                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                                                     	OFFICE OF CHEMICAL SAFETY
                                                      	AND POLLUTION PREVENTION
	



January 16, 2013							
					
SUBJECT:	Naphthalene Acetates:  Human Health Risk Assessment for a Proposed Use on Avocado, Mango, Mamey Sapote, Rambutan, and updating crop group Fruit, Pome, Group 11-10.

PC Code:  056002, 056007, 056008
DP Barcode: D397387
Decision No.:  427532
Registration No.: 5481-429, 5481-541
Petition No.:  2E7991
Regulatory Action: Section 3
Risk Assessment Type:  Single Chemical Aggregate
Case No.:  0379
TXR No.:  NA
CAS No.:  86-87-3 (NAA)
MRID No.:  NA
40 CFR: §180. 155

FROM:	Thurston G. Morton, Senior Chemist 
            Susan V. Hummel, Senior Chemist
            Abdallah Khasawinah, PhD., Toxicologist
            Risk Assessment Branch 4, Health Effects Division (7509P)

THROUGH:	Elissa Reaves, Ph.D., Branch Chief
            Risk Assessment Branch 4, Health Effects Division (7509P)

TO:		Laura Nollen/Barbara Madden, PM #5
		Risk Integration, Minor Use & Emergency Response Branch
		Registration Division (7505P)

		and

      Tony Kish, PM 22
		Fungicide Branch, Registration Division (7505P)

            
This document provides the Health Effects Division's (HED's) risk assessment for the amended Section 3 use for naphthalene acetates on Avocado, Mango, Mamey Sapote, Rambutan, and updating crop group Fruit, Pome, Group 11-10.  The document has been revised to include an assessment of aggregate risk from residential exposures to naphthalene acetates.  








1.0 	EXECUTIVE SUMMARY	5
2.0	HED RECOMMENDATIONS	8
2.1	Data Deficiencies/Conditions of Registration	8
2.2	Tolerance Considerations	9
2.2.1	Enforcement Analytical Method	9
2.2.2	International Harmonization	9
2.2.3	Recommended Tolerances	9
2.2.4	Revisions to Petitioned-For Tolerances	10
2.3	Label Recommendations	10
3.0	INGREDIENT PROFILE	10
3.1	Chemical Identity	10
3.2	Physical/Chemical Characteristics	10
3.3	Pesticide Use Pattern	11
3.3.1	Registered Products	12
3.3.2	Proposed New Uses	12
3.4 	Anticipated Exposure Pathways	12
3.5	Considerations of Environmental Justice	13
4.0	HAZARD CHARACTERIZATION/ASSESSMENT	13
4.1	Toxicology Studies Available for Analysis	13
4.2	Absorption, Distribution, Metabolism and Excretion	14
4.3	Toxicological Effects	15
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	15
4.4.1	Completeness of the Toxicology Database	16
4.4.2	Evidence of Neurotoxicity	16
4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal	17
4.4.4	Residual Uncertainty in the Exposure Database	17
4.5	Toxicity Endpoint and Point of Departure	17
4.5.1	Dose-Response Assessment	17
4.5.2	Recommendations for Combining Exposure Routes	18
4.5.3	Classification of Carcinogenic Potential	18
4.5.4	Summary of Points of Departure Used in Risk Assessment	18
5.0	DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT	19
5.1 	Metabolite/Degradate Residue Profile	19
5.1.1	Summary of Plant and Livestock Metabolism Studies	19
5.1.2 	Comparison of Metabolic Pathways	19
5.1.3 	Environmental Fate and Transport	20
5.1.4 	Residues of Concern Summary and Rationale	20
5.2	Food Residue Profile	20
5.2.1	Residues in Crops	21
5.3 	Water Residue Profile	21
5.3.1	Estimated Drinking Water Concentrations	22
5.4.1	Acute Dietary and Drinking Water Analysis	23
5.4.2	Chronic Dietary and Drinking Water Analysis	23
6.0 	RESIDENTIAL EXPOSURE AND RISK ASSESSMENT	24
6.1	Residential Bystander Postapplication Inhalation Exposure	24
6.2	Spray Drift	24
7.0 	AGGREGATE EXPOSURE AND RISK ASSESSMENT	25
7.1	Acute & Chronic Aggregate Risk	25
7.2	Short- and Intermediate-Term Aggregate Risk	25
7.3	Intermediate-Term Aggregate Risk	Error! Bookmark not defined.
8.0	CUMULATIVE RISK	28
9.0	OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION	28
9.1	 Exposure Scenarios	28
9.2	Handler Exposure	28
9.2.1 	Handler Exposure Scenarios	29
9.2.2	Handler Exposure Data	29
9.2.3 	Handler Exposure Assumptions	29
9.2.4 	Handler Exposure and Risk Estimates	32
9.3	Post Application Exposure	33
9.3.1	Post Application Exposure Scenarios	34
9.3.2	Post Application Exposure Assumptions	35
9.3.3 	Post-Application Exposure and Risk Estimates	38
9.3.4 	Restricted Entry Interval	39
10.	REFERENCES	39
A 	TOXICOLOGY DATA SUMMARY	  41
A.1 	Guideline Data Requirements	Error! Bookmark not defined.
A.2	Toxicity Profiles	.42
A.3	EXECUTIVE SUMMARIES	.51
APPENDIX C. Physical/Chemical Properties	69
APPENDIX D.  Studies Reviewed for Ethical Conduct	70






































1.0 	EXECUTIVE SUMMARY

This assessment provides information to support the Section 3 registration and establishment of tolerances for a proposed new use of naphthalene acetates on avocado, mango, mamey sapote, rambutan, and updating crop group fruit, pome, group 11-10.  The risk assessment process considers the human health effects of pesticides and incorporates an assessment of tolerances (pesticide residue limits in food) to ensure that they meet the safety standard established by the Food Quality Protection Act (FQPA) of 1996. 

Under PP#2E7991, the Interregional Research Project Number 4 (IR-4) has submitted a petition for the establishment of permanent tolerances for residues of the plant growth regulator 1-Naphthaleneacetic acid (NAA) in conjunction with requests for amended Section 3 registrations of the two pesticide formulations:  TRE-HOLD Sprout Inhibitor A112, containing 15.1% NA ethyl ester (1 lb ae/gal NAA); and Fruitone L, containing 3.1% NAA sodium salt.  

Use Profile

1-Naphthaleneacetic acid (NAA), its salts, ester, and acetamide are plant growth regulators which are collectively referred to as naphthalene acetates.  They are currently registered for use on various orchard and fruit crops and ornamentals.  Naphthalene acetates currently have tolerances in/on a number fruit commodities ranging from 0.05 ppm to 0.15 ppm (40 CFR§180.155), low residues, showing low potential for occupational exposure.  Naphthalene acetates are used to stimulate growth, delay flower induction and leaf drop, prevent preharvest fruit drop, thin fruit, and control sprout formation.  Registered formulations include dust, wettable powder, flowable concentrate, emulsifiable concentrate, soluble concentrate, and liquid ready-to-use.  Thinning and stop drop formulations containing naphthalene acetates are applied using ground spray or aerial equipment.  Formulations for control of sprout formation containing the ester and/or acetamide of 1- naphthaleneacetic acid are applied by hand held sprayer and paint brush.  Naphthalene acetate containing products used to stimulate root growth are applied as a dilute root dip or soil drench.  Residential uses are limited to root dip and sprout inhibition applications on ornamental plants.  The plant growth regulating activity of naphthalene acetates is due to structural similarity to the natural plant hormone indole acetic acid (IAA), the most common naturally occurring auxin.  IAA promotes growth in excised plant organs, induces adventitious roots, inhibits axillary bud growth, and regulates gravitropism.  

Proposed New Uses

Under consideration with this action are two formulations of the plant growth regulator NAA:  TRE-HOLD Sprout Inhibitor A112 (EPA Reg. No. 5481-429; 15.1 % NAA, ethyl ester (1 lb ae/ gal)) and Fruitone L (EPA Reg No. 5481-541 (3.1 % NAA, sodium salt)).  The NAA, ethyl ester, will be used to treat pruned branches and limbs of avocado, mango, and mayme sapote within a few days of pruning by applying the product by spray, brush, sponge, or paint roller.  NAA, Sodium Salt, will be used to treat Rambutan by spraying panicles to runoff.  The existing use on apples and pears is being expanded to include the Pome Fruit Crop Group 10-11.  This includes the same use on pruned branches and limbs, as well as chemical thinning.  Both labels include the default REI of 12 hours, and require the following PPE for direct mixers, loaders, applicators and other handlers: long-sleeved shirt and long pants, shoes plus socks, and chemical-resistant gloves.

Hazard Characterization
      
The toxicology data base is adequate to characterize the toxicity of the naphthalene acetates.  All six chemicals that comprise the naphthalene acetates are combined for the toxicity assessment because they are structurally related and are metabolized to the acid form and eliminated from the body as glycine and glucuronic acid conjugates within 48 hours after exposure.  Naphthalene acetates have low acute toxicity via the oral, inhalation and dermal routes of exposure. NAA is not a skin irritant or a dermal sensitizer.  The NAA acid and sodium salt products were found to be irritating to the eye, but the NAA ethyl ester was not an eye irritant, and neither wsa the NAA sodium salt product under consideration with this action. The NAA acetamide was not an eye irritant in a study conducted on the currently produced material.
      
Repeated exposure oral toxicity studies in rats and dogs resulted in decreased body weights and body weight gains accompanied by decreased food consumption.  The major target organs of subchronic and chronic oral exposure were the liver, stomach and lung.  Repeated oral exposure also resulted in decreased hematocrit and hemoglobin along with reduced RBC count in rats and dogs and hypocellularity of the bone marrow in dogs.  There was no developmental toxicity at highest doses of NAA tested in the rat or in the rabbit, but developmental toxicity (decreased fetal weight and minor skeletal changes) were seen in rats orally gavaged with the sodium salt.  Reproductive effects of NAA sodium salt occurred at relatively high doses and were limited to reduced litter survival and pup weight throughout lactation in both generations of offspring in a two generation reproduction study.  Carcinogencity studies of NAA acetamide in mice and NAA sodium salt in rats and mice are considered adequate for the evaluation of the oncogenicity of the NAA group.  In these three studies the tested NAA compounds were not carcinogenic in mice or rats. 

Based on structural activity relationship (SAR) and metabolism data, all forms of NAA are expected to exhibit similar toxicological effects.  Therefore the Agency concluded that required toxicity testing on any form should serve for all members of this group of chemicals. 
      
Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water, residential, and occupational exposure scenarios.  There were no toxicological effects attributable to a single exposure of naphthalene  acetates observed in oral toxicity studies.  Therefore, a POD for acute dietary exposure was not selected.  A chronic RfD was selected from a chronic toxicity study in dogs based on stomach lesions and liver effects in males.  A toxicological point of departure (POD) for dermal exposures was selected from a dermal toxicity study in rats based on reduced body weight gain and food efficiency at the highest dose tested.  A short-term inhalation exposure POD was selected from a developmental toxicity study in rats based on decreased body weight gain.  An uncertainty factor of 100X was applied to endpoints selected for exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation), and a 10x database uncertainty factor (UFDB) for lack of an inhalation study. 
   
Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water), residential, and occupational exposure pathways based on registered uses and requests for a new use of NAA sodium salt and ethyl ester on to treat pruned branches and limbs of avocado, mango, and mayme sapote within a few days of pruning by applying NAA, ethyl ester, by spray, brush, sponge, or paint roller.  Rambutan is treated with NAA, sodium salt, by spraying panicles to runoff.  Screening level acute and chronic dietary and drinking water risk assessments for naphthalene acetates conclude that dietary and drinking water exposure estimates are below HED's level of concern the general population and all population subgroups.  Residential handler exposures were assessed; residential post-application exposure is not expected, based on the registered use pattern.  Worker exposures were assessed for handler and post-application activities.  Occupational exposure and risk estimates indicate that worker handler and post-application exposures are not of concern at the maximum proposed application rate for the proposed new use.

 Use of Human Studies

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 data, which include studies from PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; the ARTF database; the Residential SOPs for Handlers for Paints and Preservatives are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.  For certain studies, the ethics review may have included review by the Human Studies Review Board.  Descriptions of data sources, as well as guidance on their use, can be found at the Agency website.  

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.  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.  

Tolerance Recommendation

Pending submission of a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting an amended Section 3 registration for the requested amended use of NAA, sodium salt, NAA, ethyl ester, nor establishment of the following tolerances for residues of naphthalene acetic acid.  
      
          Avocado.....	0.05  ppm
          Mango	0.05  ppm
          Sapote, Mamey    .....................................................................0.05 ppm
          Rambuttan  ................ .......................................................... 3.0  ppm
          Fruit, pome, group 11- 10	.........0.15  ppm

Tolerances are currently established under 40CFR§180.155(a) for the combined residues of 1-naphthaleneacetic acid and its conjugates calculated as 1-naphthaleneacetic acid from the application of 1-naphthaleneacetic acid, its ammonium, sodium, or potassium salts, ethyl ester, and acetamide in/on sweet cherry, fruit pome group 11, olive, orange, pineapple, and tangerine.  The tolerance expression is in accord with the Agency's current guidance on tolerance expressions.

A time-limited Section 18 emergency exception tolerance under 40CFR§180.155(b) is also established for avocado (expires 12/31/12).  The established tolerances range from 0.05 ppm to 0.15 ppm.  

No Codex, Canadian, or Mexican maximum residue limits (MRLs) have been established for residues of (NAA), its salts, ester, and acetamide for the use in this petition.  Thus, harmonization is not an issue.

2.0	HED RECOMMENDATIONS

2.1	Data Deficiencies/Conditions of Registration 

There are no residue chemistry issues that would preclude granting registration for the requested treatment uses of naphthalene acetates on avocado, mango, and mayme sapote, rambutan, or pome fruit group 11-10. 

Immunotoxicity and acute and subchronic neurotoxicity studies were required as part of new 40 CFR Part 158 data requirements for registration of a pesticide.  However, the HASPOC has waived the requirement for acute and subchronic neurotoxicity studies at the present time.  A 28-day inhalation study is required and in the absence of this study, a 10x database uncertainty factor (UFDB) is needed. 

Note to PM:

      Immunotoxicity study remains outstanding.
      A 28-day inhalation study is required, using NAA sodium or potassium salt.
      Revised Section F required.
      Acute and subchronic neurotoxicity studies are not needed at the present time.  
      
2.2	Tolerance Considerations

	2.2.1	Enforcement Analytical Method

An HPLC method using fluorescence detection (Method NAA-AM-001) for apples and pears and a similar method for olives and olive oil (Method NAA-AM-002) has been previously submitted for determination of NAA in plant commodities. These methods include extraction with water and incorporate a basic hydrolysis step to release bound residues.  These methods do not use benzene or diazomethane which are being discouraged by the Agency for safety reasons. Theses methods have been subjected to successful independent laboratory validations. Acceptable recoveries were obtained from apples, olives and olive oil fortified with NAA at the method LOQ (0.01 ppm) and at 1.0 ppm.  This method is suitable for enforcement.


	2.2.2	International Harmonization
      
No Codex, Canadian, or Mexican maximum residue limits (MRLs) have been established for residues of NAA, its salts, ester, and acetamide on naphthalene acetates on avocado, mango, and mayme sapote, rambutan, or pome fruit group 11-10.
      
	2.2.3	Recommended Tolerances
      
The petitioner has requested an exemption from the requirement of a tolerance for residues of NAA in/on avocado, mango, and mayme sapote, rambutan, or pome fruit group 11-10..  

There are no residue chemistry issues that would preclude granting registration for the requested seed piece treatment use of naphthalene acetates on avocado, mango, and mayme sapote, rambutan, or pome fruit group 11-10. or establishment of a tolerance for the combined residues of 1-naphthaleneacetic acid and its conjugates calculated as 1-naphthaleneacetic acid from the application of 1-naphthaleneacetic acid, its ammonium, sodium, or potassium salts, ethyl ester, and acetamide in/on the following commodities. 


Table  2.2.3.	Tolerance Summary for NAA
Commodity
                     Established/Proposed Tolerance (ppm)
                          Recommended Tolerance (ppm)
Comments; Correct Commodity Definition
                      Tolerances Proposed Under PP#2E7991
Avocado
                                     0.05
                                       

Mango
                                     0.05
                                       

Mamey Sapote
                                     0.05
                                       

Rambuttan
                                      3.0
                                      2.0

Fruit, pome, group 11-10
                                     0.15
                                       


	2.2.4	Revisions to Petitioned-For Tolerances

A revised Section F is needed to correct the proposed tolerance level for NAA on rambutan.  EPA has revised the tolerance level for rambutan based on analysis of the field trial data using the tolerance/MRL calculator in accordance with the Organization for Economic Cooperation and Development's (OECD's) "MRL Calculator User Guide Standard Operating Procedure (SOP)."  

2.3	Label Recommendations

	No Label Recommendations are required.

3.0	INGREDIENT PROFILE 

3.1	Chemical Identity

The nomenclature for NAAs is provided in Table 3.1.



Table 3.1. NAA Nomenclature
Chemical structure




Common name
                                 NAA acetamide
                                      NAA
Molecular Formula
                                   C12H11NO
                                   C12H10O2
Molecular Weight
                                    185.23
                                    186.20
IUPAC name
                            2-(1-naphthyl)acetamide
                           2-(1-naphthyl)acetic acid
CAS name
                            1-naphthaleneacetamide
                           1-naphthaleneacetic acid
CAS #
                                    86-86-2
                                    86-87-3
PC Code
                                    056001
                                    056002
Chemical structure




Common name
                              NAA potassium salt
                               NAA ammonium salt
Molecular Formula
                                   C12H10O2K
                                   C12H13NO2
Molecular Weight
                                    224.31
                                    203.24
IUPAC name
                         potassium-2(1naphthyl)acetate
                         ammonium-2(1naphthyl)acetate
CAS name
                  1-naphthalnene acetic acid, potassium salt
                    1-naphthaleneacetic acid, ammonium salt
CAS #
                                  15165-79-4
                                  25545-89-5
PC Code
                                    056003
                                    056004
Chemical structure




Common name
                                NAA sodium salt
                                NAA ethyl ester
Molecular Formula
                                  C12H10O2Na
                                   C14H14O2
Molecular Weight
                                     208.2
                                    214.26
IUPAC name
                          sodium-2(1naphthyl)acetate
                           ethyl-2(1naphthyl)acetate
CAS name
                     1-Naphthaleneacetic acid, sodium salt
                     1-Naphthaleneacetic acid, ethyl ester
CAS #
                                    61-31-4
                                   2122-70-5
PC Code
                                    056007
                                    056008

3.2	Physical/Chemical Characteristics 

      A detailed description of the physiciochemical properties of NAA is provided in Appendix C.   Based on the limited available data, NAA exhibits relatively low solubility in water and higher solubility in solvents. NAA has a relatively high vapor pressure (0.3 mmHg), but its salts and esters will have lower vapor pressures.  NAA is relatively mobile but short lived in terrestrial and aquatic environments.  NAA does not present significant concerns for bioaccumulation based on measured bioconcentration factors. 
      
3.3	Pesticide Use Pattern

	3.3.1	Registered Products	

There are 44 active registrations for naphthalene acetates, 31 Section 3s, 12 SLNs (24(c)s)., and 1 Section 18. 

