Document ID: EPA-HQ-OPP-2006-0559-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-06-13T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

May 15, 2007

MEMORANDUM

Subject:		Diuron.  Updated Aggregate Risk Assessment to Support
Permanent Tolerances for Residues in Cactus, Peppermint Tops, Spearmint
Tops, and Fish.

		PC Code:  035505

		Petition Nos.: 2E6438 [Mint]; 6E3390 [Cactus]; 6F4680 [Fish] 

		DP Barcode Number:  D335228

		Regulatory Action:

		Tolerance with a regional registration (Cactus)

		Section 3 Registration (Spearmint, Finfish)

		Risk Assessment Type:  Single Chemical Aggregate

From:		Christina Swartz, Chemist

		Registration Action Branch II

		Health Effects Division (7509P)

Through:		Richard A. Loranger, Ph.D., Branch Senior Scientist

		Registration Action Branch II

		Health Effects Division (7509P)

	

To:		Barbara Madden/Daniel Rosenblatt

		RIMUERB

		Registration Division (7505P)

Introduction/Regulatory Background

Diuron is a substituted urea herbicide used to control annual and
perennial broadleaf and grassy weeds in a variety of crop and non-crop
sites.  It is also used as a mildewcide in paints and stains, and as an
algaecide in commercial fish production.  Products containing diuron are
used in occupational settings, including agricultural food crops and
non-food crops, ornamental trees, flowers and shrubs, paints and
coatings, ornamental fish ponds and catfish production, rights-of-way
and industrial sites.  Residential uses of diuron include ponds,
aquariums and paints.

Diuron was the subject of a reregsitration eligibility decision (RED)
document issued by the Agency 9/20/2003; the Agency’s decision
included opportunities for the registrant and stakeholders to comment on
the assessment, and these comments were incorporated into the final
decision.  In conjunction with the RED, the Agency concluded that all
registered uses were eligible for reregistration, provided labeling
requirements and mitigation measures were observed.  These included:

Voluntary cancellation of all wettable powder products.

Voluntary cancellation of uses allowing application to home lawns.

Changes to application rates for some crops, including citrus (reduction
in rate, as well as limiting the number of applications and increasing
treatment intervals).

Prohibition of use of the backpack sprayer.

Additional PPE and engineering controls for some workers

Elimination of aerial application for most crops.

Use of best management practices to reduce spray drift.

In conversations with the Registration Division, HED has confirmed
cancellation of applications to lawns, reduced rates on various crops,
and the cancellation of wettable powder products.

Potential residential handler exposures from applying paints and stains
containing diuron, as well as treating residential ponds and aquariums,
were assessed in the 2003 RED.  Handler exposure associated with the
pond/aquarium uses was considered to be negligible.  For the paint/stain
scenarios, conservative assumptions included 2 days of painting per year
for 50 years of a 70 year lifetime.  However, based on information
gathered through the RED process it was determined that less than 1% of
paint sold contains diuron, and that such paints would likely only be
used in rooms subject to high moisture (e.g., bathrooms).  Therefore,
lifetime exposure to home applicators of diuron-containing products is
likely to negligible.  Postapplication inhalation exposure resulting
from the use of diuron in residential ponds and aquariums is also
expected to be minimal based on the extremely high dilution rate.
Therefore, an exposure assessment was not conducted for
non-occupational, non-dietary exposures.

In summary, the 2003 RED concluded that aggregate exposure was not of
concern for short-term and long-term exposure scenarios, including
cancer risk.

Proposed Tolerances

Several actions are the subject of the current assessment:

HED is recommending establishment of a permanent tolerance of 2 ppm for
residues of diuron and its metabolites convertible to 3,4-DCA in
farm-raised freshwater finfish, which had previously been a time-limited
tolerance for the parent alone in catfish fillets, established in
conjunction with Section 18 uses in several states.  The recommended
tolerance reflects the correct commodity definition, fish - freshwater
finfish, farm-raised.

HED is recommending the establishment of a tolerance of 1.5 ppm for
residues of diuron and its metabolites convertible to 3,4-DCA in
spearmint, tops, based on acceptable data submitted to support the use
on peppermint, and in accordance with the OPPTS residue chemistry
guidelines.  As recommended in the RED, the tolerance listing should
also be revised to reflect the correct commodity definition for
peppermint: “peppermint tops.”

HED is recommending the establishment of a tolerance of 0.05 ppm for
residues of diuron and its metabolites convertible to 3,4-DCA in cactus,
to reflect regional registration for use on prickly pear cactus grown in
CA, TX, AZ and NM.

