Document ID: EPA-HQ-OPP-2007-0460-0007
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-02-03T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: September 14, 2009

MEMORANDUM

SUBJECT:	Dithianon.  Human Health Risk Assessment for Proposed Tolerance
on Imported Grapes.  

PC Code:  099201	DP Barcode:  368428

Decision No.: 370013	Registration No.: NA

Petition No.: 6E7103	Regulatory Action: New Tolerance

Risk Assessment Type: Single Chemical Aggregate	Case No.: NA

TXR No.: NA	CAS No.:  3347-22-6

MRID No.: NA	40 CFR: 180.621

FROM:	Christine Olinger, Risk Assessor

		Risk Assessment Branch VII

		Health Effects Division (7509P)

THROUGH:	Jeff Dawson, Chemist

Michael S. Metzger, Chief 

		Risk Assessment Branch VII

		Health Effects Division (7509P)

TO:		Tony Kish/Rose Kearns

		Fungicide Branch

		Registration Division (7505P)

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc240689071"  1.0	Executive
Summary	  PAGEREF _Toc240689071 \h  3  

  HYPERLINK \l "_Toc240689072"  2.0	Ingredient Profile	  PAGEREF
_Toc240689072 \h  6  

  HYPERLINK \l "_Toc240689073"  2.1	Summary of Registered/Proposed Uses	
 PAGEREF _Toc240689073 \h  6  

  HYPERLINK \l "_Toc240689074"  2.2	Structure and Nomenclature	  PAGEREF
_Toc240689074 \h  8  

  HYPERLINK \l "_Toc240689075"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc240689075 \h  8  

  HYPERLINK \l "_Toc240689076"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc240689076 \h  9  

  HYPERLINK \l "_Toc240689077"  3.1	Hazard Characterization	  PAGEREF
_Toc240689077 \h  9  

  HYPERLINK \l "_Toc240689078"  3.1.1	Sufficiency of studies/data	 
PAGEREF _Toc240689078 \h  9  

  HYPERLINK \l "_Toc240689079"  3.1.2	Metabolism and Toxicokinetic data	
 PAGEREF _Toc240689079 \h  9  

  HYPERLINK \l "_Toc240689080"  3.2	FQPA Considerations	  PAGEREF
_Toc240689080 \h  11  

  HYPERLINK \l "_Toc240689081"  3.3	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc240689081 \h  11  

  HYPERLINK \l "_Toc240689082"  3.3.1	Acute Dietary Exposure - Females
age 13-49	  PAGEREF _Toc240689082 \h  11  

  HYPERLINK \l "_Toc240689083"  3.3.2	Acute Dietary Exposure - General
Population	  PAGEREF _Toc240689083 \h  12  

  HYPERLINK \l "_Toc240689084"  3.3.3	Chronic Dietary Exposure	  PAGEREF
_Toc240689084 \h  12  

  HYPERLINK \l "_Toc240689085"  3.3.5	Summary of Toxicological Doses and
Endpoints	  PAGEREF _Toc240689085 \h  13  

  HYPERLINK \l "_Toc240689086"  3.4	Endocrine disruption	  PAGEREF
_Toc240689086 \h  13  

  HYPERLINK \l "_Toc240689087"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc240689087 \h  14  

  HYPERLINK \l "_Toc240689088"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc240689088 \h  14  

  HYPERLINK \l "_Toc240689089"  5.1	Residues of Concern	  PAGEREF
_Toc240689089 \h  14  

  HYPERLINK \l "_Toc240689090"  5.2	Residue Profile	  PAGEREF
_Toc240689090 \h  14  

  HYPERLINK \l "_Toc240689091"  5.3	Dietary Exposure and Risk	  PAGEREF
_Toc240689091 \h  15  

  HYPERLINK \l "_Toc240689092"  5.3.1	Description of Residue Data Used
in Dietary Assessment	  PAGEREF _Toc240689092 \h  15  

  HYPERLINK \l "_Toc240689093"  5.3.2	Percent Crop Treated Used in
Dietary Assessment	  PAGEREF _Toc240689093 \h  15  

  HYPERLINK \l "_Toc240689094"  5.3.5	Cancer Dietary Risk Assessment	 
PAGEREF _Toc240689094 \h  16  

  HYPERLINK \l "_Toc240689095"  5.3.6	Summary Table of Dietary
Exposure/Risk Assessment	  PAGEREF _Toc240689095 \h  16  

  HYPERLINK \l "_Toc240689096"  5.4	Tolerance Assessment	  PAGEREF
_Toc240689096 \h  16  

  HYPERLINK \l "_Toc240689097"  5.4.1	Enforcement Analytical Method	 
PAGEREF _Toc240689097 \h  16  

  HYPERLINK \l "_Toc240689098"  5.4.2	Tolerance Recommendation	  PAGEREF
_Toc240689098 \h  17  

  HYPERLINK \l "_Toc240689099"  5.4.3	International Harmonization	 
PAGEREF _Toc240689099 \h  17  

  HYPERLINK \l "_Toc240689100"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc240689100 \h  17  

  HYPERLINK \l "_Toc240689101"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc240689101 \h  17  

  HYPERLINK \l "_Toc240689102"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc240689102 \h  17  

  HYPERLINK \l "_Toc240689103"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc240689103 \h  18  

  HYPERLINK \l "_Toc240689104"  10.0	Data Gaps	  PAGEREF _Toc240689104
\h  18  

  HYPERLINK \l "_Toc240689105"  11.0	References	  PAGEREF _Toc240689105
\h  18  

  HYPERLINK \l "_Toc240689106"  Appendix A:  Toxicology Assessment	 
PAGEREF _Toc240689106 \h  19  

  HYPERLINK \l "_Toc240689107"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc240689107 \h  19  

  HYPERLINK \l "_Toc240689108"  A.2	Toxicity Profiles	  PAGEREF
_Toc240689108 \h  20  

 1.0	Executive Summary

BASF Corp. has proposed, in PP#6E4781, the establishment of tolerances
for residues of the fungicide dithianon
[5,10-dihydro-5,10-dioxonaphtho(2,3-b)-1,4-dithiin-2,3-dicarbonitrile]
in/on grapes at a level of 3 ppm.  There are no proposed or existing
uses of dithianon in the US, so the proposed tolerances would apply only
to imported grapes.  Tolerances for imported pome fruit and hops were
established in September 2006 (71 FR 54917, September 20, 2006).

BASF previously submitted a petition (PP#6E7103) requesting an 8.0 ppm
tolerance on grapes imported into the U.S. from countries having
registered uses for dithianon on grapes.  In its review of this petition
(DP# 333117, D. Davis, 4/15/2008), the Agency concluded that the residue
chemistry database was insufficient to support establishing a tolerance
for dithianon on imported grapes.  In response to the Agency’s review,
BASF has submitted a revised petition addressing the deficiencies cited
by the Agency, along with submissions containing the relevant data.