	3.3.2	Proposed New Uses 

Under PP#2E7991, The Interregional Research Project Number 4 (IR-4) has submitted a petition for the establishment of permanent tolerances for residues of the plant growth regulator 1-Naphthaleneacetic acid (NAA) in conjunction with requests for amended Section 3 registrations of  the two pesticide formulations:  TRE-HOLD Sprout Inhibitor A112, and Fruitone L.  The use pattern for the proposed new use is provided in Table 3.3.

Table 3.3.  Summary of Directions for Use of Naphthalene Acetates
Applic. Timing, Type, and Equip.
                                  Formulation
                                       
                                 Applic. Rate 
                                   (lb ae/A)
                          Max. No. Applic. per Season
                          Max. Seasonal Applic. Rate
                                   (lb ae/A)
                                      PHI
                                    (days)
                       Avocado, Mango, and Mamey Sapote
Foliar spray/
brush/sponge/ paint roller
TRE-Hold Sprout Inhibitor A-112, EPA Reg. No. 5481-429;
                      15.1 % NAA, ethyl ester (1 lb/ gal)
0.078 lb ae/gal
 11 oz. product/gallon
                                  (1.1% w/w)
                                       
                                 two per year
                                       
                                     0.156
                                    10 days
                                       

Use Directions and Limitations:  Prune and treat pruned branches and limbs within a few days.  Apply an average of 3 fluid ounces mixture per tree.  A minimum 45-day RTI is specified.  The REI is 12 hours.
                                   Rambutan 
Foliar spray
           Fruitone L, EPA Reg No. 5481-541 (3.1 % NAA, sodium salt)
                     90 ppm solution (<0.0001 lb ae/A)

                                 one per year

                                      NS
                                    2 days


Use Directions and Limitations:  Spray Rambuttan panicles to runoff.  The REI is 12 hours.
                           Fruit, Pome, Group 11-10
For chemical thinning: Foliar spray, Aerial
           Fruitone L, EPA Reg No. 5481-541 (3.1 % NAA, sodium salt)
                           0.5 to 4.0 fl oz/100 gal
                                (0.004 lb ae/A)
                                      NS
                                      NS
                                   Fruit set

Use Directions and Limitations:  Apply at petal fall and/or early fruit set.  Ensure uniform spray coverage using tree row volume.  For ground applications use up to 500 gal water per acre.  For aerial applications, use 5-10 gallons of water per acre.  Directions provided for apples and pears.  For other fruits in crop group, follow directions for thinning.  The REI is 12 hours.
To control pre-harvest drop:  Foliar spray, Aerial
           Fruitone L, EPA Reg No. 5481-541 (3.1 % NAA, sodium salt)
                                     0.11
                                      NS
                                  150 g ae/A
                                    2 days

Use Directions and Limitations:  Use sufficient water to ensure coverage, by air a minimum of 5 gallons.  A typical application is 8-32 fl oz per acre, made 1-4 weeks prior to harvest.  If needed, repeat at weekly intervals.  Directions provided for apples and pears.  The REI is 12 hours.
[1] ae = acid equivalent

Note:  application rates are given in terms of acid equivalents (lb ae/A or gal) rather than active ingredient (lb ai/A or gal) to provide the amount of NAA applied.

Both product labels direct mixers, loaders, applicators and other handlers to wear long-sleeved shirt and long pants, shoes plus socks, and chemical-resistant gloves.


3.4 	Anticipated Exposure Pathways

Dietary (food and water) and occupational exposures via dermal and inhalation pathways are expected based on proposed uses of naphthalene acetates on avocado, mango, and mayme sapote, rambutan, and pome fruit group 11-10.  There are no residential uses for NAA resulting in exposure to children via incidental oral activities.   Exposure to residential handlers is expected from currently registered uses.  

3.5	Considerations 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 by the US Department of Agriculture (USDA) under the 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/ASSESSMENT

4.1	Toxicology Studies Available for Analysis

Based on structural activity relationship and metabolism data, all forms of NAA are expected to exhibit similar toxicological effects.  Therefore the Agency concluded that required toxicity testing on any form should serve for all members of this group of chemicals. The toxicity database for naphthalene acetates is sufficient for a full hazard evaluation and is considered adequate to evaluate risks to infants and children.  Acceptable developmental toxicity studies in the rat and rabbit and an acceptable reproduction study in the rat are available.  Based on the results of the available toxicity studies, there is no evidence for neurotoxicity or immunotoxicity. HASPOC has waived the requirement for acute and subchronic neurotoxicity at the present time. However, in accordance with the revised 40 CFR Part 158 Toxicology Data Requirements, an Immunotoxicity study (870.7800) is required.  A subchronic inhalation toxicity study is not available and is required based on weight of evidence considerations by the HASPOC (K. Rury, 10/16/12)   

The following data are available:
Acute- Oral rat, dermal rat, inhalation rat, eye irritation rabbit, dermal irritation rabbit, and skin sensitization guinea pig.
Subchronic- Oral 90-day rat, oral 90-day mouse (3), and oral 90-day dog;
Chronic- Oral rat, mouse and dog;
Reproductive/developmental- Oral developmental rabbit and rat, 2-generation reproductive rat
Other- Oral rat and mouse cancer studies, 21-day dermal rabbit toxicity and dermal penetration study, acute neurotoxicity, metabolism, mutagenicity screens and mechanistic studies (3).
      
4.2	Absorption, Distribution, Metabolism and Excretion

The absorption, distribution metabolism and excretion of NAA were studied in rats.  In one study, rats were given either a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day) of [[14]C] ring labeled -1-naphthaleneacetamide.  Recovery of administered radioactivity was 97-101%. 1-Naphthaleneacetamide was readily absorbed and excreted within 36 hours.  Urinary excretion accounted for 66-74% of the administered radioactivity for single and repeat doses.  Repeat doses did not appreciably affect the absorption/excretion processes.  Excretion via the feces accounted for the remainder of the administered radioactivity in all treatment groups.  Urinary metabolism involved amide cleavage followed by glycine conjugation with the glycine conjugate being the major metabolite of the low and repeat doses (14-47%). The glucuronide conjugate was also a major metabolite at the low doses (4.5-7%).  For feces, the major metabolite detected was the dihydrodiol of naphthaleneacetamide (4-11%).  Parent compound was detected at low concentrations (1-2% of administered) only in feces.  In another study, rats were given either a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day) of [[14]C] ring labeled 1-naphthaleneacetic acid, ethyl ester. Recovery of administered radioactivity was 99-101%. 1-Naphthaleneacetic acid, ethyl ester was readily absorbed and excreted within 36 - 48 hours following a single and repeat doses.  Urinary excretion accounted for 68-85% of the administered radioactivity following single or multiple oral low doses and 62-78% following a single high dose.  Excretion via the feces accounted for the remainder of the administered radioactivity excreted by all treatment groups. At the high dose, glucuronide conjugation appeared to play a more important role following ester cleavage.  Parent compound was detected at low concentrations (0.5-5% of administered) only in feces.  For both studies, excretory patterns exhibited no gender-related variability for the low dose groups and only minor gender difference at the high dose.  Excretion patterns of the high-dose group reflected delayed absorption.  Tissue burdens of parent and metabolites were very low at termination for both studies.  Most components in the matrices examined (urine and feces) were adequately quantified and characterized.  

The metabolism studies of the acid and its acetamide and the ethyl ester in animals provide supporting evidence that the toxicity of these various forms of NAA would be similar since all are metabolized to the acid form and eliminated from the body as glycine and glucuronic acid conjugates within 36 to 48 hours of initial exposure.

4.3	Toxicological Effects

The major target organs of repeated oral exposure of NAA to rats, dogs and mice were the liver (enlarged liver, increased liver weight with histopathological changes: vacuolation of the periportal hepatocytes, pericholangitis, sinusoidal histiocytosis in dogs) stomach (mucosal gland dilation), lung (focal alveolar macrophages).the liver, stomach and lung.  Repeated oral exposure also resulted in decreased hematocrit and hemoglobin along with reduced RBC count in rats and dogs and hypocellularity of the bone marrow in dogs. 

There was no developmental toxicity at highest doses of NAA tested in the rat or rabbit, but developmental toxicity (decreased fetal weight and minor skeletal changes) were seen in rats orally gavaged with the sodium salt. Reproductive effects of NAA sodium salts included reduced litter survival and pup weight throughout lactation in both generations of offspring in a two generation reproduction study.  

NAA and its acetamide and the ethyl ester were tested for mutagenic effects in a gene mutation bacterial assay, mouse lymphoma assay, and mouse erythrocyte micronucleus assay and were not mutagenic.  Additionally NAA was tested for mitotic gene conversion and dominant lethality in rats and found to be negative.  A published NCI carcinogenicity study of NAA acetamide in mice and a guideline chronic/oncogenicity study of NAA sodium salt in rats and mice are considered adequate for the evaluation of the oncogenicity of the NAA group.  In these three studies the tested NAA compounds were not carcinogenic in mice or rats. 
	
Naphthalene acetates have low acute toxicity via the oral (Toxicity Category III), inhalation (Toxicity Category IV), and dermal (Toxicity Category III) routes of exposure.  NAA is not a skin irritant (Toxicity Category IV).  It is not a dermal sensitizer.  The NAA acid and its sodium salt were found to be irritating to the eye, but not the NAA ethyl ester (Category IV).  The NAA acetamide was found to be an eye irritant in one old test and a non-eye irritant in another recent study conducted on the currently produced material.

The complete toxicity profile for NAA is provided in Appendix A. 
      
4.4	Safety Factor for Infants and Children (FQPA Safety Factor)	

The FQPA factor for increased susceptibility to infants and children is reduced to 1x based on the following considerations.  The toxicology data base for NAA is nearly complete and adequate for assessing increased susceptibility under FQPA.  In the recently submitted developmental toxicity study conducted with NAA sodium salt in rats (MRID 46685803) fetal toxicity (mainly decreased fetal weights and minor skeletal changes) was observed at a dose lower than the maternally toxic dose.  However, there were clear NOAELs in this developmental study and the point of departures used in the chronic dietary assessment (15 mg/kg/day) are protective of the fetal effects observed in the developmental study.   There are no residual uncertainties in the exposure database. The dietary risk assessment is conservative and will not underestimate dietary exposure to NAA.
      
An immunotoxicity study is required as a part of new data requirements in the 40 CFR Part 158 for conventional pesticide registration.  However, the toxicology database for NAA does not show any evidence of treatment-related effects on the immune system and the overall weight of evidence suggests that this chemical does not directly target the immune system.  Consequently, the Agency does not believe that conducting a functional immunotoxicity study will result in a lower POD than that currently used for overall risk assessment, and therefore, a database uncertainty factor (UFDB) is not needed to account for lack of this study.

Acute and subchronic neurotoxicity studies are required as a part of new data requirements in the 40 CFR Part 158 for conventional pesticide registration.  However, the HASPOC concluded, based on a weight of evidence (WOE) approach, that acute and sub-chronic neurotoxicity studies are not required at this time.  This approach included the following considerations: 1) the lack of neurotoxicity in the available toxicology studies for NAA; 2) liver, stomach, and lung are the target organs with dogs being the most sensitive species; 4) because the dogs are the most sensitive species, neurotoxicity studies conducted in rats would not provide a more sensitive endpoint for risk assessment; and 5) studies would be unlikely to yield PODs lower than the current PODs used for overall risk assessment.  

Based on a weight of evidence (WOE) approach, the risk assessment team concludes that a 28-day inhalation toxicity study is required for NAA and its salts.  This approach considered all of the available hazard and exposure information for NAA and its salts, including: (1) the physical/chemical properties and relatively high volatility of NAA (0.3 mm Hg at 26ºC); (2) the potential for portal of entry effects and based on the demonstrated eye irritation seen in the acute toxicity studies; and 3) that the MOEs for some occupational handler scenarios are of concern (MOE < 100) and do not meet the waiver criteria (MOE < 1,000).  

      
	4.4.1	Completeness of the Toxicology Database

The toxicity database for NAA is sufficient for a full hazard evaluation and is considered adequate to evaluate risks to infants and children.  Acceptable developmental toxicity studies in the rat and rabbit and an acceptable reproduction study in the rat are available. An immunotoxicity study is required as part of new 40 CFR Part 158 data requirements for registration of a pesticide.  An inhalation study is required and in the absence of this study, a 10x database uncertainty factor (UFDB) is needed to account for lack of this study. 

	4.4.2	Evidence of Neurotoxicity

There are no neurotoxicity studies available but the chronic and subchronic studies show no evidence of neurotoxicity or neuropathology.  HASPOC has determined that acute and subchronic neurotoxicity studies are not needed at the present time.  

	4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or Young Animal
      
There is low concern (and no residual uncertainty) for pre- and/or postnatal toxicity resulting from exposure to the naphthalene acetates.  Although the rat developmental study showed quantitative susceptibility with lower fetal NOAELs than maternal NOAELs, the chronic dietary point of departure is protective of this study.  There was no indication of increased susceptibility (quantitative or qualitative) to rabbits to in utero exposure to naphthalene acetates or to pre and post-natal exposure in rat reproduction studies.   
      
	4.4.4	Residual Uncertainty in the Exposure Database 	

There are no residual uncertainties in the exposure database.  The dietary risk assessment is conservative and will not underestimate dietary exposure to NAA and the naphthalene acetates.
4.5	Toxicity Endpoint and Point of Departure

	4.5.1	Dose-Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water), occupational, and residential exposure scenarios are summarized below.  A detailed description of the studies used as a basis for the selected endpoints for the naphthalene acetates are presented in Appendix A.  

There were no toxicological effects attributable to a single exposure of NAA observed in oral toxicity studies.  Therefore, a POD for acute dietary exposure was not selected.  A chronic POD of 15 mg/kg/day (NOAEL) was selected from a chronic feeding study in dogs with 1-Naphthaleneacetic acid, sodium salt oral feeding study in based on stomach lesions in 75% of the males and by slight sinusoidal histiocytosis in the liver of 50% of the males at the LOAEL of 75 mg/kg/day.  A UF 100x (10x to account for interspecies extrapolation and 10x for intraspecies variation) was applied to the dose to obtain a chronic reference dose (cRfD/cPAD) of 0.15 mg/kg/day.  

A NOAEL of 300 mg/kg/day was selected for short-term and intermediate term dermal exposure POD based on a subchronic dermal toxicity in rats which showed reduced body weight gain and food efficiency at the LOAEL of 1000 mg/kg/day.  Due to a lack of inhalation studies, a POD from an oral prenatal developmental study in rats was selected for inhalation risk assessments: a POD for maternal toxicity of 50 mg/kg/day (NOAEL) was selected for short-term inhalation exposure based on decreased body weight gain during the compound administration at 250 mg/kg/day.  A NOAEL of 25 mg/kg/day was selected for intermediate-term inhalation exposure from a subchronic dog study based on lesions of the GI tract and hypocellularity of the bone marrow.  An absorption factor of 100% is applied for inhalation exposures.  The level of concern (LOC) or margin of exposure (MOE) for dermal and inhalation exposures is 100 based on uncertainty factors of 10x for intraspecies variability and 10x for interspecies sensitivity.  For short-term exposure risk assessments, the dermal and inhalation exposure routes can be combined due to the common toxicity endpoint (reduced body weight gain) via the dermal and inhalation (oral equivalent) routes. 

	4.5.2	Recommendations for Combining Exposure Routes

When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures.  Exposures via the oral, dermal and inhalation routes cannot be combined for short-term assessments because oral exposure endpoints are not based on toxicological effects common to either dermal or inhalation endpoints (i.e., the chronic oral endpoint is based stomach lesions and liver effects; short-term inhalation and dermal endpoints are based on body weight effects).  
	
      4.5.3	Classification of Carcinogenic Potential	
       
A guideline study for the oncogenicity of NAA in mice is not available.  However published NCI carcinogenicity study of NAA acetamide in mice, a guideline chronic/oncogenicity study of NAA sodium salt in rats, and a chronic/oncogenicity study of NAA sodium salt mice are considered adequate for the evaluation of the oncogenicity of the NAA group.  In these three studies the tested NAA compounds were not carcinogenic in mice or rats.
 
	4.5.4	Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints selected for the NAA risk assessment are provided in Tables 4 and 5.

Table 4.5.4.1. Summary of Toxicological Endpoints for Naphthalene Acetates  for Use in Dietary Human Health Risk Assessments
Exposure/Scenario
                              Point of Departure
                        Uncertainty/FQPA Safety Factors
                       RfD, PAD, LOC for Risk Assessment
                        Study and Toxicological Effects
                                       
                                       
Acute Dietary
(General Population)
An acute RfD for the general population or any population subgroups was not selected because no effect attributable to a single (or few) day(s) oral exposure was observed in animal studies.
Chronic Dietary 
(All Populations)
NOAEL = 15 mg/kg/day
UFA= 10x
UFH=10x
FQPA SF= 1x
Chronic RfD = 0.15
mg/kg/day
cPAD = 0.15 mg/kg/day
Chronic Toxicity - Dog;
LOAEL = 75 mg/kg/day based on stomach lesions in 75% of the males and by slight sinusoidal histiocytosis in the liver of 50% of the males.  
Incidental Oral 
Dermal
Inhalation
There are no post-application residential uses for or exposures to the proposed use of naphthalene acetic acid ethyl ester that would result in incidental oral exposure.  Therefore exposure endpoints are not required and not selected for residential exposure assessment.   
Cancer (all routes)
A "not likely" human carcinogen
      
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account for the absence of key date (i.e., lack of a critical study).  FQPA SF = FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c = chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not applicable. 

Table 4.5.4.2. Endpoints selected for Assessing Occupational and Residential Risks for Naphthalene Acetates
                                   Exposure
                                   Scenario
                       Dose Used in Risk Assessment, UF 
                        Uncertainty/FQPA Safety Factors
                       RfD, PAD, LOC for Risk Assessment
                        Study and Toxicological Effects
Dermal 
Short-Term 
(1 - 30 days)
Dermal study NOAEL= 300
mg/kg/day
UFA= 10x
UFH=10x


LOC = 100
21- day dermal: NAA Na salt
LOAEL = 1000 mg/kg/day based on reduced body weight gain and food efficiency
Inhalation
Short-Term 
(1 - 30 days)
Oral study NOAEL= 50 mg/kg/day *
UFA= 10x
UFH=10x
UFDB= 10x
LOC = 1000
Developmental - Rat: NAA
LOAEL = 150 mg/kg/day based on decreased BW gain during gestation period.
Cancer

Bioassay in rats and mice not carcinogenic.  Not mutagenic.
Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and  used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.  NOAEL = no observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFDB= database uncertainty factor: lack of an inhalation specific study. FQPA SF = FQPA Safety Factor. MOE = margin of exposure.  LOC = level of concern.  
* Incidental oral, intermediate and long term exposure duration scenarios are not assessed based on use patterns; inhalation absorption is assumed to be equivalent to oral absorption


5.0	DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 	Metabolite/Degradate Residue Profile

	5.1.1	Summary of Plant and Livestock Metabolism Studies

The qualitative nature of the residue in plants and ruminants resulting from registered uses of naphthalene acetates is adequately understood based on apple, olive, and goat metabolism studies.  Based on guideline requirements, plant metabolism studies should be conducted for a minimum of three diverse crops to determine the qualitative metabolic fate of the active ingredient (OPPTS GLN 860.1300).  Although metabolism data are not available to a commodity similar to potatoes, a 3[rd] diverse metabolism study was not required.  However, if other uses are proposed on crops other than fruit crops, tree nuts, or fruiting vegetables or at a higher application rate on potatoes, a metabolism study (preferably on a root crop) will be needed. 