These proposed tolerances were the subject of a Federal Register Notice
dated 7/26/2006 (volume 71, number 143, page 42390-42392).

Assumptions Used in the Current Risk Assessments

Toxicity/Endpoints for Risk Assessment

No new toxicity data have been received in conjunction with the proposed
tolerances; therefore, the toxicology database used to support the
reregistration eligibility decision serves as the basis for the current
assessment.  The details are found in the 9/20/2003 RED; in addition,
the toxicology chapter of the human health risk assessment was
completed, and provides more detailed characterization and information
pertaining to diuron toxicity studies.

Diuron has low acute toxicity (Toxicity Category 3-4) by the oral,
dermal, or inhalation exposure routes.  Diuron is not an eye or skin
irritant, and is not a skin sensitizer.  The primary target organs are
the hematopoietic system, the bladder, and renal pelvis.  The HED
Carcinogenicity Peer Review Committee (CPRC) characterized diuron as a
“known/likely” human carcinogen based on urinary bladder carcinomas
in both sexes of the Wistar rat, kidney carcinomas in the male rat, and
mammary gland carcinomas in the female NMRI mouse.  The CPRC also
recommended a low dose linear extrapolation model with a Q1* of 1.91 x
10-2 (mg/kg/day)-1 be applied to the animal data for the quantification
of human risk, based on the urinary bladder carcinomas in the rat. 
Diuron was not mutagenic in bacteria or in cultured mammalian cells and
no indication of DNA damage in primary rat hepatocytes was observed.

There are no adverse effects attributed to a single exposure identified
in any available studies.  In addition, diuron has low acute toxicity
and no developmental or neurotoxic concerns.  Therefore, no acute
dietary endpoint was chosen and no acute dietary risk assessment was
conducted.  Also, no systemic toxicity was observed following repeated
dermal dosing up to 1200 mg/kg/day.  Therefore, no short- or
intermediate-term dermal endpoints were chosen.

For the current dietary exposure assessments, the endpoints and doses
selected as described in the RED were used.  The only exception was for
chronic dietary risk assessment; in this case, the study selected did
not identify a NOAEL for long-term exposure durations, and a 3X factor
was used in the RED to extrapolate from the LOAEL to the NOAEL.  In
accordance with current policy, a 10X factor has been retained for the
LOAEL to NOAEL extrapolation.

HED is confident the 10X factor for the lack of an NOAEL is sufficient
for the protection of infants and children for the following reasons:

i. There are no uncertainties with the toxicology database.  The only
outstanding data requirement is a 28-day inhalation study which the
Agency required to address the concern for inhalation exposure to
workers during the application of diuron.  Exposure to diuron via
inhalation is not expected to occur with infants and children. 
Therefore, the 28-day inhalation study will not change the endpoints
used in risk assessment to address potential risks to infants and
children.

 

 The EPA considers the developmental toxicity study in rats adequate for
the FQPA susceptibility assessment based on the observation that the
developmental toxicity NOAEL was higher than the maternal NOAEL, even
though the study was considered unacceptable due to analytical
methodology.  The chronic toxicity study in dogs has also been
classified as unacceptable.  However, the EPA determined that a repeated
chronic dog study is not required; a new study would not provide
additional data since the observed effects are similar in the rat and
the rat is the more sensitive species for this chemical.

The data base as a whole is adequate for pre- and post-natal toxicity
evaluation and did not reveal developmental or reproductive toxicity. 
The NOAELs for maternal/parental toxicity were either less than or equal
to the NOAELs for fetal or reproductive toxicity.

	ii. There is no indication of quantitative or qualitative increased
susceptibility of rats or rabbits to in utero or postnatal exposure.  In
the developmental toxicity study in rabbits, there were no developmental
effects at the highest dose tested.  In the developmental toxicity study
in rats and in the 2-generation rat reproduction study,
developmental/offspring effects were observed only at
maternally/parentally toxic dose levels.

	iii. There was no evidence of neurotoxicity in the submitted subchronic
or chronic studies.  A developmental neurotoxicity study (DNT) for
diuron is not required.  

	iv. There are no residual uncertainties identified in the exposure
databases. The dietary (food and drinking water) and non-dietary
(residential) exposure assessments will not underestimate the potential
exposures for infants and children.  The dietary food exposure
assessments were performed based on reliable field trial data or
tolerance level residues for some commodities as well as anticipated
residues (ARs) for other commodities, based on a combination of average
field trial data and USDA/PDP monitoring data.  Average PCT values were
assumed for chronic dietary assessment for some crops and 100 PCT
treated was assumed for the remaining uses.  Drinking water estimates
were based on monitoring studies in high diuron usage areas and USDA/PDP
monitoring data.  EPA expects any residential exposure from use of
diuron to be negligible.  The EPA is confident that these assessments
will not underestimate the exposure and risks posed by diuron.

