UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

November 18, 2015 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Naphthalene Acetates: Human Health Risk Assessment for a Proposed New 

Use on Pomegranate. 

PC Code: 05600 1, 056002, 056003, 056004, 

056007, 056008 

Decision No.: 495 105, 495110 

Petition No.: N/ A 

Risk Assessment Type: Single Chemical Aggregate 

TXRNo.: NIA 

MRID No.: NIA 

DP Barcode: 0 423654, 0 423656 

Registration No.: 5481-429, 5481-433 

Regulatory Action: Section 3 

Case No.: 0379 

CAS No.: 2 122-70-5 

40 CFR: §180.1 55 

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- Risk Assessment Branch 4 

Health Effects Division (7509P) 

THROUGH: Elissa Reaves, Ph.D., Branch Chief 

Risk Assessment Branch 4 

Health Effects Division (7509P) 

TO: Sidney Jackson/Barbara Madden 

Risk Integration, Minor Use & Emergency Response Branch 

Registration Division (7505P) 

This document provides the Health Effects Division's (HED's) risk assessment for the Section 3 

use for naphthalene acetates on pomegranate. The document has been revised to include an 

assessment of aggregate risk from residential exposures to naphthalene acetates. 

Page I of79 
1.0 EXECUTIVE SUMMARY ................................................................................................ 5 

2.0 HED RECOMMENDATIONS .......................................................................................... 8 

2.1 Data Deficiencies/Conditions of Registration ........................................................ 8 

2.2 

2.2.1 

2.2.2 

2.2.3 

2.2.4 

2.3 

Tolerance Considerations ........................................................................................ 8 

Enforcement Analytical Method ............................................................................. 8 

International Harmonization ................................................................................... 8 

Recommended Tolerances ........................................................................................ 8 

Revisions to Petitioned-For Tolerances .................................................................. 9 

Label Recomn1 endations ......................................................................................... 9 

3.0 INGREDIENT PROFILE .................................................................................................. 9 

3.1 Chemical Identity ..................................................................................................... 9 

3.2 Physical/Chemical Characteristics ....................................................................... 10 

3.3 Pesticide Use Pattern ............................................................................................. 10 

3.3.1 Registered Products ................................................................................................ 11 

3.3.2 Proposed Ne'v Uses ................................................................................................. 11 

3.4 Anticipated Exposure Path,vays ........................................................................... 11 

3.5 Considerations of Environmental Justice ............................................................ 11 

4.0 HAZARD CHARACTERIZATION/ASSESSMENT ................................................... 12 

4.1 Toxicology Studies Available for Analysis ........................................................... 12 

4.2 Absorption, Dis'tribution; Metabolism and Excretion ........................................ 13 

4.3 Toxicological Effects .............................................................................................. 14 

4.4 Safety Factor for Infants and Children (FQPA Safe ty Factor) ......................... 15 

4.4.1 

4.4.2 

4.4.3 

4.4.4 

4.5 

4.5.1 

4.5.2 

4.5.3 

Completeness of the Toxicology Database ............................................................ 16 

Evidence of Neurotoxicity ...................................................................................... 16 

Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ...... 16 

Residual Uncertainty in the Exposure Database .................................................. 16 

Toxicity Endpoint and Point of Departure .......................................................... 16 

Dose-Response Assessment .................................................................................... 16 

Recommendations for Combining Exposure Routes ........................................... 17 

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 .... 21 

5.1 Metabolite/Degradate Residue Profile ................................................................. 21 

5.1.1 Summa ry of Plant and Livestock Metabolism Studies ........................................ 21 

Page 2 of79 
Page 3 of 79

5.1.2 Comparison of Metabolic Pathways...................................................................... 21

5.1.3 Environmental Fate and Transport...................................................................... 21

5.1.4 Residues of Concern Summary and Rationale..................................................... 22

5.2 Food Residue Profile.............................................................................................. 22

5.2.1 Residues in Crops.................................................................................................... 22

5.3 Water Residue Profile............................................................................................ 23

5.3.1 Estimated Drinking Water Concentrations.......................................................... 23

5.4.1 Acute Dietary and Drinking Water Analysis ....................................................... 24

5.4.2 Chronic Dietary and Drinking Water Analysis ................................................... 24

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT .......................................... 25

6.1 Residential Bystander Post-application Inhalation Exposure ........................... 27

6.2 Spray Drift.............................................................................................................. 27

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT............................................ 28

7.1 Short-Term Aggregate Risk.................................................................................. 28

7.2 Chronic Aggregate Risk ........................................................................................ 29

8.0 CUMULATIVE RISK...................................................................................................... 29

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION.............................. 30

9.1 Short-Term Handler Risk .................................................................................... 30

9.1.1 Handler Exposure Scenarios.................................................................................. 30

9.1.2 Handler Exposure Data and Assumptions ........................................................... 30

9.1.3 Handler Exposure and Risk Estimates................................................................. 31

9.2 Post Application Exposure .................................................................................... 33

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates ................ 33

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates..................... 33

9.2.3 Restricted Entry Interval ....................................................................................... 34

10.0 REFERENCES .............................................................................................................. 34

APPENDICIES ........................................................................................................................... 36

Appendix A. Toxicology Profile and Executive Summaries .................................................. 36

A.1 Toxicology Data Requirements............................................................................. 36

A.2 Toxicity Profiles ..................................................................................................... 37

A.3 Hazard Identification and Endpoint Selection.................................................... 53

A.3.1 Acute Population Adjusted Doses (aPAD) – All Populations ............................ 53

A.3.2 Chronic Population Adjusted Dose (cPAD) – All Populations.......................... 53

A.3.3 Dermal Absorption ................................................................................................ 53
Page 4 of 79

A.3.4 Adult Oral Exposure (Short-Term) ..................................................................... 54

A.3.5 Dermal Exposure (Short-Term) ........................................................................... 54

A.3.6 Inhalation Exposure (Short-Term) ...................................................................... 54

A.4 Executive Summaries for Supporting Toxicity Studies...................................... 55

A.4.1 Subchronic Toxicity............................................................................................... 55

A.4.2 Prenatal Developmental Toxicity ......................................................................... 63

A.4.3 Reproductive Toxicity ........................................................................................... 66

A.4.4 Chronic Toxicity..................................................................................................... 67

A.4.5 Carcinogenicity ...................................................................................................... 68

A.4.6 Mutagenicity........................................................................................................... 70

A.4.7 Neurotoxicity .......................................................................................................... 71

A.4.8 Metabolism ............................................................................................................. 71

A.4.9 Immunotoxicity ...................................................................................................... 74

Appendix B. Physical/Chemical Properties............................................................................. 75

Appendix C. Occupational Handler Non-Cancer Exposure and Risk Estimate Equations77

Appendix D. Review of Human Research................................................................................ 79
Page 5 of 79

1.0 EXECUTIVE SUMMARY

1-Naphthaleneacetic acid, 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. 

This assessment provides information to support the Section 3 registration and establishment of a 

tolerance for a proposed new use of 1-Napthaleneacetic acid, ethyl ester on pomegranate. The 

product, TRE-HOLD Sprout Inhibitor A112 (EPA Reg. No. 5481-429; 15.1 % NAA ethyl ester 

(1 lb ae/ gal)), will be used as a directed spray to the lower tree trunk and immediate surrounding 

area to treat the basal trunk sprouts and root suckers. Exposure patterns for the new use on 

pomegranate are similar to those assessed for avocado, mango and mamey sapote in the most 

recent naphthalene acetate risk assessment (D404398, S. Hummel, 1/16/13). Dietary (food and 

water) and occupational exposures via dermal and inhalation pathways are expected for the 

proposed new use. There are no residential uses on pomegranate and no uses resulting in 

exposure to children via incidental oral activities. The label for the new use include the default 

REI of 12 hours, and require the following PPE for direct mixers, loaders, applicators and other 

handlers: long-sleeved shirt and long pants, shoes plus socks, and chemical-resistant gloves. 

Additionally, under PP#4E8310, the Interregional Research Project Number 4 (IR-4) submitted a 

petition for the establishment of permanent tolerances for 1-Naphthaleneacetic acid residues on 

pomegranate. 

Naphthaleneacetamide (NAA acetamide), naphthaleneacetic acid, potassium naphthaleneacetate 

(NAA potassium salt), ammonium naphthaleneacetate (ammonium NAA), sodium 

naphthaleneacetate (NAA sodium salt), and ethyl naphthaleneacetate (NAA ethyl ester) are 

assessed as a single group (the naphthalene acetates, hereafter referred to as NAA) because they 

are structurally related, are metabolized to the acid form, and are eliminated from the body as 

glycine and glucuronic acid conjugates within 48 hours after exposure (Branagan et al. 1981).

The toxicology data base is adequate to characterize the toxicity of the naphthalene acetates with 

the exception of an inhalation study which is a data gap. 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. Eye irritation was severe in animals exposed to naphthaleneacetic acid and 
Page 6 of 79

NAA sodium salt products while exposure to NAA ethyl ester and NAA acetamide led to mild, 

transient irritation. In general, NAA sodium salt was the most toxic form in subchronic and 

chronic studies. Repeated dose exposure in oral toxicity studies 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. Others 

symptoms of toxicity from oral exposure included decreased hematocrit and hemoglobin, 

reduced RBC count in rats and dogs, and hypocellularity of the bone marrow in dogs. In contrast 

to oral exposures, NAA ethyl ester was the most toxic chemical species when administered 

dermally inducing epidermal hyperplasia and hyperkeratosis, sebaceous gland hyperplasia, and 

dermal inflammation. The NAA sodium salt required a 10-fold higher dose to elicit similar 

dermal effects and no dermal effects were noted in the NAA acetamide exposure. Systemic 

toxicity was not a consequence of dermal exposure to any of the tested naphthalene acetates.

Developmental and offspring toxicity was linked to NAA sodium salt exposure but was not a 

common observation for the entire naphthalene acetate group. Developing rats exhibited 

decreased fetal weight and minor skeletal changes and were more susceptible to NAA sodium 

salt toxicity than the parent. Skeletal defects and variants were observed in rabbit fetuses after 

exposure to NAA sodium salt in the developmental rabbit study; however, these effects only 

occurred at doses that also compromised maternal health. Offspring toxicity from NAA sodium 

salt manifested as reduced litter survival and pup weight throughout lactation in two generations. 

These effects coincided with reduced body weight in both parental generations indicating the 

adults and their young were equally susceptible to NAA sodium salt. Carcinogenicity studies of 

NAA acetamide in mice and NAA sodium salt in rats and mice were 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. 

Toxicological endpoints were selected for dietary/drinking water, adult incidental oral, and 

inhalation exposures to occupational applicators. Previously, dermal exposure was assessed for 

both occupational and residential uses (D404398, S. Hummel, 1/16/13). Updated dermal studies 

reflecting current HED policy indicated no concern for systemic toxicity from dermal exposure 

up to 1000 mg/kg/day for any of the naphthalene acetates tested (NAA sodium salt, NAA, and 

NAA acetamide); therefore a dermal assessment was not conducted in this risk assessment. 

There were no toxicological effects attributable to a single exposure of naphthalene acetates 

observed in oral toxicity studies; therefore, a point of departure (POD) for acute dietary exposure

was not selected. A chronic reference dose (cRfD) of 0.25 mg/kg/day was calculated using the 

highest NOAEL (25 mg/kg/day) from two co-critical dog studies and uncertainty factors for 

interspecies (10x) and intraspecies extrapolation (10x). The NOAEL was based on lesions of the 

GI tract (ulcerative duodenitis and acute or erosive gastritis) and hypocellularity of the bone 

marrow at 150 mg/kg/day in the subchronic dog study and was protective of the stomach lesions 

(slight to moderate necrosis of fundus and pyloric epithelium), and slight sinusoidal histiocytosis 

in the liver of males observed at 75 mg/kg/day in the chronic dog study. The FQPA SF was 

reduced to 1x because the toxicology and exposure database was adequate to address 

susceptibility in infants and small children, and the selected POD was protective of

developmental and offspring effects observed at higher doses. As a result, the chronic population 

adjusted dose (cPAD) was equivalent to the cRfD. The NOAEL (25 mg/kg/day) from the cocritical dog studies was also selected as the POD for short-term oral exposure in adults and for 

inhalation exposure in occupational and residential settings. The endpoints for the co-critical dog 
Page 7 of 79

studies were protective of developmental and offspring effects manifesting from these routes of 

exposure as well. The short-term adult oral endpoint was selected exclusively for the residential 

aggregate assessment. An uncertainty factor of 100X (10x for interspecies extrapolation, 10x for 

intraspecies variation) was applied to all endpoints selected for exposure routes and an additional

10x database uncertainty factor (UFDB) was applied to the inhalation endpoint to account for the

lack of an inhalation study. 