	5.1.2 	Comparison of Metabolic Pathways
 
 In a rat metabolism studies with ring labeled 1-Naphthaleneacetamide and  ring labeled 1-naphthaleneacetic acid, ethyl ester, glucuronide conjugation was seen following ester cleavage.  Parent compound was detected at low concentrations (0.5-5% of administered) only in feces.  The rat metabolism studies of the acid and its acetamide and the ethyl ester in and animals provide supporting evidence that the toxicity of these various forms of NAA would be similar since all are metabolized to the acid form and eliminated from the body as glycine and glucuronic acid conjugates within 36 to 48 hours of initial exposure.
 
 Similar results have been seen in goat metabolism studies and in apple and olive metabolism studies.  The terminal residues of concern in plants and ruminantsare the parent compounds, NAA and its conjugates. The qualitative nature of the residues in orchard trees is adequately understood.  Additional plant metabolism studies may be required if use is expanded beyond orchard trees.
  
  
	5.1.3 	Environmental Fate and Transport

NAA appears to be generally short lived, based on measured and modeled values.  It should degrade by means of a combination of both biotic and abiotic processes.  The reported half-life for NAA of 10 days was attributed to microbial degradation.  NAA is mostly ionized in the environment so would partition preferentially with the water.  The environmental fate characteristics of the salts of NAA are expected to be similar to those of the acid.  In the environment, the NAA salts will rapidly dissociate to 1-naphthalene acetate anion and its corresponding cation.  Based on its pKa, NAA is expected to exist mostly as the anion in normal environmental conditions.  Anions generally do not adsorb to organic carbon and clay more strongly than their neutral counterparts.  Volatility may be an important route of dissipation for NAA under various environmental conditions based on NAA's relatively high measured and estimated vapor pressures (0.3 mmHg).  NAA ethyl ester is susceptible to hydrolysis at high pHs.  The product of NAA ethyl ester hydrolysis is NAA.  NAA in aqueous solution appears to be unstable to sunlight irradiation.  Upon exposure to sunlight, gaseous phase NAA reaction with hydroxyl (OH) radicals should proceed with a half-life of around 0.3 days.  NAA is mobile to moderately mobile according to the FAO mobility classification.  For NAA measured bioconcentration factors (BCFs) of only 0.15-0.59 and <1.7-4.2 were observed in carp (Cyprinus carpio) at test chemical concentrations of 0.5 and 0.05 mg/L, respectively.  These values suggest a low potential of bioconcentration for NAA.

There are considerable uncertainties in this assessment due to the lack of measured data.  Most of the environmental fate characteristics available for NAA are derived from structure activity relationships.  Furthermore, there is lack of information about possible degradates of NAA.

	5.1.4 	Residues of Concern Summary and Rationale

Residues of concern were determined by the HED risk assessment team for NAA.  The terminal residues of concern in plants and ruminants are the parent compounds, NAA and its conjugates, based on apple, olive, and goat metabolism studies.  (D293239, G. Otakie, November 18, 2003).    

Table 5.1.  NAA Residues of Concern in Plants and Ruminants.
Matrix
Residues of Concern

For Risk Assessment
For Tolerance Expression
Plants
Primary and Rotational crops
NAA and Conjugates
NAA and Conjugates
Livestock
Ruminant and Poultry
NAA and Conjugates
NAA and Conjugates
Drinking Water
NAA and Conjugates
NA

5.2	Food Residue Profile

	5.2.1	Residues in Crops

Field trials have submitted supporting the new uses for naphthalene acetates.  The results from these studies are discussed in the Residue Chemistry Chapter and the appropriate data evaluation report (DER) and summarized in the following tables.  

TABLE  5.2.1.	Residue Data from Avocado Field Trials with NAA ethyl ester.
Trial ID (City, State; Year)[1]
                                     Zone
                                    Avocado
                                    Variety
                                   Commodity
                                  Total Rate
                                 (% solution)
                                      PHI
                                    (days)
                            NAA Residues2 [Average]
Homestead, FL; 2006 (-FL41)
                                       3
                                     Lula
                                     Fruit
                                   1 x 1.27%
                                      10
                       <0.050, <0.050 [<0.050]

                                       
                                       
                                       
                                   2 x 1.27%
                                      11
                       <0.050, <0.050 [<0.050]
Exeter, CA; 2006 (-CA95)
                                      10
                                    Zutano
                                     Fruit
                                   1 x 1.27%
                                      10 
                       <0.050, <0.050 [<0.050]

                                       
                                       
                                       
                                   2 x 1.27%
                                       9
                       <0.050, <0.050 [<0.050]
Irvine, CA; 2006 (-CA96, -CA97, and -CA98) [Target PHI]
                                      10
                                     Hass
                                     Fruit
                                1 x 1.28-1.30%
                                     10-11
            <0.050, <0.050, <0.050, <0.050, <0.050,
                             <0.050 [<0.050]

                                       
                                       
                                       
                                2 x 1.28-1.30%
                                      10
            <0.050, <0.050, <0.050, <0.050, <0.050,
                             <0.050 [<0.050]
Irvine, CA; 2006 (-CA96) [Additional Decline PHIs]
                                      10
                                     Hass
                                     Fruit
                                   1 x 1.30%
                                       1
                       <0.050, <0.050 [<0.050]

                                       
                                       
                                       
                                       
                                      7 
                       <0.050, <0.050 [<0.050]

                                       
                                       
                                       
                                       
                                      15
                       <0.050, <0.050 [<0.050]

                                       
                                       
                                       
                                       
                                      21
                       <0.050, <0.050 [<0.050]

                                       
                                       
                                       
                                   2 x 1.30%
                                       1
                       <0.050, <0.050 [<0.050]

                                       
                                       
                                       
                                       
                                      6 
                       <0.050, <0.050 [<0.050]

                                       
                                       
                                       
                                       
                                      14 
                       <0.050, <0.050 [<0.050]

                                       
                                       
                                       
                                       
                                      21
                       <0.050, <0.050 [<0.050]
[1]  HED has concluded that trials -CA96/-CA97/-CA98 constitute a single trial with replicate samples for purposes of 860.1500 data requirements.
[2]  A total of two applications of solution were made at each trial site, with samples collected after each application.
[3]  Residues of NAA ethyl ester were determined by a common moiety method that converts residues of NAA acetamide and NAA ethyl ester to NAA.  The LOQ was 0.05 ppm.  




TABLE  5.2.2.  Summary of Residue Data from Avocado Field Trials with NAA ethyl ester.
Commodity
                                    Analyte
                                     Total
                                     Rate
                                 (% solution)
                                  PHI (days)
                            Residue Levels (ppm)[1]

                                       
                                       
                                       
                                       n
                                  Sample Min.
                                  Sample Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                  Std.  Dev.
Avocado, Fruit
                                    NAA[3]
                                2 x 1.28-1.30%
                                     10-11
                                       3
                                   <0.05
                                   <0.05
                                   <0.05
                                   <0.05
                                     0.05
                                     0.05
                                      N/A

                                       
                                2 x 1.28-1.30%
                                     9-11
                                       3
                                   <0.05
                                   <0.05
                                   <0.05
                                   <0.05
                                     0.05
                                     0.05
                                      N/A
[1]  Except for sample min/max, values reflect per trial averages; n = no.  of field trials.  N/A = not applicable.
[2]  LAFT = lowest average field trial; HAFT = highest average field trial.
[3]  Residues of NAA ethyl ester were determined by a common moiety method that converts residues of NAA acetamide and NAA ethyl ester to NAA.  





TABLE  5.2.3.	Residue Data from Rambutan Field Trials with NAA sodium salt.
Trial ID (City, State; Year)
                                     Zone
                                   Rambutan
                                    Variety
                                   Commodity
                                  Total Rate
                                     (ppm)
                                      PHI
                                    (days)
                            NAA Residues1 [Average]
Kurtistown, HI; 2007 (-HI08)
                                      13
                                    Jit Lee
                                     Fruit
                                      90
                                       2
                             0.0786, 0.137 [0.108]

                                       
                                       
                                       
                                      900
                                       2
                               1.25, 1.44 [1.35]
Pepeekeo, HI; 2007 (-HI09)
                                      13
                                    Jit Lee
                                     Fruit
                                      90
                                       2
                             0.605, 0.636 [0.621]

                                       
                                       
                                       
                                      900
                                       2
                               4.83, 5.06 [4.95]
[1]  Residues were determined by a common moiety method that converts residues of NAA acetamide and NAA ethyl ester to NAA.   Per trial averages were calculated by the study reviewer.




TABLE  5.2.4.  Summary of Residue Data from Rambutan Field Trials with NAA sodium salt.
Commodity
                                    Analyte
                                  Total Rate
                                     (ppm)
                                  PHI (days)
                            Residue Levels (ppm)[1]

                                       
                                       
                                       
                                       n
                                  Sample Min.
                                  Sample Max.
                                    LAFT[2]
                                    HAFT[2]
                                    Median
                                     Mean
                                  Std.  Dev.
Rambutan, Fruit
                                    NAA[3]
                                      90
                                       2
                                       2
                                    0.0786
                                     0.636
                                     0.108
                                     0.621
                                     0.365
                                     0.365
                                     0.363

                                       
                                      900
                                       2
                                       2
                                     1.25
                                     5.06
                                     1.35
                                     4.95
                                     3.15
                                     3.15
                                     2.55
[1]  Except for sample min/max, values reflect per trial averages; n = no. of field trials.  
[2]  LAFT = lowest average field trial; HAFT = highest average field trial.
[3]  Residues were determined by a common moiety method that converts residues of NAA acetamide and NAA ethyl ester to NAA.   Per trial averages were calculated by the study reviewer.


5.3 	Water Residue Profile
    
	5.3.1	Estimated Drinking Water Concentrations 

The Tier I Estimated Drinking Water Concentrations (EDWCs) for use in the human health risk assessment for 1-naphthaleneacetic acid were calculated using FIRST (surface water) and SCIGROW (ground water) drinking water models (D293886, J.L. Melendez, 9/25/03).  These values generally represent upper-bound estimates of the concentrations of 1-naphthaleneacetic acid equivalents that might be found in surface and ground water due to the use of 1-naphthalenacetic acid on olives, which represents the highest use rate scenario.  Both models provide estimates suitable for screening purposes.  Modeled EDWCs are presented in Table 5.3.



Table 5.3. Tier I Estimated Drinking Water Concentrations of 1-Naphthaleneacetic acid[1]
Chemical
Acute (peak) Surface Water Concentration (ppb)
Annual Average Surface Water Concentration (ppb)
Ground Water Concentration (ppb)
NAA
22.3
2.99
0.0226


5.4 	Dietary and Drinking Water Exposure and Risk

Naphthalene acetates chronic dietary exposure assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database DEEM-FCID(TM), Version 3.16, which incorporates consumption data from USDA's National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).  This dietary survey was conducted from 2003 to 2008.  The data are based on the reported consumption of more than 20,000 individuals over two non-consecutive survey days.  Foods "as consumed" (e.g., apple pie) are linked to EPA-defined food commodities (e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) using publicly available recipe translation files developed jointly by USDA/ARS and EPA.  For chronic exposure assessment, consumption data are averaged for the entire U.S. population and within population subgroups, but for acute exposure assessment are retained as individual consumption events.  Based on analysis of the 2003-2008 WWEIA consumption data, which took into account dietary patterns and survey respondents, HED concluded that it is most appropriate to report risk for the following population subgroups: the general U.S. population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+ years old.

For chronic dietary exposure assessment, an estimate of the residue level in each food or food-form (e.g., orange or orange juice) on the food commodity residue list is multiplied by the average daily consumption estimate for that food/food form to produce a residue intake estimate.  The resulting residue intake estimate for each food/food form is summed with the residue intake estimates for all other food/food forms on the commodity residue list to arrive at the total average estimated exposure.  Exposure is expressed in mg/kg body weight/day and as a percent of the cPAD.  This procedure is performed for each population subgroup.


	5.4.1	Acute Dietary and Drinking Water Analysis

No acute dietary risk assessment was conducted.  An acute RfD for the general population or any population subgroups was not selected because no effect attributable to a single (or few) day(s) oral exposure was observed in animal studies.
      
	5.4.2	Chronic Dietary and Drinking Water Analysis

A new dietary assessment was conducted for the proposed amended use.  The proposed amended use results dietary risk estimates below HED's level of concern; see Table 5.4.  The most highly exposed subpopulation is is children 1-2 years, with 2.0% of the cPAD. 

Table 5.4.  Summary of Chronic Dietary Exposure and Risk for NAA
                              Population Subgroup
                               cPAD (mg/kg/day)
                                    Chronic
                                       
                                       
                             Exposure (mg/kg/day)
                                    % cPAD
General U.S. Population
                                     0.15
                                   0.000513
                                     <1
All Infants (< 1 year old)
                                       
                                   0.001487
                                      1.0
Children 1-2 years old
                                       
                                   0.002945
                                      2.0
Children 3-5 years old
                                       
                                   0.001868
                                      1.2
Children 6-12 years old
                                       
                                   0.000774
                                     <1
Youth 13-19 years old
                                       
                                   0.000383
                                     <1
Adults 20-49 years old
                                       
                                   0.000305
                                     <1
Adults 50+ years old
                                       
                                   0.000303
                                     <1
Females 13-49 years old
                                       
                                   0.000317
                                     <1


6.0 	RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

Residential exposures are not expected based on the newly proposed uses, however the proposed new use will affect the aggregate exposure, and the residential SOPs have been updated, so an updated residential exposure assessment was conducted.   Each assumption and factor is detailed in the 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).  The residential handler exposure/risk characterization for cereal grains is summarized in below.

Specifics concerning residential handler exposure and risks are provided in the most recent occupational and residential exposure assessment for the naphthalene acetates (D406266, S. Hummel, 1/16/2013).
   
6.1	Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for the naphthalene acetates at this time.  However, volatilization of pesticides may be a potential source of post-application inhalation exposure to individuals nearby to 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.  The Agency received the SAP's final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html) and is in the process of evaluating the SAP report.  The Agency 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 put into place, the Agency may revisit the need for a quantitative post-application inhalation exposure assessment for propiconazole.

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 application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for the naphthalene acetates.  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 worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios. 
 
7.0 	AGGREGATE EXPOSURE AND RISK ASSESSMENT 

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 (dermal and residential).  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 aggregate exposures include food plus drinking water exposures.  As demonstrated under Section 5.4, acute and chronic aggregate risks are not of concern.

7.2	Short-Term Aggregate Risk	

Short term aggregate risk cannot be estimated for naphthalene acetates because the toxicity endpoints selected for the chronic dietary/drinking water routes of exposure and those selected for inhalation and dermal routes of exposure are not based on common effects i.e., the chronic dietary endpoint is based on stomach lesions and liver effects while the dermal and inhalation endpoints are based on decreased body weight gain.

Results of the residential handler assessment are shown below in Table 7.2.

Registrations for residential uses are limited to rooting compounds and sprout inhibitors.   The rooting compounds are applied by holding the plant and dipping the roots into solution.  Very little exposure is expected from this use.  Sprout inhibitors are applied by spray or paint brush/roller after pruning trees, or by spraying near the base of the tree after pruning root suckers.

Table 7.2.  Residential Handler Non-cancer Exposure and Risk Estimates for Naphthalene Acetates.

                              Exposure Scenario 
                               Level of Concern
                       Dermal Unit Exposure (ug/lb ae)
                     Inhalation Unit Exposure (ug/lb ae)
                          Maximum Application Rate[1]
                    Area Treated or Amount Handled Daily[2]
                                    Dermal
                                  Inhalation
                                     Total
                                       
                                       
                                       
                                       
                                       
                                       
                              Dose (mg/kg/day)[3]
                                    MOE[4]
                              Dose (mg/kg/day)[5]
                                    MOE[6]
                                    ARI[7] 
                            Mixer/Loader/Applicator
                                       
Paint-airless sprayer
                                      100
                                      160
                                     0.56
                                  0078 lb/gal
                                     2 gal
                                     0.31
                                      960
                                    0.0011
                                    46,000
                                      7.9
Paint-brush/roller
                                      100
                                      450
                                      0.2
                                  0078 lb/gal
                                     2 gal
                                     0.88
                                      340
                                    0.00039
                                    130,000
                                      3.3
Paint-manually pressurized handwand
                                      100
                                      63
                                     0.018
                                  0078 lb/gal
                                     2 gal
                                     0.12
                                     2400
                                   0.000040
                                   1,300,000
                                      24
1 Based on registered or proposed label (Reg. No.5481-429, 5481-541).
2 Exposure Science Advisory Council Policy #9.1.
3 Dermal Dose = Dermal Unit Exposure (ug/lb ae) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) x DAF (%) / BW (kg).
[4] Dermal MOE = Dermal NOAEL (mg/kg/day) / Dermal Dose (mg/kg/day).
5 Inhalation Dose = Inhalation Unit Exposure (ug/lb ae) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ae/acre or gal) x Area Treated or Amount Handled (A or gallons/day) / BW (kg).
[6] Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).
[7] Aggregate Risk Index (ARI) = 1/ (1 / RIdermal) + (1 / RIinhalation), 
Where:
Risk Index (RI) = MOE / LOC



8.0	CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider "available information" concerning the cumulative effects of a particular pesticide's residues and "other substances that have a common mechanism of toxicity."

EPA does not have, at this time, available data to determine whether NAA has a common mechanism of toxicity with other substances.  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 NAA and any other substances and, NAA does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U. S.  For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that NAA 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 OPP 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/fedrgstr/EPA_PEST/2002/January/Day_16/.


9.0	OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

9.1	 Exposure Scenarios

Occupational handler and post-application exposure scenarios were assessed for the proposed amended use.  Based on the product labels and information provided by the registrant, short- and intermediate-term exposure is assessed for handlers and post-application activities.  Dermal and inhalation exposures are aggregated for naphthalene acetates because the toxicity endpoints for these exposure routes are not based on common toxicological endpoints.  Labels for the naphthalene acetates proposed uses require that applicators and other handlers wear personal protective equipment (PPE) consisting of long-sleeved shirt, long pants and shoes with socks plus chemical resistant gloves.  

9.2	Handler Exposure 

HED uses the term handlers to describe those individuals who are involved in the pesticide application process.  HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task.  Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.  

Based on the anticipated use patterns and current labeling for naphthalene acetates, e.g, 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: (1) M/L aerial, (2) A aerial, (3) M/L airblast, (4) A airblast, (5) M/L/A manually-pressurized handwands, (5) M/L/A hose-end sprayers, (6) M/L/A backpacks, and (7) M/L/A paint brush/roller.

	9.2.1 	Handler Exposure Scenarios

Based on the anticipated use patterns and current labeling for naphthalene acetates, e.g, 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: (1) M/L aerial, (2) A aerial, (3) M/L airblast, (4) A airblast, (5) M/L/A manually-pressurized handwands, (5) M/L/A hose-end sprayers, (6) M/L/A backpacks, and (7) M/L/A paint brush/roller.


	9.2.2	Handler Exposure Data

Unit Exposures:  It is the policy of HED to use the best available data to assess handler exposure.  Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant-submitted occupational exposure studies.  Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting handler exposure that are used in this assessment, known as "unit exposures", are outlined in the "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table", which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website. 

Estimates of dermal and inhalation exposure were calculated for baseline levels of PPE.  Results are presented for "baseline," 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 naphthalene acetate product labels direct mixers, loaders, applicators and other handlers to wear long-sleeved shirt, long pants, shoes plus socks, and chemical-resistant gloves.


	9.2.3 	Handler Exposure Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments.  Each assumption and factor is detailed below on an individual basis.

