 
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION


MEMORANDUM

Date:  Aug 27, 2013

SUBJECT:  Mandipropamid:  Revised Human Health Risk Assessment For New Uses On Basil, Ginseng and Snap Beans, as Well as Crop Group Expansions for Fruiting Vegetable; Small Fruit, Vine Climbing, Except Fuzzy Kiwifruit; and Bulb Onion and Green Onion Subgroups.  

PC Code:  036602
DP Number:  D414944
Decision No.:  472747
Registration No.:   100-1254
Petition No.:  2E8126
Regulatory Action:  Section 3                               
Risk Assessment Type:  Single Chemical Aggregate 
Case No.:   7058
TXR No.:  NA
CAS No.:  374726-62-2
MRID No.:   None
40 CFR:  §180.637


FROM:	Dennis McNeilly, Chemist and Risk Assessor
	Jaime D'Agostino, Toxicologist 
      William T. Drew, Chemist
	Zaida Figueroa, Industrial Hygienist
		Risk Assessment Branch II
		Health Effects Division (7509P)

THROUGH:  Michael A. Doherty, Ph.D., Chemist
      Christina Swartz, Chief
		Risk Assessment Branch II
		Health Effects Division (7509P)

TO:	Laura Nollen/Barbara Madden, RM 05
      Risk Integration, Minor Use, Emergency Response Branch
	Registration Division (7505P)


This document is the same as D409103, except it was revised to include the Toxicity Profile Tables in Appendix B2.

                               Table of Contents
1.0	Executive Summary	4
2.0	HED Recommendations	5
2.1	Data Deficiencies	6
2.2	Tolerance Considerations	6
2.2.1	Enforcement Analytical Method	7
2.2.2	Recommended Tolerances	7
2.2.3	Revisions to Petitioned-For Tolerances	7
2.2.4	International Harmonization	8
2.3	Label Recommendations	8
3.0	Introduction	9
3.1	Chemical Identity	9
3.2	Pesticide Use Pattern	9
3.3	Anticipated Exposure Pathways	10
3.4	Consideration of Environmental Justice	11
4.0	Hazard Characterization and Dose-Response Assessment	11
4.1	Summary of Toxicological Effects	12
4.2	Safety Factor for Infants and Children (FQPA Safety Factor)	13
4.2.1	Completeness of the Toxicology Database	13
4.2.2	Evidence of Neurotoxicity	13
4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	14
4.2.4	Residual Uncertainty in the Exposure Database	14
4.3	Toxicity Endpoint and Point of Departure Selections	14
5.0	Dietary Exposure and Risk Assessment	16
5.1	Residues of Concern Summary and Rationale	16
5.2	Food Residue Profile	17
5.2.1	Crop Field Trials (860.1500)	18
5.2.2	Field Rotational Crops (860.1900)	19
5.2.3	Processed Food and Feed (860.1520)	20
5.3	Water Residue Profile	20
5.4	Dietary Risk Assessment	21
5.4.1	Description of Residue Data Used in Dietary Assessment	21
5.4.2	Percent Crop Treated Used in Dietary Assessment	22
5.4.3	Acute Dietary Risk Assessment	22
5.4.4	Chronic Dietary Risk Assessment	22
5.4.5	Cancer Dietary Risk Assessment	22
5.4.6	Summary Table	22
6.0	Residential (Non-Occupational) Exposure/Risk Characterization	23
6.1	Residential Bystander Post-application Inhalation Exposure	23
6.2	Spray Drift	23
7.0	Aggregate Exposure/Risk Characterization	24
7.1	Acute & Chronic Aggregate Risk	24
7.2	Short- and Intermediate-Term Aggregate Risk	24
8.0	Cumulative Exposure/Risk Characterization	24
9.0	Occupational Exposure/Risk Characterization	25
10.0	References	30
Appendix A.  International Residue Limits	31
Appendix B.  Toxicology Profile	32
B.1	Toxicology Data Requirements	32
B.2	Toxicity Profiles	33
B.2.3	Immunotoxicity	38
Appendix C.  Physical/Chemical Properties	40
Appendix D.  Review of Human Research	41


1.0	Executive Summary

Mandipropamid is a fungicide in the mandelamide class developed by Syngenta Crop Protection, Inc. for the control of foliar oomycete pathogens in a range of crops including Plasmopara viticola in grapes, Phytophthora infestans in potatoes and tomatoes, and Pseudoperonospora cubensis in cucurbits.

IR-4 has requested new Section 3 uses for mandipropamid and tolerances for residues of mandipropamid in/on fresh basil, dried basil, ginseng, cowpea forage, succulent beans, and for greenhouse tomatoes.  In addition, there is a proposal to expand the current use on grapes to the new crop subgroup 13-07F for small fruit vine, except fuzzy kiwifruit; to expand the use on onion, dry bulb to bulb onion (subgroup 3-07A); to expand the use on green onions to green onion (subgroup 3-07B); and finally to expand the use on fruiting vegetables (crop group 8) to the updated fruiting vegetables crop group (8-10).  Revus (EPA Reg. No. 100-1254) is a suspension concentrate (SC) formulation containing 23.3% ai by weight, equivalent to 2.08 lb ai/gal (250 grams/liter).

The toxicology database is adequate.  Mandipropamid has low acute toxicity via oral, dermal, and inhalation routes; and no dermal or eye irritation (Toxicity Category IV).  It is not a skin sensitizer.  Liver toxicity was the primary effect and was observed in rats, mice and dogs.  There was no evidence of increased neonatal or postnatal sensitivity in the developmental and reproduction toxicity studies, and no evidence of developmental effects, neurotoxicity, mutagenicity or carcinogenicity after exposure to mandipropamid.  The FQPA Safety Factor (SF) has been reduced to 1X.

Based on the available data, there are no effects attributable to a single exposure to mandipropamid which are appropriate for assessing acute risks, including acute dietary exposure.  Similarly, there are no effects associated with dermal exposure.  Only inhalation and chronic dietary endpoints and points of departure have been selected for risk assessment.

Adequate field trials were conducted on basil, ginseng, and snap beans; in addition, adequate greenhouse trials were submitted for tomatoes.  Further, metabolism data, storage stability and analytical methods are considered adequate to support the recommended tolerances for both new uses and crop group expansions.  HED notes however that the submitted data for snap beans do not support the proposed tolerances for succulent bean and cowpea forage.  In addition a tolerance cannot be established for cowpea forage, a livestock feed item, due to the lack of a validated livestock analytical enforcement method.

A screening-level dietary assessment (food + drinking water), based on tolerance-level residues and 100% of crop treated for all included commodities, and conservative assumptions with respect to mandipropamid residues in drinking water sources, indicates that chronic dietary risks are below HED's level of concern for all population subgroups.  There are no uses of mandipropamid that would result in residential exposure; therefore, chronic dietary is the only aggregate scenario, and there are no aggregate risks of concern.

Occupational risk estimates associated with the new uses are also below HED's level of concern.  No chemical-specific handler exposure data were submitted in support of this registration; therefore, HED relied on surrogate data in accordance with standard policies.  Default assumptions established by the HED Science Advisory Council for Exposure (ExpoSAC) were used for parameters such as body weight and amount handled.  Occupational assessments for mandipropamid are based on inhalation exposures only.  All occupational handler scenarios for the proposed uses resulted in MOEs greater than 100 at baseline (i.e., baseline attire with no respirator; engineering control for aerial applications (enclosed cockpits)) and, therefore, are not of concern, and no additional personal protective equipment (PPE) will be needed on the proposed label.  Although a point of departure from an oral study was used to assess handler inhalation risk, the calculated MOEs are all >=65,000, thus providing an ample margin to account for any uncertainties in the route-to-route extrapolation.    

Furthermore, since there is no difference between the occupational scenarios and the agronomics/practices previously assessed, the exposure resulting from mandipropamid use on the additional crops in the expanded crop groups are already covered by an existing risk assessment (D357873, M. Dow, 10/28/2008).  Therefore, a new occupational assessment for the registered uses was not needed to support the tolerances for crop group expansion.  

Occupational post-application risk estimates for agricultural workers following treatments to agricultural crops were not assessed, since no dermal endpoint of concern was identified.  In addition, mandipropamid is categorized as a reduced risk chemical.  Therefore, the restricted entry interval (REI) of 4 hours is considered appropriate.

Based on the Agency's current practices, a quantitative non-cancer occupational post-application inhalation exposure assessment was not performed at this time.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for mandipropamid.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies, listed in Appendix D, have been determined to require a review of their ethical conduct.  Some of these studies are also subject to review by the Human Studies Review Board.  All of the studies used have received the appropriate review. 

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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.
2.0	HED Recommendations

HED recommends in favor of establishing tolerances for residues of mandipropamid as specified in Section 2.2.2.


2.1	Data Deficiencies

No additional data are required to support HED's currently recommended tolerances, however additional data would be need to support all of the proposed tolerances associated with the petition.  The submitted snap bean data do not support the proposed tolerances in succulent beans and cowpea forage (ChemSAC meeting; 17 July 2013).  Additional field trial data on a succulent shelled bean cultivar (such as lima beans) would be necessary in order to establish a tolerance in succulent beans.  Because of the possibility of detectable residues occurring in dairy cattle commodities (fat, milk and liver) arising from the feeding of treated cowpea forage, the concurrent establishment of mandipropamid tolerances at the limit of quantitation (LOQ) in those commodities would be necessary.  However, with no validated analytical method for enforcing tolerances in livestock commodities, it is not possible to establish such tolerances.  Therefore, the proposed tolerance in cowpea forage cannot be established until a validated method for determining mandipropamid residues in livestock (cattle) commodities is available.  Any such method submitted would need an independent laboratory validation (ILV).  (If tolerances for additional livestock feed items other than cowpea forage are proposed, a livestock feeding study should be submitted.)

Since the last risk assessment, an immunotoxicity study was received which fulfills a previously identified data gap. In this study, no evidence of immunotoxicity was observed up to the highest dose tested (649 mg/kg/day). In addition, HED's Hazard and Science Policy Council (HASPOC) determined that a subchronic inhalation study in the rat is not required for mandipropamid (TXR #0056610, J. Alstine, 3/14/2013).

2.2	Tolerance Considerations

HED has examined the toxicology and residue chemistry database for mandipropamid.  There are no issues that would preclude establishing tolerances for mandipropamid for the commodities listed in Table 2.2.2.  The submitted snap bean data do not support the proposed tolerance in succulent bean, and a cowpea forage tolerance cannot be established due to the lack of a livestock analytical enforcement method.

