1 **Study Title**  Publicly Releasable Summary of the Petition for Establishment of a Tolerance for Captan in or on Ginseng
**EPA Registration A** **ction References** IR
-4 Tolerance Petition PP# 4E8257
**Au thor**  Bert Volger, Ph.D.
**Document Date** February 24 , 201 4 **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 085402

**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 g inseng 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 chem istry 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. An** **aly tical 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 enforcement3

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 g inseng growing areas, NAFTA Region 5 (2 trials in W isconsin, 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 1 2 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. Ac** **ute Toxicity** i. I n 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 (a RfD = 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 thiophosgene4

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 studies5

confi rm 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 h istopathology 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 i n 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, females6

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. Acareful 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 original ly 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

. I n 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 si nce there are sufficient data to ascertain the mode of action for the tumor response. This decision7

was based on the following weight
-of
-evidence considerations: (i) The occurrence of adenomas and adenocarcinomas in the small intestine of male and female m ice; (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 th reshold

. **6. An**  **imal 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 deg radate, 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. Ag** **gregate Exposure 1.**  **Dietary**

**Exposure** Current tolerances for residues of captan have been established in or on8

almonds; almond, hulls; animal feed, nongrass (Group 1 8); 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 (G roup 1), and livestock com modities and milk (40 CFR 180. 103)

. I n addition to the existing tolerances, this Notice of Filing includes exposure assessments for potential residues of captan in or on g inseng

. **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 (DEEM TM)

. 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 d ietary 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 DEEM TM 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 th is 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 the9

cPAD , and for i nfants 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 g inseng 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 g inseng.
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 (DW LOCs) were calculated and compared to Estimated Drinking Water Concentrations (EDWCs) that were generated by the PRZM
-EXAMS and SCI
-GROWmodels for captan residues in surface water and grou nd 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 DW LOC 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 exposu re added to the acute dietary exposure does not result in a risk concern. b

. Chronic Exposure. Chronic DW LOCs were calculated using the same inputs and similar equations as for the acute DW LOCs. Regarding the chronic aggregate exposures to captan residues, the calculated E DWCs 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 DW LOC values. The proposed captan use on g inseng 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 g inseng to the label would not result in any additional risk from the consumption of captan residues in drinking water. **2. Non -** **Dietary**

**Exposure**10

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 nonagricultural 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 i ntermediate
-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

. I n 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 the11

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**  There are no Canadian, Mexican, or Codex Maximum Residue Limits (MRLs) established for captan in or on g inseng . Therefore, international harmonization is not an issue for captan residues in or on the plant commodity, ginseng, at this time.