Application Rate:  The maximum application rate for treatment of orchards is 0.11 lb ae/A.  For sprout inhibitor applications, the maximum rate is 0.078 lb ae/gallon.

Area Treated or Amount Handled:  Aerial mixer/loader/applicators may treat up to 350 acres per day.  Airblast mixer/loader/applicators may treat up to 40 acres per day.  

However, HED expects that mixer/loader/applicators using backpack or manually-pressurized handguns or paint rollers to treat limbs or suckers after pruning, may use a maximum of 5 gallons of solution or paint may be used per day rather than up to 1000 gallons shown in the Handler SOPs, because this is not a normal painting/ground directed spray scenario.  The use is limited to treating recently pruned limbs or suckers.
  
Body Weight:  Since the dermal and/or inhalation PODs are based on decreased body weight gain, the body weight appropriate for dermal and inhalation assessments is 80 kg.

Absorption factors:  Since the short-term dermal POD was based on route-specific toxicity studies, an absorption factors was not necessary to estimate exposure.   Since the short-term inhalation POD was based on an oral study, inhalation absorption was assumed to be equivalent.

Exposure Duration: HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six months as intermediate-term.  Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site.  For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one-month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region).  

For naphthalene acetates, based on the proposed use and registered uses, only short-term exposure is expected for the following reasons:  (1) naphthalene acetate products may be used three times per year.  (2) NAA is a plant growth regulator which is used for chemical thinning and spout inhibition after pruning in orchard trees.  Chemical thinning and pruning are done only at specific times of the year.

Mitigation/Personal Protective Equipment:  Occupational handler exposure assessments are completed by HED using different levels of risk mitigation.  Typically, HED uses a tiered approach.  The lowest tier is designed as the baseline exposure scenario (i.e., long-sleeve shirt, long pants, shoes, socks, no respirator).  If risk estimates are of concern at baseline attire, then increasing levels of PPE (i.e., gloves, respirators) are evaluated.  If risk estimates remain a concern with maximum PPE, then engineering controls (i.e., enclosed cabs or cockpits, water-soluble packaging, and closed mixing/loading systems) are evaluated.  This approach is used to ensure that the lowest level of risk mitigation that provides adequate protection is selected, since the addition of PPE and engineering controls involves an additional expense to the user and (in the case of PPE) also involves an additional burden to the user due to decreased comfort and dexterity and increased heat stress and respiratory stress.


Occupational Handler Non-Cancer Exposure and Risk Estimate Equations

Potential daily exposures for occupational handlers were calculated using the following formulas:

Daily Exposure (mg ae /day) = UE (ug ae / lb ae) * AR (lb ae /A) * AT (A /day) * 1E-3 mg/ug

where:
Daily Exposure   = 	Amount (mg ae/day) that is available for dermal or inhalation absorption,
UE 		= 	Unit Exposure (ug ae / lb ae),
AR 		= 	maximum application rate according to proposed label (lb ae/acre or gal), and
AT 		= 	daily acres treated (A /day or gal/day).
 
The daily doses were calculated using the following formula:

Average Daily Dose (mg ae/kg/day) = [Daily Exposure (mg ae/day) * Absorption (%)]
                               Body Weight (kg)
where:
Average Daily Dose	= 	Absorbed dose received from exposure to a pesticide in a given scenario (mg 
		pesticide active ingredient/kg body weight/day),
Daily Exposure	=	Amount (mg ae/day) that is available for dermal or inhalation absorption,
Absorption Factor	=	A measure of the amount of chemical that crosses a biological boundary such as 
		the skin and lungs (%), and
Body Weight	=	Body weight determined to represent the population of interest in a risk 
		assessment (kg).


Margin of Exposure:  Non-cancer risk estimates for each application handler scenario are calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to the daily dose of concern.  The daily dermal and inhalation dose received by occupational handlers were compared to the appropriate POD (i.e. NOAEL) to assess the risk to occupational handlers for each exposure route.  All MOE values were calculated using the following formula:

MOE = POD (typically a NOAEL in mg/kg/day) 
       ADD (mg/kg/day)

where:
MOE		= 	Margin of Exposure: value used by HED to represent risk or risk estimates (unitless),
POD		= 	Point of Departure,
NOAEL 	= 	No Observed Adverse Effect Level (mg/kg/day): Dose level in a toxicity study, where no 
            observed adverse effects occurred in the study, and
ADD 		= 	Average Daily Dose (mg/kg/day): the absorbed dose received from exposure to a 
            pesticide in a given scenario.

Combining Exposures/Risk Estimates:

A total aggregated risk index (ARI) was used since the LOCs for dermal exposure (100) and inhalation exposure (1000) are different.  The target ARI is 1; therefore, ARIs of less than 1 are risk estimates of concern.  The aggregate risk index (ARI) was calculated as follows.

Aggregate Risk Index (ARI) = 1/ (1 / RIdermal) + (1 / RIinhalation)
Where:
Risk Index (RI) = MOE / LOC

For all dermal and inhalation exposure scenarios, risk estimates do not exceed HED's LOC (Dermal LOC = 100; Inhalation LOC = 1000) with label-specified PPE, the Aggregate Risk Index (ARI) does not exceed 1, and, therefore, are not of concern to HED.  Summaries of the combined short- and intermediate-term risk estimates for occupational handlers are included in Table 9.2.4.

	9.2.4 	Handler Exposure and Risk Estimates
 			
Summaries of the combined, dermal plus inhalation short-, and intermediate-term risks for each exposure scenario are presented in Table 9.2.4.  The combined dermal and inhalation exposure risks are not of concern (i.e., ARIs >1), provided the mixer/loaders wear chemical-resistant gloves as directed on the label.  

Exposure scenarios listed within (mixing/loading, applying, and flagging), risk estimates do not exceed HED's LOC (MOE = 100), and therefore not of concern to HED.  See Table 9.2.4. for details.

Table 9.2.4.  Short -Term Occupational Exposure and Risk Estimates for Naphthalene acetates.  All estimates are at baseline (single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator).  
                               Exposure Scenario
                                Crop or Target
                      Dermal Unit Exposure (ug/lb ae)[1]
                    Inhalation Unit Exposure (ug/lb ae)[1]
                                    Maximum
                              Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                    Dermal
                                  Inhalation
                                     Total
                                       
                                       
                           Baseline Mitigation Level
                           Baseline Mitigation Level
                                       
                                       
                              Dose (mg/kg/day)[4]
                                    MOE[5]
                              Dose (mg/kg/day)[6]
                                    MOE[7]
                                    ARI[8] 
                                 Mixer/Loader
                                       
Liquid Aerial Broadcast
                                    Orchard
                                      220
                                     0.219
                                     0.11
                                      350
                                     0.106
                                     2800
                                   0.000105
                                    410000
                                      26
Liquid Airblast 
                                    Orchard
                                      220
                                     0.219
                                     0.11
                                      40
                                    0.0121
                                     25000
                                   0.000012
                                    3600000
                                      240
                                  Applicator
                                       
Spray Aerial Broadcast
                                    Orchard
                                      8.6
                                     0068
                                     0.11
                                      350
                                    0.0024
                                    120000
                                   0.000033
                                    1300000
                                      670
Spray Airblast
                                    Orchard
                                     1770
                                     4.71
                                     0.11
                                      40
                                    0.0974
                                     3100
                                   0.000259
                                    170000
                                      27
                                    Flagger
                                       
Spray Aerial Broadcast
                                    Orchard
                                      11
                                     0.035
                                     0.11
                                      350
                                    0.00053
                                     57000
                                   0.000169
                                    260000
                                      200
                            Mixer/Loader/Applicator
                                       
Liquid ground directed backpack
                                    Orchard
                                     8260
                                     2.58
                                     0.078
                                       5
                                    0.0403
                                     7400
                                   0.0000126
                                    4000000
                                      73
Liquid Manually-pressurized Handwand
                                    Orchard
                                    100000
                                      30
                                     0.078
                                       5
                                     0.488
                                      610
                                   0.000146
                                    340000
                                      6.0
Paint-airless
                                    Orchard
                                     42600
                                      560
                                     0.078
                                       5
                                     0.208
                                     1400
                                    0.00273
                                     18000
                                      7.9
Paint-brush/roller
                                    Orchard
                                    180000
                                      280
                                     0.078
                                       5
                                     0.878
                                      340
                                    0.00136
                                     37000
                                      3.1
[1] Based on "Occupational Pesticide Handler Unit Exposure Surrogate Reference Table" (Oct 2012); includes data from PHED/ORETF/AHETF (level of mitigation: Baseline, PPE, Eng. Controls).
[2] Based on registered or proposed label (Reg. No. 5481-429, 5481-541).  Rates expressed as lb ae/A for aerial and airblast, lb ae/gal for M/L/A backpack, manually pressurized handwand, airless sprayer, and paint brush/roller.   Aerial applicator assumes enclosed cockpit.
[3] Exposure Science Advisory Council Policy #9.1. Area treated expressed as acres for aerial and airblast,gallons for M/L/A backpack, manually pressurized handwand, airless sprayer, and paint brush/roller.  
[4] Dermal Dose = Dermal Unit Exposure (ug/lb ae) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ae/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) x DAF (%)/BW (kg).
[5] Dermal MOE = Dermal NOAEL (mg/kg/day)/Dermal Dose (mg/kg/day).    NOAEL = 300 mg/kg/day.
[6] Inhalation Dose = Dermal Unit Exposure (ug/lb ae) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ae/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) /BW (kg).
[7] Inhalation MOE = Inhalation NOAEL (mg/kg/day)/ Inhalation Dose (mg/kg/day).  NOAEL = 50 mg/kg/day.
[8] Total MOE = NOAEL (mg/kg/day) / (Dermal Dose + Inhalation Dose) OR Total MOE = 1 / [(1 / Dermal MOE) + (1 /Inhalation MOE)].



9.3	Post Application Exposure 
      
HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for the naphthalene acetate at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure for NAA salts and esters compared to NAA, and the low proposed use rate (0.11 lb ae/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 the naphthalene acetates.

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.
 
	9.3.1	Post Application Exposure Scenarios

Post-application propiconazole residues are expected for individuals involved in hand weeding; scouting; thinning; hand harvesting, and irrigation. For all dermal post-application exposure scenarios, risk estimates do not exceed HED's LOC (Dermal LOC = 100), and therefore not of concern to HED.  
 

	9.3.2	Post Application Exposure Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational post-application risk assessments.  Each assumption and factor is detailed below on an individual basis.

Exposure Duration:  HED classifies exposures from 1 to 30 days as short-term, and exposures 30 days to six months as intermediate-term.  For the naphthalene acetates, based on the proposed use, only short-term post-application exposure is expected for the following reason, the uses are very limited, applications only for chemical thinning, or for sprout inhibition after pruning trees.   Post-application activities expected after treatment with naphthalene acetates include (1) hand weeding, propping, orchard maintenance, bird control, (2) scouting, hand pruning, training, (3) hand harvesting, and (4) thinning fruit.

Transfer Coefficients: It is the policy of HED to use the best available data to assess post-application exposure.  Sources of generic post-application data, used as surrogate data in the absence of chemical-specific data, are derived from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provisions of FIFRA.  The standard values recommended for use in predicting post-application exposure that are used in this assessment, known as "transfer coefficients", are presented in the ExpoSAC Policy 3, which, along with additional information about the ARTF data, can be found at the Agency website.

Application Rate: The maximum application rate on fruit trees is 0.11 lb ae/A.  Although lower rates are proposed and registered for some uses, only the maximum rate is being assessed for post-application exposure.

Body Weight: Since the inhalation POD is based on decreased body weight gain, the body weight appropriate for dermal assessments is 80 kg.
  
Absorption factor: Since the short-term dermal POD was based on a route-specific toxicity study, an absorption factor was not necessary to estimate exposure for short-term duration.

Exposure Time:  The average occupational workday is assumed to be 8 hours. 

Dislodgeable Foliar Residues:  Chemical-specific dislodgeable foliar residue data have not been submitted for the naphthalene acetates.  Therefore, this assessment uses HED's default assumption that 25% of the application is available for transfer on day 0 following the application and the residues dissipate at a rate of 10% each following day. 

Occupational Post-application Non-Cancer Dermal Exposure and Risk Estimate Equations

Average Daily Dose (ADD):  Potential daily exposures for occupational post-application workers were calculated using the following formulas:

DFRt (ug/cm[2]) = AR (lb ae/A) * F * (1-D)[t] * 4.54E8 ug/lb * 2.47E-8 acre/cm2

where:
DFRt 	=	dislodgeable foliage residue on day "t" (ug/cm[2]),
AR 	= 	Application Rate (lb ae/acre)
F 	= 	fraction of ae retained on foliage or 25% (unitless)
D 	= 	fraction of residue that dissipates daily or 10% (unitless)
t 	= 	number of days after application day (days)

Daily Exposure (mg ae /day) = TC (cm[2]/hr) * DFRt (ug/cm[2]) * ET (hrs /day) * 1E-3 mg/ug

where:
Daily Exposure    = 	Amount (mg ae/day) that is available for dermal absorption,
TC 		= 	Transfer coefficient (cm[2]/hr),
DFRt 		= 	Dislodgeable Foliar Residue on day "t" (ug/cm[2]), and
ET 		= 	Exposure Time (hours /day).
 
The daily doses were calculated using the following formula:

Average Daily Dose (mg ae/kg/day) = [Daily Exposure (mg ae/day) * Absorption (%)]
 						Body Weight (kg)

where:
Average Daily Dose	= 	Absorbed dose received from exposure to a pesticide in a given 
				scenario (mg pesticide active ingredient/kg body weight/day),
Daily Exposure	=	Amount (mg ae/day) that is available for dermal absorption,
Absorption Factor	=	A measure of the amount of chemical that crosses a biological 					boundary such as the skin (%), and
Body Weight		=	Body weight determined to represent the population of interest in a 
				risk assessment (kg).

Margin of Exposure:  Non-cancer risk estimates for each application handler scenario are calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to the daily dose of concern.  The daily dermal dose received by occupational post-application workers was compared to the appropriate POD (i.e. NOAEL) to assess the risk to occupational post-application workers.  All MOE values were calculated using the following formula:

MOE = POD (typically a NOAEL in mg/kg/day) 
       ADD (mg/kg/day)

where:
MOE		= 	Margin of Exposure: value used by HED to represent risk or risk estimates (unitless),
POD		= 	Point of Departure,
NOAEL 	= 	No Observed Adverse Effect Level (mg/kg/day): Dose level in a toxicity 
			study, where no observed adverse effects occurred in the study, and
ADD 		= 	Average Daily Dose (mg/kg/day): the absorbed dose received from
             exposure to a pesticide in a given scenario.
            
            
            
Table 9.3.2.  Anticipated Post-Application Activities and Dermal Transfer Coefficients.
                                Proposed Crops
                          Policy Crop Group Category
                                  Crop Height
                                Foliage Density
                             Transfer Coefficients
                                  Activities
                                       
                                       
                                       
                                       
                                   cm[2]/hr
                                       
       Avocado, Mango, Mamey Sapote, Rambutan, Fruit, Pome, Group 11-10
                            Tree, fruit, deciduous
                                       
                                       
                                      100
           hand weeding, propping, orchard maintenance, bird control
                                       
                                       
                                       
                                       
                                      580
                       scouting, hand pruning, training 
                                       
                                       
                                       
                                       
                                     1400
                                hand harvesting
                                       
                                       
                                       
                                       
                                     3600
                                thinning fruit 


	9.3.3 	Post-Application Exposure and Risk Estimates
 
For all dermal post-application exposure scenarios, risk estimates do not exceed HED's LOC (Dermal LOC = 1000), therefore, are not of concern to HED. 

 A summary of post-application exposure and risk calculations, assumptions, and results is provided in Table 9.3.3.




Occupational Post-application Non-Cancer Dermal Risk Estimates

A summary of post-application dermal risk estimates for the maximum application rates for naphthalene acetates, are provided below in Table 6.2.2.2.

Table 6.2.2.2.  Summary of  Short-term Occupational/Commercial Post-application Risk Estimates for Naphthalene Acetates on Day 0.
                                   Crop/Site
                                  Activities
                        Transfer Coefficient (cm[2]/hr)
                                  DFR/TTR[1]
                                 Dermal Dose 
                                (mg/kg/day)[2]
                                    MOE[3]
                                 Orchard crops
           hand weeding, propping, orchard maintenance, bird control
                                      100
                                     0007
                                    0.0001
                                   4400000 
                                       
                       scouting, hand pruning, training 
                                      580
                                     0.007
                                    0.0004
                                    760000
                                       
                                hand harvesting
                                     1400
                                     0.007
                                     0.001
                                    320000 
                                       
                                thinning fruit 
                                     3600
                                     0.007
                                     0.003
                                    120000 
1.  DFR = Application Rate x F x (1-D)t x 4.54E8 ug/lb x 2.47E-8 acre/cm[2]; where F = 0.25 and D = 0.10 per day
2.  Daily Dermal Dose = [DFR (ug/cm[2]) x Transfer Coefficient x 0.001 mg/ug x 8 hrs/day x dermal absorption (100%)]  BW (80 kg).
3.  MOE = POD (300 mg/kg/day) / Daily Dermal Dose.  Daily Dermal Dose = [DFR/TTR (ug/cm[2]) x TC x 0.001 mg/ug x 8 hrs/day x dermal absorption]  BW (80 kg)

       

	9.3.4 	Restricted Entry Interval


The Restricted Entry Interval (REI) specified on the proposed label for Tre-Hold Sprout Inhibitor A-112  is based on the acute toxicity of NAA, ethyl ester.  NAA, ethyl ester is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential.  It is not a skin sensitizer.  Short-term post-application risk estimates were not a concern on day 0 (12 hours following application) for all post-application activities.  Under 40 CFR 156.208 (c) (2) (iii), ai's classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12-hour REI.  Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to NAA, ethyl ester and NAA, sodium salt.    

The REI specified on the proposed label for Fruitone L is based on the acute toxicity of NAA, sodium salt.  NAA, sodium salt is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential.  It is not a skin sensitizer.  Short-term post-application risk estimates were not a concern on day 0 (12 hours following application) for all post-application activities.  Under 40 CFR 156.208 (c) (2) (iii), ai's classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12-hour REI.  Therefore, the [156 Subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to NAA, ethyl ester.

10.	REFERENCES

1-Naphthaleneacetic acid (NAA), its salts, ester, and acetamide .  Expansions of Existing Crop Group/Representative Commodity Uses to Fruit, Pome, Group 11-10 and New Uses in/on Avocado, Mango, Mamey Sapote, and Rambuttan.  Summary of Analytical Chemistry and Residue Data.  G. Otakie, D399621, 10/3/2012.

Naphthalene Acetates- Acute and Chronic Dietary and Drinking Water Exposure and Risk Assessment for Section 3 New Use of Naphthalene Acetic Acid-ester on Avocado, Mango, Mamey Sapote, Rambuttan, and the Expansion to Crop Subgroup 11-10.  T. Morton, D404399, 10/31/2012.

Tier I Estimated Drinking Water Concentrations (EDWCs) for use in the human health risk assessment for 1-naphthaleneacetic acid were calculated using FIRST (surface water) and SCIGROW (ground water) drinking water models.  D293886, J.L. Melendez, 9/25/03.

Naphthalene Acetic Acid and Salts, Ethyl Ester, and Acetamide (Naphthalene Acetates).  Occupational and Residential Exposure Assessment for a Proposed Use on Avocado, Mango, Mamey Sapote, Rambutan, and updating crop group Fruit, Pome, Group 11-10. S Hummel, D406255, 1/16/2013. 