Notes to RD:  a) When the crop subgroup 13-07F tolerance is established, then the grape tolerance should be deleted.  b) When the crop subgroup 3-07A tolerance is established, then the tolerance for onion, dry bulb, should be deleted.  c) When the crop subgroup 3-07B tolerance is established, then the tolerance for onion, green should be deleted.   d)  According to HED's Interim Guidance on Tolerance Expressions (S. Knizner; 27 May 2009), the tolerance expression for mandipropamid cited in 40CFR §180.637[a] should be revised to state:  Tolerances are established for residues of mandipropamid, including its metabolites and degradates, in or on the commodities listed in the table below.  Compliance with the tolerance levels specified below is to be determined by measuring only mandipropamid (4-chloro-N-[2-[3-methoxy-4-(2-propynyloxy)phenyl]ethyl]-α-(2-propynyloxy)benzeneacetamide) in or on the commodity.

2.2.1	Enforcement Analytical Method

There is an adequate enforcement method available for the quantitation of mandipropamid in plant commodities.  Method RAM 415/01, using high performance liquid chromatography with tandem mass spectrometric detection (LC/MS/MS), has been adequately validated by an independent laboratory.  It has a validated limit of quantitation (LOQ) of 0.01 ppm.  An acceptable confirmatory method is also available.  

The FDA Multiresidue methods are not adequate for determining residues of mandipropamid.

2.2.2	Recommended Tolerances

HED has examined the residue chemistry database for mandipropamid.  Pending submission of a revised Section F (to propose tolerance levels in accordance with those recommended by HED, and to correct some of the commodity definitions), there are no residue chemistry issues that would preclude establishing tolerances in the requested commodities, except for those in cowpea forage and succulent beans.  The recommended tolerances are listed in Table 2.2.2, below.


Table 2.2.2.  Tolerance Summary for Mandipropamid.

                      Commodity as Proposed by Registrant
                           Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
                    Comments; Correct Commodity Definition
Basil, fresh
                                      30
                                      30
Basil, fresh leaves
Basil, dried
                                      200
                                      200
Basil, dried leaves
Bean, succulent
                                     0.90
                                     None
Field trial data on a succulent shelled bean cultivar is needed.  
Bean, snap
                                     None
                                     0.90
The snap bean field trials support the establishment of this tolerance.  
Ginseng
                                      0.3
                                     0.30

Cowpea, forage
                                      15
                                     None
A validated method (i.e. with an ILV) for residues in cattle commodities is needed.  
Vegetable, fruiting, group 8-10
                                      1.0
                                      1.0

Fruit, small, vine climbing, subgroup 13-07F, except fuzzy kiwifruit
                                      2.0
                                      2.0
Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F. See footnote a below.
Onion, bulb, subgroup 3-07A
                                      0.1
                                     0.10
See footnote b below.
Onion, green, subgroup 3-07B
                                      7.0
                                      7.0
See footnote c below.
* Notes:  a)  When the crop subgroup 13-07F tolerance is established, then the grape tolerance should be deleted.  b)  When the crop subgroup 3-07A tolerance is established, then the tolerance for onion, dry bulb should be deleted.  c)  When the crop subgroup 3-07B tolerance is established, then the tolerance for Onion, green should be deleted.

2.2.3	Revisions to Petitioned-For Tolerances

Instead of the proposed tolerance in ginseng (0.3 ppm), HED recommends establishing the tolerance at 0.30 ppm, in order to avoid the situation where a field sample containing residues significantly above the tolerance (0.34 ppm, for example) would be considered non-violative.  For the same reason, HED recommends that the proposed tolerance of 0.1 ppm in bulb onions (subgroup 3-07A) be revised to 0.10 ppm.

The submitted snap bean data do not support the proposed tolerance in succulent beans.  A cowpea forage tolerance cannot be established due to the lack of a livestock analytical enforcement method, and a supporting livestock analytical method ILV (See Section 2.1).  Therefore, HED is not recommending in favor of the proposed tolerances in succulent beans and cowpea forage.

2.2.4	International Harmonization

Neither Codex nor PMRA have established MRLs for mandipropamid in any of the commodities associated with the proposed new uses.  As such, there is no harmonization issue associated with Codex for the proposed new uses in the current action.  PMRA and EPA are jointly reviewing the basil, ginseng and snap bean data in the current action, and EPA and PMRA are harmonized for fresh basil, dried basil, and ginseng.  PMRA is establishing an MRL in edible-podded beans at 0.9 ppm, while HED is recommending for a tolerance in snap beans at 0.90 ppm.  Although the tolerance/MRL level is harmonized, HED cannot harmonize with PMRA on the commodity definition, as the submitted snap bean data do not support use on all succulent beans, since no data were submitted for a succulent shelled bean, and/or do not meet the requirements of subgroup 6A, since no data were submitted for an edible-podded pea.

Both the current tolerance in crop group 8 (1.0 ppm) and the proposed tolerance in crop group 8-10 (1.0 ppm) are harmonized with the Codex (bell and non-bell peppers) and PMRA's (tomatoes, okras and peppers) MRLs.  For the other crop group expansions, EPA is harmonizing with Codex, even though this will result in discrepancies between US tolerances and Canadian MRLs.  The proposed tolerance of 2.0 ppm in subgroup 13-07F, translated from grape data, will be harmonized with the Codex MRL in grapes, but will no longer be harmonized with PMRA's MRL of 1.4 mg/kg in grapes.  The proposed tolerance of 0.1 ppm in subgroup 3-07A, translated from dry bulb onion data, will be harmonized with the Codex MRL in bulb onions, but will no longer be harmonized with PMRA's MRL of 0.05 ppm in various bulb onions.  The proposed tolerance of 7.0 ppm in subgroup 3-07B, translated from green onion data, will be harmonized with the Codex MRL in spring onions, but will no longer be harmonized with PMRA's MRL of 4.0 ppm in various green onions.

2.3	Label Recommendations

Because the submitted snap bean data do not support the proposed use on all succulent beans, the section containing directions for use on succulent beans ("Bean, succulent") should instead refer to snap beans ("Bean, snap"), and the listing of succulent bean commodities should be deleted.  The requested use on greenhouse tomatoes listed in the proposed label is supported by the submitted greenhouse trial data.

A cowpea forage tolerance cannot be established due to the lack of a livestock analytical enforcement method, and supporting livestock analytical method ILV. Use on cowpea forage must not be added to the label at this time.
3.0	Introduction

3.1	Chemical Identity

The chemical structure and nomenclature of mandipropamid are presented in Table 3.1.  The physicochemical properties of the technical grade mandipropamid are presented in Appendix C. Mandipropamid is a fungicide in the mandelamide class developed by Syngenta Crop Protection, Inc. for the control of foliar oomycete pathogens in a range of crops.

Table 3.1.  Test Compound Nomenclature.
Compound
                                       
Common name
Mandipropamid
Company experimental name
NOA 446510
IUPAC name
(RS)-2-(4-chloro-phenyl)-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-2-prop-2-ynyloxy-acetamide
CAS name
4-chloro-N-[2-[3-methoxy-4-(2-propynyloxy)phenyl]ethyl]-α-(2-propynyloxy)- benzeneacetamide
CAS registry number
374726-62-2
End-use product (EP)
Revus[(R)]  (2.08 lb ai/gal; EPA Reg. No. 100-1254), (Alternate Brand Name: Mandy Flowable Fungicide)

3.2	Pesticide Use Pattern
IR-4 HAS REQUESTED THAT NEW SECTION 3 USES OF THE fungicide mandipropamid be added to the label for Revus 2.08SC (EPA Reg. No. 100-1254).  The proposed new uses would be on basil, cowpea forage, ginseng, succulent beans, and greenhouse tomatoes.  The proposed use directions are summarized in Table 3.2.

Table 3.2.  Summary of Directions for Use of Mandipropamid.  
                        Application Type; Equipment[1]
                                   Use Rate
                                   (lb ai/A)
                             Max. Uses Per Season
                            Max. Seasonal Use Rate
                                   (lb ai/A)
                                 PHI[2] (Days)
            Use Directions, Application Timing, and Limitations[3]
                                     Basil
                    Foliar; any ground or aerial equipment.
                                  0.09 - 0.13
                                       4
                                     0.52
                                       1
RTI[4] of 7-10 days.  

                                    Ginseng
                    Foliar; any ground or aerial equipment.
                                  0.09 - 0.13
                                       4
                                     0.52
                                       2
RTI of 7-10 days.  

                        Succulent Beans (Cowpea Forage)
                    Foliar; any ground or aerial equipment.
                                  0.09 - 0.13
                                       4
                                     0.52
                                       1
RTI of 7-10 days.  

                              Greenhouse Tomatoes
                    Foliar; any ground or aerial equipment.
                                  0.09 - 0.13
                                       4
                                     0.52
                                       1
RTI of 7-10 days.  May be applied via chemigation.  
1. For ground application, apply in a minimum of 10 gallons of water per acre (GPA), unless specified otherwise on the label.  Do not apply through any ultra-low volume (ULV) spray system.  For aerial application, use only on crops where aerial applications are indicated.  Apply in a minimum of 5 GPA, unless specified otherwise on this label.  Do not apply through any ULV spray system.  For chemigation, use only on crops where chemigation is specified on the label.  Apply no more than 2 sequential applications unless otherwise stated in the crop-specific section. Do not use in transplant production.  
2. PHI = Pre-Harvest Interval.  
3. Begin applications prior to disease development.  Use the shorter interval and/or higher rates under high pressure, or when conditions are conducive to disease.  The addition of a spreading/penetrating type adjuvant such as a non-ionic based surfactant (NIS) or crop oil concentrate (COC) or blend is recommended.  
4. RTI = Re-Treatment Interval.  

The Personal Protective Equipment (PPE) statement on the proposed label requires applicators, flaggers and other handlers to wear: long-sleeved shirt and long pants, shoes plus socks. PPE recommended on the proposed label for early entry to treated areas include: coveralls, chemical-resistant gloves made of any waterproof material, shoes plus socks.

Conclusions:   The use directions are adequate to allow for evaluation of the residue data.  However, as the submitted snap bean data do not support the proposed use on succulent beans, the label section containing directions for use on succulent beans ("Bean, succulent") should instead refer to snap beans ("Bean, snap"), and the listing of all other succulent bean commodities should be deleted.  A cowpea forage tolerance cannot be established due to the lack of a livestock analytical enforcement method, and supporting livestock analytical method ILV. 