Risk assessments were conducted for chronic dietary (food and water) and occupational exposure 

pathways based on registered uses and requests for a new use on pomegranate. Dietary (food and 

drinking water) exposure and risk estimates were below HED’s level of concern for the general 

population and all population subgroups (< 25% of cPAD). Likewise, occupational risk estimates 

indicate that occupational handler exposures are not of concern at the maximum proposed 

application rate for the new use. Post-application occupational exposures are not expected based 

on use patterns. Residential exposures are not expected based on the newly proposed use on 

pomegranate; however, existing residential uses previously re-evaluated (D404398, S. Hummel, 

1/16/13; to reflect updates to HED’s 2012 Residential SOPs1along with policy changes for body 

weight assumptions) were updated in this memo based on new toxicological data. Revised risk 

estimates for all residential uses and aggregate risk estimates combining short-term inhalation 

and oral exposure were not of concern to HED.

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 website2. 

Tolerance Recommendation

Pending submission of analytical standards, there are no residue chemistry issues that would 

preclude granting a Section 3 registration for the requested new use of NAA, nor establishment 

of the following tolerance for residues of NAA. 

Pomegranate..... .......................................................................0.05 ppm

Tolerances are established under 40CFR§180.155(a) for the residues of 1-naphthaleneacetic acid, 

including its metabolites and degradates in or on the commodities. Compliance with the 

tolerance levels specified is to be determined by measuring only 1-naphthaleneacetic acid and its 

conjugates, calculated as the stoichiometric equivalent of 1-naphthaleneacetic acid, in or on the 

 

1 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html

2 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 79

commodity. The established tolerances range from 0.05 ppm to 2.0 ppm. The tolerance 

expression is in accord with the Agency’s current guidance on tolerance expressions.

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. 

2.0 HED RECOMMENDATIONS

HED recommends the registration and proposed tolerances for the use of NAA on pomegranate

be granted. Additional data requirements are outlined in section 2.1, specific tolerance 

recommendations in 2.2, and label modifications in section 2.3.

2.1 Data Deficiencies/Conditions of Registration 

Pending submission of analytical standards, there are no residue chemistry issues that would 

preclude granting registration for the requested use of NAA on pomegranate.

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 Hazard and 

Science Policy Council (HASPOC) has waived the requirement for each at the present time

(TXR 0056465 and 0056968). A 28-day inhalation study is required and in the absence of this 

study, a 10x database uncertainty factor (UFDB) was applied to the appropriate endpoints (TXR 

0056465). 

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. 

These 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 1-naphthaleneacetic acid, its salts, ester, and acetamide on pomegranate.

2.2.3 Recommended Tolerances

There are no residue chemistry issues that would preclude granting registration for the requested 
Page 9 of 79

new use of NAA on pomegranate or establishment of a tolerance for the combined residues of 1-

naphthaleneacetic acid and its conjugates calculated as 1-naphthaleneacetic acid from the 

application of 1-naphthaleneacetic acid, its ammonium, sodium, or potassium salts, ethyl ester, 

and acetamide in/on the following commodities. 

Table 2.2.3. Tolerance Summary for NAA

Commodity Established/Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity 

Definition

Tolerances Proposed Under PP#4E8310

Pomegranate 0.05 0.05

2.2.4 Revisions to Petitioned-For Tolerances

No revisions to petitioned-for tolerances are required.

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

O

NH2

O

OH

Common name NAA acetamide NAA

Molecular Formula C12H11NO C12H10O2

Molecular Weight 185.23 186.20

IUPAC name 2-(1-naphthyl)acetamide 2-(1-naphthyl)acetic acid

CAS name 1-naphthaleneacetamide 1-naphthaleneacetic acid

CAS # 86-86-2 86-87-3

PC Code 056001 056002
Page 10 of 79

Table 3.1. NAA Nomenclature

Chemical structure

O

O K

+

O

O NH4

+

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

O

O Na

+

O

O CH3

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 physicochemical properties of the naphthalene acetates are

provided in Appendix C. Based on the limited available data, 1-naphthaleneacetic acid and its 

ester exhibit relatively low or no solubility in water and higher solubility in organic solvents

whereas the sodium salt is highly soluble in water and insoluble in organic solutions. 1-

Naphthaleneacetic acid has a relatively high vapor pressure (0.3 mmHg), but its salts and esters 

have lower vapor pressures. 1-Naphthaleneacetic acid is relatively mobile but short lived in 

terrestrial and aquatic environments. 1-Naphthaleneacetic acid do not present significant 

concerns for bioaccumulation based on measured bioconcentration factors. 

3.3 Pesticide Use Pattern
Page 11 of 79

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#4E8310, 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 in conjunction with requests for amended Section 3 registration for TREHOLD Sprout Inhibitor A112. The use pattern for the proposed new use is provided in Table 

3.3.2.

Table 3.3.2. Summary of Directions for Use of NAA

Applic. Timing, 

Type, and 

Equip.

Formulation Applic. Rate 

(lb ae/gal)

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate

(lb ae/gal) 

PHI

(days)

Pomegranate

Directed spray 

to the lower 

tree trunks

TRE-Hold Sprout Inhibitor 

A-112, EPA Reg. No. 5481-

429;

15.1 % NAA, ethyl ester (1 lb 

ae/gal)

0.078 lb ae/gal

10 oz. 

product/gallon

(1% w/v)

two per 

year 

implied

0.156 45 days

Use Directions and Limitations: Treat early before suckers attain 12” in length. Best results are 

attained when first treatment is made after the trees resume growth and suckers become visible. 

A minimum 60-day RTI is specified. The REI is 12 hours. Aerial application is prohibited.

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.

Label 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 the proposed use of NAA on pomegranate. There are no post-application 

exposures anticipated for workers re-entering treated fields. There are no residential uses for 

NAA on pomegranate; however, exposure to residential handlers is expected from currently 

registered uses. This risk assessment considers all of the aforementioned exposure pathways 

based on the proposed new uses of the NAA, but also considers existing uses as well, particularly 

for the aggregate assessment.

3.5 Considerations of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 
Page 12 of 79

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://epa.gov/compliance/ej/resources/policy/exec_order_12898.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 U.S. Department of 

Agriculture’s (USDA’s) National Health and Nutrition Examination Survey/What We Eat in 

America, (NHANES/WWEIA), 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 members of the naphthalene 

acetate (NAA) group are expected to exhibit similar toxicological effects; therefore, the Agency 

concluded that required toxicity testing on any form should serve for all members of this group 

of chemicals. The toxicity database for NAA is sufficient for a full hazard evaluation and is 

considered adequate to evaluate risks to infants and children (Appendix A). The following 

studies were considered when setting the points of departure (PODs) for each exposure scenario:

- 90 day oral toxicity study – rat and dog

- 21 day dermal toxicity study – rabbit 

- Prenatal developmental toxicity study – rat and rabbit

- Multi-generation reproduction and fertility toxicity study – rat

- 2 year chronic toxicity study – mouse and dog

- 2 year chronic toxicity/carcinogenicity study – rat 

- Mutagenicity battery

- Metabolism pharmacokinetics study – rat 

A route specific study is not available for the inhalation assessment necessitating use of a proxy 

oral study. HASPOC concluded a subchronic inhalation study is required for future naphthalene 

risk assessments based on a weight of evidence (WOE) approach including: 1) the 

physical/chemical properties and relatively high volatility of 1-naphthaleneacetic acid (0.3 mm

Hg at 26oC); 2) the potential for portal of entry effects and demonstrated eye irritation in the 

acute toxicity studies; and 3) that the MOEs for some occupational handler scenarios are of 
Page 13 of 79

concern (MOE < 100) and do not meet the waiver criteria (MOE > 1,000). A 10x database 

uncertainty factor (UFDB) is incorporated into inhalation assessments until this requirement is 

fulfilled (TXR 0056465, K. Rury, October 16, 2012). 

An immunotoxicity study is required as a part of new data requirements in the 40 CFR Part 158 

for conventional pesticide registration. However, HAPOC recommended waiving the 

immunotoxicity study for naphthalene acetates (TXR 0056968, J. Leshin, May 21, 2014). The 

decision was supported by WOE approach that incorporated the following considerations: 1) the 

toxicology database for of naphthalene acetates does not reveal any evidence of treatment-related 

effects on the immune system suggesting that the immune system is not the primary target organ; 

and 2) an immunotoxicity study is not anticipated to provide a lower POD or result in a more 

sensitive endpoint than those already used for the naphthalene acetates risk assessment.

Acute and subchronic neurotoxicity studies are also required as a part of new data requirements 

in the 40 CFR Part 158 for conventional pesticide registration. However, HASPOC concluded, 

based on WOE approach, that acute and subchronic neurotoxicity studies are not required at this 

time (TXR 0056465, K. Rury, October 16, 2012). 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. 

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 NAA acetamide. NAA acetamide was readily absorbed and 

excreted within 36 hours. Recovery of administered radioactivity was 97-101%. 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 metabolites revealed 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 NAA acetamide (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 NAA ethyl ester. Recovery of administered 

radioactivity was 99-101%. NAA ethyl ester was readily absorbed and excreted within 36 - 48 

hours following 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 
Page 14 of 79

at low concentrations (0.5-5% of administered) only in feces. For both studies, excretory 

patterns exhibited no gender-related variability for the low dose groups and only minor gender 

difference at the high dose. Excretion patterns of the high-dose group reflected delayed 

absorption. Tissue burdens of parent and metabolites were very low at termination for both 

studies. Most components in the matrices examined (urine and feces) were adequately quantified 

and characterized. 

The metabolism studies of the acid and its acetamide and the ethyl ester in animals provide 

supporting evidence that the toxicity of the naphthalene acetates 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

1-Naphthaleneacetic acid, its salts, ester, and acetamide are plant growth regulators which are 

collectively referred to as naphthalene acetates. Its structure mimics the endogenous plant 

hormone indole acetic acid (IAA), a natural auxin that promotes growth in excised plant organs, 

induces adventitious roots, inhibits axillary bud growth, and regulates gravitropism. 

In general where comparisons were feasible, the sodium salt form was more toxic than the other 

NAA members. Nevertheless, target organs and type of effects were consistent across all 

members despite disparity in onset and severity.

The commonalities across the naphthalene acetate family was attributed to a shared ADME 

pathway. Ingested naphthalene acetates were readily absorbed, metabolized extensively (0.5-5% 

parent compound in excreta), and eliminated efficiently within 36-48 hours minimizing tissue 

accumulation. As a result, organ specific and systemic toxicity from oral exposure did not 

intensify with duration. Liver metabolism accounted for a portion of the excreted dose 

(predominantly the glucuronic acid conjugate at high and low concentrations) and was a target of 

NAA toxicity in rats, mice and dogs. Hepatic insult was characterized by inflammation of the 

tissues around the bile duct, hepatocyte degeneration, sinusoidal histiocytosis, and increased liver 

weight accompanied by elevated liver enzyme levels, necrosis, extramedullary hematopoiesis, 

and monoculear/mixed cell infiltration. The stomach and gastrointestinal tract were another 

mammalian target of the naphthalene acetates (necrosis of fundus and pyloric epithelium

mucosal gland dilation, stomach irritation, ulcerative duodenitis, acute or erosive gastritis,

emesis and soft feces) despite fecal elimination accounting for a small percentage of the 

administered dose. Dogs were the most susceptible mammal to oral subchronic and chronic 

exposures exhibiting primarily liver and stomach injury. In addition to the liver and stomach, the 

lungs of exposed rats (focal alveolar macrophages) and mice (lung adenomas) were 

compromised though whether these effects point to the lungs as a target organ remains 

equivocal. Repeated oral exposure also elicited decreased hematocrit and hemoglobin along with 

reduced RBC count in rats and dogs, and hypocellularity of the bone marrow of dogs. Reduced 

body weight and body weight gain either co-occurred with target organ toxicity or were the lone 

symptoms of toxicity. 