Dithianon is a broad spectrum multi-site protectant fungicide used
outside the U.S. for control of apple and pear scab, black rot, rust,
and leaf spot diseases in pome fruit, Peronospora in hops, and downy
mildew and anthracnose in grapes.  There are no U.S. registrations or
proposed registrations of dithianon in the U.S. at this time.

The registrant provided translated labels for the foliar use of
dithianon on grapes in Australia, Spain, France, Germany, Italy,
Argentina, and Brazil. A Codex Maximum Residue Limit (MRL) has been
established for grapes at 3 mg/kg.  The proposed tolerance (without U.S.
registration) on imported grapes is harmonized with the established
Codex MRLs with respect to the residue definition and the proposed
level. There are currently no established Canadian or Mexican MRLs for
dithianon.

The most recent risk assessment was conducted in support of the
tolerances on pome fruit and hops (D. McNeilly, 7/11/06, DP No. 235354).

Hazard Identification and Dose Response Assessment

The toxicology database is sufficient to characterize the hazards
associated with dithianon, with the exception of the developmental
toxicity study in rabbits, which was classified unacceptable.  To
account for this database gap, a 10X Food Quality Protection Act (FQPA)
database uncertainty factor (UFDB) was retained.  Due to the recent
modification to the 40 CFR Part 158 Test Guidelines, there are
additional datagaps:  acute and subchronic neurotoxicity studies and an
immunotoxicity study.

The acute toxicity is mild via the oral route (Category III).  The
toxicologically significant adverse effects of dithianon are similar
across species.  In studies with shorter durations of exposure,
including the subchronic dog and rat studies, the developmental toxicity
study in rats, and the two-generation reproduction rat study, decreases
in body weight, body weight gain, and/or food consumption were noted in
adults.  However, with continued exposure, as in the chronic and/or
carcinogenicity studies in the rat, mouse, and dog, the kidney is the
target organ for toxicity.  Signs of renal toxicity include increased
absolute and/or relative kidney weights in the rat, mouse, and dog;
non-neoplastic kidney lesions in mice and rats; and renal adenomas and
carcinomas in female rats.  Post-implantation loss due to early
resorptions was observed in the developmental rat study

The available toxicology database does not show any indication of
increased qualitative or quantitative susceptibility of the offspring. 
Dithianon did not cause reproductive or developmental toxicity in the
two-generation reproduction study.  In the developmental rat study,
decreased fetal weights were observed only at a dose higher than that
which produced similar maternal effects.  The developmental toxicity
study in rabbits was classified unacceptable/guideline.  However,
residual uncertainty due to this data gap is addressed through retention
of the 10X FQPA Safety Factor as a database uncertainty factor (UFDB).

Dithianon is not mutagenic.  The Cancer Assessment Review Committee
(CARC) classified dithianon as “Suggestive Evidence of Carcinogenic
Potential”, based on the overall weight of the evidence.  Quantitation
of carcinogenic risk is not required.

Dietary endpoints only are required to support this tolerance
assessment.  The acute dietary endpoint for women ages 13-49 is based on
post-implantation loss due to early resorptions seen in the
developmental rat study.  No endpoint attributed to a single dose was
identified for the general population, so a quantitative risk assessment
is not required.  The chronic dietary endpoint is based on kidney
effects and decreased body weight.  A combined uncertainty factor (UF)
of 1000, including 10X factors for interspecies variability,
intraspecies variability and database uncertainty, was used for all
endpoints.  The acute population adjusted dose (aPAD) for women ages
13-49 is 0.02 mg/kg/day.  The chronic population adjusted dose (cPAD) is
0.006 mg/kg/day.

Dietary Exposure/Risk Assessment

The residue of concern (ROC) in plants and animals is dithianon per se. 
There is no reasonable expectation of finite residues in animal
commodities.

Acute and chronic dietary assessments were conducted using Dietary
Exposure Evaluation Model – Food Commodity Intake Database
(DEEM-FCIDTM, version 2.03).  Both the acute and chronic dietary
assessments are based on empirical processing factors for raisins and
grape, apple and pear juices and 100 percent crop treated.  The acute
assessment is based on tolerance level residues while the chronic
analysis is based on anticipated (average) residues from field trial
data.  With no proposed U.S. registration, there is no expectation that
dithianon residues would occur in surface or ground water sources of
drinking water.  The acute exposure for Females ages 13-49 is at 79% of
the acute Population Adjusted Dose (aPAD) at the 95th percentile of
exposure, which is below the level of concern.  The chronic exposures
for all populations assessed are below the level of concern.  The
chronic exposure for the general U.S. population is at 18% of the cPAD. 
The most highly exposed sub-group is children (ages 1-2), whose exposure
is at 63% of the cPAD.  The exposure estimates represent a highly
conservative estimate of risk because of the assumption that everything
consumed in the U.S. has been treated with dithianon, and the assumption
of tolerance-level residues in the acute assessment.  Actual exposure is
likely to be much lower.

Dithianon is not registered for use in the U.S., so quantitative risk
assessments for residential, and occupational exposures were not
conducted.  

Regulatory Recommendations

The following toxicity data are outstanding:  1) developmental toxicity
study in rabbits; 2) acute neurotoxicity study; 3) subchronic
neurotoxicity study; 4) immunotoxicity study.  Despite these datagaps,
HED has sufficient information to characterize dithianon toxicity and
select endpoints for risk assessment.  Sufficient residue data are
available to support the dietary exposure assessment and tolerance
assessment.  Acute and chronic dietary exposures are below the level of
concern.  Therefore, HED has no objection to establishing a tolerance
for residues of grapes at 3 ppm.  This tolerance is harmonized with
Codex and the European Union with respect to definition and level.

The Health Effects Division (HED) has recently updated its guidance on
the language used in tolerance expressions.  The tolerance expression
should be modified to the following

Tolerances are established for residues of dithianon, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only dithianon
(5,10-dihydro-5,10-dioxonaphtho(2,3-b)-1,4-dithiin-2,3-dicarbonitrile).

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,"
http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.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.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

This risk assessment does not rely on any data from studies in which
human subjects were intentionally exposed to a pesticide or other
chemical.

2.0	Ingredient Profile

Dithianon is a broad spectrum multi-site protectant fungicide (with
spore inhibitory properties) that is used outside the U.S. for the
control of scab, downy mildew, rust, and leaf spot diseases in pome
fruit, stone fruit, small fruit, wine grapes, ornamentals, citrus,
coffee, and vegetables.  It is used in Germany for the control of downy
mildew in hops.  

