Document ID: EPA-HQ-OPP-2014-0315-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-08-01T04:00Z

Study Title PRIVATE  

Publicly Releasable Summary of the Petition

for Establishment of a Tolerance 

for Captan in or on Ginseng 

EPA Registration Action References

IR-4 Tolerance Petition

PP# 4E8257

Author

Bert Volger, Ph.D.

Document Date

February 24, 2014

Prepared by

Captan Task Force

c/o Makhteshim-Agan of North America Inc.

3120 Highwoods Blvd, Suite 100

Raleigh, NC 27604

Submitted by

Interregional Research Project No.4

Rutgers, The State University of NJ

Center for Minor Crop Pest Management

500 College Road East, Suite 201 W

New Brunswick, NJ 08540



Interregional Research Project Number 4 (IR-4)

	

EPA has received a pesticide petition (PP # 4E8257) from IR-4 Project
Rutgers, The State University of New Jersey, 500 College Road East,
Suite 201 W, Princeton, NJ 08540 proposing, pursuant to section 408(d)
of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 346a(d), to amend
40 CFR 180.103 by establishing a tolerance for residues of the
fungicide, captan
(N-trichloromethylthio-4-cyclohexene-1,2-dicarboximide) in or on ginseng
at 1.5 ppm. The Captan Task Force (CTF) represented by Makhteshim-Agan
of North America Inc., 4515 Falls of Neuse Road, Raleigh, NC 27609, and
Arysta Life Science, 15401 Weston Parkway Suite 150, Cary, NC 27513, are
basic registrants of captan. CTF prepared and summarized the following
information in support of the pesticide petition for captan. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA. However, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of the petition. Additional data
may be needed before EPA rules on the petition.

A.	Residue Chemistry

The residue chemistry data base for captan is complete.

1.     Plant Metabolism 

The qualitative nature of the residue of captan in plants is adequately
understood based on acceptable lettuce, and tomato metabolism studies.
Captan is the major residue. Minor residues identified in the plant
metabolism studies included 1,2,3,6-tetrahydrophthalimide (THPI), captan
epoxide, and THPI epoxide. Bis(trichloromethyl)disulfide,
trans-3-hydroxy-1,2,6-trihydrophthalimide (3-OHTHPI), and
trans-5-hydroxy-1,2,6-trihydrophthalimide (5-OH-THPI) may also be
present at very low levels. Based on the results observed in the
metabolism studies, the first step in the metabolism of captan is the
cleavage of captan’s N-S bond to form tetrahydrophthalimide (THPI),
and a derivative of the trichloromethylthio side chain secondary
residues, such as phthalimide and phthalic acid, which are not expected
to be of toxicological concern. Because captan is extensively
metabolized to THPI in animal tissues, and THPI comprises less than 10%
of the total captan residue for plants, the Agency concluded that the
residue of concern, which should be regulated in plants, is the parent
compound, captan, only. 

2.	  Analytical Method

An adequate analytical method, gas chromatography/electron capture
detector (GC/ECD), is available for enforcement of tolerance residues of
captan per se in or on plant commodities, and is listed as Method I, in
PAM, Vol. II Zeneca Method No. 166 for quantifying THPI in meat and milk
has been validated as the preferred enforcement method. The limit of
detection (LOD) is 0.02 mg/kg (ppm) and the lowest level of method
validation (LLMV) is 0.05 mg/kg (ppm). Captan is completely recovered
using FDA Multiresidue Protocols D (Luke Method; 232.4) and E Section
211.1 for oily matrices and partially recovered using FDA Multiresidue
Protocol E Section 212.1 for non-oily matrices. THPI is completely
recovered using FDA Multiresidue Protocol D.

3. 	Magnitude of Residues

Four field residue trials were conducted covering the major ginseng
growing areas, NAFTA Region 5 (2 trials in Wisconsin, 1 trial in
Ontario), and NAFTA Region 11 (1 trial in British Columbia) during 2005
and 2006. Captan was applied eight times, following a 6 to 8 day spray
interval, using a maximum application rate of 3.0 lbs active ingredient
per acre or 24 lbs per season, with the last application 12 to 15 days
before harvest. The ginseng samples from three of the four trials had
residues at or below the LLMV (≤ 0.05 ppm), but in the fourth trial
the samples had residues as high as 1.0 ppm (multiple analyses were
conducted to confirm the residues). CTF concludes that the generated
data set is in full support of the proposed tolerance of 2.0 ppm.