Toxicological Doses and Endpoints for Diuron for Use in Dietary Risk
Assessment

Exposure/

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

Acute Dietary [All Populations]	N/A	N/A	N/A	An acute dietary endpoint
was not selected based on the absence of an appropriate endpoint
attributed to a single dose.

Chronic Dietary (All Populations)	LOAEL=1

mg/kg/day	UFA=10X

UFH=10X

FQPA SF= 10X

[UFL]	Chronic RfD = 0.001

mg/kg/day

cPAD = 0.001

mg/kg/day	Chronic Toxicity/Carcinogenicity Study in Rats

LOAEL = 1 mg/kg/day based on Evidence of hemolytic anemia and
compensatory hematopoiesis

Cancer (oral, dermal, inhalation)	A cancer slope factor of 1.91 x 10-2
has been established based on urinary bladder carcinomas in both sexes
of the Wistar rat, kidney carcinomas in the male rat (a rare tumor), and
mammary gland carcinomas in the female NMRI mouse.

Residue Chemistry Data

No new residue data have been submitted in support of the proposed
tolerances.  The residue chemistry database reviewed for the RED
generally supports the registered uses; additional data requirements
noted in the RED did not preclude a reregistration eligibility decision.
 The nature of the residue in plants and livestock is adequately
understood; available metabolism data support regulation of diuron per
se and metabolites convertible to 3,4-DCA in the tolerance expression,
although DCA per se is not found as a metabolite in plants.  In general,
field trial data have shown that residues of diuron in crops are low or
nondetectable, and concentrate in some but not all processed
commodities.  Previously submitted and reviewed residue data support the
uses on spearmint, farmed fish and prickly pear cactus.  Therefore, a
separate residue chemistry summary document has not been prepared.  For
additional information related to prickly pear cactus, refer to the M.
Firestone memo dated 4/24/86.  For the uses included in the RED, refer
to the 7/9/03 Residue Chemistry Chapter of the HED RED.

Occupational Assessment

With the exception of the proposed use on prickly pear cactus, dietary,
aggregate and worker exposure and risk for the proposed new tolerances
were included in the 2003 RED.  The proposed use on spearmint is
identical to the currently registered use on peppermint.  Because the
occupational exposure and risk assessment completed for the RED
(Sandvig/Jarvis, 12/12/01) did not identify any risk concerns for the
use on peppermint, a new occupational exposure assessment has not been
completed for spearmint.  Likewise, occupational exposure and risk
associated with the use on farmed catfish was assessed in the 2003 RED;
no risk concerns were identified (MOEs were greater than 100, cancer
risk less than 1 x 10-6), and therefore HED has not completed a new
occupational exposure assessment for the proposed permanent tolerance.

The proposed application rate on prickly pear cactus (ground application
equipment, 2.4 lb ai/A, 1 application) is bracketed by application rates
and acreage assessed in conjunction with the 2003 RED, and therefore an
occupational assessment has not been completed for this specific use. 
However, based on the rates, timing, acreage and equipment assessed in
the RED, HED concludes that occupational handler and postapplication
exposure and risk are not of concern for the proposed use on prickly
pear cactus.

Dietary Risk Assessment/Aggregate Risk Assessment

For the current assessment, updated chronic and cancer dietary
assessments were conducted to include the newly proposed tolerances. 
Because residential exposure to diuron is considered negligible, the
dietary (food + water) assessments serve as the aggregate risk
estimates.  The new dietary assessments directly included the following:

Water monitoring data from the USDA Pesticide Data Program (a change
from the Drinking Water Level of Concern (DWLOC) approach used in the
RED).

Updated Percent Crop Treated (%CT) information generated by the
Biological and Economic Analysis Division (BEAD).

Tolerance level residues for some commodities.

Anticipated residues calculated from field trial data for some
commodities.

Residue monitoring data from the USDA Pesticide Data Program (PDP) were
used for apple, orange, orange juice, and grapes (and were translated to
other pome and citrus commodities).

When available, empirical processing factors were used; in some cases,
default processing factors were used.