Similar systemic toxicity in forms of decreased body weight/gain, and lesions in the liver, 

stomach, and lung via the oral route was not observed in dermal exposures to 1-
Page 15 of 79

naphthaleneacetic acid, NAA acetamide, and NAA sodium salt up to a dose of 1000 mg/kg/day. 

Instead dermal toxicity manifested at the point of contact with the skin. Prolonged exposure to 

NAA ethyl ester, the most toxic form for dermal exposures, resulted in epidermal hyperplasia, 

hyperkeratosis, sebaceous gland hyperplasia and dermal inflammation. Similar dermal effects 

(hyperplasia of sebaceous gland and hyperplasia and hyperkeratosis of epidermis) were observed 

following NAA sodium salt dermal exposure, but, unlike the oral exposures, the sodium salt 

form was not as toxic as the ethyl ester form. Dermal toxicity was not universal for all NAA 

compounds, however, as NAA acetamide exposure was not irritating up to 1000 mg/kg/day.

In the rat developmental study with NAA sodium salt, fetal effects (skeletal variations, decreased 

fetal weights) were observed in the absence of maternal toxicity. In contrast, rabbits exhibited 

developmental effects (skeletal defects and variants and a decrease in ossification of the manus)

from in utero exposure only at doses that also compromised maternal health (reduced body 

weight, clinical signs and stomach irritation). Reduced rat pup weights and reduced litter survival 

during lactation was also observed in both generations of the reproduction study with NAA 

sodium salt. Lower body weight in the F1 generation persisted after switching to the 

contaminated diet and remained depressed through the subsequent pre-mating, gestation and 

lactation periods. Parental body weight, body weight gain and food consumption was depressed 

at the same dose which likely contributed to the reduction in offspring survival and growth. The 

sodium salt also induced changes to reproductive organs in dogs but were considered secondary 

to the systemic, liver and stomach effects. The developmental and offspring toxicity observed 

was unique to the sodium salt.

The entire class of naphthalene acetates exhibited low acute oral (Category III), dermal 

(Category III), and inhalation toxicity (Category III/IV) and none were dermal irritants (all 

Category IV) or dermal sensitizers. The severity of eye irritation varied significantly across the 

NAA compounds. NAA and NAA sodium salt were strong eye irritants (Category I), while NAA 

ethyl ester was only a mild eye irritant (Category IV). The eye irritation potential of NAA 

acetamide was equivocal. One study indicated NAA acetamide caused severe eye irritation

(Category I) while a more recent study identified it as a mild irritant (Category IV). 

The tested naphthalene acetates did not exhibit mutagenicity or carcinogenicity. 

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

The FQPA safety factor (FQPA SF) for infants and children was reduced to 1x for noninhalation routes of exposures based on the following considerations:

1) The toxicology database for NAA is complete and adequate for assessing increased 

susceptibility under FQPA. The dietary and inhalation endpoints selected from the cocritical dog studies (NOAEL = 25 mg/kg/day) is protective of the effects observed in the 

rat developmental (LOAEL = 150 mg/kg/day), rabbit developmental (LOAEL = 300 

mg/kg/day) and rat reproduction (LOAEL = 210 mg/kg/day) studies. Therefore, the 

potential for increased susceptibility in infants and children is low.

2) There are no residual uncertainties in the exposure database. 
Page 16 of 79

3) The dietary risk assessment is conservative using the current endpoints and will not 

underestimate dietary exposure to NAA.

EPA is retaining a 10X FQPA SF for inhalation exposure scenarios in all population groups to 

account for the lack of a route specific inhalation study.

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. HASPOC did not 

waive the subchronic inhalation study and recommended use of a 10x database uncertainty factor 

(UFDB) for inhalation assessments to account for the lack of a route specific study. HASPOC 

waived the requirement for the immunotoxicity study and neurotoxicity battery for the present 

assessment. HASPOC decisions are described in more detail in Section 4.1.

4.4.2 Evidence of Neurotoxicity

There are no neurotoxicity studies available for the current assessment; however, no signs of 

neurotoxicity or neuropathology were reported in the submitted chronic and subchronic studies. 

Furthermore, the literature on IAA, a compound with structural similarity to NAA, did not 

identify a neurotoxic mode of action. HASPOC has determined that acute and subchronic 

neurotoxicity studies are not needed at the present time. 

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

There is low concern (and no residual uncertainty) for pre- and/or postnatal toxicity resulting 

from exposure to the naphthalene acetates because clear NOAEL and LOAELs were established 

for the developmental and offspring effects and the POD (25 mg/kg/day) for all exposure 

scenarios is protective of these effects. 

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 the naphthalene acetates.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose-Response Assessment

Toxicity endpoints and PODs for dietary (food and water), occupational, and residential 

exposure scenarios have been updated since the last assessment and are summarized below and 

in Table 4.5.4.1 and 4.5.4.2. A detailed description of the studies used as a basis for the selected 

endpoints for the naphthalene acetates are presented in Appendix A. 
Page 17 of 79

There were no toxicological effects attributable to a single exposure of NAA observed in oral 

toxicity studies. Therefore, an endpoint of concern was not selected for the acute dietary 

assessment. A chronic reference dose (cRfD) of 0.25 mg/kg/day was calculated using the highest 

NOAEL (25 mg/kg/day) from two co-critical dog studies and uncertainty factors for interspecies 

(UFA=10x) and intraspecies extrapolation (UFH=10x). The NOAEL was based on lesions of the 

GI tract (ulcerative duodenitis and acute or erosive gastritis) and hypocellularity of the bone 

marrow at 150 mg/kg/day in the subchronic dog study and was protective of the stomach lesions

(slight to moderate necrosis of fundus and pyloric epithelium), and slight sinusoidal histiocytosis 

in the liver of males observed at 75 mg/kg/day in the chronic dog study. The higher NOAEL 

from the subchronic study is protective of the chronic study LOAEL since the effects and 

severity were similar between the two studies and there was no evidence of progression with 

increased exposure duration. The FQPA SF was reduced to 1x because the toxicology and 

exposure database was adequate to address susceptibility in infants and small children, and the 

selected POD was protective of developmental and offspring effects observed at higher doses. As 

a result, the chronic population adjusted dose (cPAD) is equivalent to the cRfD. 

The NOAEL (25 mg/kg/day) from the co-critical NAA sodium salt dog studies was selected as 

the POD for a short-term adult oral exposure. This study was selected because it provided the 

lowest LOAEL and highest NOAEL of all the candidate studies conducted over a short duration 

(< 90 days) and it was protective of developmental and offspring effects observed at higher 

doses. The short-term adult oral endpoint was selected exclusively for the residential aggregate 

assessment. The level of concern (LOC) for the short term adult oral exposure is 100 based on 

uncertainty factors of interspecies variability (UFA=10x) and intraspecies sensitivity (UFH=10x). 

Dermal exposure up to 1000 mg/kg/day did not result in systemic toxicity for any of the 

naphthalene acetates tested (NAA sodium salt, NAA, and NAA acetamide); therefore a dermal 

assessment was not conducted. A dermal absorption study was not submitted; however, the 

absence of systemic toxicity at high dose dermal exposure suggests absorption is limited. 

Furthermore, in several naphthalene acetates (including NAA ethyl ester) irritation effects 

precede systemic effects precluding dermal exposures of > 1000 mg/kg/day (or 100 mg/kg/day in 

the case of the ethyl ester). The in utero susceptibility in the rat developmental study was not 

used to set endpoints for a dermal assessment because dermal exposure is unlikely to provide the 

internal dose required to elicit these effects based on the low absorption potential and irritant 

properties of the naphthalene acetates.

 

In lieu of an inhalation study, the NOAEL (25 mg/kg/day) from the co-critical dog studies was

adopted to assess short-term inhalation risk. An absorption factor of 100% was assumed for all 

inhalation exposures. The level of concern (LOC) for the short-term inhalation exposure is 1000

based on uncertainty factors for interspecies variability (UFA=10x), for intraspecies sensitivity

(UFH=10x), and to account for the inhalation study omission (UFDB=10x). 

4.5.2 Recommendations for Combining Exposure Routes

When there are potential residential exposures to the pesticide, the aggregate risk assessment 

must consider exposures from three major sources: oral, dermal and inhalation exposures. If the 
Page 18 of 79

toxicity endpoints for dermal, oral, and inhalation routes of exposure are similar, then the 

exposure or risk estimates from these exposure routes are combined. Endpoints for short-term 

oral and inhalation exposure are based on the same effects (stomach lesions and sinusoidal 

histiocytosis in the liver) and can be combined for risk assessment. Dermal exposure cannot be 

combined because a dermal assessment was not required.

4.5.3 Classification of Carcinogenic Potential

A 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 were 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 naphthalene acetate risk assessment are provided 

in Tables 4.5.4.1 and 4.5.4.2.

Table 4.5.4.1. Summary of Toxicological Endpoints for Naphthalene Acetates for Use in Dietary and NonOccupational Human Health Risk Assessments

Exposure/Scenario Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects 1

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 day oral exposure was observed in animal studies.

Chronic Dietary (All 

Populations)

NOAEL= 

25

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.25

mg/kg/day

cPAD = 0.25

mg/kg/day

Co-critical Dog Studies with NAA Na salt:

Subchronic Toxicity (MRID 42983801)

Chronic Toxicity (MRID 43744201)

Subchronic LOAEL = 150 mg/kg/day based 

on GI tract lesions and hypocellularity of the 

bone marrow

Subchronic NOAEL= 25 mg/kg/day

Chronic LOAEL = 75 mg/kg/day based on 

stomach lesions in 75% of the males and 

slight sinusoidal histiocytosis in the liver of 

50% of the males

Chronic NOAEL = 15 mg/kg/day
Page 19 of 79

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (c = chronic). RfD = reference dose. 

1The NOAEL/LOAEL used to set endpoints for the co-critical dog studies are in bold

2

Inhalation absorption is assumed to be equivalent to oral absorption

3FQPA SF for inhalation accounts for the lack of an inhalation study.

Adult Oral

Short-term (1-30 

Days)

NOAEL= 

25

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

LOC = 100

Co-critical Dog Studies with NAA Na salt:

Subchronic Toxicity (MRID 42983801)

Chronic Toxicity (MRID 43744201)

Subchronic LOAEL = 150 mg/kg/day based 

on GI tract lesions and hypocellularity of the 

bone marrow

Subchronic NOAEL= 25 mg/kg/day

Chronic LOAEL = 75 mg/kg/day based on 

stomach lesions in 75% of the males and 

slight sinusoidal histiocytosis in the liver of 

50% of the males

Chronic NOAEL = 15 mg/kg/day

Incidental Oral

All Durations

Incidental oral exposures are not anticipated for currently registered uses and the proposed use on 

pomegranate.

Dermal

All Durations

Dermal exposure up to the limit dose (1000 mg/kg/day) did not result in systemic toxicity for any of 

the naphthalene acetates tested (NAA sodium salt, NAA, and NAA acetamide); therefore, a dermal 

assessment was not conducted. 

Inhalation 

Short-Term (1-30 

days)

NOAEL= 

25

mg/kg/day 2

UFA = 10x

UFH = 10x

FQPA SF = 10x 3 LOC = 1000

Co-critical Dog Studies with NAA Na salt:

Subchronic Toxicity (MRID 42983801)

Chronic Toxicity (MRID 43744201)

Subchronic LOAEL = 150 mg/kg/day based 

on GI tract lesions and hypocellularity of the 

bone marrow

Subchronic NOAEL= 25 mg/kg/day

Chronic LOAEL = 75 mg/kg/day based on 

stomach lesions in 75% of the males and 

slight sinusoidal histiocytosis in the liver of 

50% of the males

Chronic NOAEL = 15 mg/kg/day

Inhalation

Intermediate and 

Long-term

Intermediate and long-term inhalation exposures are not anticipated for currently registered uses and

the proposed use on pomegranate.

Cancer Bioassay in rats and mice not carcinogenic. Not mutagenic.
Page 20 of 79

Table 4.5.4.2. Endpoints selected for Assessing Occupational Risks for Naphthalene Acetates

Exposure

Scenario1

Dose Used in Risk 

Assessment, UF 

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC 

for Risk 

Assessment

Study and Toxicological Effects1

Dermal 

Short, Intermediate, 

and Long-term 

Dermal exposure up to the limit dose (1000 mg/kg/day) did not result in systemic toxicity for any of the 

naphthalene acetates tested (NAA sodium salt, NAA, and NAA acetamide); therefore, a dermal assessment 

was not conducted. 

