 264-730) [Bayer CropScience], 2) 
Folex 6 EC Cotton Defoliant (EPA Reg. No. 5481-504) [AMVAC Chemical
Corporation], and 3)  DFT 6 EC Cotton Defoliant (EPA Reg. No. 34704-867)
[Loveland Products, Inc.].

The Agency published an interim Reregistration Eligibility Decision
(IRED) for tribufos in September 2000.  Tribufos was included in the
cumulative assessment for the organophosphate insecticides (July 2006). 
With the completion of the cumulative assessment, the tribufos IRED was
considered a completed RED document. 

2.  Hazard Identification  

Tribufos is an organophosphate (OP) pesticide. As with other OPs, the
principal clinical signs for toxic effects induced by tribufos are
related to its cholinesterase (ChE)-inhibiting activity. It produces the
associated clinical signs, such as tremors, unsteady gait, decreased
activity, salivation, and disturbed balance.  Evidence of
anticholinesterase activity occurs by all routes (oral, dermal, and
inhalation) and durations (acute, subchronic and chronic) of exposure. 
By the oral and dermal routes, technical tribufos is placed in Toxicity
Category II and by the inhalation route, Category III.  Primary skin and
eye irritation are both assigned to Toxicity Category IV.  Tribufos is
not a dermal sensitizer. The metabolism of tribufos in rats indicates
that >90% of the administered dose was excreted in 72 hours and there
was no significant tissue residue.  Absorbed material was extensively
and completely metabolized.  Tribufos is not a developmental or a
reproductive toxicant.  There was no evidence of increased
susceptibility to rat or rabbit fetuses following in utero exposures or
in the offspring following pre- or post-natal exposure to rats.

The HED Cancer Peer Review Committee (CPRC) [now designated as Cancer
Assessment Review Committee (CARC)] classified tribufos as unlikely to
be a human carcinogen at low doses since all tumor increases in mice
occurred only at the highest dose tested (48 mg/kg/day in males and 63
mg/kg/day in females) and were accompanied by severe ChE inhibition and
increased mortality in the later weeks of the study (TXR# 0012242, E.
Rinde and R. Zendzian, 22-MAY-1997).  The CPRC recommended a
non-quantitative approach for the purpose of risk characterization
utilizing the most sensitive toxic endpoint.  The most sensitive
endpoint for chronic toxicity was plasma ChE inhibition in the one year
dog study, for which the NOAEL was 0.1 mg/kg/day.  In addition, there
was no apparent concern for mutagenicity, and no structural analogs of
concern were identified.  

In the tribufos risk assessment prepared in 2000, an extra 10X database
uncertainty factor was retained because of data gaps for acute and
subchronic neurotoxicity studies in the rat and for a developmental
neurotoxicity study.  All of these studies have been submitted to the
Agency, reviewed, and found to be acceptable.  Specifically, the acute
neurotoxicity study (2000, MRID 45194401) was determined to be
acceptable/guidelines and satisfies the series 870.6200 guideline
requirement for an acute neurotoxicity screen study in rats (TXR #
0050380, J. Doherty, 13-JUN-2002).  This study determined an LOAEL for
cholinesterase inhibition of 20 mg/kg based on inhibition of both plasma
ChE and RBC AChE, with a NOAEL of 2 mg/kg.  The subchronic neurotoxicity
study (2001, MRID 45369101) was classified as acceptable/guideline and
demonstrated a NOAEL of 0.17 mg/kg/day and a LOAEL of 3.54 mg/kg/day for
systemic effects based on decreased  body weight and food consumption in
females and a NOAEL of 0.14 mg/kg/day in males and 0.17 mg/kg/day in
females and LOAEL of 2.89 mg/kg/day in males and 3.54 mg/kg/day in
females based on inhibition of plasma and RBC ChE (TXR # 0050405, J.
Doherty, 13-JUN-2002).  The developmental neurotoxicity study (2001,
MRID 45499501) was classified as acceptable/non-guideline (TXR# 0050231,
W. Greear, 13-SEP-2005).  This study determined a maternal
cholinesterase LOAEL of 3.4 mg/kg/day and a maternal cholinesterase
NOAEL of 0.4 mg/kg/day.  The offspring cholinesterase LOAEL was 16.4
mg/kg/day (the highest dose tested).  