In addition to the chronic and cancer dietary (food + water) assessments
conducted for diuron and residues convertible to 3,4-DCA, a separate
assessment was completed for the water degradate, MCPDMU
[N’-(3-chlorophenyl)-N,N-dimethyl urea], in fish and drinking water. 
The MCPDMU degradate is structurally similar to monuron, which is no
longer registered in the U.S., but is a carcinogen with a cancer potency
factor.  A similar assessment was completed in conjunction with the RED,
and has been included in this assessment.  HED had previously requested
additional fish metabolism data to determine if MCPDMU is a significant
residue in fish.  However, based on a very conservative estimate of
residues in fish and monitoring data for the degradate in drinking
water, a cancer assessment assuming equivalent potency to monuron has
resulted in cancer risks below HED’s level of concern.  Therefore, HED
has concluded that a fish metabolism study is not needed to support the
proposed tolerance for residues in farm-raised fish.

Updated chronic dietary risk assessments were conducted for existing and
proposed uses of diuron using the Dietary Exposure Evaluation Model -
Food Consumption Intake Database (DEEM-FCID(, ver. 2.03).  Chronic
exposure was compared to the chronic Population Adjusted Dose (cPAD) of
0.001 mg/kg/day and the diuron cancer potency factor of 1.91 x 10-2
(mg/kg/day)-1 in order to determine chronic non-cancer and cancer risks,
respectively.  DEEM-FCID™ incorporates the food consumption data from
the USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII;
1994-1996 and 1998).

The diuron chronic dietary risk estimates are all below HED’s level of
concern.  Dietary exposure for the general US population was 0.000074
mg/kg/day, or 7.4 % of the cPAD.  This exposure corresponds to a cancer
risk estimate of 1.4 x 10-6, which is not of concern.  For chronic
non-cancer risk, the most highly exposed population subgroup was
children 1-2 years old, with an exposure of 0.000194 mg/kg/day, or 19
%cPAD. 

Summary of Dietary (Food and Drinking Water) Exposure and Risk for
Diuron.

Population Subgroup	Chronic Dietary	Cancer

	Dietary Exposure

(mg/kg/day)	% cPAD	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	0.000074	7.4	0.000074	1.41x 10-6

All Infants (< 1 year old)	0.000119	12	N/A	N/A

Children 1-2 years old	0.000194	19

Children 3-5 years old	0.000152	15

Children 6-12 years old	0.000092	9.2

Youth 13-19 years old	0.000046	4.6

Adults 20-49 years old	0.000059	5.9

Adults 50+ years old	0.000072	7.2

Females 13-49 years old	0.000062	6.2

Recommendation for the Proposed Tolerances:

HED recommends in favor of the proposed tolerances, based on acceptable
residue chemistry data, aggregate (food + water) cancer and non-cancer
risks which are below the level of concern (cancer risk of 1.4 x 10-6,
chronic risk <19 % cPAD), and the lack of concern for occupational
exposure (MOEs >100, cancer risks below 1 x 10-6).

Diuron Toxicity Profile (Excerpted from the 2003 HED RED Chapter)

Acute Toxicity of Diuron

Guideline No.	

Study Type	

MRID #	

Results	Toxicity Category

870.1100	Acute Oral	00146144	LD50 = 4721 mg/kg (M)

          >5000 mg/kg (F)	III

870.1200	Acute Dermal	00146146	LD50 >2000  mg/kg	III

870.1300	Acute Inhalation	40228803	LC50 >7.1 mg/L	IV

870.2400	Primary Eye Irritation	00146147	At 48 hrs, all irritation had
cleared.	III

870.2500	Primary Skin Irritation	00146148	All irritation had cleared by
72 hrs.	IV

870.2600	Dermal Sensitization	00146149	Nonsensitizer	N/A

870.6200	Acute Neurotoxicity	N/A	Not available	N/A

Diuron Subchronic, Chronic and Other Toxicity

Guideline #/ Study Type	MRID # (year)/ Classification/Doses	Results

870.3100

90-Day oral toxicity in rats 	MRID 40886502 (1988)

Acceptable/Nonguideline

0, 4, 10, or 25 ppm (0, 0.3, 0.7, or 1.6 mg/kg/day for males and 0, 0.3,
0.8, 1.8 mg/kg/day for females)	The NOAEL can not be determined based on
equivocal findings in the urinary bladder including blood vessel
dilation, reduced transparency, and increased firmness.