Inhalation 

Short- Term (1-30 

days)

NOAEL= 25

mg/kg/day 2

UFA = 10x

UFH = 10x

UFDB = 10x

LOC = 1000

Co-critical Dog Studies with NAA Na salt:

Subchronic Toxicity (MRID 42983801)

Chronic Toxicity (MRID 43744201)

Subchronic LOAEL = 150 mg/kg/day based 

on GI tract lesions and hypocellularity of 

the bone marrow

Subchronic NOAEL= 25 mg/kg/day

Chronic LOAEL = 75 mg/kg/day based on 

stomach lesions in 75% of the males and 

slight sinusoidal histiocytosis in the liver of 

50% of the males

Chronic NOAEL = 15 mg/kg/day

Inhalation

Intermediate and 

Long-term

Intermediate and long-term inhalation exposures are not anticipated for currently registered uses and the 

proposed use on pomegranate.

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. LOC = level of concern. 

1The NOAEL/LOAEL used to set endpoints for the co-critical dog studies are in bold

2

Inhalation absorption is assumed to be equivalent to oral absorption
Page 21 of 79

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 NAA acetamide and ring labeled NAA 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, its acetamide and the ethyl ester provide supporting evidence that the toxicity of these 

various forms of NAA would be similar since all are metabolized to the acid form and eliminated 

from the body as glycine and glucuronic acid conjugates within 36 to 48 hours of initial 

exposure.

Similar results have been seen in goat metabolism studies and in apple and olive metabolism 

studies. The terminal residues of concern in plants and ruminants are the parent compounds, 1-

naphthaleneacetic acid, 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

1-naphthaleneacetic acid 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 1-naphthaleneacetic acid of 10 days was attributed to microbial 

degradation. 1-Naphthaleneacetic acid is mostly ionized in the environment so would partition 

preferentially with the water. The environmental fate characteristics of the salts of 1-

naphthaleneacetic acid 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, 1-naphthaleneacetic acid 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 

1-naphthaleneacetic acid under various environmental conditions based on 1-naphthaleneacetic 

acid’s relatively high measured and estimated vapor pressures (0.3 mmHg). NAA ethyl ester is 
Page 22 of 79

susceptible to hydrolysis at high pHs. The product of NAA ethyl ester hydrolysis is 1-

naphthaleneacetic acid. 1-Naphthaleneacetic acid in aqueous solution appears to be unstable to 

sunlight irradiation. Upon exposure to sunlight, gaseous phase 1-naphthaleneacetic acid reaction 

with hydroxyl (OH) radicals should proceed with a half-life of around 0.3 days. 1-

Naphthaleneacetic acid is mobile to moderately mobile according to the FAO mobility 

classification. For 1-naphthaleneacetic acid 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 

1-naphthaleneacetic acid.

There are considerable uncertainties in this assessment due to the lack of measured data. Most of 

the environmental fate characteristics available for 1-naphthaleneacetic acid are derived from 

structure activity relationships. Furthermore, there is lack of information about possible 

degradates of 1-naphthaleneacetic acid.

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, 1-naphthaleneacetic acid

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 n/a

n/a = not applicable

5.2 Food Residue Profile

5.2.1 Residues in Crops

The submitted field trial data supporting new use on pomegranate are adequate. An acceptable 

method was used for residue quantitation, and adequate storage stability data were submitted to 

support sample storage durations and conditions for all analytes. In pomegranate harvested 45 

days following the last of two applications of a 15.1% EC formulation of NAA ethyl ester 

directed to the base of the tree as a 1% w/v ai spray to run-off to pruned sprouts/suckers, residues 

of 1-naphthaleneacetic acid were below the LOQ (<0.05 ppm) in/on all samples. The results 

from these studies are discussed in the Residue Chemistry Chapter (DP423409, T. Morton, June 

8, 2015) and the appropriate data evaluation report (DER) and summarized in Table 5.2.1. 

Residue decline was not investigated. 
Page 23 of 79

Table 5.2.1. Summary of Residues from Pomegranate Field Trials with NAA ethyl ester.

Commodity Total Rate1

(% w/v ai 

solution)

Analyte PHI 

(days)

n

2 Residue Levels (ppm)

Min.3 Max.3 LAFT4 HAFT4 Median4 Mean4 SD

Pomegranate 2 X 1% NAA5 45 2 <0.05 <0.05 0.05 0.05 0.05 0.05 N/A

1 Two applications of a 1% solution were made at each trial site.

2 n = no. of independent field trials.

3 Values based on total number of samples.

4 Values based on per-trial averages. LAFT= lowest average field trip, HAFT = highest average field trial, SD = standard 

deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values <LOQ are assumed to be at the 

LOQ. N/A = Not applicable.

5 Residues of NAA ethyl ester were determined by a common moiety method that converts residues of NAA acetamide and NAA 

ethyl ester to NAA. 

5.3 Water Residue Profile

5.3.1 Estimated Drinking Water Concentrations 

Tier I Estimated Drinking Water Concentrations (EDWCs) in surface and groundwater for 1-

naphthaleneacetic acid, NAA sodium salt, NAA potassium salt, NAA ethyl ester, and NAA 

acetamide3 were provide for use in the dietary exposure assessment. The EDWCs were

calculated using the Tier 1 surface water aquatic model FIRST and the Tier I/II groundwater 

model PRZM-GW (in Tier I mode). The Environmental Fate and Effects Division (EFED) has 

reviewed a proposed Interregional Research 4 (IR-4) and registrant petition to register the use of 

NAA ethyl ester for the use on pomegranate for controlling basal trunk sprouts and root suckers

(D423410, J. Melendez, May 4, 2015). The maximum single application rate is 3.6 lb a.e./A4, 

with two applications allowed at 60 day intervals, for the product Tre-Hold® Sprout Inhibitor A112 (EPA Reg. No. 5481-429, containing 1 lb a.e./gallon). Only ground applications are allowed 

on pomegranate, diluted in a large volume of water, applied to the lower tree trunks and 

immediate surrounding area. Previously, the maximum rate allowed was for the use on olives 

(single application at 0.33 lb a.e./A). Since this new use represents a higher application rate than 

previously calculated, and no groundwater values derived from PRZM-GW were previously 

calculated, new EDWCs are hereby calculated and provided.

Table 5.3.1. Maximum Tier I Estimated Drinking Water Concentrations (EDWCs) for drinking 

water assessment for all naphthalene acetates, based on ground application of NAA ethyl ester on 

pomegranates at 3.6 lb a.e./A x 2 applications/year

DRINKING WATER SOURCE 

(MODEL USED) SCENARIO (rate modeled per crop cycle) MAXIMUM ESTIMATED DRINKING WATER CONCENTRATION (EDWC) (ppb)

Groundwater (PRZM-GW) WI sand/7.2 lb a.e./A/yr Acute 789

 

3 Collectively known as naphthalene acetates.

4 The abbreviation a.e. refers to acid equivalents (i.e., the lbs of NAA ethyl ester, expressed as lbs of NAA acid).
Page 24 of 79

DRINKING WATER SOURCE 

(MODEL USED) SCENARIO (rate modeled per crop cycle) MAXIMUM ESTIMATED DRINKING WATER CONCENTRATION (EDWC) (ppb)

WI sand/7.2 lb a.e./A/yr Chronic 646

Surface water (FIRST) Index Reservoir/7.2 lb a.e./A/yr Acute 440

Index Reservoir/7.2 lb a.e./A/yr Chronic 65.1

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 50-99

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. The resulting residue consumption 

estimate for each food/food form is summed with the residue consumption 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 day 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 new use. The proposed new use results in 

dietary risk estimates below HED’s level of concern (Table 5.4). Infants <1 year old are the most 

highly exposed subpopulation, with 15% of the cPAD. 
Page 25 of 79

Table 5.4. Summary of Chronic Dietary Exposure and Risk for Napthelene Acetates

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) % cPAD

General U.S. Population

0.25

0.013977 5.6

All Infants (< 1 year old) 0.036203 15

Children 1-2 years old 0.022367 8.9

Children 3-5 years old 0.018232 7.3

Children 6-12 years old 0.012575 5.0

Youth 13-19 years old 0.010202 4.1

Adults 20-49 years old 0.013738 5.5

Adults 50-99 years old 0.013583 5.4

Females 13-49 years old 0.013701 5.5

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

Residential exposures are not expected based on the newly proposed use on pomegranate; 

however, existing residential uses previously re-evaluated (D404398, S. Hummel, 1/16/13; to 

reflect updates to HED’s 2012 Residential SOPs5along with policy changes for body weight 

assumptions) are being updated in this memo based on new toxicological data. Revised risk 

estimates for the residential uses of naphthalene acetates (Table 6.0) are not of concern to HED 

(MOE > 1000); however, these revised existing uses will impact the human health aggregate risk 

assessment.

 

 

5 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Page 26 of 79

1Based on registered or proposed label (Reg. No.5481-429, 5481-541).

2 Exposure Science Advisory Council Policy #9.1.

3

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).

4

Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).

Table 6.0. Residential Handler Non-cancer Exposure and Risk Estimates for Naphthalene Acetates

Exposure Scenario Inhalation LOC

Inhalation Unit 

Exposure (μg/lb 

ae)

Maximum 

Application Rate1

Area Treated or Amount 

Handled Daily2

Inhalation

Dose (mg/kg/day)3 MOE4

Paint brush/rolling after pruning trees, or spraying near the base of the tree after pruning root suckers (Ornamentals)

Paint-airless sprayer

1000

0.56

0.078 lb ai/1-gal can

5 (1-gallon can) 0.0027 9,200

Paint-brush/roller 0.2 2 (1-gallon can) 0.00039 64,000

Paint-manually pressurized 

handwand 0.018 3 (1-gallon can) 0.000053 470,000
Page 27 of 79

6.1 Residential Bystander Post-application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). 

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for NAA.

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for NAA. The agency has been working with the Spray Drift Task Force (a 

task force composed of various registrants which was developed as a result of a Data Call-In 

issued by EPA), 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)6. The agency has also developed a policy on how to appropriately 

consider spray drift as a potential source of exposure in risk assessments for pesticides. The 

potential for spray drift will be quantitatively evaluated for each pesticide during the Registration

Review process which ensures that all uses for that pesticide will be considered concurrently. 

The approach is outlined in the revised (2012) Standard Operating Procedures For Residential 

Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures 

Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect 

non-occupational exposure to drift. 
Page 28 of 79

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT 

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures (dermal and 

inhalation). 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. The short-term aggregate assessment includes the 

combined exposure from short-term inhalation and oral exposures. Incidental oral exposure is 

not anticipated based on registered and proposed use patterns and is not incorporated into the 

residential handler aggregate assessment. The dermal contribution is likewise omitted because 

endpoints were not selected for dermal exposure based on low toxicity in the route specific 

studies. Aggregate risks from chronic exposure to contaminated food and drinking water sources 

are represented in the chronic dietary assessment (Section 5.4.2). Acute dietary aggregate risks 

were not assessed because points of departure were not established for acute dietary exposure 

(Section 5.4.1). 

7.1 Short-Term Aggregate Risk

Registrations for residential uses are limited to rooting compounds and sprout inhibitors. The 

rooting compounds are applied by holding the plant and dipping the roots into solution. 

Exposures from these applications are expected to be negligible and, therefore, were not 

assessed. 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.

Short-term aggregate risk was estimated for combined oral and inhalation exposure in adults 20-

49 applying naphthalene acetate products with a paint-airless sprayer. Adults 20-49 using paintairless sprayers will experience the highest background dietary (Table 5.4) and inhalation 

exposure (Table 6.0); therefore, it was considered the worst case scenario for the aggregate 

assessment. Endpoints selected for the short-term adult oral exposure and inhalation exposure 

were based on common effects and could therefore be combined in the aggregate assessment. 

Results of the aggregate residential handler assessment are shown below in Table 7.1.