2.1	Summary of Registered/Proposed Uses

BASF reported that the following countries currently have registrations
for use of dithianon on grapes:  

Argentina	Australia	Austria	Belrus	Brazil

Bulgaria	Croatia	France	Georgia	Germany

Hungary	Italy	Japan	Kyrgystan	Luxembourg

Moldova	New Zealand	Romania	Serbia	Slovenia

Slovakia	Switzerland	Thailand	Turkey	Ukraine	Uruguay

Of these countries, only Argentina, Australia, Italy, France and Germany
are significant exporters of grape commodities to the U.S.  Dithianon is
not registered in the following countries that are major exporters of
grape products to the U.S.:  Chile, Mexico, Spain, and South Africa. 
These countries account for 43% of all imported grape products.

The petitioner submitted copies of labels for dithianon products from
the seven countries that are major exporters of grape products to the
U.S., along with English translation.  In the current petition, the
dithianon label from Spain was omitted as there is not a registered use
for dithianon in Spain, and the label directions for Australia and New
Zealand were included as they are both major exporters of wine to the
U.S.  A summary of the use directions on grapes from the submitted
labels is presented in Table 2.1.  

Table 2.1	Summary of Directions for Use of Dithianon on Grapes.

Trade Name; Formulation	Application Type/Timing	Application Rate	Max.
No. Applic. Per Season	RTI 1

(days)	Max. Seasonal Applic. Rate

(g ai/ha)	PHI

(days)	Use Directions Limitations

g ai/hL	g ai/ha 2

	Argentina

DELAN 75; 750 g/L SC	Broadcast foliar applications beginning when vine
shoots are 10 cm in length and if climatic conditions favor disease
development	49	Not specified (NS)	NS	NS	NS	21

	Australia

Delan 700 WG; 70% WDG	Broadcast foliar applications beginning at bud
bust through early fruit development	35-52.5	early – 175

late - 525	NS	10-21	NS	21	Apply in a minimum of 500 L/ha early in season
and in 1000 L/ha thereafter.

Brazil

DELAN; 75% WP	Broadcast foliar applications beginning at start of leaf
growth and when condition favor disease development	93.75	937.5	NS	NS	NS
28	Apply in a volume of at least 1,000 L/ha.

France

DELAN WG; 70% WDG	Broadcast foliar applications at leaf emergence and
when first leaves open    	49	490	2 3	NS	980 3	14

	Germany

DELAN WG; 70% WDG	Broadcast foliar applications in early spring after
unfolding of the 2nd to 3rd leaf through early berry development (BBCH
75).  	35-52.5	early - 210  late – 560	8	NS	NS	49	Apply in a minimum
of 400 l/ha, or at 800-1600 l/ha from BBCH 61-75.  In areas with steep
slopes, apply at 2000 l/ha.  

Italy

DELAN 70 WG; 70% WDG	Broadcast foliar applications depending on weather
conditions and disease virulence; 

	70-84	NS	NS	7-10	NS	40	Apply using only ground equipment

New Zealand

DELAN WG; 70% WDG	Broadcast foliar applications beginning at bud swell
and during conditions favorable to disease development	38.5	early –
252

late - 501	NS 	10-14	NS	21

	1	RTI = Retreatment interval.

2	Several labels from several countries (Australia, Germany and New
Zealand) noted that higher rates are used for applications later in the
season.

3	Although the label directions for France do not explicitly state that
two applications are allowed per season, the allowed application timings
imply that two applications can be may per season.

Although the use directions from each of the above countries specify
application rates of dithianon in terms of g ai/hL, the maximum use
rates in terms of g ai/ha can only be determined on five of the labels
based on the recommended application volumes.  None of the labels
explicitly state the maximum seasonal use rate (g ai/ha/season) and only
the label from Germany specifies a maximum number of applications per
season.  BASF noted that not all countries require this information to
be specified on the label.  However, sufficient residue data reflecting
a variety of application scenarios have been submitted.

2.2	Structure and Nomenclature

Common name	Dithianon

Empirical formula	C14H4N2O2S2

Company experimental names	BAS 216 F; CL37114

IUPAC name
5,10-dihydro-5,10-dioxonaphtho(2,3-b)-1,4-dithi-in-2,3-dicarbonitrile

CAS name
5,10-dihydro-5,10-dioxonaphtho(2,3-b)-1,4-dithiin-2,3-dicarbonitrile

CAS registry number	3347-22-6

Chemical class	Quinone fungicide

Known impurities of concern	None

End-use products (EPs)	There are no products currently registered in the
U.S.; the products identified in the petition were DELAN 75 (750 g/L FlC
formulation), DELAN 70 WG (70% WDG formulation), DELAN WG (70% WDG
formulation), and DELAN (75% WP formulation).  

2.3	Physical and Chemical Properties

Table 2.3.  Physicochemical Properties of Dithianon.  

Parameter	Value	Reference1

Melting point/range ((C)	216	MRID #44092604

pH (20 (C)	4.4 to 4.8 (1% wt/wt aqueous dispersion)	MRID #44092604

Density (g/cm3 at 20 (C)	1.58	MRID #44092604

Water solubility (20 (C)	Nearly insoluble (roughly 0.02 mg/100 mL)	MRID
#44092604

Solvent solubility (at 20 (C)	Acetone	1.76 g/100 mL

Dichloromethane	2.01 g/100 mL

Ethyl acetate	0.77 g/100 mL

n-Hexane	0.96 mg/100 mL

Methanol	0.08 g/100 mL

Toluene	1.59 g/100 mL	MRID #44092604

Vapor pressure (Pa at 25 (C)	2.71 x 10-9	MRID #44092604

Dissociation constant (pKa)	Not available (insufficient solubility in
water).	MRID #44092604

Octanol/water partition coefficient (log [KOW])	3.2 ± 0.3	MRID
#44092604

UV/visible absorption spectrum	Not provided

	1  See DP# 312241, 7/11/06, W. Drew.

3.0	Hazard Characterization/Assessment

3.1	Hazard Characterization

3.1.1	Sufficiency of studies/data 

Only oral toxicity studies are required to support the proposed and
existing tolerances on imported commodities, as there are no
registrations for the use of dithianon in the U.S., and none are
proposed.  No new toxicity studies have been submitted since the most
recent risk assessment for dithianon (D. McNeilly, 7/11/06, DP No.
235354).  The following studies are available to assess toxicity:

Acute Oral Toxicity

Subchronic studies in the rat and dog

Chronic study in the dog

Chronic/Carcinogenicity studies in the rat and mouse

Developmental study in the rat

Reproduction study in the rat

A developmental toxicity in the rabbits was submitted but is
unacceptable due to excessive maternal toxicity that resulted in an
insufficient number of litters to meet guideline requirements. 
Therefore, the Agency will retain the 10X FQPA Safety Factor as a
database uncertainty factor (UFDB) to account for this deficiency.  The
Agency has recently modified the test guidelines required to support
tolerances (40 CFR Part 158), so additional studies are required to
support tolerances, including an acute neurotoxicity study, a subchronic
neurotoxicity study, and an immunotoxicity study.  Despite these
datagaps, the Agency has sufficient information at this time to select
endpoints for the proposed import tolerances.  