B.	 Toxicological Profile

1.    Acute Toxicity

i.   In general, captan has been shown to be of low acute toxicity: The
acute oral LD50 in rats is 9,000 mg/kg, and the acute dermal LD50 in
rats is greater than 2,000 mg/kg. The acute inhalation LC50 (4-hour) was
0.72 mg/l for male rats, and 0.87 mg/l for females. Captan is very
irritating to the eyes of rabbits, not irritating to the skin, but
considered a dermal sensitizer as shown in guinea pigs.  Based on these
results, captan is classified in Toxicity Category IV for acute oral and
dermal sensitization, in Category III for acute dermal and inhalation
toxicity, and in Category I for eye irritation.

ii.  The Agency selected the developmental NOAEL of 10 mg/kg/day from
the prenatal developmental toxicity study in rabbits for deriving the
acute Reference Dose (aRfD = 0.1 mg/kg/day). The Reference Dose (RfD)
equals the Population Adjusted Dose (PAD).

2.	  Genotoxicity

The mutagenic potential of captan was investigated in several in vivo
and in vitro studies.  Captan is neither mutagenic nor genotoxic in
mammals (in vivo assays). In some of the in vitro studies, mutagenic
events were observed, such as chromosome aberrations, sister chromatid
exchanges and single strand DNA breaks in mammalian cells. Overall, the
data support the contention that captan is an in vitro mutagen and
clastogen that is not active in the whole animal because it reacts with
thiols or proteins that rapidly deactivate captan or its reactive
breakdown product (thiophosgene). Captan does not present a genotoxic
risk based on the fact that captan or thiophosgene degrade with a
half-life of less than one second in blood. This fast detoxification
effectively eliminates systemic exposure to captan or thiophosgene. The
Agency concluded in its 2004 Cancer Assessment Review Committee (CARC)
meeting that captan is not genotoxic in vivo, and the
weight-of-the-evidence supports a nongenotoxic mode of action for
captan. Therefore, future quantification of cancer risk will be through
a non-linear (RfD) approach.  

3.	Reproductive and Developmental Toxicity

i.   In a three-generation reproduction study rats were treated with
captan at 25, 100, 250, and 500 mg/kg/day. Non-reproductive parental
toxicity was seen at 100 mg/kg/day and above in the absence of
reproductive effects. Pup weights were lower by 7% compared to controls
at 25 mg/kg/day. A subsequent one-generation study conducted at 0.6,
12.5, and 25 mg/kg/day showed no effect on pup weights at 25 mg/kg/day. 

 

ii.  Teratology studies were conducted in the rat, hamster and rabbit.
In rats, captan was administered at 0, 18, 90, and 450 mg/kg/day
exhibiting decreased maternal weight gain and decreased food consumption
at the high dose. No effects on post-implantation loss or fetal survival
were observed. Fetal body weight was reduced and the incidence of
"small" fetuses was increased at the high dose. There were no increases
in incidences of treatment-related malformations. The incidence of minor
skeletal variations, including the presence of a fourteenth (lumbar)
rib, incomplete fusion of vertebral hemicentra fusion, and reduced
ossification of the pubes was increased at 450 mg/kg per day. The NOAELs
for maternal and developmental toxicity in this study were 18 and 90
mg/kg/day, respectively.

In the prenatal developmental toxicity study in hamsters, delayed
ossification and post-implantation loss occurred at 400 mg/kg/day (the
developmental LOAEL), while in dams, decreased body weight and mortality
were observed at a LOAEL of 200 mg/kg/day. The developmental NOAELs for
maternal and developmental toxicity in the prenatal developmental
hamster study were 50 and 200 mg/kg/day, respectively. Studies in
hamsters and rabbits showed that developmental and reproductive toxicity
occurs only at or above doses that cause toxicity to parental animals.

In establishing an acute Population Adjusted Dose (aPAD), the Agency
determined to use 0.1 mg/kg/day, based on a NOAEL of 10 mg/kg/day from
the cited developmental study in rabbits. In this study,
post-implantation loss, reduced mean fetal weight, and increased
skeletal defects in fetuses were observed at 30 mg/kg/day. This dose
reflects application to the NOAEL of an uncertainty factor of 100X to
account for interspecies extrapolation and intraspecies variability. 

4.	Subchronic Toxicity

Rats, mice, and dogs all show the same toxicological response. These
studies confirm the irritant properties of captan, the effects of
irritation to the duodenum, and the reversibility of these effects upon
cessation of treatment. Observations in rats also include hyperkeratosis
and acanthosis of the esophagus and stomach, and in the mouse it
includes reduced weight gain and depressed food intake at high doses. 