Naphthalene Acetates:  Summary of Hazard and Science Policy Council (HASPOC) Meeting of September 13, 2012:  Recommendations on data requirements for inhalation, acute and subchronic neurotoxicity, and immunotoxicity studies. K. Rury, October 16, 2012, TXR#:  0056465.


APPENDICES

   A. TOXICOLOGY DATA SUMMARY

A.1 		Guideline Data Requirements

Guideline No.
Study Type
Technical
MRID No.


Required
Submitted

870.3100



870.3150



870.3200


870.3250
870.3465
Subchronic (Oral) Toxicity - Rodent	



Subchronic (Oral) Toxicity - Non-Rodent	



21/28-Day Dermal Toxicity	


90-Day Dermal Toxicity		
28/90-Day Inhalation Toxicity 	
Y



Y



N


N
Y
Y



Y



Y


N
N
43896001 
00043624
42932601
43896002
43895901
00136446
42983801
43914901
43581001
43134701
43581002

870.3700a
870.3700b

870.3800
Prenatal Developmental Toxicity - Rodent	
Prenatal Developmental Toxicity - Non-Rodent	
Reproduction and Fertility Effects	
Y
Y

Y
Y
Y

Y
00042765
00137821
00137822
43796301
870.4100a
870.4100b
870.4200a
870.4200b
870.4300
Chronic (Oral) Toxicity - Rodent	
Chronic (Oral) Toxicity - Non-Rodent (Dog)	
Carcinogenicity - Rat..................		
Carcinogenicity - Mouse	
Combined Chronic Toxicity /Carcinogenicity
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
44157501
43744201
44157501
Lit Study
44157501
870.6100a
870.6100b
870.6200a
870.6200b
870.6300
870.7800
Neurotoxicity - Acute Delayed Neurotox.- He
Neurotoxicity  - Subchronic - Hen	
Neurotoxicity - Acute - Rat	
Neurotoxicity -Subchronic - Rat	
Developmental Neurotoxicity..................
Immunotoxicity.............................	
N
N
N
N
N
Y
N
N
N
N
N
N
---
---


















A.2 Toxicity Profiles

Study

pc 056001: acetamide

pc 056002: NAA

pc 056007: Na salt

pc 056008: ethyl ester

Acute - oral

MRID 43495901
LD50 > 5050 mg/kg
Category III

MRID 00103128
LD50 (95% C.I.) = 2520 mg/kg (2100-3021) .

MRID 00108829
LD50: Males 1.35 (1.12 - 1.64)
Females 0.933 g/kg (0.631-1.38 )

MRID 43494101
LD50 2186 (1907-2506)  mg/kg
Category III

Acute - Dermal

MRID 43495902
LD50 > 2020 mg/kg
Category III

MRID 00103129 
LD50 is greater than 2 g/kg. Category III. 

MRID 00108829
dermal LD50 = > 2 g/kg.  Category III

MRID 43494102
LD50 > 2020 mg/kg.  Category III

Acute - Inhal.

MRID 43495903
LC50 > 2.17 mg/L
Category IV





MRID 43494103
LC50 > 2.13 mg/L
Category IV

Eye Irritation

MRID 00103051
corrosive Category I
MRID 43495904
minimally irritating
Category IV

MRID 00103127
corrosive Category I

MRID 00108829
corrosive Category I

MRID 43494104
minimally irritating
Category IV

Derm.  Irritation



MRID 00103127
Non-irritating  Category IV

MRID 00108829
Non-irritating  Category IV

MRID 00103053 & 00103218. 
non-irritating  Category IV

Sensitization

MRID 43495905
not a skin sensitizer.  No positive control.  Unacceptable

MRID 00153217
not a skin sensitizer



MRID 43494105
not a skin sensitizer.  No positive control.  Unacceptable

90-day -  rat

MRID 43896001
 0, 250, 1,000, or 4,000 ppm ( 0, 19.1, 73.8, or 292.1 mg/kg/day for males and 0, 20.4, 81.5, or 313.5 mg/kg/day for females). LOAEL is 4,000 ppm (292.1 mg/kg/day) decreased bw , bw gain & food consumption, and increased relative liver weights with adaptive histopathological changes in both sexes.  NOAEL is 1,000 ppm (73.8 mg/kg/day)

MRID 00043624
0, 50, 150, or 300 mg/kg/day to SD rats (20/sex/dose)
LOAEL for toxic effects is 300 mg/kg/day based on decreased body weight in both sexes and enlarged liver weights in females.  The NOAEL is 150 mg/kg/day.

MRID 42932601
0, 200, 2000, or 8000 ppm (13.9, 136.6, and 564.9 for males and 15.2, 149.3, and 583.4 mg/kg/day for females).  LOAEL for systemic toxicity = 2000 ppm (136.6 for males and 149.3 mg/kg/day for females) with a NOAEL for systemic toxicity of 200 ppm (13.9 for males and 15.2 mg/kg/day for females) based on decreased hematocrit and hemoglobin, increased liver weights and vacuolation of the periportal hepatocytes along with hypertrophy of the cells of the adrenal cortex zona glomerulosa.

MRID 43896002
 0, 400, 2000 or 8000 ppm (Average doses at  study end were 19-25; 92-123 ; and 388 - 519 mg/kg/day for males- females).  LOAEL= 8000 ppm (594 mg/kg/day), based on lower bw, bw  gain, and food consumption.  males and females at this dose also exhibited increased total bilirubin (19-21% higher) in conjunction with reduced RBC counts, hemoglobin, and hematocrits.  NOAEL= is 2000 ppm (144mg/kg/day).

10-day range finding - rat



MRID 00043623
0, 250, 1000 or 4000 mg/kg bw/day by gavage for 10 days (3 rats/sex/dose).  Death of all high dose rats, one female in the mid dose and none in the low dose.   Dose related depression in body weight gain and food consumption. Discoloration of lungs, liver and kidneys, distended bladder (high dose), blood and gas in the GI tract.  The MTD would be 250 mg/kg/day.





90-day - dog

 MRID 43895901
 0, 30, 100, or 300 mg/kg/day for 13 weeks.  LOAEL is 300 mg/kg/day, based on increased platelet count, decreased red cell parameters, and increased mean corpuscular volume which correlate with histopathological changes observed in the liver, spleen, and bone marrow in both sexes.  The NOAEL is 100 mg/kg/day.

MRID 00136446
0, 50, 150, or 300 mg/kg/day for 6 months to beagle dogs (4/sex/dose) by gelatin capsules. 
The LOAEL was 50 mg/kg/day, the lowest dose tested, based on hepatic liver changes (pericholangistis).  No NOAEL derived from this study.  

MRID 42983801
 0, 25, 150, or 450 mg/kg/day. LOAEL for systemic toxicity =150 mg/kg/day based on lesions of the GI tract and hypocellularity of the bone marrow. NOAEL for systemic toxicity is 25 mg/kg/day .

MRID 43914901
 0, 40, 125, or 400 mg/kg/day for 13 weeks.  LOAEL= 400 mg/kg/day, based on soft/liquid feces and depressed body weight gains of male and female dogs.  Blood parameters (RBC, hemoglobin, hematocrit and mean platelet volume) were all depressed in the male dogs at this level.   NOAEL = 125 mg/kg/day.

21-day - dermal

MRID 43581001
 0, 100, 300, or 1000 mg/kg for 6-6.5 hours/day, 5 days/week, for 3 weeks.  No LOAEL was established.  The NOAEL was the highest treatment level, 1000 mg/kg body weight.



MRID 43134701
0, 100, 300, or 1000 mg/kg for 6-6.5 hours/day, 5 days/week, for 3 weeks.  LOAEL for systemic toxicity is 1000 and NOAEL = 300 mg/kg/day based on reduced bw gain and food efficiency.   LOAEL for dermal toxicity = 1000 mg/kg Dermal Toxicity NOAEL = 300 mg/kg based on microscopic changes in the skin.

MRID 43581002
 0, 100, 300, or 1000 mg/kg for 6-6.5 hours/day, 5 days/week, for 3 weeks.  LOAEL for systemic toxicity is >1000 mg/kg/day and NOAEL =1000 mg/kg/day.  LOAEL for dermal irritation = 100 mg/kg, based on the presence of treatment-related dermal irritation in the treated ski.  No NOAEL for dermal irritation was established.

28-day inhal.

Not available

Develop.- rat



MRID 00042765
0, 10, 50 or 250 mg/kg/day gastric intubation to pregnant rats (24/group).  Developmental LOAEL is >250 mg/k/day and the NOAEL is 250 mg/kg/day.   Maternal toxicity LOAEL 250 mg/kg/day based on decreased body weight gain during the compound administration and the NOAEL is 50 mg/kg/day.

MRID 46685803
0, 15, 50 or 150 mg/kg bw/day from days 5 through 21 (inclusive) of gestation.
maternal LOAEL is >150 mg/kg bw/day, and the maternal NOAEL is 150 mg/kg bw/day
Developmental LOAEL is 150 mg/kg/day based on decreased fetal weight and minor skeletal changes (centrum 5 not ossified, cervical arch 7 cartilage fused to arch 6 cartilage, shortened 7[th] cervical rib),
compound administration and the NOAEL is 50 mg/kg/day.



Develop. - Rabbit



MRID 00137821, 00137822
doses 0, 37.5, 75 or 150 mg/kg/day
maternal toxicity NOAEL = 75 mg/kg/day based on lethality at the LOAEL of 150 mg/kg/day. The teratogenic and fetotoxic LOAEL = >150 mg/kg/day and NOAEL = 150 mg/kg/day.

MRID 46685801
dose levels of 0, 30, 100 or 300 mg/kg bw/day from days 5 through 29 (inclusive) of gestation
maternal LOAEL is 300 mg/kg/day based on reduced body weight, body weight gain and reduced food consumption, clinical signs (few/no feces) and stomach irritation (red/black spots/areas in the glandular mucosa of the stomach) and NOAEL = 100 mg/kg/day .
Developmental LOAEL is 300 mg/kg/day based on an increase in the overall incidences of fetuses with minor skeletal defects and variants (dumbell ossification of the 7[th] thoracic centrum, extra thoracolumbar ribs and 27 pre-pelvic vertebrae) and a decrease in ossification of the manus and NOAEL = 100 mg/kg/day.



Reproduction





MRID 43796301
0, 100, 1000 or 3000 ppm [0, 7, 69 or 210 and 0, 8, 81 or 239 mg/kg/day for males and  females].  Systemic and repro./develop. LOAEL = 3000 ppm (210 & 239 mg/kg/day for males & females), based upon reduced bw gain and food consum. in parental animals and reduced litter survival, and pup weight throughout lactation in both generations of offspring. Systemic and repro./develop. NOAEL = 1000 ppm (69 & 81 mg/kg/day for males & females)



Chronic/Onco - rat





MRID 44157501
 0, 100, 1000, or 5000 ppm (0, 4.4, 43.8, and 224.5 mg/kg/day for males and 0, 5.6, 55.8, and 303.6 mg/kg/day for females). LOAEL = 5000 ppm (224.5 mg/kg/day for males and 303.6 mg/kg/day for females), based on an increased incidence of stomach (mucosal gland dilation) and lung lesions (focal alveolar macrophages) in both sexes, and on lowered  bw gain and food efficiency in females.   NOAEL= 1000 ppm (43.8 mg/kg/day for males and 55.8 mg/kg/day for females).  Increased incidence (p  0.01) of uterine endometrial stromal polyps in high-dose females (2/60, 1/60, 3/60, 13/60 at 0, 100, 1000, 5000 ppm, respectively).



Chronic - mouse

NCI study .  (Innes et al 1969).   NAA acetamide was tested at one dose (MTD according to the published article) as part of a testing program of 120 chemicals.  Only the preliminary results were published.  The test materials were administered to two hybrid strains of mice : C57BL/6 x C3H/Anf and C57BL/6 x AKR (18/sex/hybrid strain).  The mice were administered NAA acetamide at one week of age by stomach intubation at 464 mg/kg/day until weaning at 4 weeks of age and administered the NAA acetamide in the diet at 1298 ppm for approx. 18 months.  Gross and hostopath. examination of the mice at the end of the feeding period did not reveal a significant increase in tumors over the controls.



MRID 46685802
0, 100, 500, or 2500 ppm [0, 10.8, 53.3, 276.0 / 0, 14.3, 70.9, 348.7 mg/kg bw/day M/F, respectively] for at least 80 weeks.
LOAEL = 2500 ppm [276 (M), 348.7 (F) mg/kg/day], based on ↓body weight, food consumption, ↑liver and kidney weights in both sexes and epididymis in males, ↓brain weights in males, hepato-cellular vacuolation in males, adenomas of the liver and lung in males, ↑in the incidence of multiple tumors in females. The NOAEL is 500 ppm [53.3 (M), 70.9 (F)] mg/kg/day. 
There was no treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate based on the effects observed on the top dose (2500 ppm/kg/day).



Chronic - dog





MRID 43744201
 0, 15, 75, or 225 mg/kg/day. LOAEL=  75 mg/kg/day in males and 225 mg/kg/day in females, based on emesis, capsular regurgitation incidences, gross and histopathologic changes in stomachs, and sinusoidal histiocytosis in livers.  NOAEL= 15 mg/kg/day in males and 75 mg/kg/day in females.



Gene mutation-bacterial

MRID 43581006
 Salmonella  five doses 100-5000 ug/plate.  No mutagenic effect with or without S9 activation

MRID 00042761 
Escherichia coli polA.  Strains W3110 and p3478 at 1, 2 or mg/ml. Not mutagenic.  
MRID 00042762
Salmonella.  At 0.5-5000 ug/plate. Not mutagenic:



MRID 43581004
 five doses 33-5000 ug/plate.  No mutagenic effect with or without S9 activation

Gene mutation - mammalian: mouse lymphoma cells

MRID 43580202
-S9: not mutagenic.
+S9 mutagenic at 100 ug/mL and above 





MRID 43580201
-S9: not mutagenic.
+S9 mutagenic at 300 ug/mL and above

erythrocyte micronuleus mice

MRID 43581005
 ip injections 250, 500 or 1000 mg/kg to 5 mice/sex.  Lethargy and death at high dose.  Did not induce a clastogenic or aneurogenic effect.

MRID 00042763
ip injections 60 or 125 mg/kg to 4 mice/sex.  No overt aymptoms at high dose.  Negative.



MRID 43581003
 ip injections 305, 610, or 1220 mg/kg to 5 mice/sex.  Lethargy and death (48%) at high dose.  Did not induce a clastogenic or aneurogenic effect

Mitotic gene conversion: Saccharomyces cervisiae



MRID 00042758, 00042759, 00042760
NAA was tested at 10[-2], 10[-3], 10[-4], 10[-5], 10[-6] M.. NAA was not mutagenic in this test system.  Unacceptable.  No purity, not run at toxic dose, no S9 activation





Rodent dominant lethal assay



MRID 00042764
oral doses of  125, 250, or 500 mg/kg/day to 10 male rats/dose for 5 days.  NAA did not produce dominant lethal effects as measured by pre implantation and post implantation losses. 





Metabolism

Dixon et al.1977.  NAA [14]C as Na salt.  60-100% of the AD was excreted in the urine by the end of 48 hours.  The glucuronic acid conjugate (GAC): major urinary metabolite in man, rhesus monkey, marmoset, rabbit, rat, and fruit bat.  In th cat, no GAC was detected; but turine and glycine conjugates  The glycine conjugate was a major urinary metabolite (>20%) in the cat, squirrel and bushbaby monkey and a minor metabolite in rabbit, rat, capuchia and marmoset monkey.  1-NAA glutamine conjugate was formed only in the cynomolgus , squirrel and capuchin monkeys and marmoset in amounts not exceeding 3% of the AD.  1-NAA turine was excreted by all species except the rabbit, rat  and the fruit bat.  It was a major excretion product (>6%) in the squirrel and capuchin monkeys, the marmoset and the cat.  When female rats were given ip doses of 5-500 mg/kg, bile duct cannulation showed that 10-44% of the radioactivity was present in the bile 3 hours after injection., while 0.6-32% was present in the urine.  At the higher doses urinary GAC predominated whereas at the lower doses the glycine conjugates predominated.  In the bile the GAC was the major metabolite (>80% of the bile radioactivity) and the glycine conjugate was a minor metabolite (<4% of the bile radioactivity).  There was no analysis of the fecal radioactivity.

Lethco and Brouwer, 1966. carboxy -[14]C-1- NAA as NA salt in male rats.  Within 3 days, 71-90% of the AD was excreted in the urine.  At the lower doses (0.1-100 mg/kg)  most of the radioactivity was excreted during the first 24 hours, while at the higher dose (250 mg/kg), excretion was highest on the second day.  Fecal excretion was 3-10% at the 0.1-1.0 mg/kg doses and 14-21% of the AD at the 100 and 250 mg/kg doses.  After the third day, no radioactivity was detected in the feces or urine at any dose.   70-93% of the urinary radioactivity was NAA glycine conjugate and NAA GAC.  The GAC predominated at the two high doses and the glycine conjugate predominated at the lower dose.  Minor amounts of  NAA and two other minor unidentified metabolites were detected in the urine.   Bile cannulation experiments demonstrated biliary metabolism and excretion of the test material.  At the high dose a maximum of 29% of the AD was recovered at 6 hours, while a maximum of 54% was recovered at the low dose at 2 hours.  At the low dose, the NAA glycine conjugate was the major urinary metabolite and the NAA GAC was a minor metabolite, while in the bile the preponderance of these two metabolites was reversed.  Unchanged NAA was detected in the bile but not in the urine at both doses.  At the high dose the NAA GAC was the major metabolite in both urine and bile while the glycine conjugate was a minor metabolite.

MRID 43961701.  Rats (5/sex) were given a single 1 or 100 mg/kg bw oral dose of [[14]C] ring labeled -1-naphthaleneacetic acid, ethyl ester, or a 14-day repeated dose (1 mg/kg/day) of unlabeled material followed by a single dose of the labeled material.  Overall recovery of AD was 98.6-101.8%.  NAA ethyl ester was readily absorbed and excreted within 36 - 48 hours following all exposure regimens (urinary excretion: 67.6-85.3% of the AD at the low dose and 61.8-78% of the AD at the high dose).  Fecal excretion was 12.3-35.2% of the AD.  Tissue radioactivity was very low.  The major pathway of metabolism involved ester cleavage followed by glycine and glucuronide conjugation at the low and low repeat doses.  At the high dose, glucuronide conjugation appeared to play a more important role following ester cleavage.  Parent compound was detected at low concentrations (0.5-4.7% of administered) only in feces. 

MRID 43963301.  Rrats (5/sex) were given either a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day) using [[14]C] ring labeled -1-naphthaleneacetamide (NAAD).  Overall recovery of the AD was 97.2-101%.  NAAD was readily absorbed and excreted within 36 hours (urinary excretion: 70.8-74.1% of the AD at the low dose, single or multiple,  66.2-69.5% of the AD excreted in urine at the high dose).  Fecal excretion was 21.6-26.2% of the AD.  Tissue radioactivity was very low (<0,5% of the AD).   Metabolism involved amide cleavage followed by glycine conjugation (13.7-47.3% of the AD) glucuronide conjugation (4.5-7.0% of the AD at the low dose and 12.8-18.1% of the AD at the high dose inthe urine).  For feces, the major metabolite detected was the dihydrodiol of naphthaleneacetamide (3.6-11.3% of the AD).  Parent compound was detected at low concentrations (0.7-1.9% of administered) only in feces. 