A comparative cholinesterase (CCA) study is required for organophosphate
pesticides that inhibit ChE.  The CCA study is required whether or not a
series 870.6300 developmental neurotoxicity study has been submitted
unless the Agency agrees that the DNT study contains equivalent CCA
data.  For tribufos, the DNT study was determined not to contain
equivalent CCA data, so the CCA study is needed (see Attachment).   

An immunotoxicity study is required based on the Revised Part 158
Toxicology Data Requirements for Conventional Pesticides for the reasons
specified in the Attachment.  Tribufos is currently regulated based on a
NOAEL of 0.1 mg/kg/day for chronic dietary exposure and 1 mg/kg/day for
acute exposure.  Once all outstanding toxicology studies have been
received and reviewed, the Tribufos Risk Assessment Team will reexamine
the endpoints and safety factors used for the tribufos risk assessment. 
A summary of the existing toxicology doses and endpoints is provided in
Table 1.  

Table 1.  Summary of Toxicological Doses and Endpoints for Tribufos Used
in Previous Dietary Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	RfD, PAD, Level of
Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary general population	NOAEL = 1.0 mg/kg	UFA= 10x

UFH=10x

FQPA SF = 10X	Acute RfD = 0.01 mg/kg

Acute PAD = 0.001 mg/kg/day	Prenatal Developmental Toxicity study in the
rat (MRID 40190601) 

LOAEL = 2 mg/kg, based on increased incidence of clinical signs, changes
in the majority of the FOB parameters and decreased plasma and brain
cholinesterase in males and females

Chronic Dietary 

all populations	

NOAEL =  0.1 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF = 10X	Chronic RfD = 0.001 mg/kg/day

Chronic PAD = 0.0001 mg/kg/day	chronic study in the dog (MRID 42007203)

LOAEL = 0.35 mg/kg/day, based on decreased plasma and brain
cholinesterase activity in males and females

Short and Intermediate Term Dermal	

LOAEL Adj = 14 mg/kg/day	UFA= 10x

UFH=10x

UFDB = 3X (lack of NOAEL)	Occupational LOC for MOE = 300	21-Day dermal
toxicity study in the rabbit (MRID 42007201)

LOAEL = 2 mg/kg/day, based on inhibition of plasma (males) and red blood
cells (females) cholinesterase activity.  Use of 7X conversion factor to
account for differences in dermal absorption between species (rabbit vs.
monkey).  No NOAEL determined.

Short and Intermediate Term Inhalation	

NOAEL = 0.9 mg/kg/day	UFA= 10x

UFH=10x

	Occupational LOC for MOE = 100	90-day Inhalation study in the rat (MRID
42399801)

LOAEL = 4.5 mg/kg/day, based on plasma and erythrocyte ChE inhibition

Long Term Dermal and Inhalation	

Long-term dermal or inhalation occupational exposures are not expected
to occur for the registered uses of tribufos.

Cancer 	Classification:  unlikely to be a  human carcinogen at low doses

Point of Departure (PoD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies). PAD = population adjusted dose (a = acute, c = chronic)
= the NOEL/all appropriate uncertainty and safety factors. RfD =
reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A
= not applicable.

3. Dietary Exposure

The following refined dietary exposure assessments for tribufos were
conducted in support of the RED:  acute analysis (D251691, S. Piper,
02-MAR-1999) and chronic analysis (D253404, S. Law, 22-FEB-1999). 
Anticipated residues used in the both assessments incorporated field
trial data, processing study data, and percent crop treated information.
 Drinking water was not included directly in the dietary assessment, but
accounted for using the drinking water level of comparison (DWLOC)
approach.  The acute and chronic dietary exposures were determined to be
well below HED’s level of concern.  Since the previous assessment, the
percent of cotton gin byproducts in the diets of ruminants has been
lowered to 5% (from 25%) (Table 1 Feedstuffs, June 2008).  In addition,
the percent crop treated value previously used for the chronic analysis
(35%) has dropped to 30% according to the latest report from BEAD
(Tribufos SLUA, 05-JUN-2008).  Consequently, a revised dietary risk
assessment is likely to find even lower exposures from food sources than
reported in past assessments.  Any new dietary risk assessment conducted
in association with registration review should directly include
potential tribufos exposures from drinking water sources.  In the
previous assessment, the estimated environmental concentrations (EECs)
provided by EFED were 5.8 ppb for acute exposure scenarios and 1.8 ppb
for chronic exposure scenarios, based on surface water models.  EFED
plans to update these EEC values for tribufos as part of registration
review, using the latest modeling methods.  Once these values are
available, they should be incorporated into a new dietary exposure
assessment together with updated percent crop treated information from
BEAD and revised anticipated residue levels taking into account the
revised dietary burden to ruminants. Additionally, any changes to
toxicity endpoints or safety factors should also be incorporated.  