3.1.2	Metabolism and Toxicokinetic data 

Rat metabolism studies were conducted reflecting a single dose as well
as multiple doses of dithianon.  Absorption of dithianon was rapid and
not affected by dose level.  Based on the amount of radioactivity
recovered in the urine and bile, 31-43% of the administered dose was
absorbed following a single dose.  In tissues other than the
gastrointestinal tract, the highest level of dithianon and/or its
metabolites was found in the kidneys.  Dithianon and/or its metabolites
were also detected in the liver, plasma, and whole blood, but it was not
detected in the brain or spinal cord.  There were no sex-related
differences in distribution.

Dithianon was rapidly metabolized to many, mostly polar, compounds. 
When metabolic fractions were isolated, 15 were found in urine samples,
>25 fractions were found in the feces, and many were found in the
kidneys and liver.  Following a single oral dose, only one metabolic
fraction was comprised of >5% of the administered dose; that fraction
was from a urine sample checked 8-24 hours after exposure and was
identified as a glucuronic acid conjugate.  No sex-related differences
in metabolism were noted.

There was no bioaccumulation of dithianon.  Recovery following repeated
dosing was complete at 120 hours.  In both studies, 67-72% of the
administered dose was found in the feces, 27-31% in the urine, 0.3-0.4%
in the cage wash, and <0.2% in the carcass.  A preliminary excretion
study found that radioactivity was not detected in exhaled air. 
Excretion through the biliary route was not examined following the
repeat dosing regimen; however, it was found to be a minor pathway
following a single exposure, since only 7.2-11.6% of a single dose of 10
or 50 mg/kg dithianon was recovered in the bile 48 hours after exposure.
 The terminal half-life of dithianon was 46-57 hours.  No sex- or
dose-related differences on excretion were observed.

3.1.3	Toxicological Effects

The toxicologically significant adverse effects of dithianon are similar
across species and generally seen at similar dose levels.  In studies
with shorter durations of exposure, including the subchronic dog and rat
studies, the developmental toxicity study in rats, and the
two-generation reproduction rat study, decreases in body weights, body
weight gains, and/or food consumption were noted in adults.  However,
with continued exposure, as in the chronic and/or carcinogenicity
studies in the rat, mouse, and dog, it becomes evident that the kidney
is the target organ for toxicity.  Signs of renal toxicity that were
observed include increased absolute and/or relative kidney weights in
the rat, mouse, and dog; non-neoplastic kidney lesions in mice and rats;
and renal adenomas and carcinomas in female rats.  In the developmental
toxicity study in rats, increased post-implantation loss due to early
resorptions was seen in conjunction with maternal toxicity.

In the species tested, males and females were equally susceptible to the
effects of dithianon on body weight, body weight gain, food consumption,
kidney weights, and the development of non-neoplastic renal lesions. 
One major difference between the sexes was seen in the carcinogenicity
study in the rat, where females developed renal adenomas and carcinomas,
but neoplasms were not found in the males.  This sex-related difference
is particularly notable because when kidney tumors develop following
exposure to a given chemical, which is rare, they are generally observed
in males.

The available toxicology database does not show any indication of
increased qualitative or quantitative susceptibility of the offspring. 
Dithianon did not cause reproductive or developmental toxicity in the
two-generation reproduction study.  In the developmental toxicity study
in rats, increased post-implantation loss due to early resorptions
(significant only when total litter losses were included) was seen in
conjunction with maternal toxicity (≥ 50 mg/kg/day), which included
decreased body weights, body weight gains, and food consumption;
therefore, there is no increased quantitative susceptibility.  These
decreased maternal body weights were seen at ≥ 50 mg/kg/day, but body
weights of the surviving fetuses were significantly decreased only at
100 mg/kg/day.  There were no apparent treatment or dose-related
external, visceral, or skeletal variations or malformations in the
developmental rat study.  The developmental toxicity study in rabbits
was classified unacceptable/guideline due to excessive maternal toxicity
that resulted in an insufficient number of litters to meet guideline
requirements and excessive pre-implantation losses at all dose levels.

There is no evidence of neurotoxicity in the toxicology database for
dithianon.  

Dithianon is not mutagenic.  Dithianon produced positive results in an
acceptable chromosomal aberration assay that was conducted in vitro
using Chinese hamster lung fibroblasts (V79 cells); in contrast, a
forward gene mutation assay tested in this same cell line was negative. 
A second forward gene mutation assay with V79 cells was also negative,
but it was classified unacceptable due to inadequate cytotoxicity at the
highest concentration tested.  Negative responses were seen in bacteria
(two acceptable reverse gene mutation assays in Salmonella), Wistar rat
systems (an acceptable in vivo cytogenetic assay and an acceptable in
vitro UDS assay), and NMRI mice (an unacceptable in vivo micronucleus
assay).

In accordance with the EPA’s Final Guidelines for Carcinogen Risk
Assessment (March 2005), the Cancer Assessment Review Committee (CARC)
classified dithianon as “Suggestive Evidence of Carcinogenic
Potential”, based on several weight-of-evidence considerations. 
Quantification of carcinogenic risk is not required.  See Section 3.3.4
for details.  

3.2	FQPA Considerations

The FQPA SF will be retained as a database uncertainty factor for lack
of an acceptable rabbit developmental study.  This recommendation is
based on the following:

residual uncertainty concerning the lack of an acceptable developmental
toxicity study in rabbits;

there is no indication of increased quantitative or qualitative
susceptibility of rats to in utero and/or postnatal exposure to
dithianon; 

the dietary food exposure assessment utilizes average residues from crop
field trials and 100% crop treated information for all commodities; by
using these screening-level assessments, acute and chronic
exposures/risks will not be underestimated; and

3.3	Hazard Identification and Toxicity Endpoint Selection

Note:  Executive summaries for the toxicity studies used for endpoint
selection may be found in the previous risk assessment for dithianon. 
Endpoints for incidental oral, dermal, and inhalation exposures were not
selected since there are no existing or proposed uses of dithianon in
the U.S.

3.3.1	Acute Dietary Exposure - Females age 13-49

Study Selected:  Developmental toxicity study in rats

MRID Number:  44092611.  

Point of Departure:  20 mg/kg/day (NOAEL), based on post-implantation
loss due to early resorptions seen at 50 mg/kg/day (LOAEL).