APPENDIX A.3	HAZARD IDENTIFICATION AND ENDPOINT SELECTION 

A.3.1	Acute Population Adjusted Doses (aPAD)  -  All Populations

Selected Study: Developmental Toxicity Study in Rats 
MRID 46685803

Dose and Endpoint for Establishing an aPAD: On the basis of this study, the dose selected is 50 mg/kg/day based on decreased body weight gain at 250 mg/kg/day during the gestation period.  This dose and endpoint is protective of the general population and is representative of the exposure duration of concern (effects occurred during administration of NAA during short period of exposure).  This was also the only available study on NAA with short exposure duration. 

Uncertainty Factor (UF): 100 This includes 10X for interspecies extrapolation and 10x for intraspecies variation.
General Population aPAD =        (NOAEL) 25 mg/kg    =  0.25 mg/kg
                                                              (UF) 100	





A.3.2	Chronic Population Adjusted Dose (cPAD)  -  All Populations

Selected Study: Chronic/Oncogenicity Study in Dogs 
MRID 43744201
Dose and Endpoint for Establishing an cPAD: On the basis of this study, the dose selected is 15 mg/kg/day based on stomach lesions in 75% of the males consisting of necrosis of the fundic or pyloric epithelium and by slight sinusoidal histiocytosis in the liver of 50% of the males occurring  at 75 mg/kg/day of oral feeding of the NAA sodium salt.  The sodium salt also appeared to be the more toxic in subchronic testing among the NAA group of chemicals.  A chronic study in rats with NAA sodium salt showed a NOAEL of 44-56 mg/kg/day based on increased incidence of stomach (mucosal gland dilation) and lung lesions (focal alveolar macrophages) in both sexes, and on lowered body weight gain and food efficiency in female rats at 224 - 303 mg/kg/day.  Therefore, this dose and endpoint is appropriate for protecting the general population from dietary chronic exposure to NAA group of chemicals. 

Uncertainty Factor (UF): 100 This includes 10X for interspecies extrapolation and 10x for intraspecies variation.

General Population  cPAD  =         (NOAEL) 15 mg/kg/day    = 0.15 mg/kg/day
		                                          (UF) 100
	


A.3.4	Dermal Absorption


	A dermal absorption factor (DAF) is applied when dermal exposure endpoints are selected from oral toxicity studies.  The dermal factor converts the oral dose to an equivalent dermal dose for the risk assessment.  A DAF of 6% was selected for use in risk assessment based on available in vivo dermal absorption studies in rat and in vitro dermal absorption studies conducted with rat and human skin.  The DAF was selected by a special working group of the  Antimicrobials Division Toxicity Endpoint Selection Committee (12/18/08 memorandum from J. Chen to M. Swindell  -  Attachment A.3).

4.3.5	Dermal Exposure (Short and Intermediate-Term)

Selected Study: 21-day dermal toxicity study 
MRID 42090018

Dose and Endpoint for Establishing POD: In this study, the systemic NOAEL was 300 mg/kg/day based on reduced body weight gain and food efficiency at the LOAEL of 1000 mg/kg/day.  Therefore, the dermal dose for risk assessment is 300 mg/kg/day.  A margin of Exposure (MOE) of 100 is applied.

Uncertainty Factor (UF): An MOE 100 is required for the short- and intermediate-term scenarios for dermal exposure is based on the conventional uncertainty factor of 100.  This includes 10x for interspecies extrapolation and 10x for intraspecies variation..

A.3.6 	Inhalation Exposure (Short- and Term) 

Selected Study: Developmental Toxicity Study in Rats
See Section A.3.1

A.3.6  Inhalation Exposure (Intermediate Term)

Selected Study: 90 day oral toxicity study in dogs 
MRID 42983801

Dose and Endpoint for Establishing POD:  In this study, the systemic NOAEL was 25 mg/kg/day based on lesions of the GI tract and hypocellularity of the bone marrow at the LOAEL of 150 mg/kg day.  Therefore, the dose for risk assessment is 25 mg/kg/day.  

Uncertainty Factor (UF): An MOE 100 is required for the intermediate-term scenarios for dermal exposure is based on the conventional uncertainty factor of 100.  This includes 10x for interspecies extrapolation and 10x for intraspecies variation..





A.4		EXECUTIVE SUMMARIES FOR SUPPORTING TOXICITY STUDIES 

A.4.1	Subchronic Toxicity

870.3100: 	90-Day Oral Toxicity - Rat

In a subchronic oral toxicity study (MRID 00043624), 1-naphthaleneacetic acid, technical (Lot # not reported; purity not reported) was administered, in the diet, to Sprague Dawley rats (20/sex/dose) at dose levels of  0, 50, 150 or 300 mg/kg bw/day for 13 weeks.  Two additional group of 10 rats/sex were administered 0 or 300 mg/kg bw/day and sacrificed after 30 days and necropsied.  All rats survived except for one death in the control group.  No abnormal behavior or toxic effects were observed in the treated rats.  Fluctuations in food consumption occurred in control and treated groups.  Body weights in males and females of the high dose group were depressed particularly in the females where they gained only one third of the body weight achieved by the controls.  All hematologic values were within the reference limits.  Hematocrit, hemoglobin, and/or RBC values in the mid and high dose males and females were slightly reduced, but considered not compound related.  Alkaline phosphatase in the high dose group was elevated, probably associated with the rate of body growth.  Urinalysis values were comparable in all groups.  There were no visible macroscopic lesions in male rats except for one control male with enlarged spleen and liver and red, depressed areas in the stomach.  In the females, clear fluid in the uterus (hydrometra) was noted in 3 controls, 2 low dose, 7 mid dose and 5 high dose.  These and other lesions (ovarian cyst in one mid dose female, focal omental fat necrosis in one high dose female, one nenocortical cyst in another high dose female) observed were considered not be compound induced.  The absolute and relative liver weight in the high dose females appeared to be significantly increased with no histopathological findings. It was concluded that the LOAEL for toxic effects in this study is 300 mg/kg/day based on decreased body weight in both sexes and enlarged liver weights in females.  The NOAEL is 150 mg/kg/day.  This subchronic toxicity study in the rat was conducted prior to the current testing guidelines. 


In a subchronic toxicity study (MRID 43896001), 1-Naphthaleneacetamide (Lot # I940415; 98.7% a.i.) was administered to CRL:CD BR rats (10/sex/dose) by feeding at dose levels of 0, 250, 1,000, or 4,000 ppm (mean measured concentrations of 0, 19.1, 73.8, or 292.1 mg/kg/day for males and 0, 20.4, 81.5, or 313.5 mg/kg/day for females) for 90 days.  In the 4,000 ppm treatment groups, mean body weights were lower for males (10-15%) and females (9-12%) throughout the study, compared to controls.  Final mean body weight gains were lower for males (14%) and females (20%).  In addition, food consumption was consistently reduced for males (11-28%) and females (2-20%) throughout the study.  Mean relative liver weights were significantly increased in both 4,000 ppm males (14%; p0.05) and females (32%; p0.01) with accompanying histopathological changes consisting of enlarged (hypertrophied) centrilobular hepatocytes with an abundance of fine granular eosinophilic cytoplasm.  No rats died during the study.  No treatment-related differences in clinical appearance, ophthalmology, hematology, clinical blood chemistry or urinalysis parameter or gross pathology were observed in any treatment group.  No neoplastic tissue was observed in any of the treatment groups.  The LOAEL is 4,000 ppm (292.1 mg/kg/day), based on decreased body weight, reduced body weight gain, reduced food consumption, and increased relative liver weights with histopathological changes in both sexes.  The NOAEL is 1,000 ppm (73.8 mg/kg/day).

In a 90 day oral (diet) toxicity study (MRID 42932601), male and female Crl:CDBR (Sprague-Dawley) rats (10/group/sex) received 1-Napthaleneacetic Acid Sodium Salt (Lot # 214001; 96.44% purity) either 0, 200, 2000, or 8000 ppm (equivalent to 13.9, 136.6, and 564.9 mg/kg/day for males and 15.2, 149.3, and 583.4 mg/kg/day for females, respectively) for 13 weeks.  Dose levels were based on a 14-day dietary study with 1-Na-NAA, no information was provided.  No clinical toxicity or mortality related to the treatment was reported in any of the groups.  The absolute body weights for both sexes in the high dose groups were statistically significantly different from control from day 7 for males and day 14 for females, approximately 18 to 20 % lower than control for both sexes at the end of 90 days.  Systemic toxicity was noted at 2000 ppm and above based on statistically significant (p<0.05 -p<0.01) decreased hematocrit and hemoglobin, increased liver weights and vacuolation of the periportal hepatocytes along with hypertrophy of the cells of the adrenal cortex zona glomerulosa in females and increased kidney weights in males.  Further, at the 8000 ppm dose group there were decreased body weight gains (25-30% decrease), decreased food consumption and decreased food efficiency along with decreased red blood cell parameters, platelet counts, total serum protein and albumin.  The liver and kidney weights (absolute and relative to body weight) were increased in high dose males and females along with hepatocellular hypertrophy (4/10 in high dose males and females) and vacuolation of the periportal hepatocytes (10/10 in mid and high dose females) and hypertrophy of the cells of the adrenal cortex zona glomerulosa (6/10 in the mid dose females and 7/10 in the high dose females, and 3/10 in high dose males) and urinary bladder mucosa (9/10 in high dose males and 7/10 in high dose females).  The LOAEL for systemic toxicity is 2000 ppm (136.6 mg/kg/day for males and 149.3 mg/kg/day for females) with a NOAEL for systemic toxicity of 200 ppm (13.9 mg/kg/day for males and 15.2 mg/kg/day for females) based on decreased hematocrit and hemoglobin, increased liver weights and vacuolation of the periportal hepatocytes along with hypertrophy of the cells of the adrenal cortex zona glomerulosa. 


In a subchronic oral toxicity study (MRID 43896002), 1-naphthaleneacetic acid, ethyl ester (Lot # AM 315002; 100% ai) was administered, in the diet, to CRL:CD BR rats (10/sex/dose) at dose levels of 400, 2000 or 8000 ppm for 13 weeks. The actual average doses at the end of the study were 19-25 mg/kg/day for the 400 ppm group, 92-123 mg/kg/day for the 2000 ppm group, and 388 - 519 mg/kg/day for the 8000 ppm group, for males and females, respectively. Lower body weight, body weight gain, food consumption and food efficiency were observed for the 8000 ppm males and females compared to the controls.  Body weights for the males were 7-13% lower and for the females were 9-21% lower than the corresponding controls throughout the study.  Body weight gains were significantly reduced for both sexes at various weekly intervals throughout the study, and by the end of the study, were 18 and 38% lower for males and females, respectively, than the control gains.  Mean food consumption by the males and females was 5-11 and 15-22 lower, respectively, than the control values for most weekly intervals; decreased food efficiency for both sexes was observed at most weekly intervals.  Increased relative and/or absolute liver and kidney weights were observed for the 2000 and 8000 ppm treatment groups.  Relative liver weights were 21% higher for the 2000 ppm females and 20 and 58% higher for the 8000 ppm males and females, respectively, compared to the control weights.  Absolute liver weights were 13 and 24% higher for the 2000 and 8000 ppm females, respectively, compared to the controls.  Relative kidney weights were higher for both sexes from the 2000 ppm (11% higher) and 8000 ppm (17-23% higher) treatment groups.  Absolute kidney weight for the 2000 ppm males was 16% higher than the controls but was not increased for the 8000 ppm males.  No associated macroscopic or microscopic changes were observed in the livers and kidneys of rats from any treatment group.  Decreased red blood cell counts, hemoglobin, and hematocrits for both sexes from the 2000 and 8000 ppm groups were not considered clinically significant, but appeared to be treatment-related since they were dose-dependent.  The 8000 ppm males and females also exhibited increased total bilirubin (19-21% higher) in conjunction with reduced red blood cell counts, hemoglobin, and hematocrits.  No other treatment-related effects were observed during the study.  No rats died during the study.  No differences in clinical signs, ophthalmology, macroscopic or microscopic pathology were observed between any of the treatment and control groups.  Decreased urine protein in the 2000 and 8000 ppm males was not observed in the corresponding females.  The LOAEL for this study is 8000 ppm (594 mg/kg/day) for male and female rats, based on lower body weight, suppressed body weight gain, and reduced food consumption as compared to the controls.  Absolute and/or relative liver and kidney weights for both sexes were seen at this dose but were not accompanied by any macroscopic or microscopic changes, however, males and females at this dose also exhibited increased total bilirubin (19-21% higher) in conjunction with reduced red blood cell counts, hemoglobin, and hematocrits.  The NOAEL is 2000 ppm (144 mg/kg/day) for both sexes. 
 
870.3150:	90-Day Oral Toxicity - Dog


In a subchronic oral toxicity study (MRID 00136446), 1-naphthaleneacetic acid, technical (Lot # 16388; purity not reported) was fed (gelatin capsules) to beagle dogs (4/sex/dose) at dose levels of 0, 50, 150, or 300 mg/kg/day for 180 consecutive days.  Clinical signs of toxicity were evident in the high dose group.  These included anorexia lasting several days, tenderness in the mouth while dosing, icteric and pale mucous membranes, steady loss in weight, lethargy, an uncoordinated gait, dark urine, and dark stools.  Two of four males and all the females showed some or all of these effects at the end of the study.  One dog had a great amount of edema in the hind legs progressing over 3 days until its legs were swollen to approximately the coxo femoral joint.  This dog was sacrificed on day 126 of the study.  Urine collected from this dog prior to sacrifice showed large amounts of bilirubin, urobilinogen and a small amount of RBC and blood.  These effects are considered to treatment-related.  The mean body weight and body weight gain was significantly depressed in the high dose females (p<0.01) at 2, 3, 4,5 and 6 months in comparison to the control dogs.  The male dogs had also reduced body weight and body weight gain during the last two months of the study.  Hematological parameters were within reference limits for the four groups.  The hematology of the dog that was sacrificed showed slightly increased WBC count with a relative and absolute neutrophilia and lymphopenia which may be compound related.  The clinical chemistry analysis showed that alanine amino transferase (SGPT) were elevated at 4 months (slightly) and 6 months (2x the normal value) for the high dose females.  The clinical chemistry of the male dog that was sacrificed in moribund condition showed lower protein, cholesterol and glucose and greatly elevated levels of total bilirubin, direct bilirubin, alkaline phosphatase, aspartate amino transferase (SGOT) and SGPT.  Dose-related increases in relative weights of kidneys occurred in both males and females of the high dose group.  Dose-related weight increases in liver, adrenals, brain and heart occurred in high dose females.  The low dose group males had increased relative kidney weights and the mid dose group females had an increase in relative heart weights.  Histopathologisal examination revealed very slight evidence of pericholangistis in the low dose group (2/8), very slight to moderate degree of hepatic insult in the mid dose group (7/8)and slight to severe degree of hepatic insult in the high dose group (8/8).  This hepatic insult was characterized by pericholangistis, toxic degeneration of hepatocytes and hepatocellular hypertrophy in the mid dose group and additionally centrilobular necrosis, periportal fibrosis in the high dose group and hyperplastic nodule in the male dog that was sacrificed moribund.  There was also evidence of squamoid metaplasi in the tracheal epithelium of 2/8 dogs and a slight degree of myocarditis (1/8) in the high dose group.  Hyperkeratosis of the skin at the thoroacolumbar junction was seen in 2/8 dogs of the mid dose and 4/8 dogs of the high dose groups.  It was concluded that there was no NOAEL derived from this study.  The LOAEL was 50 mg/kg/day, the lowest dose tested, based on hepatic liver changes (pericholangistis).  This subchronic toxicity study in the dog was conducted prior to the current testing guidelines. 


In a subchronic toxicity study (MRID 43895901), 1-Naphthaleneacetamide (Lot/Batch #  I940415;  98.7% a.i.) was administered via capsule to four beagle dogs/sex/dose at dose levels of 0, 30, 100, or 300 mg/kg/day for 13 weeks.  In the 300 mg/kg/day treatment group, all livers contained accumulations of a hemosiderin-containing pigment in the reticuloendothelial cells and bilirubin in the intracanicular spaces.  The spleens of 3/4 males and 2/4 females also contained hemosiderin and hematopoiesis was increased in the bone marrow in 3/4 animals of both sexes.  Decreases in red blood cell counts, hematocrit, and hemoglobin occurred in both sexes.  Platelet counts and mean corpuscular volumes were increased in both sexes.  Total bilirubin was increased in 1/4 males and 3/4 females, but the increases were significant (p<0.05 or 0.01) only for females.  Body weights were reduced in males only.  Clinical signs of toxicity in both sexes were soft or liquid feces.  No treatment-related effects were observed in the 30 or 100 mg/kg/day treatment groups.  No dogs died during the study.  No treatment-related differences in clinical appearance, food consumption, ophthalmology, urinalysis parameters, organ weights, or gross pathology were observed in any treatment group.  No neoplastic tissue was observed in any of the treatment groups.  The LOAEL is 300 mg/kg/day, based on increased platelet count, decreased red cell parameters, and increased mean corpuscular volume which correlate with histopathological changes observed in the liver, spleen, and bone marrow in both sexes.


In a 13 week oral toxicity study (MRID 42983801), 6-month old beagle dogs (4/group/sex) received by capsule either 0, 25, 150, or 450 mg/kg/day 1-Naphthaleneacetic Acid Sodium Salt (Lot# 214001, Purity - 96.44% 1-NAA & 1.79% 2-NAA).  Due to inappetence at the high dose, the feeding regimen was altered for several high dose animals to reduce excessive weight loss.  Dose levels were based on a previous 6 month study with Naphthalene Acetic Acid (MRID 00136446) where male and female dogs receiving 50, 150, or 300 mg/kg/day experienced severe toxicity at the 300 mg/kg/day dose.  These included depressed body weight and body weight gain, histopathological changes and mortality.  In the current study with NAA sodium salt, none of the animals died.  Regurgitation of intact or partially digested capsules and emesis were the most common treatment- related clinical sign and was toxicologically significant at the high dose.  Body weight gain was significantly reduced in the high dose males (15% of controls, p<0.05) and females (29% of controls, p<0.05) accompanied by decreased food consumption and food efficiency.  There were statistically significant increases in relative organ weight for the liver, adrenals, thyroids/parathyroids, kidneys and brain and a decrease in gonad absolute and relative weights for the high dose males.  The high dose females only showed a statistically significant increase in relative kidney weights, although the relative weights for other organs did show a tendency towards an increase.   Gross examination of the genital tract revealed small prostates, small testes and epididymides in all high dose males.  Microscopic examination in these males revealed an increased incidence of hypospermatogenesis, characterized by less spermatogonia and spermatocytes and were associated with aspermia in the epididymides.  These may be secondary effects to the condition of the animals, but deserve further examination. Systemic toxicity was noted at 150 mg/kg/day and above based on  lesions of the gastrointestinal tract (ulcerative duodenitis and acute or erosive gastritis), hypocellularity of the bone marrow along with changes in liver enzymes (increased alkaline phosphatase in the high dose group), increased relative liver weights, histopathological changes of the liver (single cell necrosis, centrilobular necrosis, pigment accumulation, extramedullary hematopoiesis and mononuclear or mixed cell infiltration), depression in erythrocyte parameters (red blood cell count, hemoglobin and hematocrit levels in high dose females with a slight similar effect in males), decreased body weight gains, food consumption and food efficiency, inappetence and emesis in the high dose group.  The NOAEL for systemic toxicity is 25 mg/kg/day with a LOAEL for systemic toxicity of 150 mg/kg/day based on lesions of the gastrointestinal tract and hypocellularity of the bone marrow.