4.  Residue Chemistry

The tribufos risk assessment in 2000 determined that the residue
chemistry database was complete except for the following two data
deficiencies:  1) Independent Laboratory Validation LV) of the
analytical method for milk, and 2) crop field trials in support of
ultra-low volume (ULV) applications to cotton.  The ILV data deficiency
was satisfied through submission of a study described in MRID 44077401,
entitled “Independent Laboratory Validation for the Determination of
Tribuphos Residue in Animal Tissues and Milk” (D273879, C. Eiden,
18-MAY-2001).  A detailed review of the ILV method is available
(D229479, C. Eiden, 05-MAR-1997).  The current tribufos labels do not
include ULV application methods.  Hence residue data supporting ULV
applications are not needed.  

During the registration review process, the tribufos tolerance levels
for livestock commodities should be reassessed in light of the update to
livestock feedstuff (Table 1 Feedstuffs, June 2008).  The only
tribufos-treated livestock feedstuff, cotton gin byproducts, has had a
significant reduction in the percent of diet (25 to 5%), thus resulting
in a lower dietary burden and likely lower tolerance levels than
previously recommended.  

5.  Residential Exposure

There are currently no registered tribufos products intended for sale to
homeowners.  There are also currently no tribufos products that have
been identified as intended for use in homes, in/around schools, parks
or other public areas.

6.  Aggregate Risk Assessment  

There are no residential uses of tribufos.  The aggregate assessments in
the most recent analyses considered only food and water.  Both the acute
and chronic aggregate analyses showed no risks of concern.  However, in
view of the identified data gaps in the toxicity database, likely
revisions to drinking water estimates, percent crop treated information
and anticipated residue levels, a new aggregate risk assessment may be
needed in registration review.  

7. Occupational Exposures

	7.1 Occupational Handlers

Occupational handlers are likely to be exposed to tribufos during
mixing, loading, application, and other handling activities associated
with the use patterns of tribufos. In the most recent US EPA Human
Health Risk Assessment (2000), Pesticide Handlers Exposure Database
(PHED) Version 1.1 and chemical specific handler study data were used to
assess four major occupational handler exposure scenarios:

	(1a)	mixing/loading liquids for aerial application;

	(1b)	mixing/loading liquids for groundboom applications;

	(2) 	applying sprays with a fixed-wing aircraft;

	(3)	applying sprays with groundboom equipment; and; 

	(4)	flagging for aerial spray applications.

In the most recent tribufos HED risk assessment (2000), handler risk
calculations were performed using the short and intermediate-term dermal
endpoint (LOAEL = 14mg/kg/day) from a 21-day dermal toxicity study in
rabbits (LOAEL = 2 mg/kg/day) with a conversion factor of seven to
compensate for the species difference in dermal absorption (rabbit vs.
monkey).  The short- and intermediate-term inhalation endpoint (NOAEL =
0.9 mg/kg/day) was established with a 90-day inhalation study in rats.
Given the registered uses of tribufos, long-term dermal or inhalation
occupational related exposures are not expected to occur, therefore only
short- and intermediate- term occupational risks were assessed. 

At the time of the IRED, the maximum registered application rate for
tribufos was 1.875 pounds of active ingredient per acre (lb ai/A). The
registrant has since then proposed to reduce the application rate from
1.875 lbs ai/A to 1.125 lbs ai/A. Review of the product labels shows
that the reduction in application rate has taken effect. The reduction
in application rate applies to all cotton growing states except for
California and Arizona. The two states grow hardier varieties of the
cotton and thus require more defoliant.

Occupational handler risk assessments were conducted for all four
scenarios at application rates of both 1.875 lbs ai/A and 1.125 lb ai/A
(see Table 2 below).  Dermal risk estimates, using engineering controls,
for mixing/loading liquids for aerial applications and applying liquids
via aerial equipment both result in risks of concern (MOE <300) at an
application rate of 1.875 lb ai/A. The resulting Aggregate Risk Index
(ARI) for these two scenarios also resulted in risks of concern (ARI <
1).  Dermal risk estimates, using engineering controls, for
mixing/loading liquids for aerial applications and applying liquids via
aerial equipment also both result in risks of concern (MOE <300) at an
application rate of 1.125 lb ai/A. The resulting ARI for these two
scenarios also resulted in risks of concern (ARI < 1).   