870.3200

21/28-Day dermal toxicity in rabbits	MRID 42718301 (1992)

Acceptable/Guideline

0, 50, 500, or 1200 mg/kg/day 	Systemic toxicity NOAEL =1200 mg/kg/day
(HDT)

870.3465

90-Day inhalation toxicity	Not available	Not available

870.3700a

Prenatal developmental toxicity in rats	MRID 40228801 (1986)

Unacceptable/Guideline

0, 16, 80, or 400  mg/kg/day	Maternal toxicity NOAEL = 16 mg/kg/day.
Maternal toxicity LOAEL = 80 mg/kg/day, based on decreased body weight
gain and food consumption.

Developmental toxicity NOAEL= 80 mg/kg/day.

Developmental toxicity LOAEL = 400 mg/kg/day, based on whole litter
resorption, reduced fetal body weights, and delayed ossification of the
vertebrae and sternebrae.

870.3700b

Prenatal developmental toxicity in rabbits	MRID 40228802 (1986)

Acceptable/Guideline

0, 2, 10, or 50 mg/kg/day	Maternal toxicity NOAEL = 10 mg/kg/day.
Maternal toxicity LOAEL = 50 mg/kg/day, based on decreased body weight
and food consumption.

Developmental toxicity NOAEL = 50 mg/kg/day (HDT).

870.3800

Reproduction and fertility effects in rats	MRID 41957301 (1990)

Acceptable/Guideline

0, 10, 250, or 1750 ppm. (0, 0.58, 14.8, or 101 mg/kg/day for males and
0, 0.71, 18.6, or 132 mg/kg/day for females, respectively.	Parental
NOAEL = 250 ppm (18.6 mg/kg/day).

Parental LOAEL =1750 ppm (132 mg/kg/day)  based on decreased body
weight, body weight gain, food consumption and food efficiency in both
generations.  

Reproductive NOAEL = 1750 ppm (HDT).

Offspring NOAEL = 250 ppm (18.6 mg/kg/day). Offspring LOAEL = 1750 ppm
(132 mg/kg/day) based on decreased body weight of the F1 and F2 pups
during lactation.

870.4200b

Chronic toxicity in dogs	MRID 00091192 (1964)

Unacceptable/Guideline

0, 25, 125, 250, or 2500/1250 ppm (0, 1.8, 9.4, 18.8, or 93.8 mg/kg/day
by conversion factor of 0.075) for 24 months.	NOAEL = 125 ppm (9.4
mg/kg/day) in males and 250 ppm (18.8 mg/kg/day) for females.

LOAEL = 250 ppm (18.8 mg/kg/day) for males and 1250 ppm (93.8 mg/kg/day)
for females based on anemia and body weight losses.

870.4300

Combined Chronic/

Carcinogenicity in rats	MRID 40886501,43871901, 43804501, 44302003
(1986)

Acceptable/Guideline

0, 25, 250, 2500 ppm (0, 1.0, 10, or 111 mg/kg/day for males and 0, 1.7,
17, or 203 mg/kg/day for females) for 24 months. 	NOAEL = Not
established.

LOAEL = 25 ppm (1.0 mg/kg/day for males and 1.7 mg/kg/day for females)
based on evidence of hemolysis and compensatory hematopoiesis (decreased
erythrocyte counts, increased reticulocyte counts, increased spleen
weight and bone marrow activation).

Dosing was considered adequate.

870.4300

Carcinogenicity in mice 	MRID 42159501 (1983)

Acceptable/Guideline

0, 25, 250, or 2500 ppm (0, 5.4, 50.8, or 640.13 mg/kg/day for males and
0, 7.5, 77.5, or 867.0 mg/kg/day for females) for 24 months	NOAEL = 250
ppm (50.8 and 77.5 mg/kg/day) for males and females.

LOAEL = 2500 ppm (640.1 and 867.0 mg/kg/day) for males and females based
on hemolytic anemia and liver toxicity in both sexes and urinary bladder
toxicity in females.

Dosing was considered adequate.

870.5100

Gene mutation

Salmonella typhimurium reverse gene mutation	MRID 00146608 (1985),
40228805 (1991)

Acceptable/Guideline

	Independent trials were negative in  S. typhimurium strains TA1535,
TA97, TA98 and TA100 up to the highest doses tested (10 μg/plate -S9;
250 μg/plate +S9); higher concentrations ((50 μg/plate -S9; 500
μg/plate +S9) were cytotoxic.