In a subchronic oral toxicity study (MRID 43914901), 1-naphthaleneacetic acid, ethyl ester (Lot/Batch # AM 315002; 97.75% ai) was fed (gelatin capsules) to beagle dogs (4/sex/dose) at dose levels of 0, 40, 125, or 400 mg/kg/day for 13 weeks.  All dogs survived the treatment.  Treatment-related clinical signs were limited to soft or liquid feces particularly in males and to a lesser extent in females at the high dose of 400 mg/kg/day.  Male dogs in the 40, 125, or 400 mg/kg/day treatment groups had a 4- to 5.5-fold increase in soft/liquid feces (maximum 65 instances during 13 weeks in the 400 mg/kg/day group) compared to the control group.  For females, there was one incident of soft/liquid feces in the control group, five in the 40 mg/kg/day group, eight in the 125 mg/kg/day group, and 19 in the 400 mg/kg/day group during the 13-week study.  A treatment-related lower body weight gain (20% less than the control) was seen in the males and females of the high dose group.  Males in the 40 or 125 mg/kg/day treatment group were 25-29% heavier, and males in the 400 mg/kg/day treatment group were 20% lighter than males in the control group; all three groups consumed 19% more food than the control during the study.   Female dogs in the 400 mg/kg/day treatment groups consumed 11% less food over the course of the study.  Male dogs in the 40, 125, or 400 mg/kg/day treatment groups had significantly (p <0.05 or 0.01) lower red blood cell, hemoglobin, and hematocrit levels, and lower mean platelet volumes (MPV) than the controls throughout the study.  In the high dose males at 12 weeks,  these were 18%, 17%, 17% and 22% lower than the controls for RBC, hemoglobin, hematocrit and MPV levels, respectively.  Although , these parameters were within the historical range values for this dog type, they were at the lower end of the range and may suggest anemic affects caused by the administration of this material at this dose.  Low white blood cell counts in female dogs in the 125 or 400 mg/kg/day treatment groups after 12 weeks of treatment were also within expected biological ranges.  No other treatment-related responses were observed during the study.  No differences were observed in clinical blood chemistry, ophthalmology, urine volume or chemistry, organ weights, or macroscopic or microscopic organ morphology between dogs in the treated and the control groups.  No neoplastic tissue was observed.  The LOAEL for this study is 400 mg/kg/day, based on soft/liquid feces and the depressed body weight gains of male and female dogs at this treatment level.  Additionally some blood parameters (RBC, hemoglobin, hematocrit and mean platelet volume) were all depressed in the male dogs at this level.  The NOAEL was 125 mg/kg/day. 

A.4.2	Prenatal Developmental Toxicity

870.3700a:	 Prenatal Developmental Toxicity Study - Rat

In a prenatal developmental study (MRID 00042765), NAA technical (Lot # NAA 73323G; purity not reported, white powder) was administered by gastric intubation to groups (24/group) of healthy timed pregnant albino CD rats at dose levels of 0, 10, 50 or 250 mg/kg/day in 0.05% sodium carboxymethylcellulose from days 6 through 15 of gestation.  The dams were observed daily for signs of toxicity and weighed on day 1, 3, 6-15, 17 and 20 of gestation.  On day 20 of gestation the dams were euthanized with ether and the ovaries and uterine contents were immediately examined for viable and nonviable fetuses, resorptions, number of implantations, and number of corpora lutea.  Fetuses were examined for visceral and skeletal anomalies using proper techniques.   No deaths or toxic symptoms were reported at any dose level.  There was a statistically significant decrease in the mean body weight gain in the 250 mg/kg/day rats with the onset of the compound administration.  The dams in the 10 and 50 mg/kg/day groups did not show significant decrease in body weight gain during compound administration but showed a decrease compared to the controls from days 17-20.  Litter size and fetal loss were not affected by the treatment.  A slight decrease (statistically insignificant) in mean litter size (9.3, 9.3, 8.8 and 7.9 in the control, low-, mid-, and high-dose groups, respectively) was considered unrelated to treatment.  There was a statistically increased (p<0.05) mean preimplantation loss in the mid- and high dose groups (38.1-42.6%) in comparison to the control animals (20.6%).  However the means were within the range of the individual values of the control animals and were considered not treatment related. The incidence of major malformations and minor anomalies were comparable in all groups.  It was concluded that NAA is not teratogenic in pregnant rats at 250 mg/kg/day, the highest dose tested.  Therefor the developmental LOAEL is >250 mg/k/day and the NOAEL is 250 mg/kg/day.  The maternal toxicity LOAEL 250 mg/kg/day based on decreased body weight gain during the compound administration and the NOAEL for maternal toxicity is 50 mg/kg/day.


In another  developmental toxicity study (MRID 46685803), 1-Naphthaleneacetic acid sodium salt (97.4% a.i., batch/lot # 014-S0401-001) was administered to 24 female SD (Wistar-derived) rats/dose by gavage at dose levels of 0, 15, 50 or 150 mg/kg bw/day from days 5 through 21 (inclusive) of gestation.  All animals survived the duration of the study and all were pregnant with live fetuses in utero at scheduled termination on day 22 of gestation.  There were no treatment-related clinical signs.  Cesarean section data did not reveal any differences among all groups including the controls.  Maternal body weights of the 150 mg/kg/day females adjusted for initial weight were statistically significantly (p<0.01) lower than the control group from day 6 through day 17.  For the 50 mg/kg/day females body weights were lower during the first 4 days following the test material administration. Females in the low dose groups were not affected. Body weight gains were lower following the first day of treatment and recovered completely on the second day (low-dose group) and third day of treatment for the mid-and high-dose groups.  Sporadic lower food consumption occurred in the mid- and high-dose groups. Although the lower body weights seen in the high and mid dose groups were statistically significant, these are considered not to be biologically significant or adverse since these changes were only 1-4% lower than the controls. Therefore, the maternal LOAEL is >150 mg/kg bw/day, and the maternal NOAEL is 150 mg/kg bw/day.

A treatment-related effect at the high dose resulted in reduced mean fetal weights of male and female fetuses.  The only notable visceral anomaly was increased slightly dilated ureters with statistical significance in the mid (p<0.05) and the high doses (p<0.01). There were no treatment-related external malformations or variations of the fetuses.  Minor treatment-related skeletal malformations were seen at the high dose of 150 mg/kg/day.  These included an increased number of unossified centrum 5, increased number of cervical arch 7 cartilage fused to arch 6 cartilage, increased interruptions of thoracic rib 10 costal cartilage, increased number of long length cervical rib.  A treatment-related increased incidence of fetuses but not litters with a shortened 7[th] cervical rib was observed in the 50 and 150 mg/kg/day groups. The incidence of both fetuses and litters with an ossified calcaneum was lower than in the control group and indicated a reduction in ossification, in the 150 mg/kg/day group.  Reduced ossification of the mania and pes was seen at the high dose.  A statistically significant higher mean score for the pes was reported for the 50 mg/kg/day group, but the difference from the control mean was minimal. The developmental LOAEL is 150 mg/kg bw/day, based on decreased fetal weight and minor skeletal changes (centrum 5 not ossified, cervical arch 7 cartilage fused to arch 6 cartilage, shortened 7[th] cervical rib).  The developmental NOAEL is 50 mg/kg bw/day.

870.3700b:	Prenatal Developmental Toxicity Study - Rabbit


In a prenatal developmental study (MRID 00137822), NAA (Lot # RTS2846AC; 98.55% purity)  was administered by oral gavage to groups (16/group) of artificially inseminated Dutch Belted rabbits  (4 (1/2) to 5 months old) at dose levels of 0, 37.5, 75, or 150 mg/kg/day from days 6 through 27 of gestation.  These doses were selected on the basis of a range finding study (MRID  00137821) where groups (5 rabbits/group) were dosed NAA once daily by gavage at dose levels of 0, 28, 80 or 240 mg/kg/day from days 6 through 27 of gestation.  Animals were observed twice daily for mortality and once daily for toxic signs during the dosing period.  Animals that died were necropsied. Body weights were taken on days 0, 6, 12, 18, 24 and 28.  Surviving animals were sacrificed on day 28 and the uterus and ovaries were examined for viable and nonviable fetuses, resorptions, number of implantations, and number of corpora lutea.  One animal in the range finding study dosed at 240 mg/kg/day aborted on GD 28 following signs of toxicity consisting of hair loss, decreased feces and significant weight loss.  In the main study, one low dose animal died on GD 25 and three high dose gravid animals died during the study on GD 20, 22 and 27.  Only two of the high dose animals showed signs of toxicity (hair loss on the forelimbs, clear or white nasal discharge with dried material around the nose, decreased defecation and dry red material, presumably died blood, beneath the cage) prior to death.  Necropsy observations of the dead animals showed foamy fluid or congested lining in the trachea, congested lungs, fluid in the thoracic and/or abdominal cavities., reddening and/or erosions on the stomach mucosa, mucoid material or fluid in the intestines and pale liver or pitted kidneys.  Weights of the pregnant animals varied over the gestation period with some indication of treatment related loss in the high dose.  No compound-related abnormalities were observed in the pregnant animals at necropsy.  No compound-related effect was observed on implantation or fetal viability.  However, in the range finding study, an increase in the mean preimplantaion loss (23.2% at the low dose to 42.1% at the high dose compared to 11.4% in the concurrent control) occurred at all doses in the treated animals and appeared to be treatment related.  However, this increased preimplantation loss was considered problematic by the EPA reviewer since historical control data on 343 animals showed a preimplantaion loss of 30.8%.  Examination of the fetuses derived from the main study did not reveal any teratogenic effects.  It was concluded that the maternal toxicity NOAEL is 75 mg/kg/day based on lethality at the LOAEL of 150 mg/kg/day. The teratogenic and fetotoxic NOAEL was 150 mg/kg/day based on lack of developmental and fetoxic effects at the highest dose of 150 mg/kg/day tested.


In another developmental toxicity study (MRID 46685801) 1-Naphthaleneacetic acid sodium salt (97.4% a.i., batch/lot # 014-S0401-001) was administered to 24 female New Zealand White rabbits/dose in water by gavage at dose levels of 0, 30, 100 or 300 mg/kg bw/day from days 5 through 29 (inclusive) of gestation.  All animals survived the duration of the study except for one rabbit at the high dose which died on GD 22 due to a dosing error and one control rabbit was sacrificed on GD 24 following accidentally biting the dosing catheter into its esophagus.  A treatment related reduction in body weight and body weight gain was noted following the initial oral administration of 1-NAA Na salt to pregnant rabbits at the high dose of 300 mg/kg/day.  This was accompanied by initial reduction in food consumption.  Final body weights were comparable in all treatment groups.  Several dams receiving this dose were observed with few/no feces during the study.  Post mortem examination revealed red/black spots/areas in the glandular mucosa of the stomach in several of these dams indicating local irritation by the test material.  No adverse effects were noted in the dams at the lower dose of 30 and 100 mg 1-NAA Na salt /kg/day.  Cesarean section data did not reveal any statistically significant differences among all groups including the controls.  The LOAEL for maternal toxicity is 300 mg/kg/day based on reduced body weight, body weight gain and reduced food consumption, clinical signs (few/no feces) and stomach irritation (red/black spots/areas in the glandular mucosa of the stomach).  The maternal toxicity NOAEL of 1-NAA Na in pregnant rabbits derived from this study is 100 mg/kg/day.  

Developmental Toxicity.   The oral administration of 1-NAA Na salt during gestation to rabbits resulted in decreased mean fetal weights (males and females) at the high dose of 300 mg/kg/day. Mean fetal weights at the low- and mid-dose were comparable to the control group.  There was no effect by l-NAA-Na salt administration on the overall incidence of major external/visceral, skeletal or Bouin's head defects or on the incidence of any specific major fetal abnormalities. The defects were considered to be spontaneous in origin. Fetuses with minor defects of the head following Bouin's fixation and sectioning, and fetuses with minor external/visceral defects were comparable in all groups including the control.  There was no indication that any of the specific effects were attributable to the test material. Fetuses with minor skeletal defects were statistically significantly higher in the 300 mg/kg/day.  However, only one specific defect (dumbbell shaped ossification of the 7[th] thoracic centrum) was statistically significantly higher (p<0.01) in the 300 mg/kg/day group in comparison with the control group.  No variants were detected in the heads of the fetuses following Bouin's fixation and serial sectioning and no external/visceral findings were detected in any fetus.  The overall proportion of fetuses with skeletal variants was statistically significantly higher in the 30, 100 and 300 mg/kg/day groups in comparison with the control group, but there was no specific increase in any specific variant and is not attributable to the test material administration.  The incidence of lengthened costal cartilage of the 10[th] thoracic rib was statistically significantly higher in all groups administered 1-NAA-Na in comparison with the control group, although there was no evidence of a dose-related trend. However, the incidences of fetuses with shortened or lengthened 13[th] thoracolumbar ribs (i.e. extra ribs) and with 27 bilateral pre-pelvic vertebrae were statistically significantly increased in the 300 mg/kg/day group in comparison with the control group and were considered to be attributable to 1-NAA-Na administration.  The LOAEL for developmental toxicity is 300 mg/kg/day based on an increase in the overall incidences of fetuses with minor skeletal defects and variants (dumbell ossification of the 7[th] thoracic centrum, extra thoracolumbar ribs and 27 pre-pelvic vertebrae) and a decrease in ossification of the manus.  The NOAEL is 100 mg/kg/day.

A.4.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects  -  Rat MRID 42090018

870.3800:	Reproduction and Fertility Effects - Rat


In a 2-generation reproduction study (MRID 43796301) 1-Na-NAA (Lot # 214001; 96.44% a.i.) was administered to 35 Crl:CD(R)BR, rats/sex/group in diet at dose levels of 0, 100, 1000 and 3000 ppm [0, 7, 69 and 210 mg/kg/day for males and 0, 8, 81 and 239 mg/kg/day for females, respectively].  The dose levels were selected on the basis of previous toxicity studies in rats.  At 3000 ppm (HDT), treatment-related decreases in body weight  gain and food consumption were observed in the P1 and P2 females during premating and gestation periods and decrease in body weight gain in P2 males during the premating period.  Reductions in P2 male and female premating body weight gain, although appearing systemic in nature, may have been secondary to developmental toxicity in these animals.  Reduced survival and growth were observed in both F1 and F2 offspring.  No adverse effects were noted at 1000 ppm.  Systemic and reproductive/developmental LOAEL = 3000 ppm (210 mg/kg/day for males, 239 mg/kg/day for females), based upon reduced body weight gain and food consumption in parental animals and reduced litter survival, and pup weight throughout lactation in both generations of offspring.  Systemic and reproductive/developmental NOAEL = 1000 ppm (69 mg/kg/day for males, 81 mg/kg/day for females).

A.4.4	Chronic Toxicity

870.4100a:	Chronic Toxicity  -  Rat


In a combined chronic toxicity/oncogenicity study (MRID 44157501), 1- Naphthaleneacetic acid sodium salt (1-Na-NAA) (96.44% 1-NAA; 1.79% 2-NAA w/w; Lot no. 214001) was administered to Crl:CD(R) BR rats (80/sex/dose) in the diet at concentrations of 0, 100, 1000, or 5000 ppm (corresponding to 0, 4.4, 43.8, and 224.5 mg/kg/day for males and 0, 5.6, 55.8, and 303.6 mg/kg/day for females).  An interim sacrifice was performed at 12 months on 20 rats/sex/dose;  terminal sacrifice (main study) was after 20.5-23 months due to the high mortality and poor health in the treated and control groups.  There were no treatment-related effects on survival or clinical observations.  High-dose females had lower mortality than the controls (p  0.05).  Weekly body weights of the high-dose males were significantly lower for days 14-119 and 238-259 ( 8.8%; p  0.05 or 0.01), but their overall weight gain was similar to that of the controls.  The low- and mid-dose females' weekly body weights and overall weight gains were within 7.4% and 14% of controls, respectively (p  0.05 or 0.01).  High-dose females, however, had lowered weekly body weights ( 35%; p  0.01), total weight gain (61% of controls), and overall food consumption and efficiency (15% and 36% lower than controls, respectively).  Serum triglyceride levels were about 50% lower than control levels at 6 and 12 months in high-dose males, and were 66-78% lower at 12 and 18 months in high-dose females (p  0.05 or 0.01).  The urine protein content of high-dose females was decreased from 12 months to terminal sacrifice to only 4.1-6.1% of control values (p  0.05 or 0.01).  These clinical chemistry changes had no histopathological correlates and their toxicological significance is unknown.  High-dose males and females had a significantly increased incidence and severity of stomach mucosal gland dilation (p  0.05).  The incidence of focal alveolar macrophages (in some cases accompanied by focal chronic inflammation) was increased in mid- and high-dose females, and was correlated at the high dose with an increased incidence of grossly observed lung nodules (p  0.05 or 0.01).  The incidence of focal alveolar macrophages was also slightly increased in high-dose males (p = 0.071).  The LOAEL is 5000 ppm (224.5 mg/kg/day for males and 303.6 mg/kg/day for females), based on an increased incidence of stomach (mucosal gland dilation) and lung lesions (focal alveolar macrophages) in both sexes of rats, and on lowered body weight gain and food efficiency in females.  The corresponding NOAEL is 1000 ppm (43.8 mg/kg/day for males and 55.8 mg/kg/day for females).  The only neoplastic finding (p  0.01) was an increased incidence of uterine endometrial stromal polyps in high-dose females (2/60, 1/60, 3/60, 13/60 at 0, 100, 1000, 5000 ppm, respectively).  The longer survival time of the high-dose females (about 88 days) did not account for the greater incidence of these benign neoplasms.  The rats were dosed adequately, judging by the toxicologic findings in both sexes of high-dose rats.

870.4100b:	Chronic Toxicity - Dog

In a chronic toxicity study (MRID 43744201), 1-napthaleneacetic acid, sodium salt (Lot # 214001; 96.44% ai) was administered (gelatin capsules) to beagle dogs (4/sex/dose) at dose levels of 0, 15, 75, or 225 mg/kg/day for 52 weeks.  At 225 mg/kg/day, Na-NAA administration resulted in gross pathological changes in the stomach of one male and one female and histopathological changes in the stomachs of four males and one female. The latter were characterized by mucosal atrophy (3) and congestion (1) in males and hemorrhaging in the female.  Slight sinusoidal histiocytosis was observed in the livers of four males and three females.  Both males and females exhibited a high incidence of emesis and capsule regurgitation at the 225 mg/kg/day dose level.  At 75 mg/kg only males exhibited dose-related toxic response to Na-NAA as characterized by stomach lesions in three animals consisting of necrosis of the fundic or pyloric epithelium and by slight sinusoidal histiocytosis in the liver of two males.  No other definitive treatment-related changes were noted in organ weights or gross pathological changes. All microscopic tissue abnormalities, other than those mentioned, occurred randomly and sporadically in all study groups.  No neoplastic tissue was observed in beagles in the treatment or control groups.  No dogs died during the study.  No treatment-related differences were observed between the clinical appearance, body weights, food consumption, biochemistry, hematology, urinalysis, or ophthalmology of the treated and control animals.  The LOAEL is 75 mg/kg/day in males and 225 mg/kg/day in females, based on emesis, capsular regurgitation incidences, gross and histopathologic changes in stomachs, and sinusoidal histiocytosis in livers. The NOAEL is 15 mg/kg/day in males and 75 mg/kg/day in females.
         