3.3	Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed tolerances for mandipropamid on basil, ginseng, succulent beans (including snap beans), and greenhouse tomatoes, as well as addition of the use on basil, ginseng, succulent beans, and greenhouse tomatoes to the Revus[(R)] label.  Humans may be exposed to mandipropamid in food and drinking water, since it may be applied directly to growing crops and application may result in mandipropamid reaching surface and ground water sources of drinking water.  There are no residential uses of mandipropamid, so there is not likely to be exposure in residential or non-occupational settings.  In an occupational setting, handlers may be exposed while handling the pesticide prior to application, as well as during application.  There is a potential for post-application exposure for workers re-entering treated fields.

Risk assessments have been previously conducted for mandipropamid; toxicity data submitted prior to the last risk assessment but not incorporated into HED's review have been evaluated in the current assessment, but did not affect HED's conclusions with respect to hazard characterization and endpoint selection.  A detailed description of the toxicity data and metabolism information may be found in the risk assessment dated 6/12/2008 (D. Dotson, D344351).  The current risk assessment considers all of the aforementioned exposure pathways based on the existing uses of mandipropamid, and also considers the potential for increased dietary (food + water) exposure associated with the new uses.
THERE HAVE BEEN NO CHANGES TO ANY OF THE PREVIOUSLY SELECTED ENDPOINTS, POINTS OF DEPARTURE, OR THE CANCER CLASSIFICATION FOR MANDIPROPAMID FROM THE PREVIOUS RISK ASSESSMENT (D365919, D. RATE, 7/8/2009).

3.4	Consideration of 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.eh.doe.gov/oepa/guidance/justice/eo12898.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 from the U.S. Department of Agriculture's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) 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 post-application 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.
4.0	Hazard Characterization and Dose-Response Assessment

A comprehensive human health risk assessment for mandipropamid was conducted in 2009 (D. Rate, 8 July 2009, D365919).  Since the last risk assessment, an immunotoxicity study (MRID 48771701) was received which fulfills a previously identified data gap.  In this study, no evidence of immunotoxicity was observed up to the highest dose tested (649 mg/kg/day).  In addition, HED's Hazard and Science Policy Council (HASPOC) determined that a subchronic inhalation study in the rat is not required for mandipropamid (Alstine, J. 14 March 2013, TXR #0056610).  Therefore, the toxicology database for mandipropamid is considered to be complete.  No other changes have been made to the hazard characterization of mandipropamid since the 2009 risk assessment.

4.1	Summary of Toxicological Effects

Subchronic and chronic studies indicate that the liver is the primary target organ for mandipropamid.  Liver effects were identified in subchronic studies with rats, mice, and dogs.  Liver effects included: periportal hypertrophy (rats), increased eosinophilia(rats and mice), increased plasma albumin, total protein, cholesterol, and gamma-glutamyl transferase (rats), increased liver weights (rats, mice and dogs), increased liver enzymes (dogs), increased pigment in hepatocytes and Kupffer cells (dogs), and centrilobular hepatocyte vacuolation (dogs).  In the chronic dog study, increases in microscopic pigment in the liver and increased liver enzymes were observed.  No liver effects were observed in chronic rat and mouse studies up to the highest doses tested.  Instead, nephrotoxicity was observed in the chronic rat study and only decreased body weight and food utilization was observed in the chronic mouse study.  The findings of liver toxicity and nephrotoxicity are consistent with the results from metabolism studies where the tissues with the highest levels of radioactivity were the liver followed by the kidney. 

No evidence of neurotoxicity was observed in the acute or subchronic neurotoxicity screening battery.  No systemic or dermal toxicity was observed following dermal exposure for 28 days up to the limit dose. 

No evidence of increased quantitative or qualitative susceptibility was seen in developmental toxicity studies in rats and rabbits or in a reproduction study in rats.  The only effects observed in fetuses or pups were in the two-generation reproduction study, where decreased pup body weight was observed in the presence of maternal toxicity (decreased body weight, body weight gain, and food utilization).  In addition, there was a delay in preputial separation in F1 males which was considered to be the result of lower body weights.

There was no evidence of tumors in the carcinogenicity study in mice or in the chronic/carcinogenicity study in rats and there was no evidence that mandipropamid was mutagenic or clastogenic.  Therefore, mandipropamid is classified as "not likely to be carcinogenic to humans."

In metabolism studies, absorption of [[14]C]-mandipropamid was 67-74% at 3 mg/kg and 30-45% at 300 mg/kg after 48 hours.  The rate of absorption was higher in females resulting in a blood Tmax at 3 mg/kg of 8.5 hours for males and 4.5 hours for females; at 300 mg/kg Tmax was 24 hours for males and 10 hours for females.  Most of the radioactivity was eliminated in the feces except for the 3 mg/kg females where elimination in urine and feces were similar.  In bile cannulated rats, elimination in the bile was high at 3 mg/kg (55-73% of the dose) but was lower at 300 mg/kg (22-28% of the dose, with a corresponding increase of residues in feces in males and urine in females).  The highest level of radioactivity in tissues was in the liver followed by the kidney.

Bioaccumulation was not observed in any tissue and the dose remaining in the body after 168 hours was less than 1.1%.  The parent and the following metabolites were detected at >=5% of the applied dose at 3 and/or 300 mg/kg: NOA 458422, NOA 458422 glucuronide, SYN 534133 and CGA 380778.  The amount of NOA 458422 glucuronide in females was almost 3-fold more than in males, which coincided with a lesser amount of parent and NOA 458422 in females.  Parent was the major residue detected in feces of animals of both sexes regardless of bile duct cannulation status, while SYN 534133 was the major metabolite in the urine of male rats that didn't undergo bile duct cannulation and NOA 458422 glucuronide was the major metabolite in the urine and bile of male rats that did undergo bile cannulation.  NOA 458422 glucuronide was also the major metabolite in urine and bile of female rats regardless of bile duct cannulation status.  The major metabolic transformations involved loss of one or both propargyl groups followed by glucuronidation and O-demethylation.  A dermal penetration study in rats was conducted for mandipropamid.  In the study, <0.17-3.44% of the applied dose was absorbed.

Mandipropamid has low acute toxicity via oral, dermal, and inhalation routes (Toxicity Category IV); and no dermal or eye irritation (Toxicity Category IV).  It is not a skin sensitizer.

4.2	Safety Factor for Infants and Children (FQPA Safety Factor)

HED has determined that the required 10X Food Quality Protection Act (FQPA) Safety Factor should be reduced to 1X in assessing the risk posed by mandipropamid.  This recommendation was based on the following considerations:

   oo The toxicity database is complete with no data gaps for the assessment of the effects of mandipropamid following in utero and/or postnatal exposure. 
   oo There is no evidence of neurotoxicity following exposure to mandipropamid.
   oo There is no indication of quantitative or qualitative susceptibility of rats or rabbits to in utero and/or postnatal exposure to mandipropamid.
   oo The risk assessment does not underestimate exposure, since the dietary assessment is based on conservative assumptions such as tolerance-level residues in foods, 100% crop treated, and upper-bound modeled estimates of residues in drinking water.  In addition, there are no registered residential uses for mandipropamid.

4.2.1	Completeness of the Toxicology Database

The toxicology database is considered complete and is adequate for the purpose of assessing pre- and postnatal susceptibility.  Acceptable/guideline developmental toxicity studies in rats and rabbits and a reproduction study in rats, as well as acute and subchronic neurotoxicity studies in rats were available for FQPA assessment.  There is no concern for increased susceptibility in the developing young, and no evidence of neurotoxicity in the database.  Therefore, a developmental neurotoxicity study is not required.

4.2.2	Evidence of Neurotoxicity

There was no evidence of neurotoxicity observed in any of the studies in the toxicology database.  In the acute neurotoxicity study, the rats were dosed up to the limit dose (2000 mg/kg).  In the 90-day neurotoxicity study in rats, the only effects appeared to be decreased body weight, body weight gain and food utilization in males up to the highest dose tested (192.5 mg/kg/day for males and 206.7 mg/kg/day for females).

4.2.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There were no treatment-related effects observed in dams or fetuses in the developmental toxicity studies in rats or rabbits up to the limit dose of 1000 mg/kg/day.  In the rat reproductive study, decreased pup weight occurred only in the presence of comparable maternal toxicity (decreased body weight.  Therefore, HED concludes that there is no increased quantitative or qualitative susceptibility to rat or rabbit offspring exposed in utero and/or postnatally to mandipropamid, and there are no residual uncertainties with respect to pre- or postnatal exposure.

4.2.4	Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database.  There are no exposure data gaps and the current dietary exposure assessment is based on high-end assumptions such as tolerance-level residue values, 100% crop treated, and modeled estimates of drinking water residues.  There are currently no registered or proposed residential uses for mandipropamid, so exposure is limited to dietary exposure.  Therefore, the assessment is conservative and does not underestimate exposure.

4.3	Toxicity Endpoint and Point of Departure Selections

The toxicological endpoints and points of departure selected for dietary and occupational exposure and risk assessment are summarized in Tables 4.3.1 and 4.3.2.  There have been no changes to any of the previously selected endpoints, points of departure, or the cancer classification for mandipropamid from the previous risk assessment (D365919, D. Rate, 7/8/2009).



Table 4.3.1.  Summary of Toxicological Doses and Endpoints for Mandipropamid Use in Dietary and Non-Occupational Human Health Risk Assessments.
                                   Exposure
                                   Scenario
Point of Departure 
Uncertainty/FQPA Safety Factors 
                RfD, PAD, Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary (General population, including Infants and Children and females 13-49)
N/A
N/A
N/A
No appropriate endpoint was identified in the TOX databases.
Chronic Dietary
(all populations)
NOAEL =  5 mg/kg/day


UFA=10X
UFH=10X
FQPA SF = 1X

Chronic RfD = 0.05 mg/kg/day 

cPAD = 0.05 mg/kg/day 
Chronic Toxicity Study in Dogs
LOAEL = 40 mg/kg/day, based on increased incidence and severity of microscopic pigment in the liver and increased alkaline phosphatase activity in both sexes as well as increased alanine aminotransferase activity in males.
Cancer (oral, dermal, inhalation) 
No Evidence of Carcinogenicity.  Classified as "Not Likely to be Carcinogenic to Humans."
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).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  N/A = not applicable.