Uncertainty Factor(s):  1000X (10X for interspecies variability, 10X for
intraspecies variability, 10X for database uncertainty)

Comments:  

Post-implantation loss resulting from early resorptions can be
attributed to a single oral dose and is an appropriate endpoint for the
population of concern.

3.3.2	Acute Dietary Exposure - General Population

No appropriate dose and endpoint could be identified to set a reference
dose for acute dietary exposure in the general population, including
infants and children.  Therefore, a quantitative risk assessment is not
required.  

3.3.3	Chronic Dietary Exposure 

Study Selected: Combined chronic toxicity/carcinogenicity study in rats.
 

MRID Number: 44092616.  

Point of Departure:  6 mg/kg/day (NOAEL), based on decreased body weight
gain and increased relative to body kidney weights (M&F), grossly
observed kidney lesions in males (irregular surfaces, pale kidneys,
cysts, and enlarged kidneys) and females (masses), and non-neoplastic
lesions of the kidneys in males (tubular nephrosis, renal cysts, and
end-stage kidney lesions) and females (tubular nephrosis, proliferative
tubules, and glomerulonephropathy) seen at 30 mg/kg/day (LOAEL).

Uncertainty Factor(s):  1000X (10X for interspecies variability, 10X for
intraspecies variability, 10X for database uncertainty)

Comments:  The chronic duration and dietary route of exposure in the
selected study, as well as the types of adverse effects observed, are
appropriate to set a chronic reference dose.

The chronic dog study (MRID 44092608) was considered a co-critical study
because the NOAEL, LOAEL, and target organ toxicity were similar to what
was seen in the combined chronic/carcinogenicity rat study.  In this
study, the LOAEL is 37.1/35 mg/kg/day [M/F]), based on increased
absolute and relative liver and kidney weights, increased alkaline
phosphatase, decreased blood urea nitrogen, hepatocellular hypertrophy,
histiocyte pigmentation, and renal pigmentation (M&F).  The NOAEL for
this study, 6.7/7.6 mg/kg/day [M/F], is well established and could have
detected changes in body weights in the 90-day dog study.  Therefore,
the lower NOAEL found in the 90-day dog study, 2.95/3.00 mg/kg/day
[M/F], is an artifact of dose selection.

3.3.4	Classification of Carcinogenic Potential

In accordance with the EPA’s Final Guidelines for Carcinogen Risk
Assessment (March 2005), the Cancer Assessment Review Committee (CARC)
classified dithianon as “Suggestive Evidence of Carcinogenic
Potential”, based on several weight-of-evidence considerations. 
First, treatment-related rare kidney tumors, primarily adenomas, were
seen only at the highest dose tested (600 ppm) in one sex (females) and
in one species (rats).  The highest dose tested was considered adequate,
but not excessive, to assess the carcinogenicity of dithianon; however,
significant renal toxicity occurred at this dose.  Second, although the
CARC concluded that there was not a sufficient or cohesive dataset at
the time to fully support a mode of action, the Registrant’s
hypothesized non-genotoxic mode of action involving nephrotoxicity and
sustained regenerative proliferation was considered to be biologically
plausible.  Finally, there is no mutagenicity concern for dithianon. 
The CARC determined that quantification of carcinogenic potential is not
required (J. Kidwell, 2/23/06).

3.3.5	Summary of Toxicological Doses and Endpoints 

Table 3.1. Summary of Toxicological Doses and Endpoints for Dithianon
for Use in Dietary Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD 
Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)	No
appropriate dose and endpoint could be identified for these population
groups.  Therefore a quantitative risk assessment is not required.

Acute Dietary

(Females 13-49 years of age)	NOAEL = 20 mg/kg/day	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 10x	Acute RfD = aPAD = 0.02 mg/kg/day	Developmental
toxicity study in rats

LOAEL = 50 mg/kg/day 

based on post-implantation loss due to early resorptions

Chronic Dietary (All Populations)	NOAEL = 6 mg/kg/day	UFA= 10x

UFH = 10x

FQPA SF (UFDB)= 10x	Chronic RfD = cPAD = 0.006

mg/kg/day	Combined chronic toxicity/carcinogenicity study in rats

LOAEL = 30 mg/kg/day 

based on decreased body weight gains and increased relative to body
kidney weights, grossly observed kidney lesions, and non-neoplastic
lesions of the kidney 

Cancer	Classification:  “Suggestive Evidence of Carcinogenic
Potential”.  A quantitative assessment is not required.

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).  UFDB = to account for the absence of key data (i.e.,
lack of a critical study).  FQPA SF = FQPA Safety Factor.  PAD =
population adjusted dose (a = acute, c = chronic).  RfD = reference
dose.  N/A = not applicable.

3.4	Endocrine disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

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

4.0	Public Health and Pesticide Epidemiology Data

There are no registered uses of dithianon in the U.S.  Therefore,
incident data are not available and it has not been evaluated in any
epidemiology studies of which the Agency is aware.

5.0	Dietary Exposure/Risk Characterization

5.1	Residues of Concern

The petitioner has submitted three plant metabolism studies for
dithianon on apples, oranges, and wheat.  Metabolism of dithianon is
similar on all crops.  Dithianon does not appear to be highly
metabolized in plants, with a significant amount of the unchanged parent
compound remaining on the plant surface, and little to no movement from
the application site.  A confined rotational crop study is not required
for import tolerances.  The ruminant metabolism study indicated
extensive metabolism of dithianon, which is consistent with the results
of the rat metabolism study.  A poultry study is not required to support
the existing or proposed tolerances, as there are no poultry feed items
associated with this petition.  A summary of the residues of concern for
dietary risk assessment and tolerance assessment may be found in Table
5.1.

Table 5.1.  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants	Primary Crop	Dithianon	Dithianon

Plants	Rotational Crop	Not Applicable, since the proposed tolerances are
for imported commodities only.

Livestock	Ruminants	Dithianon	Dithianon

	Poultry	There are no feed items for which tolerances are proposed or
established.

Drinking Water	Not Applicable, since the proposed tolerances are for
imported commodities only.

5.2	Residue Profile

Current and proposed tolerances for dithianon are intended to support
imported commodities only and there are no existing or proposed U.S.
registrations.  Therefore, there is no expectation that dithianon
residues would occur in surface or ground water sources of drinking
water

Plant metabolism studies indicate that most of the dithianon residues
are surface residues, with minimal translocation from the application
site in apples and oranges.  Some metabolism of residues was observed in
the wheat study at longer intervals between application and harvest. 
The petitioner submitted crop field trials conducted in France, Brazil,
Spain, and Italy, and are adequate for dietary exposure assessment. 
Residues of dithianon are quantifiable at the minimum pre-harvest
intervals (PHI) identified on the product labels, and decreased with
increasing intervals between application and harvest.  The maximum
residue observed at the label PHI was 2.6 ppm.  Residues of dithianon
decreased upon processing into raisins and juice, which is consistent
with the apple processing study discussed in the previous dithianon
petition. 