870.5300

Gene mutation 

Chinese hamster ovary (CHO)/ HGPRT cell forward gene mutation assay	MRID
00146609  (1985)

Acceptable/Guideline

	Independent tests were  negative up to cytotoxic doses without S9
activation (1.250 mM,( 291 μg/mL) and with S9 activation (0.5 mM ( 117
μg/mL).

870.5375

Chromosomal aberration in vivo rat bone marrow cytogenetic assay

	MRID00146611 (1985)

MRID 44350301 (1997) (revised)

Acceptable/Guideline

	The test was negative in Sprague Dawley rats up to cytotoxic doses.  A
significant (p<0.05) increase in the percentage of abnormal cells and
the average number of aberrations per cell was seen but only when the
data were combined for the high-and mid-dose males and females at the
48-hour sampling time. A significant positive linear trend was also
recorded for the combined (by sex) aberrations per cell and percentage
abnormal cells.  Nevertheless, the values fell well within the range of
historical control ranges.

870.5375

Mouse Bone Marrow Micronucleus 	MRID 45494502 (1995) 80% ai, 45494503
(1995) 42.4% ai, 45494504 (1996) 80% ai, 45494505 (1998) 98.1% ai

Acceptable/Guideline	Preliminary review indicates no evidence of
cytogenetic effect in mice administered either technical grade or
formulated diuron.

870.5550

Unscheduled DNA Synthesis	MRID 00146610 (1985)

Acceptable/Guideline

	The test was negative up to cytotoxic doses ((0.33 mM, equivalent to
(76 µg/mL).

870.7485

Metabolism and pharmacokinetics	MRID 42010501 (1996)

Acceptable/Guideline

	Diuron was rapidly absorbed, metabolized and excreted. Urine was the
major route of excretion. Metabolism of diuron involved N-oxidation,
ring hydroxylation, demethylation, dechlorination, and conjugation to
sulfate and glucuronic acid.  

870.7600

Dermal penetration	Not available for diuron.

	Not available.

Diuron Doses and Endpoints for Risk Assessment

Note that these endpoints were cited in the 2003 HED RED Chapter, but
have been put into the updated format HED currently uses in its risk
assessments.  Furthermore, for chronic dietary exposure/risk, an
additional 10X factor has been retained for the lack of a NOAEL, whereas
a 3X factor was retained in the 2003 RED.

Summary of Toxicological Doses and Endpoints for Diuron for Use in
Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

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

Acute Dietary	N/A	N/A	N/A	No appropriate endpoint attributed to a single
dose was identified.  Therefore, an acute RfD was not established.

Chronic Dietary (All Populations)	LOAEL= 1 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 10x [UFL]	Chronic RfD = 0.001

mg/kg/day

cPAD = 0.001 mg/kg/day	Chronic toxicity/carcinogenicity study in rats

LOAEL = 1 mg/kg/day based on evidence of hemolytic anemia and
compensatory hematopoiesis

Incidental Oral Short-Term (1-30 days)	NOAEL= 10 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x	Residential LOC for MOE = 100	Developmental toxicity study
in rabbits

LOAEL = 50 mg/kg/day based on decreased body weight and food
consumption.

Incidental Oral Intermediate-Term (1-6 months)	NOAEL =1 mg/kg/day	UFA=
10x

UFH=10x

FQPA SF= 1X	Residential LOC for MOE = 100	Chronic
toxicity/carcinogenicity study in rats

LOAEL=10 mg/kg/day based on altered hematological parameters observed at
6 months.

Dermal Short-Term and Intermediate-Term	N/A	N/A	N/A	No systemic toxicity
was seen following repeated dermal dosing at 1200 mg/kg/day in the
rabbit dermal toxicity study.  A dermal risk assessment is not
applicable

Inhalation Short- Term (1-30 days)	NOAEL= 10 mg/kg/day

100 % IA	UFA= 10x

UFH=10x

FQPA SF= 1x	Residential LOC for MOE = 100	Developmental toxicity study
in rabbits

LOAEL = 50 mg/kg/day based on decreased body weight and food
consumption.

Inhalation Intermediate-Term (1-6 months)	NOAEL= 1 mg/kg/day

100 %IA	UFA= 10x

UFH=10x

FQPA SF= 1x	Residential LOC for MOE = 100	Chronic
toxicity/carcinogenicity study in rats

LOAEL=10 mg/kg/day based on altered hematological parameters observed at
6 months.

Cancer (oral, dermal, inhalation)	A cancer slope factor of 1.91 x 10-2
has been established based on urinary bladder carcinomas in both sexes
of the Wistar rat, kidney carcinomas in the male rat (a rare tumor), and
mammary gland carcinomas in the female NMRI mouse.