Table 4.3.2.  Summary of Toxicological Doses and Endpoints for Mandipropamid Use in Occupational Human Health Risk Assessments.
                                   Exposure
                                   Scenario
Point of Departure 
Uncertainty Factors 
                     Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Dermal 
Short-Term (1 - 30 days) and Intermediate-Term (1-6 months)
N/A 
N/A
N/A
No appropriate endpoint was identified, and a risk assessment was not conducted.
28-day dermal toxicity study  -  rat,
no systemic or dermal effect up to the limit dose of 1000 mg/kg/day; there were no neurotoxicity or developmental concerns.
Inhalation 
Short-Term
(1 - 30 days) and Intermediate-Term (1-6 months)
NOAEL = 41 mg/kg /day

UFA=10X
UFH=10X


LOC =100 

90-day oral toxicity  -  rats
LOAEL = 260 mg/kg/day, based on decreased body weights, body weight gains and food utilization in males and slight hepatotoxicity in both sexes.
Cancer (oral, dermal, inhalation) 
No Evidence of Carcinogenicity.  Classified as "Not Likely to be Carcinogenic to Humans."
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  MOE = margin of exposure.  LOC = level of concern. 
5.0	Dietary Exposure and Risk Assessment 

5.1	Residues of Concern Summary and Rationale

The nature of the residue in plants, rotational crops, and ruminants is adequately understood.  For the purposes of tolerance enforcement and risk assessment, the residue of concern in primary crops, rotational crops, and ruminants is the parent mandipropamid, with the exception of root and tuber vegetables, where the metabolite SYN 500003 is included for risk assessment.  The metabolism data indicate that there is no reasonable expectation of finite residues in milk, meat, and/or meat byproducts (40 CFR §180.6, Category 3) as a result of the proposed uses, except for the use on cowpea forage which is a feed item for dairy cows.  There are no poultry feed items associated with the proposed uses.

Drinking Water
D409108; R. Shamblen; 7/9/2013.

The assessment included mandipropamid and its major aquatic degradates, SYN 500003 and SYN 504851, in drinking water.  Two significant degradates were observed in the aerobic aquatic metabolism study SYN 504851 (maximum 29% of applied material; very mobile) and SYN 500003 (maximum 9.4%; mobile).  Based on the European Union monograph, SYN 500003 has a short residence time in soil (DT50 = 2 days), but is considerably more stable under aerobic aquatic conditions (DT50 = 30 days).  Five degradates were found in the aerobic soil metabolism study, but the maximum level of any of these was 4.25% of applied material.

An acute oral and Ames-test were performed for the metabolite SYN 500003.  This metabolite was not detected in rat metabolism studies.  SYN 500003 was administered once by oral gavage to female rats at doses of 550 or 2000 mg/kg.  The oral LD50 was calculated to be 1049 mg/kg, indicating  it's more acutely toxic via the oral route than the parent compound (however, it is only 0.005-0.006 ppm or 10.5-12.7% of the TRR in root and tuber crops).  The study is acceptable/guideline, with the SYN 500003 degradate classified as Toxicity Category III for oral toxicity.  In addition, a bacterial reverse gene mutation assay (Ames Test) with SYN 500003 was conducted.   No evidence of induced mutant colonies over background was detected in that study.

HED notes that SYN 500003 still possesses a propargyl side chain like those found in the parent.  Loss of this side chain could produce the reactive compound propiolaldehyde.  The latter is believed to be the source of the liver toxicity of propargyl alcohol, for which the petitioner has submitted a 14-day repeat exposure study with rats showing similar hepatotoxicity as seen with mandipropamid.  Therefore, HED concludes that metabolites and degradates still having a propargyl side should be considered comparably as toxic as the parent fungicide.

No toxicity data were submitted for the metabolite SYN 504851.  While SYN 504851 does not have the propargyl side chain, it could generate a reactive aldehyde (e.g., acrolein) similar to propiolaldehyde with a vinyl group instead of the alkyne function.  Therefore, in the absence of repeated dose studies, HED concludes this degradate should also be considered toxicologically equivalent to the parent.


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
Mandipropamid
(Parent + SYN 500003 for root and tuber vegetables )
Mandipropamid

Rotational Crop
Not applicable
Mandipropamid*
Livestock


Ruminant
Not applicable
Not applicable 

Poultry
Not applicable
Not applicable
Drinking Water

Parent, SYN 504851 and SYN 500003
Not Applicable
*Although the parent compound is a residue of concern in rotational crops, tolerances are not needed for the existing or proposed,uses based on the absence of residues in the field rotational crops study following the label's 30-day plantback interval. 

5.2	Food Residue Profile

The nature of the residue in plants, rotational crops, and ruminants is adequately understood.  For the purposes of tolerance enforcement and risk assessment, the terminal residue of concern in primary crops, rotational crops, and ruminants is the parent mandipropamid, with the exception of root and tuber vegetables, where the metabolite SYN 500003 is included for risk assessment.  

The only significant livestock feed item associated with the proposed new uses is cowpea forage, which is not fed to beef cattle, swine or poultry.  It is fed to dairy cattle at up to 20% of the diet in select locations, or as seasonally available.  At the proposed tolerance level of 15 ppm, the calculated dietary burden to dairy cattle is 10 ppm (the contribution to dietary burden from the only current feed items, potato culls and processed waste, is negligible at 0.025 ppm).  

No livestock feeding studies were submitted with this petition.  An acceptable ruminant metabolism study is available.  Goats were dosed with radiolabeled mandipropamid at 30-36 ppm (3-3.6X the dietary burden to dairy cattle) in the feed for 7 consecutive days.  The parent compound was identified only in fat (0.013-0.019 ppm), milk (0.013 ppm), and liver (0.004-0.007 ppm).  Based on the highest detected residue of 0.019 ppm in goat fat, anticipated residues from feeding cowpea forage containing mandipropamid at the recommended tolerance level of 15 ppm would be roughly 0.006 ppm.  HED's ChemSAC recommended against establishing a tolerance in cowpea forage, due to the potential for finite residues in cattle commodities (fat, milk and liver).  Establishing a tolerance in cowpea forage would necessitate the concurrent establishment of tolerances at the LOQ in cattle fat, milk and liver, which would require a suitable method for the enforcement of tolerances in these commodities.  However, with no validated method for enforcing tolerances in cattle commodities, it is not possible to establish tolerances in them (minutes from ChemSAC meeting of 17 July 2013).  The proposed tolerance in cowpea forage cannot be established until a validated method for determining mandipropamid residues in livestock (cattle) commodities is available.
5.2.1	Crop Field Trials (860.1500)
D409363; W. Drew; Aug 27, 2013.

Adequate field trial data were provided to support the proposed tolerances for residues in basil and dried basil.  The residue data in snap beans are adequate to support tolerances in snap beans, but not in all succulent beans (ChemSAC meeting; 17 July 2013); if tolerances in succulent beans are desired, then additional field trial data on a succulent shelled bean cultivar (such as lima beans) will be necessary.  Adequate field trial data were submitted to support the use on ginseng, as well as on greenhouse tomatoes.  The additional data for tomatoes grown in a greenhouse do not indicate the need for any change to the existing tolerances.  In all cases, the studies were considered to have been conducted in geographically representative locations (except greenhouse tomatoes for which no location is specified), with application rates, re-treatment intervals and pre-harvest intervals (PHIs) reflecting the proposed label directions for use.  In all cases, the tolerances are based on detectable residues in the crops/commodities.  A table reflecting the results of the submitted field trial data is provided below.
  


TABLE 5.2.1	Summary of Residue Data from Crop Field and Greenhouse Trials with Mandipropamid.  
                                   Commodity
                                Total Use Rate
                                   (lb ai/A)
                                  PHI (Days)
                             Residue Levels (ppm)
                                       
                                       
                                       
                                       n
                                     Min.
                                     Max.
                                     LAFT*
                                     HAFT*
                                    Median
                                     Mean
                                   Std. Dev.
                         Basil (field and greenhouse)
Fresh stems and leaves
                                  0.520-0.528
                                       1
                                     12[1]
                                      3.5
                                      19
                                       -
                                       -
                                      9.0
                                      9.3
                                      4.8

                                       
                                       
                                     6[2]
                                       -
                                       -
                                      3.6
                                      19
                                      8.8
                                      9.4
                                      5.0
Dried stems and leaves
                                  0.520-0.528
                                       1
                                    6[1, 2]
                                      36
                                      91
                                       -
                                       -
                                      63
                                      63
                                      20
                             Ginseng (field only)
                                 Mandipropamid
                                     Roots
                                  0.521-0.547
                                       2
                                     8[1]
                                    0.0222
                                     0.167
                                       -
                                       -
                                    0.0586
                                    0.0717
                                    0.0551
                                       
                                       
                                       
                                     4[2]
                                       -
                                       -
                                    0.0271
                                     0.119
                                    0.0705
                                    0.0718
                                    0.0475
                             Metabolite SYN500003
                                     Roots
                                  0.521-0.547
                                       2
                                     8[1]
                                   <0.005
                                   <0.005
                                       -
                                       -
                                   <0.005
                                   <0.005
                                       -
                                       
                                       
                                       
                                     4[2]
                                       -
                                       -
                                   <0.005
                                   <0.005
                                   <0.005
                                   <0.005
                                       -
                            Snap bean (field only)
                                Pods with seed
                                  0.490-0.540
                                       1
                                     20[1]
                                    0.0858
                                     0.761
                                       -
                                       -
                                     0.210
                                     0.256
                                     0.175
                                       
                                       
                                       
                                     10[2]
                                       -
                                       -
                                     0.10
                                     0.58
                                     0.220
                                     0.256
                                     0.164
                               Plants with pods
                                  0.490-0.540
                                       1
                                     20[1]
                                     1.24
                                     9.84
                                       -
                                       -
                                     4.15
                                     4.14
                                     2.34
                                       
                                       
                                       
                                     10[2]
                                       -
                                       -
                                     1.27
                                     9.27
                                     4.35
                                     4.14
                                     2.36
                           Tomato (greenhouse only)
                                     Fruit
                                  0.480-0.651
                                       1
                                     8[1]
                                     0.045
                                     0.339
                                       -
                                       -
                                     0.147
                                     0.168
                                     0.101
                                       
                                       
                                       
                                     4[2]
                                       -
                                       -
                                     0.059
                                     0.289
                                     0.115
                                     0.168
                                     0.105
* LAFT = Lowest Average Field Trial; HAFT = Highest Average Field Trial.  
1. n = total number of samples.  
2. n = total number of field trials.