Aggregated risk indices (ARI) less than 1 are considered risk estimates of concern. Combined 

exposure to adults 20-49 using a paint-airless sprayer resulted in an ARI greater than 1; 

therefore, aggregate exposure to residential handlers is not of concern to HED.
Page 29 of 79

1 HED is concerned if the Aggregated Risk Index (ARI) is less than 1

2 Dietary MOE = (short-term oral NOAEL)/ (chronic dietary exposure); Short-term oral NOAEL = 25 mg/kg/day; 

Chronic dietary exposure for adults 20-49 years old = 0.013738

3 Dietary ARI = (Dietary MOE dietary)/ (Target MOE); Target MOE = 100

4 Residential Inhalation MOE = (short-term inhalation NOAEL)/ (short-term inhalation exposure); Short-term 

inhalation NOAEL = 25 mg/kg/day; Short-term inhalation exposure = 0.0027 mg/kg/day

5

Inhalation ARI = (Inhalation MOE)/ (Target MOE); Target MOE = 1000

6 Aggregate ARI = 1/ [(1/Dietary ARI) + (1/Inhalation ARI)]

7.2 Chronic Aggregate Risk

Chronic aggregate exposures include food plus drinking water exposures. As demonstrated 

under Section 5.4.2, chronic aggregate risks are not of concern.

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/.

Table 7.1. Short-term Aggregate Risk Calculations Using ARI Approach1

Population Exposure 

Scenario

Background Dietary Dermal Residential 

Exposure

Inhalation Residential 

Exposure

Aggregate 

ARI (food, 

water, and 

residential) MOE2 ARI3 MOE ARI MOE4 ARI5 6

Adults 20-49

years old

Paintairless 

sprayer

1810 18.1 N/A N/A 9200 9.2 6.1
Page 30 of 79

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

9.1 Short-Term Handler Risk

9.1.1 Handler Exposure Scenarios

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, types of equipment and techniques 

that can potentially be used, short-term occupational handler exposure is expected from the 

proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is 

based on the following scenarios: 

 mixing/loading/applying liquids with a backpack; and

 mixing/loading/applying liquids with a mechanically-pressurized handgun.

9.1.2 Handler Exposure Data and 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 sprout inhibitor applications is 0.078 lb 

ai/gallon.

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 ORETF database, or other registrant-submitted 

occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and 

subject to the data protection provisions of FIFRA. The standard values recommended for use in 

predicting handler exposure that are used in this assessment, known as “unit exposures”, are 

outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”6, 

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 website7.

Area Treated or Amount Handled: The area treated or amount handled based on guidance in 

ExpoSAC Policy 9.1.

 

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

7 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Page 31 of 79

 

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 the standard body 

weight for the general population, 80 kg.

Absorption factors: 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. 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: Estimates of dermal and inhalation exposure were 

calculated for various levels of personal protective equipment (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, and for the recommended PPE on the

naphthalene acetate product labels (baseline attire with chemical-resistant gloves).

Occupational Handler Non-Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate non-cancer exposure and dose for occupational handlers can be 

found in Appendix C.

9.1.3 Handler Exposure and Risk Estimates

Summaries of the short-term risks for each exposure scenario are presented in Table 9.1.3. The 

inhalation exposure risks are not of concern to HED (i.e., MOE > 1000) for 

mixers/loaders/applicators wearing basic PPE (e.g. single layer of clothing, shoes, no gloves, no 

respirator). 
Page 32 of 79

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (Oct 2012); includes data from PHED/ORETF/AHETF

2

Inhalation Dose = Inhalation Unit Exposure (μg/lb ae) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/gal) x Area Treated or Amount Handled Daily (gal/day) /BW (kg).

3

Inhalation MOE = Inhalation NOAEL (mg/kg/day)/ Inhalation Dose (mg/kg/day). NOAEL = 25 mg/kg/day.

9.1.3 Short-term Occupational Exposure and Risk Estimates for Naphthalene Acetates.

Exposure Scenario Application 

Rate

Amount Handled / 

Area Treated

Inhalation Unit 

Exposures (ug/lb ai)1

Inhalation Dose 

(mg/kg-day)2

Inhalation 

MOE3

No Respirator

Mixing/Loading/Applying a Liquid Formulation to Orchards (Pomegranate Trees)

Backpack

Soil-/Grounddirected0.078

lb ai/gallon

40

gallons 2.58 0.000101 250,000

Mechanicallypressurized Handgun1000

gallons 3.9 0.0038 6,600
Page 33 of 79

9.2 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.

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for naphthalene acetates.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

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.

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates 

Dermal exposure up to 1000 mg/kg/day did not result in systemic toxicity for any of the 

naphthalene acetates tested (NAA sodium salt, NAA, and NAA acetamide); therefore, a dermal 

post-application assessment and DFR study are not required at this time.
Page 34 of 79

9.2.3 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. 

10.0 REFERENCES

1-Naphthaleneacetic acid (NAA), its salts, ester, and acetamide. New Use in/on Pomegranate. 

Summary of Analytical Chemistry and Residue Data. D423409. T. Morton. November 18, 2015.

Naphthalene Acetates- Chronic Dietary and Drinking Water Exposure and Risk Assessment for 

Section 3 New Use of Naphthalene Acetic Acid-ester on Pomegranate. D426996, T. Morton, 

November 18, 2015.

1-Naphthaleneacetic acid: Summary of Hazard and Science Policy Council (HASPOC) Meeting 

of May 8, 2014: Recommendations on the requirement of immunotoxicity. TXR 0056968, J. 

Leshin, May 21, 2014.

Tier 1 Drinking Water Analysis for the IR-4 Petition to Register the Use of 1-Naphthaleneacetic 

Acid, Ethyl Ester for the Use on Pomegranate. D423410, J.L. Melendez, May 14, 2015.

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. D404398, T. 

Morton, January 16, 2013.

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. D406255, S 

Hummel, January 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. TXR 0056465, K. Rury, October 16, 

2012.

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 
Page 35 of 79

Avocado, Mango, Mamey Sapote, and Rambuttan. Summary of Analytical Chemistry and 

Residue Data. D399621, G. Otakie, October 3, 2012.

Branagan MF, Audia W, Ballard G, Boyd H, Dickson D, Dodd N, Garczynski L, Holst R, 

Johnston T, and Sullivan E. Naphthaleneacetic acid its salts, ester, and acetamide. Pesticide 

registration standard. USEPA. July 31, 1981.
Page 36 of 79

APPENDICIES

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for naphthalene acetate food use are in Table 1. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent) .........................................

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

yes1

yes

yes

yes

-

no

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

870.5xxx Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Develop. Neurotoxicity .................................................

no

no

waived2

waived2

no

-

-

-

-

-

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

no

wavied3

yes

-

-

1Required per HED HASPOC (TXR 0056465)

2Waived per HED HASPOC (TXR 0056465)

3Waived per HED HASPOC (TXR 0056968)
Page 37 of 79

A.2 Toxicity Profiles

Note: Only guideline studies for NAA acetamide, NAA, NAA sodium salt, and NAA ethyl ester are included in the toxicity profile table. End use 

product specific acute studies are available for ammonium NAA and NAA potassium salt but were not considered in the assessment for the new use on 

pomegranate. 

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

Acute - Oral MRID 43495901 (1994)

LD50 > 5050 mg/kg

Category IV

MRID 00103128 (1982)

LD50 (95% C.I.) = 

2520 mg/kg (2100-3021)

Category III

MRID 00108829 

(1982)

LD50 (95% C.I.) = 

(M) 1.35 g/kg (1.12–

1.64)

(F) 0.933 g/kg (0.631-

1.38)

Category III

MRID 43494101 

(1994)

LD50 (95% C.I.) = 

2186 (1907-2506) 

mg/kg

Category III

Acute - Dermal MRID 43495902 (1994)

LD50 > 2020 mg/kg

Category III

MRID 00103129 (1982) 

LD50 > 2 g/kg

Category III 

MRID 00108829 

(1982)

dermal LD50 > 2 g/kg

Category III

MRID 43494102 

(1994)

LD50 > 2020 mg/kg 

Category III

Acute - Inhalation MRID 43495903 (1994)

LC50 > 2.17 mg/L

Category IV

MRID 00128256 (1983)

LC50 > 0.45 mg/L

Category III 

MRID 43494103 

(1994)

LC50 > 2.13 mg/L

Category IV

Eye Irritation MRID 00103051 (1982)

corrosive Category I

MRID 43495904 (1994)

minimally irritating

Category IV

MRID 00103127 (1982)

corrosive Category I

MRID 00108829 

(1982)

corrosive Category I

MRID 43494104 

(1994)

minimally irritating

Category IV
Page 38 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

Dermal Irritation MRID 00103220 (1982)

Non-irritating

Category IV

MRID 00103127 (1982)

Non-irritating 

Category IV

MRID 00108829 

(1982)

Non-irritating 

Category IV

MRID 00103053/ 

00103218 (1982) 

Non-irritating 

Category IV

Sensitization MRID 43495905 (1994)

Not a skin sensitizer. No 

positive control. 

Unacceptable

MRID 00153217 (1984)

Not a skin sensitizer

MRID 43494105 

(1994)

Not a skin sensitizer. 

No positive control. 

Unacceptable
Page 39 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

Subchronic - Rat MRID 43896001 (1995)

Acceptable/Guideline

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) in 

the diet for 90 days

LOAEL = 292.1 

mg/kg/day based on 

decreased bw, bw gain & 

food consumption, and 

increased relative liver 

weights with adaptive 

histopathological changes in 

both sexes. 

NOAEL = 73.8 mg/kg/day

MRID 00043624 (1979)

Acceptable/Guideline

0, 50, 150, or 300 

mg/kg/day to SD rats 

(20/sex/dose) in diet for 13 

weeks

LOAEL = 300 mg/kg/day

based on decreased body 

weight in both sexes and 

enlarged liver weights in 

females. 

NOAEL = 150 mg/kg/day

MRID 42932601 

(1993)

Acceptable/Guideline

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) 

in the diet for 13 weeks 

LOAEL = 136.6 

mg/kg/day for males 

and 149.3 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.

NOAEL = 13.9

mg/kg/day for males

and 15.2 mg/kg/day 

for females

MRID 43896002 

(1995)

Acceptable/Guideline

0, 400, 2000 or 8000 

ppm (Average doses at 

study end were 19-25; 

92-123; and 388 - 519 

mg/kg/day for malesfemales) in the diet for 

13 weeks 

LOAEL= 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= 144 

mg/kg/day

10-day range finding - rat MRID 00043623 (1976)

Acceptable/Non-
Page 40 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

Guideline

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. 

MTD = 250 mg/kg/day

Subchronic - Dog MRID 43895901 (1995)

Acceptable/Guideline

0, 30, 100, or 300 

mg/kg/day via capsule for 

13 weeks. 

LOAEL = 300 mg/kg/day

based on increased platelet 

count, decreased red cell 

parameters, and increased 

mean corpuscular volume 

which correlate with 

MRID 00136446 (1979)

Acceptable/Guideline

0, 50, 150, or 300 

mg/kg/day via gelatin 

capsule for 6 months 

LOAEL = 50 mg/kg/day, 

the lowest dose tested, 

based on hepatic liver 

changes (pericholangistis) 

NOAEL = not derived in 

MRID 42983801 

(1993)

Acceptable/Guideline

0, 25, 150, or 450 

mg/kg/day via capsule 

for 13 weeks

LOAEL =150 

mg/kg/day based on 

lesions of the GI tract 

and hypocellularity of 

the bone marrow 

MRID 43914901 

(1995)

Acceptable/Guideline

0, 40, 125, or 400 

mg/kg/day via gelatin 

capsules for 13 weeks. 

LOAEL= 400 

mg/kg/day based on 

soft/liquid feces and 

depressed body weight 

gains of male and 
Page 41 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

histopathological changes 

observed in the liver, 

spleen, and bone marrow in 

both sexes. 

NOAEL = 100 mg/kg/day

this study. 

NOAEL = 25 

mg/kg/day

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 (1995)

Acceptable/Guideline

0, 100, 300, or 1000 mg/kg 

for 6-6.5 hours/day, 5 

days/week, for 3 weeks. 

LOAEL = was not 

established 

NOAEL = 1000 mg/kg 

bw/day (the highest dose 

tested)

MRID 43134701 

(1994)

Acceptable/Guideline

0, 100, 300, or 1000 

mg/kg for 6-6.5 

hours/day, 5 days/week, 

for 3 weeks. 