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).  UFL = use of a LOAEL to extrapolate a NOAEL.  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  N/A = not applicable.  IA = Inhalation absorption, relative
to oral absorption.



Summary of Toxicological Doses and Endpoints for Diuron for Use in
Occupational Human Health Risk Assessments

Exposure/

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

Dermal (Short- and Intermediate-Term)	N/A	N/A	N/A	No systemic toxicity
was seen following repeated dermal dosing at 1200 mg/kg/day in the
rabbit dermal toxicity study.  A dermal risk assessment is not
applicable

Inhalation Short-Term 

(1-30 days)	NOAEL= 10 mg/kg/day

100 % IA	UFA= 10x

UFH=10x	Occupational LOC for MOE = 100	Developmental toxicity study in
rabbits

LOAEL = 50 mg/kg/day based on decreased body weight and food
consumption.

Inhalation Intermediate-term (1-6 months)	NOAEL= 1 mg/kg/day

100 %IA	UFA= 10x

UFH=10x	Occupational LOC for MOE = 100	Chronic toxicity/carcinogenicity
study in rats

LOAEL = 10mg/kg/day based on altered hematological parameters observed
at 6 months.

Inhalation long-term	N/A	N/A	N/A	No long-term exposure scenarios were
identified based on the use pattern.

Cancer (oral, dermal, inhalation)	A cancer slope factor of 1.91 x 10-2
has been established based on urinary bladder carcinomas in both sexes
of the Wistar rat, kidney carcinomas in the male rat (a rare tumor), and
mammary gland carcinomas in the female NMRI mouse.

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).  MOE = margin of exposure.  LOC = level of concern.  N/A
= not applicable.  IA = Inhalation absorption, relative to oral
absorption.

Diuron Physical/Chemical Properties (Excerpted from the 2003 HED RED
Chapter)

Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea]

Empirical formula:	C9H10Cl 2N2O	

Molecular weight:	233.1

CAS Registry No.:	330-54-1

PC Code:	035505

	Generic Series 830 Physical and Chemical Properties

GLN

	MRID	Data

6302	Color		1	White

6303	Physical state		1	Crystal

6304	Odor		1	None

7200	MP		1	158o C

7840	Water solubility		1	42 ppm @ 25o C

7950	vp		1	2 x 10-7 mm Hg @ 30o C

7550	Log Pow		2	2.68

6320	Corrosion characteristics	43842201	Not corrosive

6313	Stability to normal and elevated temperatures, metals, and metal
ions	43842201	Stable for 2 yrs. in double polyethylene bag inside a
fiber drum under warehouse conditions.  Metals and metal ion data not
given.

7050	UV/Visible absorption	NG

	

NG: Not Given.

1 Diuron.  CASRN: 330-54-1. 
http://toxnet.nlm.nih.gov/egi-bin/sis/search.

2 Reddy, K.N. and M.A. Locke.  1996.  Molecular Properties as
Descriptors of Octanol-Water Partition Coefficients of Herbicides. 
Water, Air and Soil Pollution Vol. 86: pp 389-405.

Updated Language for Cumulative Risk Assessment in Accordance with FQPA

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to diuron and any other
substances.  Although diuron, propanil and linuron all contain 3,4
dichloroaniline (3,4-DCA) in their structures, HED has previously
concluded that the 3 active ingredients do not share a common mechanism
of toxicity.

Propanil readily metabolizes to 3,4-DCA, but neither diuron nor linuron
metabolize to 3,4–DCA in plant or animal metabolism studies.  HED
previously recommended against aggregating residues of 3,4 DCA for the
propanil and diuron risk assessments [Personal communication. Christine
Olinger (MARC Chair) to Sherrie Kinard. September 19, 2001].  The
following considerations support the recommendation:

3,4-DCA is a significant residue of concern for propanil, but is not a
residue of concern per se for diuron;

The analytical method for quantifying residues of concern from
applications of diuron converts all residues to 3,4-DCA as a technical
convenience.  However, 3,4-DCA is not a significant residue in diuron
plant and animal metabolism or hydrolysis studies.  Therefore, the MARC
recommended that all residues hydrolyzable to 3,4-DCA would be included
in the tolerance expression for diuron, because no validated enforcement
method is available for quantification for the actual residues of
concern for diuron [Diuron.  Results of the Health Effects Division
(HED) Metabolism Assessment Review Committee (MARC) Meeting Held on
03-JULY-2001.  John Punzi.  August 10, 2001].