For the crop group expansions, the requested tolerances are supported by existing data.  These include Vegetable, fruiting, crop group 8-10; Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F; Onion, bulb, subgroup 3-07A; and Onion, green subgroup 3-07B.  Concomitant with the establishment of the new crop subgroup tolerances, the grape, dry bulb onion and green onion tolerances should be deleted.

5.2.2	Field Rotational Crops (860.1900)
D328534, D337543; D. McNeilly; 28 August 2007

An adequate limited field rotational crop study was reviewed in Petitions #6F7057 and #7F7184.  Mandipropamid residues were below the LOQ (<0.01 ppm) in all samples of rotated radish roots, radish tops, spinach leaves, fall wheat forage, spring wheat forage, wheat hay, wheat grain, and wheat straw planted at the 28/31-day and 61-day PBIs.  HED has determined that the rotational crop restriction on the label which states "do not plant any crop which is not registered for use with mandipropamid for a period of 30 days after the last application" is appropriate.  Given the label restriction, tolerances in rotational crops are not needed.


5.2.3	Processed Food and Feed (860.1520)

Because there are no processed commodities for ginseng or succulent beans, processing studies are not required for these RACs.  The processed commodity for basil is dried basil, for which adequate data were provided in support of the petition.  A processing study is not needed for tomatoes, as this requirement was addressed in a previous document (D328534; D. McNeilly; August 28, 2007).  

5.3	Water Residue Profile
D409108; R. Shamblen; Jul 9, 2013.

The estimated drinking water concentrations (EDWCs) used in the dietary risk assessments were provided by the Environmental Fate and Effects Division (EFED), (D409108, R. Shamblen, 7/9/2013).  The EDWCs were incorporated directly into these dietary assessments in the food categories "water, direct, all sources" and "water, indirect, all sources."  The EDWCs for mandipropamid were generated using the FQPA Index Reservoir Screening Tool (FIRST) Version 1.1.1 model for surface water, and both the Pesticide Root Zone Model for Ground Water (PRZM-GW v. 1.01) and Screening Concentration in Ground Water (SCI-GROW version 2.3) models for groundwater.  Modeled surface water and groundwater EDWCs are based on the maximum label application rate to tomato and basil (chronic value).

A Total Residue (TR) modeling approach was used to estimate aerobic aquatic half-lives, and estimate drinking water concentrations in surface waters.  Previous drinking water assessments calculated separate half-lives for the parent compound and two degradates of concern, for which exposure was estimated with separate model runs.  Simple addition of the exposure estimates for mandipropamid and it's degradates of concern was used to generate estimated drinking water concentrations.  Previous authors acknowledge this approach is conservative because the exposure estimates may not be temporally coincident.  The TR method, however, tallies the parent compound and its degradates of concern prior to calculating a Total Residue half-life.

The Environmental Fate and Effects Division (EFED) conducted a Tier 1 drinking water exposure assessment for the fungicide mandipropamid.  Tier 1 exposure modeling results are summarized in Table 5.3.  PRZM-GW resulting in the highest estimate of the potential for mandipropamid residues in ground water sources of drinking water.  Maximum estimated drinking water concentrations (EDWC) in ground water are 87 and 79 ug/L for acute and chronic exposures, respectively.  These values are as much as 480 times higher than SCI-GROW model results.  Maximum acute and chronic EDWCs in surface waters are 79 and 9.0 ug/L, respectively.


Table 5.3. Tier 1 Estimated Drinking Water Concentrations (EDWC) for Maximum Mandipropamid Use Patterns.
                             Drinking Water Source
                               (Model, Version)
                                      PCA
                                      (%)
                               Crop Use Pattern
                             (Maximum Annual Rate)
                                     Acute
                                    (μg/L)
                                Chronic (μg/L)
Surface Water (FIRST, 1.1.1)
                                      91
                              Tomato & Basil 
                               (2.08 lbs a.i./A)
                                      79
                                      9.0
Ground Water (PRZM-GW, 1.01)
                                      N/A
                              Tomato & Basil 
                               (2.08 lbs a.i./A)
                                      87
                                      79
Ground Water (SCI-GROW, 2.3)
                                      N/A
                              Tomato & Basil 
                               (2.08 lbs a.i./A)
                                     0.18
Abbreviations: A= acre; a.i. = active ingredient; ha = hectare; kg = kilograms; μg = micrograms; lbs = pounds (US); N/A = not applicable
      
Two previous Tier 1 drinking water assessments of mandipropamid produced nearly identical exposure estimates (USEPA, 2007; and, 2011).  Results of multiple FIRST (v.1.1.0) model scenarios indicated EDWCs in surface waters ranging from 7 to 36 ug/L for chronic and acute exposures.  Ground water exposure estimates in both assessments were about 2.4 ug/L when calculated by SCI-GROW (v. 2.3).  PRZM-GW (v. 1.01) was not used in the 2007 and 2011 assessments.

Differences between the previous two and current drinking water exposure assessments reveal that ground water exposure concentrations decreased by more than a factor of 13 (as determined using the SCI-GROW model), whereas acute surface water exposure concentrations nearly doubled.  These differences are likely attributed to a variety of recent changes incorporated into the drinking water assessment (see D409108, R. Shamblen, 7/9/2013).

Note that although EFED provided HED with estimates of acute surface and ground water estimates, these have not been incorporated into the dietary model due to the lack of an acute endpoint for mandipropamid.

The drinking water models and descriptions are available at the EPA internet site:  http://www.epa.gov/oppefed/models/water/.

5.4	Dietary Risk Assessment

5.4.1	Description of Residue Data Used in Dietary Assessment
D412238; D. McNeilly; Aug 27, 2013.

A chronic dietary exposure assessment was performed for mandipropamid.  The assumptions underlying this unrefined assessment were 100% crop treated (CT), HED-recommended tolerance levels or tolerance-level residues (with the exception of vegetable, tuberous and corm, crop subgroup 1C), and default DEEM-FCID (ver. 7.81) processing factors (with the exception of chemical-specific processing factors for grape wine and sherry).  The mean (i.e., relevant to chronic exposure) drinking water estimate of 79 ppb was provided by the Environmental Fate and Effects Division (EFED) and directly incorporated into the chronic assessment.

5.4.2	Percent Crop Treated Used in Dietary Assessment

The chronic dietary assessment is based on 100% crop treated assumptions for all commodities.

5.4.3	Acute Dietary Risk Assessment

No acute dietary toxicity endpoint could be identified based on the toxicology data currently available for mandipropamid.

5.4.4	Chronic Dietary Risk Assessment

All populations were evaluated for chronic dietary risk.  No risks of concern were identified in the chronic dietary exposure analysis.  The most highly exposed population subgroup is children 1-2 years old which utilizes 46% of the cPAD (Table 5.4.6).  The general U.S. population utilizes 27% of the cPAD.  Since highly conservative assumptions were used in the assessment, actual dietary exposures for all population subgroups is expected to be much lower than those shown in Table 5.4.6.

5.4.5	Cancer Dietary Risk Assessment

The Cancer Assessment Review Committee (CARC) classified mandipropamid as "Not likely to be a human carcinogen;" therefore a cancer assessment was not performed.

5.4.6	Summary Table
D412238; D.McNeilly; Aug 27, 2013.

The results of the dietary exposure and risk analysis for chronic dietary exposures are summarized below in Table 5.4.6.

Table 5.4.6.  Summary of Dietary Exposure and Risk for Mandipropamid (Food and Drinking Water).
                              Population Subgroup
                                 Acute Dietary
                                Chronic Dietary
                                    Cancer
                                       
                         Dietary Exposure (mg/kg/day)
                                    % aPAD
                               Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD
                               Dietary Exposure
                                  (mg/kg/day)
                                     Risk
General U.S. Population
                                      N/A
                                      N/A
                                   0.013475
                                      27
                                      N/A
                                      N/A
All Infants (< 1 year old)
                                       
                                       
                                   0.011653
                                      23
                                       
                                       
Children 1-2 years old
                                       
                                       
                                   0.022893
                                      46
                                       
                                       
Children 3-5 years old
                                       
                                       
                                   0.020342
                                      41
                                       
                                       
Children 6-12 years old
                                       
                                       
                                   0.012364
                                      25
                                       
                                       
Youth 13-19 years old
                                       
                                       
                                   0.009617
                                      19
                                       
                                       
Adults 20-49 years old
                                       
                                       
                                   0.013459
                                      27
                                       
                                       
Adults 50-99 years old
                                       
                                       
                                   0.013425
                                      27
                                       
                                       
Females 13-49 years old
                                       
                                       
                                   0.013293
                                      27
                                       
                                       
 N/A = Not applicable.
6.0	Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered or proposed residential uses for mandipropamid.  Therefore, a residential exposure assessment is not required.

6.1	Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for mandipropamid at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (<7.0 x 10[-9] mm Hg at 25ºC), and the low proposed use rate (0.13 lb ai/A).  However, volatilization of pesticides may be a source of post-application inhalation exposure to individuals nearby pesticide applications.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010.  The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are developed, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for mandipropamid.

6.2	Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial applications allowed on mandipropamid labels, but, to a lesser extent, could also be a potential source of exposure from ground application methods employed for mandipropamid.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm).  On a chemical-by-chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling.  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risks associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers.  This exposure scenario is representative of a worst-case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios.   

7.0	Aggregate Exposure/Risk Characterization
      
In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated.  When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.  
7.1	Acute & Chronic Aggregate Risk

Acute and chronic (both cancer and non-cancer) aggregate exposures include food plus drinking water exposures.  No acute dietary toxicity endpoint could be identified based on the toxicology data currently available for mandipropamid.  As demonstrated under Section 5.4, chronic aggregate risk is not of concern.

7.2	Short- and Intermediate-Term Aggregate Risk

Short-and intermediate-term aggregate exposures take into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level).  For mandipropamid, there are no residential uses, and therefore short- and/or intermediate-term aggregate risks are not of concern.  