 

Dermal and inhalation risk estimates for groundboom application handlers
(mixers, loaders, applicators) are not of concern with baseline attire.
The ARI was determined to be greater than 1 for all groundboom
application activities and aggregate risks are not of concern.

For more details regarding the occupational handler exposure and risk
assessment, see the tribufos RED.  

Table 2 - Tribufos Handler Risks in Margin of Exposure (dermal LOC= 300;
Inhalation LOC= 100)

Exposure Scenario	Handler Risks at 1.875 lb ai/ acre	Handler Risks at
1.125 lb ai/ acre

	Short & Intermediate Term Dermal 	Short & Intermediate Term Inhalation
ARI	Short & Intermediate Term Dermal 	Short & Intermediate Term
Inhalation	ARI

(1a) mixing/loading liquids for aerial applicationa	49	330	0.16	82	560
0.26

(1b) mixing/loading liquids for groundboom applicationsb	760	5100	2.4
1300	8400	4.1

(2)  applying sprays with a fixed-wing aircrafta	90	410	0.2	150	690	0.47

(3) applying sprays with groundboom equipmentb	470	570	1.2	780	950	2.5

(4) flagging for aerial spray applicationsa	2000	4000	5.9	3300	6700	9.5

a Based on maximum level of engineering controls

b Based on baseline assumptions

	7.2 Occupational Postapplication

Occupational postapplication exposure to tribufos was assessed in the
2000 HED risk assessment for tribufos. A chemical-specific study (MRID
42701601-01) from the registrant was used to determine both dermal and
inhalation exposures for the four major postapplication exposure
activities:

Picker Operators

Module Builder Operators

Rakers

Trampers- Trail-Harvesting System

The tribufos postapplication study was used to develop dermal transfer
coefficients for the four activities: picker operator 92.36 (50g
bolls/hour), module building operator 26.13 (50g bolls/hour), rakers
15.9 (50g bolls/hour), and trampers 212.76 (50g bolls/hour).
Occupational postapplication risk assessments were conducted at
application rates of 1.875 lbs ai/A and 1.125 lb ai/A (see Table 3
below) using the calculated dermal transfer coefficients. At 24 hours
after application, dermal MOEs resulted in risks of concern (MOE < 300)
at both application rates. At 7 days after application, MOEs for all
postapplication scenarios except building module activities resulted in
risks of concern at an application rate of 1.875 lb ai/A. All
postapplication activities were not of concern at an application rate of
1.125 lb ai/A. 

The tribufos postapplication inhalation data does not provide exposure
information for activities that may be conducted prior to 15 days after
treatment.  According to the 2000 HED risk assessment, the risks to
inhalation exposure prior to day 15 were not estimated due to the
introduction of uncertainties that would arise from extrapolating the
data monitored on one day to another.  Given the physical and chemical
properties of tribufos, inhalation exposure is not likely to be a
concern 7 days after treatment. 

The tribufos restricted entry interval (REI) was changed from 24 hours
to 7 days per the 2000 IRED. Based on the reduced application rate
(1.125 lb ai/A) and the 7 day REI, the MOEs for postapplication
activities do not exceed the level of concern. [Note: Risks of concern
still remain for most postapplication activities using the higher
application rate of 1.875 lbs ai/A (used only in CA and AZ) at the
current REI of 7 days.]

Table 3 - Tribufos Postapplication Dermal Risks in Margin of Exposure
(dermal LOC= 300)

Exposure Scenario	Postapplication Risks at 1.875 lb ai/ acre
Postapplication Risks at 1.125 lb ai/ acre	Postapplication Risks at
1.875 lb ai/ acre	Postapplication Risks at 1.125 lb ai/ acre

	Results at 24 hours after treatment	Results at 7 days after treatment

Picker Operators	47	78	210	350

Module Builder Operators	110	180	480	820

Rakers	45	74	200	340

Trampers	52	88	230	390



There is sufficient information available to assess occupational
exposure.  All of the occupational exposure scenarios for the registered
uses of tribufos have been assessed adequately. There remain risks of
concern regarding aerial mixing, loading, and application scenarios at
maximum engineering controls, and to workers entering cotton fields
following treatment at the 1.875 lb ai/A rate.  All other occupational
exposures were assessed adequately and do not present risks of concern. 