Systemic LOAEL was 

not established

Systemic NOAEL = 

1000 mg/kg/day 

Dermal LOAEL = 

1000 mg/kg/day based 

on microscopic changes 

in the skin

Dermal NOAEL = 300 

mg/kg/day 

MRID 43581002 

(1995)

Acceptable/Guideline

0, 100, 300, or 1000 

mg/kg for 6-6.5 

hours/day, 5 days/week, 

for 3 weeks. 

Systemic LOAEL was 

not established

Systemic NOAEL 

=1000 mg/kg/day 

Dermal LOAEL = 100 

mg/kg/day based on the 

epidermal hyperplasia 

and hyperkeratosis, 

sebaceous gland 

hyperplasia, and dermal 

inflammation in the 
Page 42 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

treated skin. 

Dermal NOAEL < 100 

mg/kg/day

28-day inhalation Not available

Developmental Rat MRID 00042765 (1977)

Acceptable/Guideline

0, 10, 50 or 250 mg/kg/day 

via gastric intubation to 

pregnant rats (24/group) 

from days 6 through 15 of 

gestation

Maternal LOAEL = 250 

MRID 46685803 

(2004)

Acceptable/Guideline

0, 15, 50 or 150 mg/kg 

bw/day via gavage to 

24 female SD rats/dose 

from days 5 through 21 

(inclusive) of gestation.
Page 43 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

mg/kg/day based on 

decreased body weight 

gain during the compound 

administration 

Maternal NOAEL = 50 

mg/kg/day

Developmental LOAEL 

>250 mg/k/day

Developmental NOAEL = 

250 mg/kg/day 

Maternal LOAEL 

>150 mg/kg bw/day

Maternal NOAEL = 

150 mg/kg bw/day 

(HDT)

Developmental 

LOAEL = 150 

mg/kg/day based on 

decreased fetal weight 

and minor skeletal 

changes (centrum 5 not 

ossified, cervical arch 7 

cartilage fused to arch 6 

cartilage, shortened 7th

cervical rib)

Developmental 

NOAEL = 50 

mg/kg/day

Developmental - Rabbit MRID 00137821, 

00137822 (1983)

Acceptable/Guideline

0, 37.5, 75 or 150 

mg/kg/day via oral gavage 

from days 6 through 27 of 

gestation

Maternal LOAEL = 150 

mg/kg/day based on day 

MRID 46685801 

(2003)

Acceptable/Guideline

0, 30, 100 or 300 mg/kg 

bw/day in water via 

gavage from days 5 

through 29 (inclusive) 

of gestation

maternal 
Page 44 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

based on lethality

Maternal NOAEL = 75 

mg/kg/day 

Developmental LOAEL = 

>150 mg/kg/day 

Developmental NOAEL = 

150 mg/kg/day (HDT)

Maternal LOAEL= 

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 

Maternal NOAEL = 

100 mg/kg/day 

Developmental 

LOAEL = 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 

Developmental 
Page 45 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

NOAEL = 100 

mg/kg/day

Reproduction MRID 43796301 

(1995)

Acceptable/Guideline

0, 100, 1000 or 3000 

ppm (0, 7, 69, and 210 

mg/kg/day for males 

and 0, 8, 81, and 239 

mg/kg/day for females) 

via diet

Systemic and 

repro./develop 

LOAEL = 210

mg/kg/day for males 

and 239 mg/kg/day for 

females based upon 

reduced bw gain and 

food consumption in 

parental animals and 

reduced litter survival, 

and pup weight 

throughout lactation in 

both generations of 

offspring. 

Systemic and 

repro./develop 

NOAEL = 69 

mg/kg/day for males 
Page 46 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

and 81 mg/kg/day for 

females

Chronic/Oncogenicity - Rat MRID 44157501 

(1996)

Acceptable/Guideline

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) via diet to 

Crl:CD® BR rats 

LOAEL = 224.5 

mg/kg/day for males 

and 303.6 mg/kg/day 

for females based on an 

increased incidence of 

stomach (mucosal gland 

dilation) and lung 

lesions (focal alveolar 

macrophages) in both 

sexes, and on lowered 

bw gain and food 

efficiency in females 

NOAEL= 43.8 

mg/kg/day for males 

and 55.8 mg/kg/day 

for females
Page 47 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

*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)

Acceptable/Non-Guideline

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 

MRID 46685802 

(2004)

Acceptable/Guideline

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] via 

diet to CD-1 Alpk mice 

for at least 80 weeks

LOAEL = 276 

mg/kg/day for males 

and 348.7 mg/kg/day 

for females 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 
Page 48 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

months. 

*Gross and histopath 

examination of the mice at 

the end of the feeding 

period did not reveal a 

significant increase in 

tumors over the controls.

liver and lung in males, 

↑in the incidence of 

multiple tumors in 

females

NOAEL = 53.3 

mg/kg/day for males 

and 70.9 mg/kg/day 

for females

*There was no 

treatment related 

increase in tumor 

incidence when 

compared to controls. 

Dosing was considered 

adequate based on the 

effects observed on the 

top dose (2500 

ppm/kg/day).

Chronic - Dog MRID 43744201 

(1995)

Acceptable/Guideline

0, 15, 75, or 225 

mg/kg/day via gelatin 

capsule for 52 weeks 

LOAEL= 75 

mg/kg/day in males 

and 225 mg/kg/day in 

females based on 
Page 49 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

emesis, capsular 

regurgitation 

incidences, gross and 

histopathologic changes 

in stomachs, and 

sinusoidal histiocytosis 

in livers. 

NOAEL= 15 

mg/kg/day in males 

and 75 mg/kg/day in 

females.

Gene mutation-bacterial MRID 43581006 (1996)

Acceptable/Guideline

Salmonella 

Five doses 100-5000 

ug/plate. No mutagenic 

effect with or without S9 

activation

MRID 00042761 (1978)

Acceptable/Guideline

Escherichia coli polA. 

Strains W3110 and p3478 

at 1, 2 or mg/ml. Not 

mutagenic. 

MRID 00042762 (1978)

Acceptable/Guideline

Salmonella. 

At 0.5-5000 ug/plate. Not 

mutagenic

MRID 43581004

Acceptable/Guideline

Salmonella

Five doses 33-5000 

ug/plate. No mutagenic 

effect with or without 

S9 activation 

Gene mutation - mammalian: 

mouse lymphoma cells

MRID 43580202 (1995)

Acceptable/Guideline

-S9: not mutagenic

+S9 mutagenic at 100 

ug/mL and above 

MRID 43580201

(1994)

Acceptable/Guideline

-S9: not mutagenic

+S9 mutagenic at 300 

ug/mL and above
Page 50 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

Erythrocyte micronuleus 

mice

MRID 43581005 (1994)

Acceptable/Guideline

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 (1979)

Acceptable/Guideline

IP injections 60 or 125 

mg/kg to 4 mice/sex. No 

overt symptoms at high 

dose. Negative.

MRID 43581003 

(1994)

Acceptable/Guideline

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 

(1978)

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 (1979)

Acceptable/Guideline

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 
Page 51 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

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 the cat, no GAC was detected; but taurine 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 taurine was excreted by all 

species except the rabbit, rat and the fruit bat. It was a major excretion product (>6%) in the squirrel and 

capuchin monkeys, the marmoset and the cat. When female rats were given ip doses of 5-500 mg/kg, bile duct 

cannulation showed that 10-44% of the radioactivity was present in the bile 3 hours after injection. While 0.6-

32% was present in the urine. At the higher doses urinary GAC predominated whereas at the lower doses the 

glycine conjugates predominated. In the bile the GAC was the major metabolite (>80% of the bile radioactivity) 

and the glycine conjugate was a minor metabolite (<4% of the bile radioactivity). There was no analysis of the 

fecal radioactivity.

Lethco and Brouwer, 1966. Carboxy -

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 (1996), Acceptable/Guideline. 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 
Page 52 of 79

Table A.2 Acute, Subchronic and Chronic Toxic Profile – Naphthalene Acetates

Study PC 056001: Acetamide PC 056002: NAA PC 056007: Na salt PC 056008: Ethyl ester

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 (1996), Acceptable/Guideline. Rats (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 in the 

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 53 of 79

A.3 Hazard Identification and Endpoint Selection 

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

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

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

Selected Study: Subchronic and Chronic Study in Dogs 

MRID No.: 42983801 (Subchronic), 43744201 (Chronic)

Executive Summary: See Appendix A.4, Guideline [§ 870.3150, 870.4100b] 

Dose and Endpoint for Risk Assessment: The NOAEL (25 mg/kg/day) from two co-critical 

dog studies was based on stomach lesions (slight to moderate necrosis of fundus and pyloric 

epithelium), and slight sinusoidal histiocytosis in the liver of males observed at 75 mg/kg/day in 

the chronic dog study.

Uncertainty Factors (UF): 100 (10X for interspecies extrapolation, 10x for intraspecies 

variation, and 1x FQPA SF)

Comments about Study/Endpoint: The POD for the chronic dietary assessment was based on 

lesions of the GI tract (ulcerative duodenitis and acute or erosive gastritis) and hypocellularity of 

the bone marrow at 150 mg/kg/day in the subchronic dog study. This endpoint was protective of 

the stomach lesions (slight to moderate necrosis of fundus and pyloric epithelium), and slight 

sinusoidal histiocytosis in the liver of males observed at 75 mg/kg/day in the chronic dog study 

and the developmental and offspring effects observed at > 150 mg/kg/day. The higher NOAEL 

from the subchronic study was an acceptable chronic endpoint without additional uncertainty 

factors because the two studies based endpoints around similar adverse effects and there was no 

evidence of progression with increased exposure duration. The sodium salt is the most toxic in 

the subchronic studies thus the endpoints selected from this study are protective of NAA and 

NAA ethyl ester subchronic and chronic exposures.

A.3.3 Dermal Absorption

General Population cPAD = (NOAEL) 25 mg/kg/day = 0.25 mg/kg/day

 (UF) 100
Page 54 of 79

A dermal penetration study was not submitted for the naphthalene acetates. 

A.3.4 Adult Oral Exposure (Short-Term)

Selected Study: Subchronic and Chronic Study in Dogs 

MRID No.: 42983801 (Subchronic), 43744201 (Chronic)

Executive Summary: See Appendix A.4, Guideline [§ 870.3150, 870.4100b] 

Dose and Endpoint for Risk Assessment: The NOAEL (25 mg/kg/day) from two co-critical 

dog studies was based on stomach lesions (slight to moderate necrosis of fundus and pyloric 

epithelium), and slight sinusoidal histiocytosis in the liver of males observed at 75 mg/kg/day in 

the chronic dog study.

Uncertainty Factors (UF): 100 (10X for interspecies extrapolation and 10x for intraspecies 

variation)

Comments about Study/Endpoint: The short-term oral endpoint was selected exclusively for 

the aggregate assessment. The POD for the short-term adult oral assessment was based on 

lesions of the GI tract (ulcerative duodenitis and acute or erosive gastritis) and hypocellularity of 

the bone marrow at 150 mg/kg/day in the subchronic dog study. This endpoint was protective of 

the stomach lesions (slight to moderate necrosis of fundus and pyloric epithelium), and slight 

sinusoidal histiocytosis in the liver of males observed at 75 mg/kg/day in the chronic dog study 

and the developmental and offspring effects observed at > 150 mg/kg/day. The higher NOAEL 

from the subchronic study was an acceptable chronic endpoint without additional uncertainty 

factors because the two studies based endpoints around similar adverse effects and there was no 

evidence of progression with increased exposure duration. The sodium salt is the most toxic in 

the subchronic studies thus the endpoints selected from this study are protective of NAA and 

NAA ethyl ester short-term exposures.

A.3.5 Dermal Exposure (Short-Term)

Dermal exposure up to 1000 mg/kg/day did not result in systemic toxicity for any of the 

naphthalene acetates tested (NAA sodium salt, NAA, and NAA acetamide); therefore a dermal 

assessment was not conducted. A dermal absorption study was not submitted; however, the 

absence of systemic toxicity at high dose dermal exposure suggests absorption is limited. 

Furthermore, in several naphthalene acetates (including NAA ethyl ester) irritation effects 

precede systemic effects precluding dermal exposures of > 1000 mg/kg/day (or 100 mg/kg/day in 

the case of the ethyl ester). The in utero susceptibility in the rat developmental study was not 

used to set endpoints for a dermal assessment because dermal exposure is unlikely to provide the

internal dose required to elicit these effects based on the low absorption potential and irritant 

properties of the naphthalene acetates.