A.4.5	Carcinogenicity

870.4200a:	Carcinogenicity Study - Rat

This study is described above in the chronic studies section.  An increased incidence of uterine endometrial stromal polyps occurred in female rats at 303 mg/kg/day dietary feeding of Na NAA for two years.  According to HED consulting pathologist, Dr.  John Pletcher these are considered to be benign proliferative lesions of no carcinogenic concern (email to Dr.  William Burnam of HED on 04/04/2002).  Na NAA was not carcinogenic in the rat. 

870.4200b:	Carcinogenicity (feeding) - Mouse

There is an NCI study published in 1969 where NAA acetamide was tested at one dose (maximum tolerated dose: according to the published article) as part of a testing program of 120 compounds.  Only the preliminary results were published (Innes et al, Innes JR, Ulland BM, Valerio MG, Petrucelli L, Fishbein L, Hart ER, Pallotta AJ, Bates RR, Falk HL, Gart JJ, Klein M, Mitchell I, Peters J. 1969.  Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: a preliminary note.  J.  Natl Cancer Inst.  42: 1101-1114).  The test materials were administered to two hybrid strains of mice : C57BL/6 x C3H/Anf and C57BL/6 x AKR (18/sex/hybrid strain).  The mice were administered NAA acetamide at one week of age by stomach intubation at 464 mg/kg/day until weaning at 4 weeks of age and administered the NAA acetamide in the diet at 1298 ppm (equivalent to 195 mg/kg/day at the conversion rate of 0.15 mg/kg for 1ppm) for approximately 18 months.  Gross and hostopathologic examination of the mice at the end of the feeding period did not reveal a significant increase in tumors over the controls.

In a carcinogenicity study (MRID # 46685802), Naphthaleneacetic Acid Sodium Salt (97.4%, batch/lot # 014-S0401-001) was administered to 50 C57BI/10JfCD-1 Alpk mice/sex/dose in the diet at dose levels of 0, 100, 500, or 2500 ppm [equivalent to 0, 10.8, 53.3, 276.0 / 0, 14.3, 70.9, 348.7 mg/kg bw/day M/F, respectively] for at least 80 weeks.  There were no statistically significant differences in survival or clinical signs between treated groups and controls in either sex. At the top dose (2500 ppm), bodyweights in males and females were statistically significantly lower than controls throughout the study with a maximum effect of 11% at week 77 in males, and 5% in females at week 41. Food consumption in males and females at this dose level was statistically significantly lower than controls at some time points throughout the study while food utilization in males was statistically significantly lower than controls in weeks 1-4 and overall in weeks 1-13. Total white blood cell, monocytes and large unstained cell counts were statistically significantly higher than controls in females at the top dose. This apparent elevation is due to higher counts in 2 individual animals and is considered to reflect animals with lymphomas in which there is also a leukaemic response. This effect was not compound-related. Also, at the top dose, liver and kidney weights in both sexes and epididymis in males were statistically higher than controls while brain weights in males were statistically lower.  Masses in the liver were identified in 3 male rats at the top dose, and in one female at 100 ppm. Pancreatic masses were also identified in 2 females at 2500 ppm and in 1 female at 500 ppm. A four-fold increase, compared to controls, in the incidence of hepato-cellular vacuolation in the liver was observed in males dosed at 2500 ppm. A slight increase in the presence of mononuclear cell infiltration in the liver was also observed in both males and females at this dose level. An increase in the incidence of intratubular microlithiasis and tubular basophilia within the kidney was observed in females and an increase in interstitial mononuclear cell infiltration in the kidney of males at 2500 ppm. There was an increase in the incidence of marked degeneration in the testes in males dosed with 2500 ppm of compound. Associated with this change, there was an increase in the incidence of decreased spermatozoa within the epididymis and dilated rete within the testis.  At 2500 ppm, adenomas of the liver were observed in one male rat, and adenomas of the lung were observed two males. Adenocarcinomas of the liver were observed in one control male and two males given 2500 ppm. None of these changes achieved statistical significance. There was a statistically significant increase in the incidence of histiocytic sarcoma in females at 2500 ppm but it was within historical control levels. There was a statistically significant increase (overall) in the incidence of multiple tumors in females given 2500 ppm. However there was no statistically significant increase in any individual tumor type, the incidence was low, and there was no dose-response relationship. Therefore this difference was considered not to be compound related.  The LOAEL is 2500 ppm [276 (M), 348.7 (F) mg/kg/day], based on lower body weight, food consumption, increased liver and kidney weights in both sexes and epididymis in males, lower brain weights in males, hepato-cellular vacuolation in males, adenomas of the liver and lung in males, increase in the incidence of multiple tumors in females. 
The NOAEL is 500 ppm [53.3 (M), 70.9 (F)] mg/kg/day.  At the doses tested, there was no treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate based on the effects observed on the top dose (2500 ppm/kg/day).

A.4.6	Mutagenicity

Gene Mutation

GLN 870.5100, 
MRID 43581006: NAA Acetamide
MRID 00042761: NAA
MRID 43581004: NAA Ethyl Ester

No mutagenic effect was noted with or without microsomal activation at concentrations up to the toxic range of 5000 micrograms/plate in the initial tests or in the confirmatory assay.


Chromosomal Aberrations

GLN 870.5395
MRID 43581005 NAA Acetamide
MRID 00042763 NAA
MRID 43581003 NAA Ethyl Ester

In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay in Mice.  There was no indication that NAA technical or the acetamide or the ethyl ester induced a clastogenic or aneugenic effect in either sex at any dose or sacrifice time. 



GLN 870.5300
MRID 43580202: NAA Acetamide
MRID 43580201: NAA Ethyl Ester

In Vitro mammalian cell gene mutation -  L5178Y TK+/- Mouse Lymphoma Mutagenesis Assay.  NAA acetamide was tested up to cytotoxic levels (1250 μg/mL -S9 and 150 μg/mL +S9).  NAA Ethyl ester was tested up to cytotoxic levels (100 μg/mL -S9 and 300 μg/mL +S9).  Both were non mutagenic without S9 activation system, but positive with S9 activation system at or above 100 ug/mL for the acetamide and 300 ug/mL for the ethyl ester.



GLN 870.5450
MRID 00042764 NAA


Rodent Dominant Lethal Assay.  NAA did not produce dominant lethal effects in mice at oral doses of 125, 250 or 500 mg/kg/day as measured by pre implantation and post implantation losses

A.4.7	Neurotoxicity

A neurotoxicity screening battery is required.  The registrant has committed to either develop new data or submit existing data to satisfy this requirement by early 2014. AMVAC is in the process of determining the value of certain acute neurotoxicity data that have successfully supported foreign registrations. If applicable to EPA standards these data could be submitted this year.  However, HASPOC has determined that these studies are not required at the present time.

A.4.8	Metabolism

870.7485	Metabolism  -  Rat 

In a study (MRID 43963301) conducted to examine the metabolism and disposition of 1-naphthaleneacetamide, five male and five female Sprague-Dawley rats were given either a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day).  Groups of male and female rats were subjected to the dosing regimens above using [[14]C] ring labeled -1-naphthaleneacetamide (Batch No. 94-516-38-10; 99.7% radiochemical purity, specific activity 55.5 mCi/mmol), and nonlabeled test article (Batch No. KP 0100487, chemical purity not available).  Excretion, tissue distribution, and metabolite profiles were determined.  There were no biologically significant treatment-related effects noted during the course of the study.  Overall recovery of administered radioactivity was an excellent 97.2-101%. 1-Naphthaleneacetamide was readily absorbed and excreted within 36 hours following a single 1 mg/kg bw, a 14-day repeat oral dose of 1 mg/kg bw, or a single 100 mg/kg bw oral dose. Following single or multiple oral low doses (1 mg/kg bw) of [C[14]]-1-naphthaleneacetamide, urinary excretion accounted for 70.8-74.1% of the administered radioactivity suggesting that a multiple exposure regimen did not affect the absorption/excretion processes.  Urinary excretion was unaffected following a single 100 mg/kg dose with 66.2-69.5% of the administered radioactivity excreted in urine.  Excretion via the feces accounted for the remainder of the administered radioactivity in all treatment groups (21.6-26.2%).  Excretory patterns did not exhibit gender-related variability but reflected delayed absorption in the high-dose group.  Because tissue burdens were very low at termination, neither 1-naphthaleneacetamide nor its metabolites appear to undergo significant sequestration.  Both  urinary and fecal metabolites were quantified by HPLC and most were identified using HPLC and HPLC/MS in conjunction with known standards.  Urinary metabolism involved amide cleavage followed by glycine conjugation with the glycine conjugate being the major metabolite of the low and repeat doses (13.7-47.3% of the administered radioactivity).  The glucuronide conjugate was also a major metabolite at the low doses (4.5-7.0% of administered).  For feces, the major metabolite detected was the dihydrodiol of naphthaleneacetamide (3.6-11.3% of administered.  Parent compound was detected at low concentrations (0.7-1.9% of administered) only in feces.  Extraction efficiencies appeared to be excellent and most components in the matrices examined (urine and feces) were adequately quantified and characterized.  The available data, based upon studies using labeled 1-naphthaleneacetamide, affirmed the metabolism pathway proposed by the investigators.


In another study (MRID 43961701) conducted to examine the metabolism and disposition of 1-naphthaleneacetic acid, ethyl ester, male and female Sprague-Dawley rats were given a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day).  Groups of male and female rats were subjected to the dosing regimens above using [[14]C] ring labeled -1-naphthaleneacetic acid, ethyl ester (Batch No. CSL-94-516-33-25, 99.3% radiochemical purity, specific acttivity 56.2 mCi/mmol), and nonlabeled test article (Batch No. GAB 69-34-02, chemical purity not available).  Excretion, tissue distribution, pharmacokinetic parameters, and metabolite profiles were determined.  There were no biologically significant treatment-related effects noted during the course of the study.  Overall recovery of administered radioactivity was an excellent 98.6-101.8%. 1-Naphthaleneacetic acid, ethyl ester was readily absorbed and excreted within 36 - 48 hours following a single 1 mg/kg bw, a 14-day repeat oral dose of 1 mg/kg bw, or a single 100 mg/kg bw oral dose.  Following single or multiple oral low doses (1 mg/kg bw) of [C[14]]-1-naphthaleneacetic acid, ethyl ester, urinary excretion accounted for 67.6-85.3% of the administered radioactivity.  Urinary excretion was unaffected following a single 100 mg/kg bw dose with 61.8-78% of the administered radioactivity excreted in urine.  Excretion via the feces accounted for the remainder of the administered radioactivity excreted by all treatment groups (12.3-35.2%).   Excretory patterns did not exhibit gender-related variability for the low dose groups although a minor difference was observed at the high dose.  Excretion patterns of the high-dose group reflected delayed absorption.  Because  - tissue burdens were very low at termination, neither 1-naphthaleneacetic acid, ethyl ester nor its metabolites appear to undergo significant sequestration.  Both  urinary and fecal metabolites were quantified by HPLC, TLC and most were identified using HPLC, GC/MS, and HPLC/MS in conjunction with known standards.  The major pathway of metabolism involved ester cleavage followed by glycine and glucuronide conjugation at the low and low repeat doses.  At the high dose, glucuronide conjugation appeared to play a more important role following ester cleavage.  Parent compound was detected at low concentrations (0.5-4.7% of administered) only in feces.  Extraction efficiencies appeared to be excellent and most components in the matrices examined (urine and feces) were adequately quantified and characterized.  The available data, based upon studies using labeled 1-naphthaleneacetic acid, ethyl ester, affirmed the metabolism pathway proposed by the investigators.

There are two published reports dealing with the metabolism of NAA in animals.  In one study (Dixon et al, 1977), carboxy -[14]C-1-naphthylacetic acid (aqueous equivalent NaOH solution) at 100 mg/kg was administered intramuscularly to 6 primate species (rhesus monkey: 1M, 1F; cynomolgus monkey: 1F; squirrel monkey: 2F; capuchin: 2F; marmoset: 1M and bushbaby: 1M, 1F), and intraperitoneally to cats (2F, 1M), rat (3F) and fruit bat (1F, 1M), orally to the rabbit (2F) and orally to 2 human males at 5 mg/individual.  Urine was collected for 24 hours and analyzed for radioactivity and metabolites, by liquid scintillation counting, chromatography,  radiochromatography scanning, and reverse isotope dilution.  In most species tested, 60-100% of the administered radioactivity was excreted in the urine by the end of 48 hours.  The glucuronic acid conjugate was the major urinary metabolite in man, rhesus monkey, marmoset, rabbit, rat, and fruit bat.  In the cat, no glucuronic acid conjugate was detected; turine and glycine conjugates were the major excretion products.  The 1-Naphthylacetyl glycine conjugate was a major urinary metabolite (>20%) in the cat, squirrel and bushbaby monkey and a minor metabolite in rabbit, rat, capuchia and marmoset monkey.  1-Naphthylacetylglutamine conjugate was formed only in the cynomolgus , squirrel and capuchin monkeys and marmoset in amounts not exceeding 3% of the administered dose.  1-Naphthylacetylturine was excreted by all species except the rabbit, rat  and the fruit bat.  It was a major excretion product (>6%) in the squirrel and capuchin monkeys, the marmoset and the cat.  In addition, when female rats were administered intraperitoneally doses of 5-500 mg/kg, bile duct cannulation showed that 10-44% of the radioactivity was present in the bile 3 hours after injection, while 0.6-32% was present in the urine.  At higher doses, urinary glucuronic acid predominated whereas at the lower doses the glycine conjugates predominated.  In the bile, the glucuronic acid conjugate was the major metabolite (>80% of the bile radioactivity), and the glycine conjugate was a minor metabolite (<4% of the bile radioactivity).  There was no analysis of the fecal radioactivity reported. 


In another study (Lethco and Brouwer, 1966) carboxy -[14]C-1-naphthylacetic acid metabolism was investigated in male rats.  [14]C-NAA (neutralized with NaOH) was administered orally by stomach intubation at 0.1, 1.0, 100 and 250 mg/rat (2 rats/dose, weighing 250-280 g).  Urine and feces were collected for 3 days.  For bile cannulation study, [14]C-NAA was administered orally to 8 and 7 rats (weighing 350-435 g) at 0.1 and 100 mg/ rat, respectively, and urine and bile were collected at 2 and 6 hours after administration.  Radioactivity was analyzed by liquid scintillation counting, column and paper chromatography and enzymatic analysis.  Within 3 days, 71-90% of the administered [14]C was excreted in the urine.  At the lower doses (0.1-100 mg/kg)  most of the radioactivity was excreted during the first 24 hours, while at the higher dose (250 mg/kg), excretion was highest on the second day.  Fecal excretion accounted for 3-10% at the 0.1-1.0 mg/kg doses and 14-21% of the administered dose at the 100 and 259 mg/kg doses.  After the third day, no radioactivity was detected in the feces or urine at any dose.  Fractionation of the urinary radioactivity by column chromatography and subsequent paper chromatography, UV spectral analysis and B-glucuronidase enzyme hydrolysis, revealed that 70-93% of the urinary radioactivity was NAA glycine conjugate and NAA glucuronic acid conjugate.  The glucuronic acid conjugate predominated at the two high doses and the glycine conjugate predominated at the lower dose.  Minor amounts of unchanged NAA and two other minor unidentified metabolites were also detected in the urine.  The fecal radioactivity was not characterized.  In the bile cannulation experiment, excretion  of radioactivity into the bile and urine varied by the administered dose.  At the low dose of 0.1 mg/kg radioactivity in the urine was nearly four times the radioactivity detected in the bile after 2 hours, while at the higher dose of 100 mg/kg the ratio was reversed.  At the high dose a maximum of 29% of the administered radioactivity was recovered at 6 hours, while a maximum of 54% was recovered at the low dose at 2 hours.  At the low dose, the NAA glycine conjugate was the major metabolite and the NAA glucuronic conjugate was a minor metabolite, while in the bile the preponderance of these two metabolites was reversed.  Also unchanged NAA was detected in the bile but not in the urine at both doses.  At the high dose the NAA glucuronic conjugate was the major metabolite in both urine and bile while the glycine conjugate was a minor metabolite. 

A.4.9	Immunotoxicity

	870.7800	Immunotoxicity  -  Rat

An immunotoxicity study is required.  The registrant has committed to begin this study in early 2013 and submit to EPA in early 2014.



B.  PHYSICAL/CHEMICAL PROPERTIES

Table 2.  Physicochemical Properties of NAA[1]
Parameter
Value
Reference
Active Ingredient
NAA acetamide
Melting point/range
182-184 C
Farm Chemicals Handbook
pH of 1% aqueous suspension
5.1
Product CSF
Density or specific gravity
0.221 g/cm[3]
Product CSF
Water solubility  (20̊C)
not available

Solvent solubility (20̊C)
not available

Vapor pressure at 20̊C
not available

Dissociation constant (pKa)
not available

Octanol/water partition coefficient (Kow)
not available

UV/vis  absorption spectrum
not available

Active ingredient
NAA
Melting point/range
130 C
Farm Chemicals Handbook
pH of 1% aqueous suspension
3.45
RD D265117, 5/15/00, B. Kitchens
Density or specific gravity
0.45 g/mL
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Water solubility  (26̊C)
0.042 g/100 mL
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Solvent solubility (26̊C)
xylene 5.5 g/100 mL
CCl4 1.06 g/100 mL
freely soluble in acetone, ether, and chloroform
CB Nos. 3468 and 3469, 6/3/88, F. Suhre

Farm Chemicals Handbook
Vapor pressure at 20̊C
0.3 mm Hg at 26 C
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Dissociation constant (pKa)
3.16 x 10[-4]
CB Nos. 3970 and 3971, 7/5/88, F. Suhre
Octanol/water partition coefficient (Kow)
not applicable; polar compound

UV/vis  absorption spectrum
not available

Active ingredient
NAA sodium salt
Melting point/range
>300 C
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
pH of 1% aqueous suspension
9.1
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Density or specific gravity
0.46 g/mL
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Water solubility  (26̊C)
340 g/100 mL
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Solvent solubility (26̊C)
insoluble in nonpolar solvents
CB Nos. 3468 and 3469, 6/3/88, F. Suhre
Vapor pressure at 20̊C
not available

Dissociation constant (pKa)
3.16 x 10[-4]
CB Nos. 3970 and 3971, 7/5/88, F. Suhre
Octanol/water partition coefficient (Kow)
not applicable; polar compound

UV/vis  absorption spectrum
not available

Active ingredient
NAA ethyl ester
Boiling point/range
>150 C
Old unreviewed Union Carbide data
pH of 1% aqueous suspension
not available

Density or specific gravity
1.11 at 20 C
Old unreviewed Union Carbide data
Water solubility  (26̊C)
insoluble
Old unreviewed Union Carbide data
Solvent solubility
soluble in xylene, toluene, ethanol, acetone, and methyl ethyl ketone
Old unreviewed Union Carbide data
Vapor pressure at 20̊C
not available

Dissociation constant (pKa)
not available

Octanol/water partition coefficient (Kow)
not available

UV/vis  absorption spectrum
not available


   C.  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 were determined to require a review of their ethical conduct, have received that review and have been determined to be ethical.

Klonne, D. (1999) Integrated Report for Evaluation of Potential Exposures to Homeowners and Professional Lawn Care Operators Mixing, Loading, and Applying Granular and Liquid Pesticides to Residential Lawns:  Lab Project Number:  OMA005: OMA001: OMA002.  Unpublished study prepared by Riceerca, Inc., and Morse Laboratories.  2213 p. (MRID 44972201).

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.