Propanil and its metabolite 3,4-DCA were found to induce
methemoglobinemia, the endpoint of concern for propanil.  Diuron has not
been shown to cause this effect.  Diuron induces hemolytic anemia and
compensatory hematopoiesis, which are mechanistically different from
methemoglobinemia.

Linuron and diuron metabolism studies show that both chemicals
metabolize to DCPU and DCPMU.  However, for reasons that are yet
unknown, these chemicals do not induce the same toxic effects in
mammals.  Submitted data indicate that diuron is primarily (though not
exclusively) metabolized by the hydroxylation of the urea group in
either the methyl or the amino position and conjugated.  Linuron, on the
other hand, appears to be primarily ring-hydroxylated and conjugated. 
The methoxy group is removed, followed by the methyl group, with ring
hydroxylation.  Unlike linuron, hydroxylation of the phenyl ring is not
a major metabolite pathway of diuron and, both methyl groups are lost.

Methemoglobinemia is the dominant toxic effect of concern for linuron. 
As mentioned above, diuron does not induce methemoglobinemia. 
Mechanistic and reproductive studies show that linuron, and to some
extent propanil, is an androgen receptor antagonist and that linuron
induces testicular abnormalities in rodents.  Studies with diuron showed
no indications of any endocrine effects and no developmental or
reproductive effects.

Although the mechanisms of action for the differing effects induced by
the two ureas, diuron and linuron, are not entirely known, there is
sufficient cause to believe that exposures from the two compounds should
not be cumulated.

The estimated dietary cancer risk for diuron did not include residues
from linuron and propanil since it was recognized that the target organs
for tumor induction for diuron are different from those for linuron and
propanil, and data were available which indicated that the mechanism of
action may be different for diuron.

For the purposes of this tolerance action, therefore, EPA has not
assumed that diuron has a common mechanism of toxicity with other
substances. For information regarding EPA’s efforts to determine which
chemicals have a common mechanism of toxicity and to evaluate the
cumulative effects of such chemicals, see the policy statements released
by EPA’s Office of Pesticide Programs concerning common mechanism
determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA’s website at   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

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).

In the available toxicity studies on diuron, there was no estrogen,
androgen, and/or thyroid mediated toxicity.  When additional appropriate
screening and/or testing protocols being considered under the Agency’s
EDSP have been developed, diuron may be subjected to further screening
and/or testing to better characterize effects related to endocrine
disruption.

References – Agency Documents Supporting the RED and the Proposed
Tolerances

HED notes that this list is not comprehensive, but provides the
documents that are most relevant to the currently proposed tolerances.

Reregistration Eligibility Decision, 9/20/2003:

  HYPERLINK "http://www.epa.gov/oppsrrd1/REDs/diuron_red.pdf" 
http://www.epa.gov/oppsrrd1/REDs/diuron_red.pdf 

[Note that the RED provides a list of additional supporting technical
documents].

Diuron – Disciplinary Toxicology Chapter for the Reregistration
Eligibility Decision, Y. Yang, D274490, 10/2/2001.

PP#6E3390 (RCB No. 771) – Diuron Prickly Pear Cactus – Evaluation of
Analytical Methodology and Residue Data (Accession No. 262183), M.
Firestone, 4/24/86.

Revised Residue Chemistry Chapter for the Diuron Reregistration
Eligibility Decision (RED) Document, S. Kinard, D291550, 7/9/03.

Occupational and Residential Exposure Assessment and Recommendations for
the Reregistration Eligibility Decision Document for Diuron, R. Sandvig,
C. Jarvis, D274491, 12/12/01.

Diuron. List A Reregistration Case 0046. PC Code 035505. Product
Chemistry Chapter for the Reregistration Eligibility Decision [RED]
Document, K. Dockter, D274489, 6/26/01.

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Anticipated Residues for Chronic (Including Carcinogenic) Dietary Risk
Assessment for Diuron.  Chemical# 035505, R. Loranger, D250038, 10/8/98.

Diuron.  Anticipated residue assessment. Chemical ID No. 035505. CBRS
No. 8660, C. Swartz, D169227, 2/13/92.

Diuron.  Chronic and Cancer Dietary Exposure Assessments to Support
Permanent Tolerances for Residues in Farm-Raised Fish, Prickly Pear
Cactus, and in Spearmint and Peppermint Tops. DP Barcode No. D335227, C.
Swartz, 5/14/07.

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