A biomonitoring study was requested in the 2000 IRED to confirm risk
management decisions. In 2001, the request for the biomonitoring study
was placed on hold, pending submission of requested neurotoxicity
studies.  These studies have since been submitted and reviewed and found
not to change the dermal toxicity endpoint.  Accordingly, submission of
the previously requested biomonitoring study or similar study that
provides exposure data that can be used to refine occupational handler
and post-application risk estimates is required.  

8.  Tolerance Assessment and International Harmonization

A summary of US tolerances, Codex Maximum Residue Limits (MRL), Mexican
MRLs, and Canadian MRLs is provided in Table 4 (see Attachments).  There
are no MRLs set for tribufos in Canada, Mexico, or through Codex; thus,
there are no international harmonization issues to resolve.

9.  Public Health and Pesticide Epidemiology Data.  A summary report
listing reported incidents for tribufos has been provided in the
memorandum entitled Updated Review of Tribuphos Incident Reports (M.
Hawkins and J. Cordova, 10/30/2008).  Only two incidents were cited,
however, the effects seen in those incidents were consistent with the
type of toxicological effects that are seen in the animal studies for
tribufos.  The reported incident data will be evaluated in more detail
during the development of the Final Work Plan (FWP) for tribufos.

10. Environmental Justice  

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pd
f" 
http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf
.  The Office of Pesticide Programs (OPP) typically considers the
highest potential exposures from the legal use of a pesticide when
conducting human health risk assessments, including, but not limited to,
people who obtain drinking water from sources near agricultural areas,
the variability of diets within the U.S. (including different ages,
regions, and ethnicities), and people who may be exposed when harvesting
crops.  Should these highest exposures indicate potential risks of
concern, OPP further refines the risk assessments to ensure that the
risk estimates are based on the best available information.

11. Cumulative

The Food Quality Protection Act (FQPA) requires the Agency to consider
the cumulative risks of chemicals sharing a common mechanism of
toxicity.  Tribufos is a member of the organophosphate common mechanism
group.  The most recent cumulative risk assessment for the
organophosphates was published on July 31, 2006 and is available at  
HYPERLINK
"http://www.epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf" 
http://www.epa.gov/pesticides/cumulative/2006-op/op_cra_main.pdf .  No
cumulative risks of concern for tribufos were identified in that
assessment.  

Prior to a final tolerance review decision for tribufos, the Agency will
determine if there is any new information, such as new hazard or
exposure data or information on changes to the use pattern, which would
affect the cumulative risk assessment.  Should the Agency determine that
new information on tribufos is available that could potentially impact
the cumulative risk assessment and result in a risk of concern, the
Agency will revisit the cumulative risk assessment.  

12.  Human Studies

Tribufos risk assessments rely in part on data from studies in which
adult human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), have been reviewed by the Agency and found on the basis
of available evidence to have been neither fundamentally unethical nor
significantly deficient relative to standards of ethical research
conduct prevailing when they were conducted.  There is no barrier in the
Agency’s “Protection of Human Subjects” regulation to reliance on
these studies.

13.  Data Needs

Toxicology

The following toxicity studies are required.  Detailed rationale for
requiring these studies is attached to this document.

870.7800 Immunotoxicity.  This study is required based on the Revised
Part 158 Toxicology Data Requirements for Conventional Pesticides. 

870.6300 Comparative Cholinesterase Assay.  This study is needed to
address uncertainties with regard to susceptibility in the young
animals.

Occupational Exposure

Submission of the previously requested biomonitoring study or a similar
study that provides exposure data that can be used to refine
occupational handler and post-application risk estimates is required.  

14.  References

Author	Barcode	Date	Title

M. Hawkins and J. Cordova	--	10/30/2008	Updated Review of Tribuphos
Incident Reports

R. Travaglini et al.

6/26/2000	Tribufos: Human Health Risk Assessment.   

J. Doherty	TXR 0050380	6/13/2002	Tribufos: Review of an acute
neurotoxicity screen study.   

J. Doherty	TXR 0050405	6/13/2002	Tribufos: Review of an subchronic
neurotoxicity study.   

W. Greear	TXR 0050231	9/13/2005	Tribufos.  Evaluation of a Developmental
Neurotoxicity Study

E. Rinde and R. Zendzian	TXR# 0012242	5/22/1997	Carcinogenicity Peer
Review (2nd) of Tribufos (DEF)

C. Eiden	D273879	5/18/2001	Tribuphos.  RED Data Call-in (DCI)
Requirement for Independent Laboratory Validation (ILV) for Residue
Analytical Method for Animal Tissues.   