8.0	Cumulative Exposure/Risk Characterization

FQPA (1996) stipulates that when determining the safety of a pesticide chemical, EPA shall base its assessment of the risk posed by the chemical on, among other things, available information concerning the cumulative effects to human health that may result from dietary, residential, or other non-occupational exposure to other substances that have a common mechanism of toxicity.  The reason for consideration of other substances is due to the possibility that low-level exposures to multiple chemical substances that cause a common toxic effect by a common mechanism could lead to the same adverse health effect as would a higher level of exposure to any of the other substances individually.  A person exposed to a pesticide at a level that is considered safe may in fact experience harm if that person is also exposed to other substances that cause a common toxic effect by a mechanism common with that of the subject pesticide, even if the individual exposure levels to the other substances are also considered safe.

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 mandipropamid and any other substances, and mandipropamid 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 mandipropamid has a common mechanism of toxicity with other substances.  For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.
9.0	Occupational Exposure/Risk Characterization
D412239; Z. Figueroa; Aug 27, 2013

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses.  The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios: 

Mixer/Loaders
   1. Mixing/loading liquid concentrates to support aerial applications, 
   2. Mixing/loading liquid concentrates to support chemigation applications,
   3. Mixing/loading liquid concentrates to support groundboom applications,
Applicators
   4. Applying sprays with aircraft (enclosed cockpit),
   5. Applying sprays with groundboom equipment, 
Flaggers
   6. Flagging to support aerial spray applications, and
Mixer/Loader/Applicators
   7. Mixing/loading/applying liquid concentrates to support mechanically-pressurized handgun applications.

The maximum single application rates for the proposed uses ranged from 0.09-0.13 lb ai/acre.  The inputs for area treated were based on information in ExpoSAC Policy 9.1.

Based on the proposed use pattern, directions (e.g., 2-4 applications per season with a minimum 7-10 day spray interval) and resistance management practices (e.g., no more than 2 consecutive applications), short- and intermediate-term exposures are expected for occupational handlers.  Since the same endpoint and point of departure were selected for short- and intermediate-term durations, short-term exposure and risk estimates are considered to be protective of intermediate-term exposure and risk.  Long-term exposures are not expected; therefore, a long-term assessment was not conducted.

Results of inhalation exposure are presented for "baseline" level of PPE, defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator.  The mandipropamid product labels direct mixers, loaders, applicators and other handlers to wear long-sleeved shirt and long pants, shoes plus socks.  PPE recommended on the proposed label for early entry to treated areas include: coveralls, chemical-resistant gloves made of any waterproof material, shoes plus socks. 

The maximum application rate for each exposure scenario is presented as the worst-case, and standard assumptions were used with respect to the area treated for each crop/application method, along with the assumption of 80 kg body weight.  Since no short- or intermediate-term dermal endpoints of concern were identified, there is no dermal risk associated with exposure to mandipropamid.  Only inhalation risk estimates have been assessed.  Summaries of the risks for occupational handlers are included in Table 9.1.

All occupational handler scenarios resulted in inhalation MOEs greater than the level of concern (MOEs > 100 for inhalation) at some level of risk mitigation (i.e., baseline attire with no respirator; engineering control for aerial applications (enclosed cockpits)).  No additional PPE recommendations are needed on the proposed label.

The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential.  While HED presents quantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades.  According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for swath guidance in agricultural aviation has grown steadily from the mid 1990's.  Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990's to only 1% in the most recent (2012) NAAA survey.  The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.

HED has no data to assess exposures to pilots using open cockpits.  The only data available reflect exposure to pilots in enclosed cockpits.  Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long-sleeve shirt, long pants, shoes, and socks); per the Agency's Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves duration the application.  With this level of protection, there are no risk estimates of concern for applicators.

Table 9.1.  Occupational Handler Non-Cancer Exposure and Risk Estimates for Mandipropamid.
                               Exposure Scenario
                                Crop or Target
                    Inhalation Unit Exposure (μg/lb ai)[1]
                                    Maximum
                             Application Rate [2]
                           Amount or Area Treated[3]
                                  Inhalation
                                       
                                       
                               Mitigation Level
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                                 Mixer/Loader
                      M/L Liquids for Aerial Applications
                                 [AHETF/PHED]
                           Basil, Snap bean, Ginseng
                                     0.219
                           (Baseline; No Respirator)
                                     0.13
                                     350 A
                                   0.000125
                                    330,000
                          M/L Liquids for Chemigation
                                 [AHETF/PHED]
                           Basil, Snap bean, Ginseng
                                     0.219
                           (Baseline; No Respirator)
                                     0.13
                                     350 A
                                   0.000125
                                    330,000
                    M/L Liquids for Groundboom Applications
                                 [AHETF/PHED]
                           Basil, Snap bean, Ginseng
                                     0.219
                           (Baseline; No Respirator)
                                     0.13
                                     80 A
                                   0.0000285
                                   1,400,000
                                  Applicator
                        Sprays for Aerial Applications
                                    [PHED]
                           Basil, Snap bean, Ginseng
                                    0.0049
                    Engineering control (enclosed cockpits)
                                     0.13
                                     350 A
                                   0.0000028
                                  15,000,000
                      Sprays for Groundboom Applications
                                 [AHETF/PHED]
                           Basil, Snap bean, Ginseng
                                     0.34
                           (Baseline; No Respirator)
                                     0.13
                                     80 A
                                   0.000044
                                    930,000
                                    Flagger
                        Sprays for Aerial Applications
                                    [PHED]
                           Basil, Snap bean, Ginseng
                                     0.35
                           (Baseline; No Respirator)
                                     0.13
                                     350 A
                                   0.000199
                                    210,000
                            Mixer/Loader/Applicator
        M/L/A Liquids for Mechanically-pressurized Handgun Applications
                                    [PHED]
                           Basil, Snap bean, Ginseng
                                      3.9
                           (Baseline; No Respirator)
                                     0.013
                                  1,000 gals
                                   0.000634
                                    65,000
1.	Based on the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (March, 2013); Level of mitigation: Baseline; Eng. control for aerial applications (enclosed cockpits).
2.	Based on registered or proposed label (EPA Reg. No. 100-1254).
3.	Exposure Science Advisory Council Policy #9.1.
4.	Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/A) x Area Treated (A/day) / BW (80 kg).
5. Inhalation MOE = Inhalation NOAEL (41 mg/kg/day) / Inhalation Dose (mg/kg/day). LOC=100.
Occupational Post-Application Assessments

Dermal

Although there is potential for dermal post-application exposure, no dermal endpoint was selected because the rat 28-day dermal toxicity study demonstrated no toxicity up to the limit dose (1,000 mg/kg/day).  Therefore, a quantitative dermal post-application exposure assessment was not conducted.

The restricted entry interval (REI) listed on the master label is based on the acute toxicity of the technical material.  Mandipropamid has low acute dermal toxicity (Toxicity Category IV), and is not an ocular or dermal irritant, nor a dermal sensitizer.  Mandipropamid is not classified as a carcinogen or a neurotoxicant.  In addition, it is not associated with known reproductive or developmental effects.  Based on this information, mandipropamid is categorized as a reduced risk chemical.  Therefore, the REI of 4 hours is adequate to protect agricultural workers from post-application exposures to mandipropamid.  

Inhalation

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for mandipropamid at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (<7.0 x 10[-9] mm Hg at 25ºC), and the low proposed use rate (0.13 lb ai/A).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides.  The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010. The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post-application inhalation exposure into the Agency's risk assessments.  If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post-application inhalation exposure assessment for mandipropamid.

Although a quantitative occupational post-application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers.  Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post-application exposure.  Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post-application inhalation exposure scenarios.


10.0	References

Mandipropamid:  Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action on Fresh Basil, Dried Basil, Ginseng, Fruiting Vegetable (Crop Group 8-10); Small Fruit, Vine Climbing (Crop Subgroup 13-07F), except Fuzzy Kiwifruit; Snap Bean, Bulb Onion (Crop Subgroup 3-07A), and Green Onion (Crop Subgroup 3-07B).  D412238, D.McNeilly; Aug 27, 2013.

Mandipropamid.  Occupational and Residential Exposure Assessment for the Proposed Uses on Basil, Snap Bean, and Ginseng, and the Request to Update Several Existing Crop Groups with Revised Crop Group Definitions.  D412239, Zaida Figueroa; Aug 27, 2013.

Mandipropamid.  Petition to Establish Permanent Tolerances (and Section 3 Registration) for Residues Resulting from Use of the Fungicide on Basil, Succulent Beans, Cowpea Forage, Ginseng and Greenhouse Tomatoes; to Update Fruiting Vegetables Group 8 to Group 8-10; to Extend the Tolerance in Grapes to Subgroup 13-07F, the Tolerance in Dry Bulb Onions to Subgroup 3-07A, and the Tolerance in Green Onions to Subgroup 3-07B.  Summary of Analytical Chemistry and Residue Data.  D409363, W. Drew; Aug 27, 2013.

Drinking Water Exposure Assessment for Proposed Section 3 New Uses on: Basil, Ginseng and Succulent Beans; and Expanded Uses on Bulb Vegetables, Cucurbits, Grapes, and Fruiting Vegetables including Tomatoes., D409108, R. Shamblen, 7/9/2013.

Mandipropamid.  Section 3 Registration Request to Register New Uses on Hops and Tobacco and Confirmatory Residue Analytical Method for Determination of Residues in Crop Matrices.  Summary of Analytical Chemistry and Residue Data.; D348229, D352322, D. Rate; 11 December 2008.  

Mandipropamid.  Request to Register New Food/Feed Uses on Head and Stem Brassica, Leafy Brassica Greens, Cucurbit Vegetables, Fruiting Vegetables, Leafy Vegetables (except Brassica), Tuberous and Corm Vegetables, Grapes, and Onions (Dry Bulb and Green).  Summary of Analytical Chemistry and Residue Data.  Petition Numbers 6F7057 and 7F7184.; D328534, D337543; D. McNeilly; 28 August 2007.  

Ecological Risk Assessment for the Mandipropamid Section 3 New Use on Outdoor/Non-food Ornamentals and Listed Vegetables Grown for Transplant and Retail Sale to Consumers; D382369; C. Wendel; 26 July 2011.  



Appendix A.  International Residue Limits


                        Mandipropamid (PC Code 036602)
      Summary of US Tolerances and International Maximum Residue Limits.
                              Residue Definitions
                             US (40CFR §180.637)
                                    Canada
                                     Codex
Plants:  Mandipropamid (4-chloro-N-[2-[3-methoxy-4-(2-propynyloxy)phenyl] ethyl]-α-(2-propynyloxy)- benzeneacetamide).  
Mandipropamid (4-chloro-N-[2-[3-methoxy-4-(2-propynyloxy) phenyl]ethyl]-α-(2-propynyloxy)- benzeneacetamide).  
Mandipropamid.  