Wistar rats treated for 4 weeks with captan at 0, 2,000, 4,000, 8,000,
or 12,000 ppm were observed to have a dose-related decrease in body
weight gain and food intake. At the top two doses, there were increases
in basophilia of hepatocytes in the periportal area of the liver
accompanied by increases in relative liver weight. A similar finding was
observed in the females at the next lower dose (4,000 ppm). The relative
organ to body kidney weights were statistically increased at all doses.

Male CD-I mice (four or five per group) treated with 3,000 ppm for 1, 3,
7, 14, or 28 days showed shortened duodenal villi due to damage by
captan. This effect was observable in the crypts within 3 days of
treatment initiation. Immature cells were observed at the villi tips
from day 7 onward, indicating a higher turnover of cells. There was some
focal gastritis and parakeratosis noted in one mouse. When captan is fed
to mice at 6,000 ppm for 28-90 days, villus atrophy occurs, together
with a crypt hypertrophy and crypt cell hyperplasia.

CD-l mice administered captan for 56 days as 0, 400, 800, 3,000, or
6,000 ppm were evaluated for proliferative changes in the duodenum. An
assessment of the duodenum was made using histopathology and a
bromodeoxyuridine-labeling index to measure crypt cell proliferation.
Captan induced hyperplasia of the crypt cells, an increase in the crypt
cell labeling index, and an increase in the number of cells in the crypt
cell population. At 3,000 ppm, the villus-to-crypt height ratio
decreased from 5.4 in males and 5.9 in females to 1.4 and 2.6,
respectively. These observed changes are consistent with an irritant
action of captan on the duodenum. The no observed effect limit (NOEL)
for duodenal hyperplasia is 400 ppm.

Beagles, two per sex per treatment group, were administered captan at 0,
30, 100, 300, 600, or 1,000 mg/kg/day for 4 weeks. The results included
treatment-related emesis and a dose-related decrease in food intake and
body weight gain. There was an increase in relative liver weight in
males at 600 and 1,000 mg/kg/day and relative kidney weight in females
at 1,000 mg/kg/day. Some fatty changes were seen in the kidney and liver
of one male at 1,000 mg/kg/day.

5.	Chronic Toxicity

i.   Chronic toxicity and oncogenicity was evaluated in the rat, mouse
and dog. Based on recent chronic toxicity and carcinogenicity studies
performed in rats, the NOAEL for systemic effects was 25 mg/kg/day. At
the LOAEL of 100 mg/kg/day, males displayed hepatocellular hypertrophy;
increased relative organ weight for kidneys (males and females);
increased relative organ weight for heart, brain, liver and
thyroid/parathyroid (males); and decreased body weight. At the same
dosage, females displayed increased relative organ weight for kidneys,
and decreased body weight. There was a significant increasing trend in
males for the combined adenomas and carcinomas of the kidney in male
rats. There was no increased incidence of renal cortical/tubular cell
neoplasia in females. 

In mice, prolonged ingestion of high dose levels of captan causes an
increased incidence of tumors (adenomas and adenocarcinomas) in the
small intestine (primarily the proximal portion of the duodenum) in both
sexes of mice.  Tumors are observed in females only at dietary levels of
at least 800 ppm (120 mg/kg/day) and in males at levels of at least
6,000 ppm (900 mg/kg/day) that exceed the maximum tolerated dose.  In
all studies, the tumorigenic response exhibits a clear dose threshold
below which no effect occurs.  A careful evaluation of the results of
the rat bioassays provides no evidence that captan is associated with
increased incidences of either renal tumors in males or of uterine
sarcomas in females.

Dogs were treated with captan at 0, 12.5, 60, and 300 mg/kg/day for 1
year. Only the high-dose animals differed from control in increased
incidence of emesis and soft stool, increased relative liver weight, and
decreased total serum protein and albumin, resulting in a NOAEL of 60
mg/kg/day. 

