Page 1 of 70

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. 
Page 2 of 70

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
Page 3 of 70

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.
Page 4 of 70

A.2 Toxicity Profiles......................................................................................................... .42

A.3 EXECUTIVE SUMMARIES ................................................................................... .51

APPENDIX C. Physical/Chemical Properties.......................................................................... 69

APPENDIX D. Studies Reviewed for Ethical Conduct.......................................................... 70
Page 5 of 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 
Page 6 of 70

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 
Page 7 of 70

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 website1. 

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 

 

1 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
Page 8 of 70

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. 
Page 9 of 70

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. 
Page 10 of 70

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

O

NH2

O

OH
Page 11 of 70

Table 3.1. NAA Nomenclature

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

O

O K

+

O

O NH4

+

O

O Na

+

O

O CH3
Page 12 of 70

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 preharvest 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
Page 13 of 70

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
Page 14 of 70

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 [14C] 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 [14C] 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 
Page 15 of 70

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 
Page 16 of 70

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 
Page 17 of 70

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 
Page 18 of 70

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.

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 4.5.4.1. 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
Page 19 of 70

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 3rd 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.
Page 20 of 70

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
Page 21 of 70

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. 
Page 22 of 70

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.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Avocado, 

Fruit

NAA32 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.

LAFT2 HAFT2 Median Mean Std. 

Dev.

Rambutan, Fruit NAA390 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.
Page 23 of 70

Table 5.3. Tier I Estimated Drinking Water Concentrations of 1-Naphthaleneacetic acid1

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 DEEMFCIDTM, 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 foodform (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. 
Page 24 of 70

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-exposuresop.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 postapplication 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 
Page 25 of 70

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 
Page 26 of 70

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.
Page 27 of 70

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

Exposure 

Scenario 

Level of 

Concern

Dermal 

Unit 

Exposure 

(μg/lb ae)

Inhalation 

Unit 

Exposure 

(μg/lb ae)

Maximum 

Application 

Rate1

Area Treated or 

Amount Handled 

Daily2

Dermal Inhalation Total

Dose 

(mg/kg/day)3 MOE4 Dose (mg/kg/day)5 MOE6 ARI7

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 (μg/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 (μg/lb ae) x Conversion Factor (0.001 mg/μg) 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
Page 28 of 70

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 
Page 29 of 70

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 Table2”, 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 website3. 

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 

 

2 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

3 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Page 30 of 70

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, watersoluble 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 
Page 31 of 70

formulas:

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

where:

Daily Exposure = Amount (mg ae/day) that is available for dermal or inhalation absorption,

UE = Unit Exposure (μg 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 
Page 32 of 70

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.
Page 33 of 70

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 (μg/lb 

ae)1

Inhalation Unit 

Exposure (μg/lb 

ae)1 Maximum

Application Rate2

Area Treated or 

Amount Handled 

Daily3

Dermal Inhalation Total

Baseline 

Mitigation Level

Baseline Mitigation 

Level

Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 ARI8

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 Manuallypressurized HandwandOrchard 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 (μg/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 (μg/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)].
Page 34 of 70

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 reentry 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 postapplication 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. 
Page 35 of 70

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 postapplication 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 website4.

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

 

4 Available: http://www.epa.gov/pesticides/science/post-app-exposure-data.html
Page 36 of 70

Average Daily Dose (ADD): Potential daily exposures for occupational post-application workers 

were calculated using the following formulas:

DFRt (μg/cm2) = AR (lb ae/A) * F * (1-D)t* 4.54E8 μg/lb * 2.47E-8 acre/cm2

where:

DFRt = dislodgeable foliage residue on day "t" (μg/cm2),

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 (cm2/hr) * DFRt (μg/cm2) * ET (hrs /day) * 1E-3 mg/μg

where:

Daily Exposure = Amount (mg ae/day) that is available for dermal absorption,

TC = Transfer coefficient (cm2/hr),

DFRt = Dislodgeable Foliar Residue on day “t” (μg/cm2), 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:
Page 37 of 70

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.
Page 38 of 70

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.
Page 39 of 70

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 

(cm2/hr) DFR/TTR1 Dermal Dose (mg/kg/day)2 MOE3

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)tx 4.54E8 μg/lb x 2.47E-8 acre/cm2; where F = 0.25 and D = 0.10 per day

2. Daily Dermal Dose = [DFR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (100%)] BW (80 

kg).