                                 Commodity[2]
                              Tolerance (ppm)[3]
                                   Commodity
                                  MRL (mg/kg)
                                   Commodity
                                MRL[4] (mg/kg)
Basil, fresh leaves
                                      30

                                       

                                       
Basil, dried leaves
                                      200

                                       

                                       
Bean, succulent
Bean, snap
                                      NA
                                      0.9

                                       

                                       
Ginseng
                                     0.30

                                       

                                       
Cowpea, forage
                                      NA

                                       

                                       
Vegetable, fruiting, group 8-10
                                      1.0
Bell peppers, eggplants, ground-cherries, non-bell peppers, okras, pepinos, pepper hybrids, tomatillos, tomatoes
                                       1
Bell peppers, non-bell peppers
                                       1

                                       

                                       
Dried chili peppers
                                      10

                                       

                                       
Tomatoes
                                      0.3
Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13-07F
                                      2.0
Grapes
                                      1.4
                                       
Grapes
                                       2
Onion, bulb, subgroup 3-07A
                                     0.10
Chinese onions, daylilies, dry bulb onions, fritillaria, bulbs, garlic, great-headed garlic, lilies, pearl onions, potato onions, serpent garlic, shallot bulbs
                                     0.05
Bulb onions
                                      0.1
Onion, green, subgroup 3-07B
                                      7.0
Beltsville bunching onions, elegans hosta, fresh Chinese chive leaves, fresh chive leaves), fresh onions, fritillaria leaves, green onions, kurrats, lady's leek, leeks, macrostem onions, shallot leaves, tree onion tops, Welsh onion tops, wild leeks
                                       4
Spring onions
                                       7

                                       

                                       

                                       
Completed:  M. Negussie, 27 June 2013.  
1. Mexico adopts US tolerances, and/or Codex MRLs, for its export purposes.  
2. Includes only commodities of interest for this action.  
3. Tolerance values are those recommended by HED, not those proposed by the petitioner.  
4. * = absent at the LOQ.  Po = post-harvest treatment, such as treatment of stored grains.  PoP = processed post-harvest treated commodity, such as a processed commodity of post-harvest treated stored wheat.  (Fat) = to be measured in the fat portion of the sample.  MRLs indicated as "proposed" have not been finalized by the CCPR and the CAC.  


Appendix B.  Toxicology Profile

B.1	Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses of mandipropamid are in Table B1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.  The acute and chronic toxicity profiles are shown in Tables B.2.1 and B.2.2, respectively.

                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity	
870.1200    Acute Dermal Toxicity	
870.1300    Acute Inhalation Toxicity	
870.2400    Acute Eye Irritation	
870.2500    Acute Dermal Irritation	
870.2600    Skin Sensitization	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.3100    90-Day Oral Toxicity in Rodents	
870.3150    90-Day Oral Toxicity in Nonrodents	
870.3200    21/28-Day Dermal Toxicity	
870.3250    90-Day Dermal Toxicity	
870.3465    28/90-Day Inhalation Toxicity	
                                      yes
                                      yes
                                      yes
                                      no
                                      no
                                      yes
                                      yes
                                      yes
                                       -
                                       -
870.3700a  Prenatal Developmental Toxicity (rodent)	
870.3700b  Prenatal Developmental Toxicity (nonrodent)	
870.3800    Reproduction and Fertility Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)	
870.4100b  Chronic Toxicity (nonrodent)	
870.4200a  Carcinogenicity (rat)	
870.4200b  Carcinogenicity (mouse)	
870.4300    Combined Chronic Toxicity/Carcinogenicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.5100    Mutagenicity -- Bacterial Reverse Mutation Test	
870.5300    Mutagenicity -- Mammalian Cell Gene Mutation Test	
870.5385    Mutagenicity -- Structural Chromosomal Aberrations	
870.5550    Mutagenicity -- Other Genotoxic Effects	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.6200a  Acute Neurotoxicity Screening Battery (rat)	
870.6200b  90-Day Neurotoxicity Screening Battery (rat)	
870.6300    Developmental Neurotoxicity	
                                      no
                                      no
                                      no
                                       -
                                       -
                                       -
870.7485    Metabolism and Pharmacokinetics	
870.7600    Dermal Penetration	
870.7800    Immunotoxicity	
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes

B.2	Toxicity Profiles


Table B.2.1	Acute Toxicity Profile - Mandipropamid
                                 Guideline No.
Study Type
MRID(s)
                                    Results
                               Toxicity Category
870.1100
Acute oral rat
                                   46800201
LD50 > 5000 mg/kg 
                                      IV
870.1200
Acute dermal rat
                                   46800202 
LD50 > 5050 mg/kg 
                                      IV
870.1300
Acute inhalation rat
                                   46800204 
LC50 > 5.19 +- 0.55 mg/L 
                                      IV
870.2400
Acute eye irritation rabbit
                                   46800206
Iritis and positive signs of conjunctivitis clearing within 24 hours.
                                      IV
870.2500
Acute dermal irritation rabbit
                                   46800208
PDI = 0.33 
                                      IV
870.2600
Skin sensitization guinea pig
                                   46800210
Replaced by 47259001.
                                      N/A
870.2600
Skin sensitization mouse
                                   47259001
Test substance is not a dermal sensitizer.
                                   Negative


Table B.2.2	Subchronic, Chronic and Other Toxicity Profile  for Mandipropamid
                                Guideline No. 
                                  Study Type
                       MRID No. (year)/ Classification 
                                  Dose levels
                                    Results
870.3100

90-Day oral toxicity (rat)
46800216
(2005)
Acceptable/
Guideline
ppm= 0, 100, 500, 3000, 5000
mg/kg/day=
M: 0, 8, 41, 260, 435
F: 0, 9, 45, 260, 444
NOAEL = 41/45 mg/kg/day M/F
LOAEL = 260 mg/kg/day both sexes, based on decreased body weights, weight gains and food utilization in males and slight hepatotoxicity in both sexes
830.3100
28-Day oral toxicity (rat)
46800214
(2005)
Acceptable/
Guideline
ppm = 0, 1000, 3000, 10,000, 16,000 [10,000 & 16,000 died < day 4]
mg/kg/day =
M: 0, 135, 418, 624, 604
F: 0, 121, 381, 784, 1410
NOAEL = not established
LOAEL = M=135, F=121 mg/kg/day, based on decreased food consumption in both sexes and decreased body weights and weight gains in males (liver changes at 418/381 mg/kg/day M/F).
870.3100

90-Day oral toxicity (mouse)
46800213 46800217
 (2005)
Acceptable/
Guideline
 
ppm= 0, 300, 800, 2000, 5000
mg/kg/day=
M: 0, 37, 98, 248, 624
F: 0, 47, 129, 316, 800
NOAEL = M/F = 248/316 mg/kg/day
LOAEL =  M/F = 624/800 mg/kg/day, based on decreased body weight gain in males and females (as well as the suggestion of effects on the liver: increased weights in both sexes and microscopic pathology).
870.3150

90-Day oral toxicity (dog)
46800218
46800219
46800220
(2005)
Acceptable/
Guideline

mg/kg/day= 
0, 5, 25, 100, 400 (capsule)
NOAEL = 100 mg/kg/day
LOAEL = 400 mg/kg/day, based on liver toxicity (increased cholesterol, alkaline phosphatase activity, ALT activity, liver weights and microscopic pigment in hepatocytes and Kupffer cells in both sexes and centrilobular hepatocyte vacuolation in females).
870.3200

21/28-Day dermal toxicity (rat)
46800222
46800221
( 2005)
Acceptable/
Guideline
mg/kg/day= 
0, 250, 500, 1000 (limit dose) 
Systemic/Dermal NOAEL = 1000 mg/kg/day
LOAEL = not determined
870.3700a

Prenatal developmental  (rat)
46800224
46800223
(2005)
46800228
(2001)
Acceptable/ Guideline
mg/kg/day= 
0, 50, 200, 1000
Maternal NOAEL = 1000 mg/kg/day
LOAEL = not determined
Developmental NOAEL = 1000 mg/kg/day
LOAEL = not determined
870.3700b

Prenatal developmental (rabbit)
46800227 46800225  46800226 46800229 (2005)
Acceptable/ Guideline
mg/kg/day= 
0, 50, 250, 1000
Maternal NOAEL = 1000 mg/kg/day
LOAEL = not determined
Developmental  NOAEL = 1000 mg/kg/day
LOAEL = not determined
870.3800

Reproduction and fertility effects
(rat)
46800230
46800231 (2005)
Acceptable/ Guideline


ppm=(males/
females)
0, 50, 250, 1500
mg/kg/day= 
(mean of premating both sets of parents) = 0/0, 4.6/5.0, 22.9/24.5, 146.3/148.2

Parental/Systemic NOAEL = M/F = 22.9/24.5 mg/kg/day
LOAEL = M/F = 146.3/148.2 mg/kg/day, based on decreased body weights, weight gains, food consumption and food utilization in males
Reproductive NOAEL = M = 146.3/148.2 mg/kg/day
LOAEL = not determined
Offspring NOAEL = M/F = 22.9/24.5 mg/kg/day
LOAEL = M/F = 146.3/148.2 mg/kg/day, based on decreased pup body weights in both sexes.
870.4100

Chronic toxicity (dog)
46800232 (2005)
Acceptable/ Guideline
mg/kg/day=
0, 5, 40, 400 (capsule)

NOAEL = 5 mg/kg/day
LOAEL = 40 mg/kg/day, based on evidence of liver toxicity (increased incidence and severity of microscopic pigment in the liver and increased alkaline phosphatase activity in both sexes as well as increased alanine aminotransferase activity in males).
870.4300

Combined chronic toxicity/ carcinogenicity
(rat)
46800234 (2005)
Acceptable/ Guideline
ppm = 0, 50, 250, 1000
mg/kg/day= M/F =
0/0, 3.0/3.5, 15.2/17.6, 61.3/69.7

NOAEL = M/F = 15.2/17.6
LOAEL = 61.3/69.7mg/kg/day, based on decreased body weight gain and food utilization and increased nephrotoxicity in males.
There was no evidence of carcinogenicity in rats.
870.4200