The Agency’s CARC agreed in 2004 that the results of the rat bioassays
provide no evidence that captan is associated with kidney tumors in male
rats or uterine tumors in female rats, and, therefore, these tumors do
not add to the weight-of-evidence considerations for the carcinogenicity
of captan.  

ii.    A three-generation reproduction study in rats is the basis for
the chronic RfD. The NOAEL in the study was 12.5 mg/kg/day based on
decreased mean litter weights at the next higher dose level of 25
mg/kg/day. For the chronic dietary exposure assessment the chronic PAD
of 0.13 mg/kg/day is obtained by application of an uncertainty factor of
100 for interspecies and intraspecies variability. 

iii. The Agency originally classified captan as a “B2 - probable human
carcinogen” using the linear (Q1*) methodology based on an increased
incidence of intestinal tumors in mice, using a (body weight) scaling
factor. In September 2004, the Agency, in accordance with the new
Carcinogen Risk Assessment Guidelines, determined that captan acts
through a non-genotoxic threshold mode of action, and considers captan
to be a potential carcinogen at prolonged high doses that cause
cytotoxicity and regenerative cell hyperplasia. However, these high
doses of captan are many orders of magnitude above those likely to be
consumed in the diet, or encountered by individuals in occupational or
residential settings. Therefore, captan is not likely to be a human
carcinogen nor pose cancer risks of concern when used in accordance with
approved product labels. Since the CARC determined that there is a
plausible mode of action, captan should be regulated based on a
non-linear risk assessment, and a non-linear point of departure (RfD)
will be selected since there are sufficient data to ascertain the mode
of action for the tumor response. This decision was based on the
following weight-of-evidence considerations: (i) The occurrence of
adenomas and adenocarcinomas in the small intestine of male and female
mice; (ii) Captan is not likely to be genotoxic in vivo; (iii) The
weight-of-evidence suggests that captan induces small intestine tumors
by a nongenotoxic mode of action involving cytotoxicity and regenerative
cell hyperplasia that exhibits a clear dose threshold.

Animal Metabolism

The metabolism of captan in animals is adequately understood. When
ingested, captan is relatively stable in the acidic environment of the
stomach. It is hydrolyzed more rapidly in the neutral environment of the
duodenum to THPI and thiophosgene. Captan can also react chemically with
sulfhydryl-containing compounds present in the gut or in the gut
epithelial cells. The cytoplasm of most animal tissues contains high
concentrations of GSH S-transferases that will increase the rate of
reaction between thiophosgene and GSH. 

In the unlikely event that captan survives long enough to enter the
systemic circulation, it will be broken down very rapidly by thiols in
the blood to THPI and thiophosgene. The Agency concluded that
thiophosgene is so labile that residues after oral ingestion of captan
are not quantifiable. Thiophosgene, in fact, is broken down with a
half-life of approximately 0.6 seconds.

7.   Metabolite Toxicology

   

The Agency concluded that there are no captan metabolites of
toxicological concern and therefore, the tolerance expression for raw
and processed agricultural commodities should remain as captan per se.
Because captan is extensively metabolized to THPI in animal tissues, the
Agency determined that the tolerance expression for animal commodities
should include THPI as well as captan. For drinking water assessment the
major captan soil degradate, THPI, is considered besides the parent,
captan. 

 8.	  Endocrine Disruption

   	

No special studies investigating potential estrogenic or other endocrine
effects of captan have been conducted.  However, no evidence of such
effects is reported in the standard battery of required toxicology
studies, which have been completed and found acceptable. Based on these
observations, there is no evidence to suggest that captan has an adverse
effect on the endocrine system. 

C.    Aggregate Exposure

1.  Dietary Exposure 

Current tolerances for residues of captan have been established in or on
almonds; almond, hulls; animal feed, nongrass (Group 18); apple;
apricot; blueberry; caneberry (Subgroup 13A), cherry, sweet; cherry,
tart; cotton, undelinted seed; dill, seed; flax, seed; grape; grain,
cereal, forage, fodder and straw (Group 16); grain, cereal (Group 15);
grass, forgae; grass, hay; nectarine, okra, peach, peanut, peanut, hay;
pear, plum, prune,fresh; rapeseed, forage; rapeseed, seed; safflower,
seed; sesame, seed; strawberry; sunflower, seed; vegetable, brassica
leafy (Group 5); vegetable, bulb (Group 3); vegetable, cucurbit (Group
9); vegetable, foliage of legume (Group 7); vegetable, fruiting (Group
8); vegetable, leafy, except brassica (Group 4) , vegetable, leaves of
root and tuber, (Group 2), vegetable, legume (Group 6); vegetable, root
and tuber (Group 1), and livestock commodities and milk (40 CFR
180.103).  In addition to the existing tolerances, this Notice of Filing
includes exposure assessments for potential residues of captan in or on
ginseng. 