Exposure to dithianon in livestock commodities is not expected based on
the proposed uses of dithianon.  There are no feed items associated with
the subject commodity, grapes.  However, there is a potential for
residues of dithianon in livestock commodities from the existing uses. 
Although it is unlikely that apple wet pomace will be imported into the
U.S., or that imported fresh apples will be processed within the U.S.,
apple wet pomace from dithianon-treated apples may be fed to livestock
in the countries in which dithianon is used on apples, and the livestock
may be imported into the U.S..  The maximum residues of dithianon
observed in the goat metabolism study were 0.011 ppm in kidney from the
goat dosed at 30 ppm.  Based on these results, HED concludes that the
proposed uses of dithianon in this petition result in a 40CFR
§180.6[a][3] situation for ruminant commodities; specifically, there is
no reasonable expectation of finite residues in ruminant commodities. 
Therefore, no ruminant feeding study is needed to support the subject
petition.

5.3	Dietary Exposure and Risk

5.3.1	Description of Residue Data Used in Dietary Assessment

The existing tolerance levels for pome fruit and hops, as well as the
proposed tolerance for grapes were used in the acute dietary assessment.
 Average residues from crop field trial data were used in the chronic
dietary assessment for all commodities.  Empirical processing factors
were used for pome fruit juices (0.2), grape juice (0.1), and raisins
(0.7).  DEEM 7.81 default processing factors were used for the dried
pome fruits (8.0 for apples and 6.25 for pears).

5.3.2	Percent Crop Treated Used in Dietary Assessment

No percent crop treated data were used in this assessment.  

5.3.3	Acute Dietary Risk Assessment

A summary of the dietary assessment may be found in Table 5.3.6.  Only
exposure for Females ages 13-49 is reported, as no acute endpoint was
identified for the general population.  The exposure for females (age
13-49) is at 79% of the aPAD at the 95th percentile of exposure, which
is below the level of concern.  This assessment is highly conservative
as it assumes residues are at tolerance level and assumes 100% crop
treated.  

5.3.4	Chronic Dietary Risk Assessment

The results of the chronic dietary exposure analysis are reported in
Table 5.3.6.  The exposures for all populations assessed are below the
level of concern.  The exposure for the general U.S. population is at
18% of the cPAD.  The most highly exposed sub-group is children (ages
1-2), whose exposure is at 63% of the cPAD.  This assessment is slightly
refined with the use of average residue values and empirical processing
factors, but is still highly conservative with the assumption of 100%
crop treated.

5.3.5	Cancer Dietary Risk Assessment

A quantitative cancer assessment is not required as discussed in Section
3.3.4.  

5.3.6	Summary Table of Dietary Exposure/Risk Assessment

Table 5.3.6  Summary of Dietary (Food Only) Exposure and Risk for
Dithianon

Population Subgroup	Acute Dietary

(95th  Percentile)	Chronic Dietary	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD1	Dietary Exposure

(mg/kg/day)	% cPAD1	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	N/A 2	N/A	0.001082	18	N/A	N/A

All Infants (< 1 year old)

	0.003413	57

Children 1-2 years old

	0.003791	63

Children 3-5 years old

	0.002734	46

Children 6-12 years old

	0.001230	20

Youth 13-19 years old

	0.000420	7.0

Adults 20-49 years old

	0.000881	15

Adults 50+ years old

	0.000862	14

Females 13-49 years old	0.01583	79	0.000689	12

1The values for the highest exposed population for each type of risk
assessment are bolded.

2N/A = Not applicable

5.4	Tolerance Assessment

5.4.1	Enforcement Analytical Method

An adequate LC/MS/MS method (BASF 244882) is available for enforcing the
proposed tolerance on grapes.  For this method, residues are extracted
with acetonitrile:water:2N HCl (70/25/5, v/v/v) and centrifuged. 
Residues are then analyzed directly by LC/MS/MS using external standards
and two ion transitions for quantitation.  This method has been
adequately validated using fortified samples of grapes, apples, lettuce,
oranges, wheat grain, rapeseed, and dried hop cones.  The validated LOQ
is 0.01 ppm for each plant, with the exception of dried hop cones (LOQ =
1.0 ppm).  Adequate multi-residue method testing data are available for
dithianon, and these data have been forwarded to the FDA for evaluation.
 The data indicate that FDA multi-residue methods are not suitable for
determining residues of dithianon.

5.4.2	Tolerance Recommendation

Sufficient residue data are available to support the proposed tolerance.
 The level proposed by the petitioner, 3 ppm, is appropriate.  Processed
commodity tolerances are not needed since residues do not concentrate
upon processing.  

The Health Effects Division (HED) has recently updated its guidance on
the language used in tolerance expressions.  The tolerance expression
should be modified to the following

Tolerances are established for residues of dithianon, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only dithianon
(5,10-dihydro-5,10-dioxonaphtho(2,3-b)-1,4-dithiin-2,3-dicarbonitrile).

5.4.3	International Harmonization

There are currently no established Canadian or Mexican maximum residue
limits (MRLs) for dithianon on grapes.  The proposed tolerance will be
harmonized with Codex and the European Union.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization

There are no proposed or existing uses of dithianon in the U.S. 
Tolerances have been proposed or established only on imported
commodities.  Therefore, there is no expectation that exposure to
dithianon residues would occur in residential settings and no
residential risk assessment was performed.  

7.0	Aggregate Risk Assessments and Risk Characterization

Since dithianon is proposed for use only on imported grapes, and
tolerances have been established on imported pome fruit and hops, the
only anticipated exposure route for the U.S. population is via dietary
(food) exposure.  There are no proposed or existing U.S. registrations
so there is no expectation of exposure to dithianon in drinking water or
in residential settings.  Therefore, an aggregate risk assessment is not
required.

8.0	Cumulative Risk Characterization/Assessment

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 dithianon and any other
substances, and dithianon does not appear to produce a toxic metabolite
produced by other substances.  For the purposes of this tolerance
action, therefore, EPA has not assumed that dithianon 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
(OPP) 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/ .  

9.0	Occupational Exposure/Risk Pathway

There are no proposed or existing uses of dithianon in the U.S. 
Tolerances have been proposed or established only on imported
commodities.  Therefore, there is no expectation that exposure to
dithianon residues would occur via occupational use and no occupational
risk assessment was performed.  

10.0	Data Gaps 

There are no residue chemistry data deficiencies.  The following
toxicity studies are typically required to support tolerances and are
not available in the dithianon database:

870.3700b  Rabbit developmental Toxicity Study

870.6200a  Acute neurotoxicity study

870.6200b  Subchronic neurotoxicity study

870.7800  Immunotoxicity study.

11.0	References

The following Agency memoranda were cited in this risk assessment.