3. MOE = POD (300 mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm2) x TC x 0.001 mg/μg 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 postapplication 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 postapplication 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.
Page 40 of 70

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.
Page 41 of 70

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

---

---
Page 42 of 70

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 

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 

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 = 

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 malesfemales). LOAEL= 8000 ppm 
Page 43 of 70

A.2 Toxicity Profiles

Study pc 056001: acetamide pc 056002: NAA pc 056007: Na salt pc 056008: ethyl ester

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)

enlarged liver weights in 

females. The NOAEL is 150 

mg/kg/day.

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.

(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 

MRID 00136446

0, 50, 150, or 300 mg/kg/day

for 6 months to beagle dogs 

(4/sex/dose) by gelatin 

MRID 42983801

0, 25, 150, or 450 mg/kg/day. 

LOAEL for systemic toxicity 

=150 mg/kg/day based on 

MRID 43914901

0, 40, 125, or 400 mg/kg/day 

for 13 weeks. LOAEL= 400 

mg/kg/day, based on soft/liquid 
Page 44 of 70

A.2 Toxicity Profiles

Study pc 056001: acetamide pc 056002: NAA pc 056007: Na salt pc 056008: ethyl ester

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.

capsules. 

The LOAEL was 50 

mg/kg/day, the lowest dose 

tested, based on hepatic liver 

changes (pericholangistis). No 

NOAEL derived from this 

study. 

lesions of the GI tract and 

hypocellularity of the bone 

marrow. NOAEL for systemic 

toxicity is 25 mg/kg/day .

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 

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 
Page 45 of 70

A.2 Toxicity Profiles

Study pc 056001: acetamide pc 056002: NAA pc 056007: Na salt pc 056008: ethyl ester

body weight gain during the 

compound administration and 

the NOAEL is 50 mg/kg/day.

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 7th

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 7th thoracic 

centrum, extra thoracolumbar 

ribs and 27 pre-pelvic 

vertebrae) and a decrease in 

ossification of the manus and 
Page 46 of 70

A.2 Toxicity Profiles

Study pc 056001: acetamide pc 056002: NAA pc 056007: Na salt pc 056008: ethyl ester

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 
Page 47 of 70

A.2 Toxicity Profiles

Study pc 056001: acetamide pc 056002: NAA pc 056007: Na salt pc 056008: ethyl ester

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. 

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, hepatocellular 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 
Page 48 of 70

A.2 Toxicity Profiles

Study pc 056001: acetamide pc 056002: NAA pc 056007: Na salt pc 056008: ethyl ester

examination of the mice at the 

end of the feeding period did 

not reveal a significant increase 

in tumors over the controls.

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 mutationbacterial

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
Page 49 of 70

A.2 Toxicity Profiles

Study pc 056001: acetamide pc 056002: NAA pc 056007: Na salt pc 056008: ethyl ester

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 14C 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 
Page 50 of 70

A.2 Toxicity Profiles

Study pc 056001: acetamide pc 056002: NAA pc 056007: Na salt pc 056008: ethyl ester

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 -

14C-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 [14C] 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 

[

14C] 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. 
Page 51 of 70

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.

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 aPAD = (NOAEL) 25 mg/kg = 0.25 mg/kg

 (UF) 100

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

 (UF) 100
Page 52 of 70

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..
Page 53 of 70

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%; p0.05) and females (32%; p0.01) 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
Page 54 of 70

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 (SpragueDawley) 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 
Page 55 of 70

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 
Page 56 of 70

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. Doserelated 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 
Page 57 of 70

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 
Page 58 of 70

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 midand 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.
Page 59 of 70

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 treatmentrelated 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 7th 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 7th 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 
Page 60 of 70

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 
Page 61 of 70

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 7th 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 10th 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 13th 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 7th thoracic centrum, extra thoracolumbar ribs and 27 prepelvic 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®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 
Page 62 of 70

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® 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 highdose 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 
Page 63 of 70

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 
Page 64 of 70

(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 
Page 65 of 70

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 
Page 66 of 70

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 [14C] 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 [C14]-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 [14C] 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 [C14]-1-naphthaleneacetic acid, ethyl ester, urinary excretion accounted for 67.6-
Page 67 of 70

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 -

14C-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. 
Page 68 of 70

In another study (Lethco and Brouwer, 1966) carboxy -

14C-1-naphthylacetic acid metabolism 

was investigated in male rats. 14C-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, 

14C-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 14C 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.
Page 69 of 70

B. PHYSICAL/CHEMICAL PROPERTIES

Table 2. Physicochemical Properties of NAA1

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/cm3Product 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
Page 70 of 70

Table 2. Physicochemical Properties of NAA1

Parameter Value Reference

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.