Carcinogenicity
(mouse)
46800233 (2005)
Acceptable/
Guideline
ppm = 0, 100, 500, 2000
mg/kg/day= M/F =
0/0, 10.6/13.2, 55.2/67.8, 222.7/284.6
NOAEL = M/F = 55/68  mg/kg/day
LOAEL = 223/285 mg/kg/day, based on decreased body weight gain in both sexes and decreased food utilization in males. 
There was no evidence of carcinogenicity in mice.
870.5100
Bacterial Reverse Mutation Assay 
46800235 (2005)
Acceptable/ Guideline
Tested up to limit dose of 5000 ug/plate
Negative



870. 5300
In Vitro Mammalian Cell Gene Mutation Test  -  Mouse Lymphoma  
46800236 (2005)
Acceptable/ Guideline
Tested up to limit dose (4119 ug/mL)
                                       
                                       
Negative


870. 5375
In Vitro Chromosome Aberration test  -  Human Peripheral Blood Lymphocytes
46800237 (2002)
Acceptable/ Guideline
Up to cytotoxic concentrations
Negative
870.5395
Micronucleus Assay in Rats
46800238 (2005)
Acceptable/ Guideline
Limit dose of 2000 mg/kg
Negative
870.5550
In Vivo/In Vitro Unscheduled DNA Synthesis Assay in Primary Rat Hepatocytes
46800239
Acceptable/ Guideline

mg/kg = 0 or 2000
Negative

870.6200a
Acute neurotoxicity (rats)
46800242
(2005)
46800241
(2003)
Acceptable/ Guideline
mg/kg = 0, 200, 600, 2000 (limit dose)
NOAEL = M/F = 2000 mg/kg
LOAEL = M/F = not observed
870.6200b
Subchronic neurotoxicity (rats)
46800240 (2005)
Acceptable/ Guideline
ppm = 0, 100, 500, 2500
mg/kg/day = M/F = 0/0, 7.4/8.4, 37.3/41.0, 192.5/206.7
NOAEL = M/F = 37/41 mg/kg/day
LOAEL = M/F = 192/207 mg/kg/day, based on slightly decreased body weight, weight gain and food utilization in males.  
870.7485

Metabolism and pharmacokinetics
(rat)
46800243-46800246 (2005)
Acceptable/ Guideline
mg/kg/day =
single oral 3 or 300 methoxy label

repeated 3 methoxy label

single oral 3 or 300 methoxy/chloro labels





After 48 hours, absorption was 67-74% at 3 mg/kg and 30-45% at 300 mg/kg.  Blood Tmax at 3 mg/kg was 8.5 hours for M and 4.5 hours for F; at 300 mg/kg was 24 hours for M and 10 hours for F (rate of resorption greater in F; extent and rate greater in low dose).  Recoveries at 168 hours 88-99% (most eliminated by 48 hours). Excluding 3 mg/kg F, most excreted in feces; at 3 mg/kg F, feces and urine similar.  Elimination after 48 hours in bile was high at 3 mg/kg (55-73%), but was 22-28% at 300 mg/kg.  Liver had highest concentration at all measurements.  More radioactivity in  plasma than whole blood.  Identified compounds 66-94% of administered dose in each group (168 hours).  Parent and following metabolites at >=5% at 3 and/or 300 mg/kg: NOA 458422, NOA 458422 glucuronide, SYN 534133 and CGA 380778.  Differences in metabolic profile due to sex, dose and radiolabel position.  Each unknown  compound < 5%.  Major metabolic transformations involved loss of one or both propargyl groups followed by glucuronidation and O-demethylation. 
870.7600
Dermal Penetration (rat)
46800248 (2005)
Acceptable/ Guideline
Nominal doses: mg/cm[2] skin = 0.00152, 0.0076, 2.54.
Spray strength dilutions of 1/333 and 1/1667 v/v.
Recovery was 96-112%.  Minimal absorption (<0.17 to 3.44% of applied dose).  91-105% recovered from 6 hour skin wash.  Greatest absorption in 1/1667 aqueous dilution 114 hours after 6 hours of exposure (3.44% absorbed).
870.7800
Immunotoxicity  (mouse)
48771701 (2011)
Acceptable/Guideline
0, 56,187 and 649 mg/kg/day
NOAEL = 649 mg/kg/day
LOAEL = not established
Non-Guideline
Methods Development and Validation for Dietary Formulation Analyses
46800215 (2002)
Acceptable/ Non-Guideline
N/A
Validation of analytical method for determining concentrations, stability and homogeneity of test article in dietary formulations.
Non- Guideline
In Vitro Dermal Penetration Study, Rat epidermis
46800247 (2003)
Acceptable/ Non-Guideline
ug/cm[2] skin = 2570 or 2510
Absorption rate greatest during first 30 minutes of exposure, 0.715-0.746 ug/cm[2]/hour.  Absorption rates over 24 hours were 0.077-0.091 ug/cm[2]/hour.  
Non-Guideline
In Vitro Dermal Penetration Study, Rat epidermis
46800251 (2005)
Acceptable/ Non-Guideline
ug/cm[2] skin = 1.35, 6.69, 2538
Absorption was poor (recovery of applied radioactivity 99-105%).  Absorption rates over 24 hours were <0.04 ug/cm[2]/hour in concentrate formulation and 0.01 ug/cm[2]/hour in aqueous spray dilutions. 
Non-
Guideline
In Vitro Dermal Penetration Study, Pig epidermis
46800249
(2003)
Acceptable/
Non-Guideline
ug/cm[2] skin = 
neat: 38,600
in acetone: 39.9
Absorption was poor  (<0.01%).  Absorption rate for neat was greatest during first 4 hours (0.03 ug/cm[2]/hour) and was 0.02 ug/cm[2]/hour over 24 hours.  Absorption rate for acetone was 3.58% (first hour = 0.56, 24 hours = 0.05 ug/cm[2]/hour).  Absorption enhanced by acetone.
Non-
Guideline
In Vitro Dermal Penetration Study, Human epidermis
46800250
(2005)
Acceptable/
Non-Guideline
ug/cm[2] skin = 1.35, 6.69, 2538
Recovery of radioactivity was 95-102%.  Absorption was minimal.  Over 24 hours, absorption was <0.04 ug/cm[2]/hour in the concentrate formulation and <=0.001 ug/cm[2]/hour in the aqueous spray dilutions.

B.2.3	Immunotoxicity

Immunotoxicity study in mice.

In an immunotoxicity study (MRID 48771701), Mandipropamid (96.5% a.i., Lot No. SEZ2BP007) was administered to female CD-1 mice (10/dose) in the diet at con - cen - trations of 0, 300, 1000, or 3000 ppm (equivalent to 0, 56, 187, and 649 mg/kg bw/day, respectively) for 28 consecutive days.  A con - current (positive control) group of 10 female mice received cyclophos - pha - mide monohydrate (CPH) 10 mg/kg bw/day by gavage for the duration of the study.  On Day 25, all mice were im - mun -  - ized with sheep red blood cells (SRBC), a single intravenous (IV) injection 0.25 mL (dose volume of 2 x 10[8]/mL).  During the study, clinical condition, bodyweight, food and water consumption were evaluated.  At sacrifice, blood was collected for the deter - mination of anti-SRBC specific IgM, and the liver, thymus, and spleen were removed and weighed.  The anti-SRBC IgM concentration was measured with Enzyme Linked Immunosorbent Assay (ELISA).

The positive control group treated with cyclophosphamide (CPH) had one death on Day 3 but the cause was unable to determine.  There were no treatment related clinical signs of toxicity or effects on body weight, food intake, or organ weights.  The positive control group had statistically significant decreased (p< 0.05) body weight throughout the study, and the terminal body weight gain was ~50% of the concurrent control.  The average absolute spleen weight of CPH-treated mice was decreased by 16% at study termina - tion, but there was no difference in relative spleen weight when compared to the controls.  

The systemic NOAEL was 3000 ppm (equivalent to 649 mg/kg bw/day), the highest dose tested.  A systemic LOAEL was not established.

There were no statistically significant decreased in anti-SRBC specific IgM levels in the in treated groups when compare to the vehicle control group.  High inter-individual variability was noted in all the treatment groups as well as in the control group.  Evaluation of the individual animal data of this study did not show any trend or distribution that would demonstrate significant suppression of anti-SRBC antibody response. Positive control group had 91% decreased in the IgM response. This confirmed the ability of the test system to detect immuno-suppressive effects and confirmed the validity of the study design.

 The Natural Killer (NK) cells activity was not evaluated in this study.  The toxicology database for mandipropamid does not reveal any evidence of immunotoxicity.  The overall weight of evidence suggests that the chemical does not directly target the immune system.  Under HED guidance a NK cell activity assay is not required at this time.

The immunotoxicity NOAEL was 3000 ppm (equivalent to 649 mg/kg bw/day), the highest dose tested.  Immunotoxicity LOAEL was not established.

This immunotoxicity study is classified Acceptable/Guideline and satisfies the guideline

Appendix C.  Physical/Chemical Properties



Table A.C.   Physical and chemical Properties of the Technical Grade of Mandipropamid.
Parameter
Value
Reference
Melting point/range
96.4-97.3ºC
MRID 46800006 (100-REIR.doc, S. Mathur, 22/MAY/2007)
Molecular formula/weight
C23H22ClNO4  /  411.9

pH
6-8 at 25ºC (1% aqueous dispersion)

Density
1.24 x 10[3] kg/m[3] at 22ºC

Water solubility (25°C)
4.2 mg/L 

Solvent solubility (25°C)
n-hexane	 42 mg/L
n-octanol	 4.8 g/L
toluene		 29 g/L
methanol	 66 g/L
ethyl acetate	 120 g/L
acetone		 300 g/L
dichloromethane	 400 g/L

Vapor pressure
<9.4 x 10[-7] Pa at 25°C or <7.0 x 10[-9] mmHg

Dissociation constant, pKa
No dissociation constant in the pH range of 1 to 12

Octanol/water partition coefficient, Log(POW)
3.3 at 25ºC




Appendix D.  Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.  These studies, listed below, have been reviewed for ethical conduct.  The studies were considered appropriate for use in risk assessments.

      The PHED Task Force, 1995.  The Pesticide Handlers Exposure Database, Version 1.1.  Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.
      
      The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table.  U.S. Environmental Protection Agency.  Released June 21, 2011.