i. 	 Food

a.   Acute Dietary Exposure. For the purposes of assessing acute dietary
risk, CTF has used the results of the Agency’s completed risk
assessment from November 2004 (Amendment to the 1999 Captan RED). The
Agency selected for the acute toxicological endpoint the developmental
NOAEL of 10 mg/kg/day from the prenatal developmental toxicity study in
rabbits determining acute dietary risks to the general population
including infants and children. The Agency conducted an acute
probabilistic dietary (food) exposure analysis using the Dietary
Exposure Evaluation Model (DEEMTM). Residues in food items were
estimated from residue field trials, USDA/PDP and FDA pesticide
monitoring data, and reduction/concentration factors when available. The
acute analysis evaluated the dietary exposure based on individual
consumption data from USDA's 1989-1992 Nationwide Continuing Surveys for
Food Intake by Individuals (CSFII). For the acute assessment, exposure
is compared to the acute population adjusted dose (aPAD). The aPAD
refers to the acute RfD of 0.1 mg/kg/day, which has been adjusted to
take into account the FQPA safety factor. For captan, the acute RfD
equals the aPAD, since the FQPA safety factor is 1. The calculated
dietary exposure for the most exposed subgroup, females 13 - 50 years,
at the 99.9th percentile is 36% of the aPAD. In view of the negligible
residue situation by adding the minor use crop, ginseng, as a food-crop
to the label, CTF concludes that the acute probabilistic dietary risk
for captan is below the Agency’s level of concern. 

b.   Chronic Dietary Exposure.  To assess chronic dietary exposure, a
DEEMTM chronic exposure analysis was performed using anticipated
residues and percent of crop treated information to estimate the
anticipated residue contribution (ARC) for the general U.S. population
and 22 subgroups. It should be noted that residues of captan plus the
metabolite, THPI, were included in the ARC for acute and chronic
exposure in meat and milk. For this assessment, exposure was compared to
the chronic population adjusted dose (cPAD) of 0.013 mg/kg/day based on
the NOAEL of 12.5 mg/kg/day from the three-generation reproduction study
in rats, and based on an uncertainty factor of 100 and a FQPA safety
factor of 1. Considering these assumptions the chronic dietary exposure
estimate for the overall U.S. population is 0.5% or 0.000664 mg/kg/day
of the cPAD, and for infants less than 1 year old, the most exposed
population subgroup, it is 1.3% or 0.001629 mg/kg/day of the cPAD. Based
on the existing uses and the insignificant residue contribution from the
proposed use on ginseng as a food-crop, it has been demonstrated that
the chronic dietary risk from exposure to captan does not exceed the
Agency's level of concern, since all population subgroups having
exposure values below 2% of the cPAD. Therefore, CTF concludes that
there is reasonable certainty of no harm for the additional, new use of
captan on ginseng.

c.  Cancer. Based on the Agency’s 2004 cancer reassessment, it can be
concluded that captan acts through a non-genotoxic threshold mode of
action, and captan is not likely a human carcinogen nor poses cancer
risks of concern when used in accordance with approved product labels.
Therefore, a quantitative cancer risk assessment has not been conducted.

ii.     Drinking Water

Since drinking water monitoring data for captan were not available,
Drinking Water Levels Of Comparison (DWLOCs) were calculated and
compared to Estimated Drinking Water Concentrations (EDWCs) that were
generated by the PRZM-EXAMS and SCI-GROW models for captan residues in
surface water and ground water, respectively. Based on the model
predictions and the environmental fate characteristics of THPI, the
Agency predicts how much captan will reach as THPI in drinking water
from the current use pattern. 

a.    Acute Exposure. The acute DWLOC of 1,920 µg/L is a far greater
value than the conservative numbers that were estimated for the acute
drinking water exposure through Tier 1 modeling (668 µg/L for surface
water and 3.40 µg/L for ground water). Therefore, CTF concludes acute
drinking water exposure added to the acute dietary exposure does not
result in a risk concern. 

  

b.   Chronic Exposure. Chronic DWLOCs were calculated using the same
inputs and similar equations as for the acute DWLOCs. Regarding the
chronic aggregate exposures to captan residues, the calculated EDWCs
were 10.8 and 3.4 µg/L for surface water and ground water,
respectively, while the chronic DWLOC for the US population was 4,550
µg/L, and for infants (less than 1 year old) it was 1,300 µg/L.
Therefore, the EDWCs for captan residues of concern in ground and
surface water did not exceed the Agency’s calculated DWLOC values. The
proposed captan use on ginseng has an annual maximum application rate of
24 lbs a.i./A, which is far less than the total annual application rate
for peaches (32 lbs a.i./A), which was considered in this assessment.
Therefore, adding ginseng to the label would not result in any
additional risk from the consumption of captan residues in drinking
water.