C. Eiden	D229479	3/5/1997	Tribufos - Report of the FQPA Safety Factor
Committee

C. Eiden	--	4/27/1995	Tribuphos.  Issues to be Presented to the HED
Metabolism Committee.

C. Eiden	--	6/7/1995	Tribuphos.  Outcome of the 5/9/1995 Meeting of the
HED Metabolism Committee.

S. Law	D253404	2/22/1999	Tribufos – Chronic Dietary Exposure Analysis

S. Piper	D251691	3/2/1999	Monte Carlo Acute Dietary Exposure Estimates
for Tribufos

S. Knizner	D253352	2/18/1999	Revised Chronic Anticipated Residues for
Tribufos.

--	--	7/31/2006	Organophosphorus Cumulative Risk Assessment – 2006
Update



Attachments

Table 4.  Summary of US and International Tolerances and Maximum Residue
Limits 

US	Canada	Mexico1	Codex

Residue Definition:

40CFR  180.272

Tribuphos (S,S,S-tributylphosphorotrithioate)  

	None	None	None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

Commodity	US	Canada	Mexico	Codex

Cattle, fat	0.15	None	None	None

Cattle, meat	0.02



	Cattle, meat byproducts	0.02



	Cotton, gin byproducts	40



	Cotton, undelinted seed	4.0



	Goat, fat	0.15



	Goat, meat	0.02



	Goat, meat byproducts	0.02



	Hog, fat	0.15



	Hog, meat	0.02



	Hog, meat byproducts	0.02



	Horse, fat	0.15



	Horse, meat	0.02



	Horse, meat byproducts	0.02



	Milk	0.01



	Sheep, fat	0.15



	Sheep, meat	0.02



	Sheep, meat byproducts	0.02



	1 As of 2004, latest date for available information.  General practice
is for Mexico to defer to US or Codex tolerances for its export
purposes.  

(*) = absent at the limit of quantitation.

Po = post harvest

Rationale for Requiring Immunotoxicity and CCA Studies  

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 assessing functional immunotoxic endpoints are helpful
in fully characterizing a pesticide’s potential immunotoxicity.  These
data will be used in combination with data from hematology, lymphoid
organ weights, and histopathology in routine chronic or subchronic
toxicity studies to characterize potential immunotoxic effects.  



Practical Utility of the Data

How will the data be used?

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.

 

 

Guideline Number: NA

Study Title:   Comparative Cholinesterase Assay

Rationale for Requiring the Data



Tribufos is a member of the organophosphate (OP) family of pesticides. 
The mode of toxic action for OP pesticides is inhibition of the enzyme,
acetylcholinesterase (AChE) via phosphorylation of the active site
leading to accumulation of acetylcholine and to clinical signs of
neurotoxicity.

The CCA is needed to evaluate any potential for increased cholinesterase
sensitivity in juvenile animals compared with that of adult animals. 
Inhibition of acetylcholinesterase (AChE) is the critical regulatory
endpoint for tribufos.  CCA studies have been submitted to HED for more
than 20 other organophosphates (OPs), and for many of these OPs the CCAs
have shown juveniles to be more sensitive than adults.  Based on this
additional knowledge gained since 1999 and because there is food use for
tribufos, a CCA is required. 

Typically for the OPs, the CCA includes several components:  1)
Gestational exposures to pregnant dams followed by sacrifice at
gestational day 20.  Brain and blood ChE activity is measured in dams
and fetuses; 2) Acute, direct dosing to post-natal day (PND) 11 and
young adult rats; and  3) Eleven (11) day repeated, direct, dosing to
juvenile rats (PND 11-21) and young adult rats.  Each study includes a
control group and at least 3 treatment groups.  Both the acute and the
repeat-dose studies are typically accompanied by range-finding and time
to peak effect study.   All three components are required for tribufos. 

 

Practical Utility of the Data



How will the data be used?

CCA studies provide critical scientific information needed to
characterize potential hazard to the human population on the inhibition
of cholinesterase from pesticide exposure. Since epidemiologic data on
the effects of chemical exposures on cholinesterase inhibition are
limited and are inadequate to characterize a pesticide’s potential for
effects 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. The current endpoints are based on adult
data, and it is likely that young animals may be more sensitive to ChE
inhibition based on data for other organophosphate pesticides.

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

If the CCA study shows that the test material poses either a greater or
a diminished risk to the young animal 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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