A.3.6 Inhalation Exposure (Short-Term) 
Page 55 of 79

Selected Study: Subchronic and Chronic Study in Dogs 

MRID No.: 42983801 (Subchronic), 43744201 (Chronic)

Executive Summary: See Appendix A.4, Guideline [§ 870.3150, 870.4100b] 

Dose and Endpoint for Risk Assessment: The NOAEL (25 mg/kg/day) from two co-critical 

dog studies was based on stomach lesions (slight to moderate necrosis of fundus and pyloric 

epithelium), and slight sinusoidal histiocytosis in the liver of males observed at 75 mg/kg/day in 

the chronic dog study.

Uncertainty Factor (UF): 1000 (10x for interspecies extrapolation, 10x for intraspecies 

variation and 10x for the lack of subchronic inhalation study).

Comments about Study/Endpoint: A subchronic inhalation study was not submitted by the 

registrant. In lieu of a route specific study the NOAEL from the co-critical dog study was used to 

set inhalation endpoints. The POD for the inhalation assessment was based on lesions of the GI 

tract (ulcerative duodenitis and acute or erosive gastritis) and hypocellularity of the bone marrow 

at 150 mg/kg/day in the subchronic dog study. This endpoint was protective of the stomach 

lesions (slight to moderate necrosis of fundus and pyloric epithelium), and slight sinusoidal 

histiocytosis in the liver of males observed at 75 mg/kg/day in the chronic dog study and the 

developmental and offspring effects observed at > 150 mg/kg/day. The higher NOAEL from the 

subchronic study was an acceptable chronic endpoint without additional uncertainty factors 

because the two studies based endpoints around similar adverse effects and there was no 

evidence of progression with increased exposure duration. The sodium salt is the most toxic in 

the subchronic studies thus the endpoints selected from this study are protective of NAA and 

NAA ethyl ester short-term exposures.

A.4 Executive Summaries for Supporting Toxicity Studies 

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat MRID 00043624

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 
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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 neocortical 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.

870.3100: 90-Day Oral Toxicity - Rat MRID 43896001

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 

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). The 

study is classified as Acceptable/Guideline.

870.3100: 90-Day Oral Toxicity - Rat MRID 42932601

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 % 
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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. The study is classified as 

Acceptable/Guideline.

870.3100: 90-Day Oral Toxicity - Rat MRID 43896002

In a subchronic oral toxicity study (MRID 43896002), 1-naphthaleneacetic acid, ethyl ester

(Lot # AM 315002; 100% ai) was administered, in the diet, to CRL:CD BR rats (10/sex/dose) at 

dose levels of 400, 2000 or 8000 ppm for 13 weeks. The actual average doses at the end of the 

study were 19-25 mg/kg/day for the 400 ppm group, 92-123 mg/kg/day for the 2000 ppm group, 

and 388 - 519 mg/kg/day for the 8000 ppm group, for males and females, respectively. Lower 

body weight, body weight gain, food consumption and food efficiency were observed for the 

8000 ppm males and females compared to the controls. Body weights for the males were 7-13% 

lower and for the females were 9-21% lower than the corresponding controls throughout the 

study. Body weight gains were significantly reduced for both sexes at various weekly intervals 

throughout the study, and by the end of the study, were 18 and 38% lower for males and females, 

respectively, than the control gains. Mean food consumption by the males and females was 5-11 

and 15-22 lower, respectively, than the control values for most weekly intervals; decreased food 

efficiency for both sexes was observed at most weekly intervals. Increased relative and/or 

absolute liver and kidney weights were observed for the 2000 and 8000 ppm treatment groups. 

Relative liver weights were 21% higher for the 2000 ppm females and 20 and 58% higher for the 

8000 ppm males and females, respectively, compared to the control weights. Absolute liver 

weights were 13 and 24% higher for the 2000 and 8000 ppm females, respectively, compared to 

the controls. Relative kidney weights were higher for both sexes from the 2000 ppm (11% 

higher) and 8000 ppm (17-23% higher) treatment groups. Absolute kidney weight for the 2000 

ppm males was 16% higher than the controls but was not increased for the 8000 ppm males. No 

associated macroscopic or microscopic changes were observed in the livers and kidneys of rats 

from any treatment group. Decreased red blood cell counts, hemoglobin, and hematocrit for both 
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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 hematocrit. 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 

hematocrit. The NOAEL is 2000 ppm (144 mg/kg/day) for both sexes. The study is 

classified as Acceptable/Guideline. 

870.3150: 90-Day Oral Toxicity - Dog MRID 00136446

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) was elevated at 4 months (slightly) and 6 months (2x the normal value) for the high dose 

females. The clinical chemistry of the male dog that was sacrificed in moribund condition 

showed lower protein, cholesterol and glucose and greatly elevated levels of total bilirubin, 

direct bilirubin, alkaline phosphatase, aspartate amino transferase (SGOT) and SGPT. 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. Histopathological examination revealed 
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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. Additionally 

centrilobular necrosis, periportal fibrosis occurred in the high dose group. A hyperplastic nodule 

was observed 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. 

870.3150: 90-Day Oral Toxicity - Dog MRID 43895901

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 intracanalicular 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. 

The NOAEL is 100 mg/kg/day. The study is classified as Acceptable/Guideline.

870.3150: 90-Day Oral Toxicity - Dog MRID 42983801

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 
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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. The study is classified as Acceptable/Guideline.

870.3150: 90-Day Oral Toxicity - Dog MRID 43914901

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 
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course of the study. Male dogs in the 40, 125, or 400 mg/kg/day treatment groups had 

significantly (p <0.05 or 0.01) lower red blood cell, hemoglobin, and hematocrit levels, and 

lower mean platelet volumes (MPV) than the controls throughout the study. In the high dose 

males at 12 weeks, these were 18%, 17%, 17% and 22% lower than the controls for RBC, 

hemoglobin, hematocrit and MPV levels, respectively. Although, these parameters were within 

the historical range values for this dog type, they were at the lower end of the range and may 

suggest anemic affects caused by the administration of this material at this dose. Low white 

blood cell counts in female dogs in the 125 or 400 mg/kg/day treatment groups after 12 weeks of 

treatment were also within expected biological ranges. No other treatment-related responses 

were observed during the study. No differences were observed in clinical blood chemistry, 

ophthalmology, urine volume or chemistry, organ weights, or macroscopic or microscopic organ 

morphology between dogs in the treated and the control groups. No neoplastic tissue was 

observed. 

The LOAEL for this study is 400 mg/kg/day, based on soft/liquid feces and the depressed 

body weight gains of male and female dogs at this treatment level. Additionally some blood 

parameters (RBC, hemoglobin, hematocrit and mean platelet volume) were all depressed in 

the male dogs at this level. The NOAEL was 125 mg/kg/day. The study is classified as 

Acceptable/Guideline.

870.3200 21-day Dermal Toxicity Study MRID 43581001

In a repeated dose dermal toxicity study (MRID 43581001), 1-Naphthaleneacetamide (Lot # 

I940415; 98.71% ai) was applied to the shaved skin of Crl:CD BR rats (5/sex/dose) at dose 

levels of 0, 100, 300, or 1000 mg/kg for 6-6.5 hours/day, 5 days/week, for 3 weeks. No 

treatment-related effects were observed at any dose level. There were no clinical signs of 

toxicity, and body weights, body weight gains, and food consumption were similar between the 

treated and control groups. No differences were observed in hematology parameters or clinical 

blood chemistry. Skin irritations occurred at similar rates in rats in all groups. Although males 

in the 1000 mg/kg treatment group had absolute liver weight which was 16.4% heavier (p <0.05) 

than the control, no accompanying anatomical or functional changes were observed, and the 

mean liver weights of females in the 1000 mg/kg treatment group were lower than the control. 

No other differences in the organ weights and no differences in macroscopic or microscopic 

organ morphology were observed between rats in the treated and the control groups. No 

neoplastic tissue was observed at any dose level. Ophthalmoscopic examinations and urinalysis

were not performed during the study. 

No LOAEL was established. The NOAEL was the highest treatment level, 1000 mg/kg 

body weight. The study is classified as Acceptable/Guideline.

870.3200 21-day Dermal Toxicity Study MRID 43134701

In a 21 day dermal toxicity study (MRID 43134701), male and female Crl:CDBR rats 

(5/group/sex) received either 0, 100, 300, or 1000 mg/kg/day 1-Naphthaleneacetic Acid Sodium 

Salt (96.44% 1-NAA & 1.79% 2-NAA) applied to clipped, unabraded dorsal surface of the skin, 
Page 62 of 79

5days/week for 3 weeks. Doses were based on a 7-day dermal range finding study in rats where 

no overt signs of toxicity or dermal irritation was noted at doses of 250, 500 and 1000 

mg/kg/day. 

No treatment-related or clinical signs of systemic toxicity were observed in any of the treatment 

groups. Slight decreases in absolute body weight of high dose animals were not statistically or 

biologically significant despite reduced body weight gain (76.3% of the controls in the males and 

71.2% of the controls in females) and food efficiency. Accordingly, these effects were not 

considered adverse. Dermal toxicity was noted in the high dose group as microscopic changes of 

the skin of the treated areas. These changes included minimal to slight hyperplasia of the 

sebaceous gland and minimal to slight hyperplasia and hyperkeratosis of the epidermis. 

The systemic LOAEL was not established. The systemic NOAEL is 1000 mg/kg. The 

dermal LOAEL is 1000 mg/kg based on microscopic changes in the skin (slight hyperplasia 

of the sebaceous gland and minimal to slight hyperplasia and hyperkeratosis of the 

epidermis). The dermal NOAEL is 300 mg/kg.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 

28-day dermal toxicity study (OCSPP 870.3200; OECD 410) in the rat.

870.3200 21-day Dermal Toxicity Study MRID 43581002

In a repeated dose dermal toxicity study (MRID 43581002), 1-naphthaleneacetic acid, ethyl ester 

(Lot # 315002; 97.75% ai) was applied to the shaved skin of Crl:CD BR rats (5/sex/dose) at dose 

levels of 0, 100, 300, or 1000 mg/kg for 6-6.5 hours/day, 5 days/week, for 3 weeks.

For all treatment groups, there were no clinical signs of toxicity, and body weights, body weight 

gains, and food consumption were similar to the controls. There were no differences in 

hematology parameters, clinical blood chemistry, organ weights, or macroscopic or microscopic 

organ morphology between rats in the treated and the control groups. No neoplastic tissue was 

observed. Ophthalmoscopic examinations and urinalysis were not performed during the study.

Treatment-related dermal irritation was seen in the treated skin of all animals exposed to 1-

Naphthaleneacetic acid ethyl ester. As the dose level was increased, the incidence and/or 

severity of epidermal hyperplasia and hyperkeratosis, sebaceous gland hyperplasia, and dermal 

inflammation in skin from the treated areas increased in the treated rats compared to the controls. 

In general, the severity of the reactions increased from minimal/slight to slight/moderate with 

increasing dose rate. No systemic responses were observed. 

The LOAEL for systemic toxicity is >1000 mg/kg/day and the NOAEL for systemic toxicity 

is 1000 mg/kg/day. The LOAEL for dermal irritation is 100 mg/kg, based on the presence 

of treatment-related dermal irritation in the treated skin of rats in the 100, 300, and 1000 

mg/kg treatment groups. No NOAEL for dermal irritation was established. The study is 

classified as Acceptable/Guideline.
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A.4.2 Prenatal Developmental Toxicity

870.3700a: Prenatal Developmental Toxicity Study - Rat MRID 00042765

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. 

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. The 

study is classified as Acceptable/Guideline.

870.3700a: Prenatal Developmental Toxicity Study - Rat MRID 46685803

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. 
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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. The maternal LOAEL is >150 mg/kg bw/day, and the maternal 

NOAEL is 150 mg/kg bw/day (highest tested dose).

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. The 

study is classified as Acceptable/Guideline.