2.   Non-Dietary Exposure 

Occupational handler exposure was assessed in the 1999 RED using PHED as
surrogate exposure data, and then re-evaluated in 2004 (Amendment to the
1999 Captan RED) in support of using captan on various agricultural
crops and non- agricultural crops; including seed treatment and
residential use sites which may include ornamentals, fruit trees, and
strawberries.

The recent occupational handler exposure assessments indicated that most
short- and intermediate-term risks to handlers using captan were above
100, the level of concern, with Margins of Exposure (MOEs) ranging from
240 to 43,000 for multiple activities. MOEs for mixer/loader/applicators
and flaggers ranged from 840 to 270,000. A MOE of 2,400 was calculated
for on-farm seed planters. Also residential exposure from the use of
captan around the home did not exceed the level of concern when
aggregated with food and drinking water.

 

 No chronic exposure scenarios are expected from residential uses of
captan. The Agency’s aggregate residential exposure assessment
(Amendment to the 1999 Captan RED - November 2004) resulted in
acceptable margins of exposure (MOEs >100) for all population subgroups
and scenarios based on conservative screening-level assumptions.
Therefore, CTF concludes that captan does not pose a risk due to short-
and intermediate-term non-dietary aggregate exposure.  

D.	Cumulative Effects

FQPA requires the Agency to consider the cumulative exposure to
pesticides operating by a common mechanism of toxicity. Adequate policy
permitting the estimation of cumulative exposure and effects is
currently under development but is not yet complete. Although folpet and
captan share the common metabolite thiophosgene, its role in folpet’s
and captan’s toxicity has not been determined because thiophosgene is
transient and not easily measurable. At such time as policy defining how
to conduct a cumulative assessment has been finalized, the risk
assessments will be revisited to determine whether captan shares a
common mechanism of toxicity with any other substances, such as folpet,
and whether a cumulative risk assessment is warranted. Thus only the
potential risks of captan have been considered in this assessment of its
aggregate exposure.

E.	Safety Determination

1.   U.S. Population

Using the conservative exposure assessment described above, the
estimated chronic aggregate exposure from food and water to the U.S.
Population is 0.000664 mg/kg/day, equal to 0.5% of the cPAD.  In
addition, the chronic exposure estimates for the most exposed subgroup,
infants less than 1 year old, is 0.001629 mg/kg/day, utilizing 1.3% of
the cPAD.  Concerning the acute aggregate exposure the only population
of concern is females 13 to 50 years old, utilizing 36% of the aPAD at
the 99.9th percentile. As described before, the calculations for the
aggregate short-term risk assessments, which provide estimates resulting
from residential exposures of 1 to 7 days duration, plus food and water
exposures, do not exceed the Agency’s level of concern. No cancer
aggregate risk assessment was conducted because the Agency’s 2004
cancer reassessment concluded that captan acts through a non-genotoxic
threshold mode of action, and captan should be regulated based on a
non-linear risk assessment. In view of these assessments, CTF concludes
that there is reasonable certainty that no harm will result from the
proposed use of captan.	

2.	   Infants and Children

Section 408 of FFDCA provides that EPA may apply an additional safety
factor for infants and children to account for prenatal and postnatal
toxicity and the completeness and adequacy of the toxicity and exposure
data bases, the nature and severity of the effects observed in pre- and
post-natal studies, and other information such as epidemiological data.
The toxicology database for captan is complete including acceptable
prenatal developmental toxicity studies in hamsters, rats and rabbits,
and two reproduction studies in rats that have been used to assess the
potential for increased sensitivity of infants and children. The data
provided no quantitative or qualitative evidence of increased
susceptibility of rats, rabbits or hamsters to in utero and/or postnatal
exposure to captan. The Agency has determined, based on a
weight-of-the-evidence review of the available data, a developmental
neurotoxicity study is not required for captan. The Agency has
determined that the 10X safety factor for enhanced sensitivity to
infants and children (as required by FQPA) for captan should be removed
(reduced to 1X). As previously stated, aggregate exposure assessments
utilize less than 36% of the aPAD, and less than 1.3% of the cPAD for
either the entire U.S. Population or any of the population subgroups
including infants and children.  Therefore, CTF concludes that there is
reasonable certainty that no harm will result to infants and children
from aggregate exposure to captan residues from the proposed use.

F.	International Residue Limits

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