Author	DP Number	Date	Title

C. Olinger

In Review	Dithianon. Acute and Chronic Aggregate Dietary (Food Only)
Exposure and Risk Assessments for the Proposed Tolerance in/on Grapes

C. Olinger	361351	In Review	Dithianon.  Petition for a Tolerance on
Imported Grapes.  Petitioner’s Response to Deficiencies Noted in HED
Review dated April 15, 2008. Summary of Analytical Chemistry and Residue
Data.

D. Davis	333117	4/15/08	Summary of Analytical Chemistry and Residue Data
to Support a Petition for Establishment of Import Tolerance on Grapes.

D. McNeilly	235354	7/11/06	Dithianon.  Human Health Risk Assessment for
Proposed Food Uses of the Fungicide on Imported Pome Fruit and Hops.

Appendix A:  Toxicology Assessment

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use (tolerances on imported
commodities only) of dithianon are in Appendix Table 1.  Use of the new
guideline numbers does not imply that the new (1998) guideline protocols
were used.

TABLE A.1.  Toxicology Data Requirements.

Test	Technical

	Required	Satisfied

870.1100  Acute Oral Toxicity	

870.1200  Acute Dermal Toxicity	

870.1300  Acute Inhalation Toxicity	

870.2400  Primary Eye Irritation	

870.2500  Primary Dermal Irritation	

870.2600  Dermal Sensitization		yes

no

no

no

no

no	yes

N/A

N/A

N/A

N/A

N/A

870.3100  Oral Subchronic (rodent)	

870.3150  Oral Subchronic (nonrodent)	

870.3200  21-Day Dermal	

870.3250  90-Day Dermal	

870.3465  90-Day Inhalation		yes

yes

no

no

no	yes

yes

N/A

N/A

N/A

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800 Reproduction		yes

yes

yes	yes

no

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300  Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100  Mutagenicity—Gene Mutation - bacterial	

870.5300  Mutagenicity—Gene Mutation - mammalian	

870.5375  Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx  Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90 Day Neuro. Screening Battery (rat)	

870.6300  Develop. Neuro		no

no

yes

yes

no	N/A

N/A

no

no

N/A

870.7485  General Metabolism	

870.7600  Dermal Penetration	

870.7800  Immunotoxicity		yes

no

yes	yes

N/A

no



A.2	Toxicity Profiles

TABLE A.2	Acute Toxicity Profile for Dithianon.

Test Material* [% ai]	Guideline Number	Study Type	MRID Number	Results
Toxicity

 (♂+♀) = 702 mg/kg 

(95% C.I. = 597-893 mg/kg)	III

Technical Product	870.1200	Acute dermal - rat	Not applicable for
proposed use pattern (Import tolerance).

Technical Product	870.1300	Acute inhalation - rat	Not applicable for
proposed use pattern (Import tolerance).

Technical Product	870.2400	Acute eye irritation - rabbit	Not applicable
for proposed use pattern (Import tolerance).

Technical Product	870.2500	Acute dermal irritation - rabbit	Not
applicable for proposed use pattern (Import tolerance).

Technical Product	870.2600	Skin sensitization - guinea pig	Not
applicable for proposed use pattern (Import tolerance).

TABLE A.3	Subchronic, Chronic, and Other Toxicity Profile for Dithianon.

Guideline Number	Study Type/

Classification	MRID Number	Doses	Results

870.3100	90-Day oral toxicity rodents - rat

Acceptable/guideline	44092606	0, 30, 180, 1080 ppm 

M:  0, 2.53, 14.64, 86.66 mg/kg/day

F:  0, 2.97, 16.32, 99.53 mg/kg/day	NOAEL = 14.64/16.32 mg/kg/day (M/F)

LOAEL = 86.66/99.53 mg/kg/day (M/F) based on decreased body weights and
overall body weight gains in both sexes.

870.3150	90-Day oral toxicity in nonrodents - dog

Acceptable/guideline	44092607	0, 40, 200, 1000 ppm

M:  0, 0.63, 2.95, 12.58 mg/kg/day

F:  0, 0.66, 3.00, 12.61 mg/kg/day	NOAEL = 2.95/3.00 mg/kg/day (M/F)

LOAEL = 12.58/12.61 mg/kg/day (M/F) based on decreased body weights (F
only), decreased body weight gains and food consumption (M&F), and
increased alkaline phosphatase activity (M&F).

870.3700	Developmental toxicity in rodents - rat

Acceptable/guideline	44092611

44092612	0, 20, 50, 70, 100 mg/kg/day

Dosing period: GD 6-15	Maternal 

NOAEL = 20 mg/kg/day

LOAEL = 50 mg/kg/day  

based on decreased body weights, body weight gains, and food
consumption.

At 100 mg/kg/day, 5/25 dams died between GD 13 and 17. 

Developmental 

NOAEL = 20 mg/kg/day

LOAEL = 50 mg/kg/day

based on increased incidence of total litter loss (20-42% at ≥ 50
mg/kg/day) and post-implantation loss due to early resorptions (showed
decidual or placental tissues only). 

At 100 mg/kg/day, weights of the surviving fetuses were decreased.

870.3700	Developmental toxicity in nonrodents - rabbit

Unacceptable/guideline	44092613

44092614

	0, 10, 25, 40 mg/kg/day

Dosing period: GD 6-18, beginning prior to implantation.	The Maternal
NOAEL and LOAEL could not be determined due to improper gavage
techniques, which resulted in abortions and deaths.

The developmental NOAEL and LOAEL could not be determined due to
excessive pre-implantation loss (44%, 38%, 32%, and 58% per group in the
0, 10, 25, and 40 mg/kg/day dose levels, respectively).  High
pre-implantation loss alters litter size, fetal weights, and other
parameters, hindering the ability to assess post implantation loss. 
Additionally, the number of litters was insufficient to meet guideline
requirements, due to high maternal mortality.

870.3800	Reproduction and fertility effects - rat

Acceptable/guideline	44092615	0, 35, 200, 600 ppm 

M:  0, 2.2, 12.6, 37.8 mg/kg/day

F:  0, 2.5, 14.5, 42.7 mg/kg/day	Parental/Systemic 

NOAEL = 12.6/14.5 mg/kg/day (M/F)

LOAEL = 37.8/42.7 mg/kg/day (M/F) based on decreased body weights, body
weight gains, and food consumption during pre-mating.

Reproductive 

NOAEL = 37.8/42.7 mg/kg/day (M/F)

LOAEL = Not determined.

Offspring

NOAEL = 37.8/42.7 mg/kg/day (M/F)

LOAEL = Not determined.