870.3700b: Prenatal Developmental Toxicity Study - Rabbit MRID 00137821

In a prenatal developmental study (MRID 00137822), NAA (Lot # RTS2846AC; 98.55% purity) 

was administered by oral gavage to groups (16/group) of artificially inseminated Dutch Belted 

rabbits (4 1⁄2 to 5 months old) at dose levels of 0, 37.5, 75, or 150 mg/kg/day from days 6 

through 27 of gestation. These doses were selected on the basis of a range finding study (MRID 

00137821) where groups (5 rabbits/group) were dosed NAA once daily by gavage at dose levels 

of 0, 28, 80 or 240 mg/kg/day from days 6 through 27 of gestation. Animals were observed 

twice daily for mortality and once daily for toxic signs during the dosing period. Animals that 

died were necropsied. Body weights were taken on days 0, 6, 12, 18, 24 and 28. Surviving 

animals were sacrificed on day 28 and the uterus and ovaries were examined for viable and 

nonviable fetuses, resorptions, number of implantations, and number of corpora lutea. One 

animal in the range finding study dosed at 240 mg/kg/day aborted on GD 28 following signs of 

toxicity consisting of hair loss, decreased feces and significant weight loss. In the main study, 

one low dose animal died on GD 25 and three high dose gravid animals died during the study on 

GD 20, 22 and 27. Only two of the high dose animals showed signs of toxicity (hair loss on the 

forelimbs, clear or white nasal discharge with dried material around the nose, decreased 

defecation and dry red material, presumably died blood, beneath the cage) prior to death. 

Necropsy observations of the dead animals showed foamy fluid or congested lining in the 
Page 65 of 79

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 

preimplantation 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 preimplantation loss of 30.8%. 

Examination of the fetuses derived from the main study did not reveal any developmental 

effects. 

The maternal toxicity NOAEL is 75 mg/kg/day based on lethality at the LOAEL of 150 

mg/kg/day. The developmental and fetotoxic NOAEL was 150 mg/kg/day based on lack of 

developmental and fetotoxic effects at the highest dose of 150 mg/kg/day tested. The study 

is classified as Acceptable/Guideline. 

870.3700b: Prenatal Developmental Toxicity Study - Rabbit MRID 46685801

In another developmental toxicity study (MRID 46685801) 1-Naphthaleneacetic acid sodium salt 

(97.4% a.i., batch/lot # 014-S0401-001) was administered to 24 female New Zealand White

rabbits/dose in water by gavage at dose levels of 0, 30, 100 or 300 mg/kg bw/day from days 5 

through 29 (inclusive) of gestation. All animals survived the duration of the study except for one 

rabbit at the high dose which died on GD 22 due to a dosing error and one control rabbit was 

sacrificed on GD 24 following accidentally biting the dosing catheter into its esophagus. A 

treatment related reduction in body weight and body weight gain was noted following the initial 

oral administration of 1-NAA Na salt to pregnant rabbits at the high dose of 300 mg/kg/day. 

This was accompanied by initial reduction in food consumption. Final body weights were 

comparable in all treatment groups. Several dams receiving this dose were observed with few/no 

feces during the study. Post mortem examination revealed red/black spots/areas in the glandular 

mucosa of the stomach in several of these dams indicating local irritation by the test material. 

No adverse effects were noted in the dams at the lower dose of 30 and 100 mg 1-NAA Na salt 

/kg/day. Cesarean section data did not reveal any statistically significant differences among all 

groups including the controls. 

The LOAEL for maternal toxicity is 300 mg/kg/day based on reduced body weight, body 

weight gain and reduced food consumption, clinical signs (few/no feces) and stomach 

irritation (red/black spots/areas in the glandular mucosa of the stomach). The maternal 

toxicity NOAEL of 1-NAA Na in pregnant rabbits derived from this study is 100 

mg/kg/day. 

Developmental Toxicity. The oral administration of 1-NAA Na salt during gestation to rabbits 

resulted in decreased mean fetal weights (males and females) at the high dose of 300 mg/kg/day. 
Page 66 of 79

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 (dumbbell ossification 

of the 7th thoracic centrum, extra thoracolumbar ribs and 27 pre-pelvic vertebrae) and a 

decrease in ossification of the manus. The NOAEL is 100 mg/kg/day. The study is classified 

as Acceptable/Guidelines.

A.4.3 Reproductive Toxicity

870.3800: Reproduction and Fertility Effects - Rat MRID 43796301
Page 67 of 79

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 

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). The study is classified as 

Acceptable/Guideline.

A.4.4 Chronic Toxicity

870.4100a: Chronic Toxicity – Rat MRID 44157501

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 
Page 68 of 79

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 

study is classified as Acceptable/Guideline.

870.4100b: Chronic Toxicity - Dog MRID 43744201

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 change 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. The study is classified as Acceptable/Guideline.

A.4.5 Carcinogenicity

870.4200a: Carcinogenicity Study - Rat MRID 44157501

This study is described above in the chronic studies section. An increased incidence of uterine 
Page 69 of 79

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 William Burnam of HED 

on 04/04/2002). Na NAA was not carcinogenic in the rat. 

870.4200b: Carcinogenicity (feeding) - Mouse

There is an NCI study published in 1969 where NAA acetamide was tested at one dose 

(maximum tolerated dose: according to the published article) as part of a testing program of 120 

compounds. Only the preliminary results were published (Innes et al, Innes JR, Ulland BM, 

Valerio MG, Petrucelli L, Fishbein L, Hart ER, Pallotta AJ, Bates RR, Falk HL, Gart JJ, Klein 

M, Mitchell I, Peters J. 1969. Bioassay of pesticides and industrial chemicals for tumorigenicity 

in mice: a preliminary note. J. Natl Cancer Inst. 42: 1101-1114). The test materials were 

administered to two hybrid strains of mice: C57BL/6 x C3H/Anf and C57BL/6 x AKR 

(18/sex/hybrid strain). The mice were administered NAA acetamide at one week of age by 

stomach intubation at 464 mg/kg/day until weaning at 4 weeks of age and administered the NAA 

acetamide in the diet at 1298 ppm (equivalent to 195 mg/kg/day at the conversion rate of 0.15 

mg/kg for 1ppm) for approximately 18 months. Gross and histopathologic examination of the 

mice at the end of the feeding period did not reveal a significant increase in tumors over the 

controls.

870.4200b: Carcinogenicity (feeding) - Mouse MRID 46685802

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 leukemic 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 
Page 70 of 79

increase in the incidence of intratubular microlithiasis and tubular basophilia within the kidney 

was observed in females and an increase in interstitial mononuclear cell infiltration in the kidney 

of males at 2500 ppm. There was an increase in the incidence of marked degeneration in the 

testes in males dosed with 2500 ppm of compound. Associated with this change, there was an 

increase in the incidence of decreased spermatozoa within the epididymis and dilated rete within 

the testis. At 2500 ppm, adenomas of the liver were observed in one male rat, and adenomas of 

the lung were observed two males. Adenocarcinomas of the liver were observed in one control 

male and two males given 2500 ppm. None of these changes achieved statistical significance. 

There was a statistically significant increase in the incidence of histiocytic sarcoma in females at 

2500 ppm but it was within historical control levels. There was a statistically significant increase 

(overall) in the incidence of multiple tumors in females given 2500 ppm. However there was no 

statistically significant increase in any individual tumor type, the incidence was low, and there 

was no dose-response relationship. Therefore this difference was considered not to be compound 

related. 

The LOAEL is 2500 ppm [276 (M), 348.7 (F) mg/kg/day], based on lower body weight, food 

consumption, increased liver and kidney weights in both sexes and epididymis in males, 

lower brain weights in males, hepato-cellular vacuolation in males, adenomas of the liver 

and lung in males, increase in the incidence of multiple tumors in females. 

The NOAEL is 500 ppm [53.3 (M), 70.9 (F)] mg/kg/day. At the doses tested, there was no 

treatment related increase in tumor incidence when compared to controls. The study is 

classified as Acceptable/Guideline. 

A.4.6 Mutagenicity

Gene Mutation

GLN 870.5100, 

MRID 43581006: NAA 

Acetamide

MRID 00042761 & 00042762: 

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. 
Page 71 of 79

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

There are no neurotoxicity studies available but the chronic and subchronic studies show no 

evidence of neurotoxicity or neuropathology. The HED HASPOC waived the requirement for 

the neurotoxicity battery (TXR 0056465).

A.4.8 Metabolism

870.7485: Metabolism – Rat MRID 43963301 

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 non labeled 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 
Page 72 of 79

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.

870.7485: Metabolism – Rat MRID 43961701

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 non labeled 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-

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, neither 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 
Page 73 of 79

(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.

Metabolism - Published Studies

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; taurine and glycine 

conjugates were the major excretion products. The 1-Naphthylacetyl glycine conjugate was a 

major urinary metabolite (>20%) in the cat, squirrel and bushbaby monkey and a minor 

metabolite in rabbit, rat, capuchia and marmoset monkey. 1-Naphthylacetylglutamine

conjugate was formed only in the cynomolgus, squirrel and capuchin monkeys and marmoset in 

amounts not exceeding 3% of the administered dose. 1-Naphthylacetylturine was excreted by 

all species except the rabbit, rat and the fruit bat. It was a major excretion product (>6%) in the 

squirrel and capuchin monkeys, the marmoset and the cat. In addition, when female rats were 

administered intraperitoneally doses of 5-500 mg/kg, bile duct cannulation showed that 10-44% 

of the radioactivity was present in the bile 3 hours after injection, while 0.6-32% was present in 

the urine. At higher doses, urinary glucuronic acid predominated whereas at the lower doses the

glycine conjugates predominated. In the bile, the glucuronic acid conjugate was the major 

metabolite (>80% of the bile radioactivity), and the glycine conjugate was a minor metabolite 

(<4% of the bile radioactivity). There was no analysis of the fecal radioactivity reported. 

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

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 
Page 74 of 79

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

No immunotoxicity studies were available for the risk assessment. The naphthalene acetate 

toxicity database does not contain evidence of immunotoxicity or any indication the immune 

system is a target. As a result the HED HASPOC waived the requirement for the immunotoxicity 

study (TXR 0056968).
Page 75 of 79

Appendix B. Physical/Chemical Properties 

Table 2. Physicochemical Properties of the Naphthalene Acetates

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/cm3 Product CSF

Water solubility (20 °C) not available

Solvent solubility (20 °C) not available

Vapor pressure at 20 °C 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 (26 °C) 0.042 g/100 mL CB Nos. 3468 and 3469, 6/3/88, F. 

Suhre

Solvent solubility (26 °C) 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 20 °C 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 (26 °C) 340 g/100 mL CB Nos. 3468 and 3469, 6/3/88, F. 

Suhre

Solvent solubility (26 °C) insoluble in nonpolar 

solvents

CB Nos. 3468 and 3469, 6/3/88, F. 

Suhre

Vapor pressure at 20 °C 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
Page 76 of 79

Table 2. Physicochemical Properties of the Naphthalene Acetates

Parameter Value Reference

Active ingredient NAA ethyl ester

Boiling point/range >150 °C Old un-reviewed Union Carbide data

pH of 1% aqueous suspension not available

Density or specific gravity 1.11 at 20 °C Old un-reviewed Union Carbide data

Water solubility (26 °C) insoluble Old un-reviewed Union Carbide data

Solvent solubility soluble in xylene, toluene, 

ethanol, acetone, and methyl 

ethyl ketone

Old un-reviewed Union Carbide data

Vapor pressure at 20 °C not available

Dissociation constant (pKa) not available

Octanol/water partition coefficient (Kow) not available

UV/vis absorption spectrum not available
Page 77 of 79

Appendix C. Occupational Handler Non-Cancer Exposure and Risk Estimate Equations

Potential daily exposures for occupational handlers were calculated using the following 

formulas:

Daily Exposure (mg ae /day) = UE (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)

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 (%)

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:
Page 78 of 79

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

ADD = Average Daily Dose (mg/kg/day): the absorbed dose received from 

exposure to a pesticide in a given scenario.

Combining Exposures/Risk Estimates:

A total aggregated risk index (ARI) was used since the LOCs for dermal exposure (100) and 

inhalation exposure (1000) are different. The target ARI is 1; therefore, ARIs of less than 1 are 

risk estimates of concern. The aggregate risk index (ARI) was calculated as follows.

Aggregate Risk Index (ARI) = 1÷ (1 ÷ RIdermal)+ (1 ÷ RIinhalation)

Where:

Risk Index (RI) = MOE ÷ LOC
Page 79 of 79

Appendix D. Review of Human Research 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies 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.