870.4100	Chronic toxicity - rodents	See 870.4300.  This study includes
requirements of both 870.4100 and 870.4200.

870.4100	Chronic toxicity - dog

Acceptable/guideline	44092608	0, 40, 200, 1000 ppm

M:  0, 1.5, 6.7, 37.1 mg/kg/day

F:  0, 1.6, 7.6, 35.0 mg/kg/day	NOAEL = 6.7/7.6 mg/kg/day (M/F)

LOAEL = 37.1/35.0 mg/kg/day (M/F) based on increased absolute and
relative liver and kidney weights, increased alkaline phosphatase,
decreased blood urea nitrogen, hepatocellular hypertrophy, histiocyte
pigmentation, and renal pigmentation (M&F).

870.4200	Carcinogenicity - rat	See 870.4300.  This study includes
requirements of both 870.4100 and 870.4200.

870.4200	Carcinogenicity - mouse

Acceptable/guideline	44092609

44092610	0, 20, 100, 500 ppm

M: ~ 0, 3, 15, 75 mg/kg/day

F: ~ 0, 3, 15, 75 mg/kg/day

Doses were estimated using the conversion ratio.	NOAEL = ~ 15 mg/kg/day
(M&F)

LOAEL = ~ 75 mg/kg/day (M&F)

based on increased mortality (M), increased kidney weights, (M&F), and
increased incidences and severity of kidney lesions (chronic
nephropathy, cortical cysts, tubular dilatation, and infarct) in both
sexes.

No evidence of carcinogenicity

870.4300	Combined chronic toxicity/

carcinogenicity - rat

Acceptable/guideline	4409261644092617

44092618	0, 20, 120, 600 ppm

M: ~ 0, 1, 6, 30 mg/kg/day

F: ~ 0, 1, 6, 30

 mg/kg/day

Doses were estimated using the conversion ratio.	NOAEL = ~ 6  mg/kg/day
(M&F)

LOAEL = ~ 30 mg/kg/day (M&F) based on decreased body weight gain and
increased relative to body kidney weights (M&F), grossly observed kidney
lesions in males (irregular surfaces, pale kidneys, cysts, and enlarged
kidneys) and females (masses), and non-neoplastic lesions of the kidney
in males (tubular nephrosis, renal cysts, and end-stage kidney lesions)
and females (tubular nephrosis, proliferative tubules, and
glomerulonephropathy).

Evidence of carcinogenicity: renal adenomas and carcinomas observed in
600 ppm females.

870.5100	Gene mutation - bacterial reverse mutation assay

Acceptable/guideline	4409261944280401

	0.1 - 333.3 µg/plate (-S9) 

10 - 3333.3 µg/plate (+S9)

	Negative.

870.5100	Gene mutation - bacterial reverse mutation assay

Acceptable/guideline	44092619

44280402	1 - 333.3 µg/plate (-S9) 

33.3 - 3333.3 µg/plate (+S9)

	Negative.

870.5300	Cytogenetics -  in vitro mammalian cell gene mutation test (CHL
Cells)

Unacceptable/guideline	44092619

44280403	0, 20, 50, 100, 200 µg/ml (-S9)

60, 150, 300, 600 µg/ml (+S9)	Negative.

This study is unacceptable due to inadequate cytotoxicity at the HDT.

870.5300	Cytogenetics -  in vitro mammalian cell gene mutation test (CHO
Cells)

Acceptable/guideline	4409261944280404	Trial 1: 0.03-1.33

g/ml (-S9); 0.33-1.33 g/ml (+S9).

Trial 2: 0.33-1.00

g/ml (-S9); 0.33-1.33 g/ml (+S9).

Trial 3: 0.10-1.33

g/ml (+S9).

Trial 4: 0.03-1.00

g/ml (-S9); 0.10-1.33 g/ml (+S9).	Negative.

870.5375	Cytogenetics -  in vitro mammalian cell chromosome aberration
test

Acceptable/guideline	44092620

44280405	7 hours fixation:

0 or 600 ng/ml (-S9);

0 or 5000 ng/ml (+S9).

18 hours fixation:

0, 25, 500, 600 ng/ml (-S9); 0, 500, 1000, 5000 ng/ml (+S9).

28 hours fixation:

0 or 300 ng/ml (-S9);

0 or 3500 ng/ml (+S9).	Mutagenic: Evidence of structural chromosome
aberrations induced over background.

870.5385	Cytogenetics -  mammalian bone marrow chromosomal aberration
test (rats).

Acceptable/guideline	44092620

44280406	0, 22.3, 106.0, 393.5 mg/kg	Negative.

870.5395	Cytogenetics - mammalian erythrocyte micronucleus test (mice)

Unacceptable/guideline	44092620

44280407

	0, 1, 10, 100 mg/kg	Negative.

This study is unacceptable due to missing information on test material
purity.

870.5550	Other effects - unscheduled DNA synthesis in mammalian cells in
culture (rats)

Acceptable/guideline	44092621	0, 0.1, 1.0, 5.0, 10.0, 15.0, or 20.0 g/ml
for 3 hours.	Negative.

870.7485	Metabolism and pharmacokinetics - rat

Acceptable/guideline	44092622

44092623	(1) 10 or 50 mg/kg radiolabeled, single dose by oral gavage. 

(2) 10 mg/kg/day unlabeled, 14 days by oral gavage, PLUS 10 mg/kg
radiolabeled, single dose by oral gavage. 

(3) 10 mg/kg/day radiolabeled, 7 days by oral gavage.	Absorption: 
Rapid.  Dithianon was detected in plasma within 15 min.  As measured in
urine and bile, 31-43% was absorbed after a single dose of 10 or 50
mg/kg (23.5-33% in urine; 7.2-11.6% in bile).  Not dose-dependent.

Distribution:  Besides the GI tract, highest levels in kidneys.  Also
detected in liver, plasma, and whole blood.  Not detected in brain or
spinal cord.  No sex-related differences.

 

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摧㟂ༀdneys and liver.  Only 1 fraction was >5% of the
radioactivity from the single administered dose; that was a glucuronic
acid conjugate found in the 8-24 hr urine sample.  No sex-related
differences.

Excretion:  No bioaccumulation.  Within 120 hours after repeated
exposure to 10 mg/kg/day for 14 days (unlabeled) plus 10 mg/kg (labeled)
for 1 day, the radioactivity recovered was 64-72% of the administered
dose in feces, 27-31% in urine, <0.7% cage wash, <0.2% in carcass, 0% in
exhaled air.  Biliary excretion was not measured in the repeated
exposure study, although 7.2-11.6% of the radioactivity was recovered
following a single dose.  Therefore, % recovery for the repeated
exposure study was not expressed in terms of absorbed dose.  The
terminal half-life was 46-57 hrs.  No sex- or dose-related

differences were noted.

 

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