UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: November 20,2014 

OFFICE OF CHEMICAL SAFETY 

AND I'OLLUTION PREVENTION 

SUBJECT: 1-Naphthaleneacetic acid (NAA): Human Health Risk Assessment Scoping 

Document in Support of Registration Review 

PC Code: OS600 I, OS6002, OS6003, OS6004, 

OS6007, 0S6008 

Decision No.: 4%.111 

Petition No.: NA 

Risk Assessment Type: Single Chemical Aggregate 

TXRNo.: NA 

MRIDNo.: NA 

DP Barcode: D42324S 

Registration No.: NA 

Regulatory Action: Registration Review 

Case No.: 0379 

CAS No.: 86-87-3 (NAA) 

40 CFR: §180. ISS 

FROM: Thurston Morton, Senior Chemist 

Abdallah Khasawinah, PhD., Toxicologist 

Susan Hummel, Senior Chemist 

Ivan Nieves, Chemist -f? r-(jl ~ 

Risk Assessment Branch IV 

Health Effects Division (7509P) 

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

Risk Assessment Branch IV 

Health Effects Division (7509P) 

TO: Christina Scheltema, Chemical Review Manager 

Risk Management and Implementation Branch III 

Pesticide Re-Evaluation Division (7508P) 
Executive Summary 

HED has considered the available risk assessments for 1-Naphthaleneacetic acid (NAA), its salts, 

ester, and acetamide and its toxicity, exposure and usage databases, as well as the most current 

Agency science and assessment policies. HED performed this evaluation in order to determine 

the scope of work necessary to evaluate the established tolerances and existing registrations 

during registration review. The primary source of information for this evaluation was the most 

recent comprehensive NAA Human Health Risk Assessment conducted January 16, 2013 

(0404398) and the 2004 RED. For the purposes of human health risk assessment, all six active 

ingredients in the NAA registration review case will be assessed together since studies have not 

shown significant differences between the six active ingredients. 

1-Naphthaleneacetic acid (NAA), its salts, ester, and acetamide are plant growth regulators 

which are collectively referred to as naphthalene acetates and hereafter will be referred to as 

NAA. They are currently registered for use on various orchard and fruit crops and ornamental 

trees. NAA currently has tolerances inion a number fruit commodities ranging from 0.05 ppm to 

0.15 ppm ( 40 CFR§ 180.155). NAA is 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. NAA 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 .. 

The toxicity and residue chemistry databases for NAA are inadequate for Registration Review 

and additional data are required. The toxicity database for NAA is considered incomplete. A 

subchronic inhalation study is required. The study should be conducted with the sodium or 

potassium salt. As part of registration review, however, the endpoints, doses, and safety factors 

(SFs) used in the most recent human health risk assessment may need to be re-evaluated 

according to current HED policy. No storage stability data on the processed commodities of 

apples (or citrus fruits) and olives are available, and these data are required for Registration 

Review. In addition, a citrus processing study is required for Registration Review. Updated 

exposure and risk assessments may be conducted if there are any significant changes to standard 

operating procedures, NAA toxicological endpoints, points of departure, safety factors, estimated 

drinking water concentrations (EDWCs), exposure data, and/or assumptions. 

Based on structural activity relationships (SAR) and metabolism data, all forms ofNAA 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 most 

prevalent toxic effects associated with NAA exposure are weight loss, decreased body weight 

gain and decreased food consumption. The major target organs of subchronic and chronic oral 

Page 2 of26 
Page 3 of 26

exposure were the liver, stomach and lung. Repeated oral exposure also resulted in decreased

hematocrit and hemoglobin along with reduced RBC count in rats and dogs and hypocellularity

of the bone marrow in dogs. There was no developmental toxicity at the highest doses of NAA

tested in the rat or in the rabbit, but developmental toxicity (decreased fetal weight and minor

skeletal changes) were seen in rats orally gavaged with the sodium salt. Reproductive effects of

NAA sodium salt occurred at relatively high doses and were limited to reduced litter survival and

pup weight throughout lactation in both generations of offspring in a two generation

reproduction study. Carcinogenicity studies of NAA acetamide in mice and NAA sodium salt in

rats and mice are considered adequate for the evaluation of the oncogenicity of the NAA group. 

In these three studies the tested NAA compounds were not carcinogenic in mice or rats. 

No acute dietary risk assessment was conducted. No acute RfD for the general population or any

population subgroups was selected because no effect attributable to a single day oral exposure was

observed in animal studies. A new chronic dietary assessment was conducted at the time of the last

risk assessment and resulted in dietary risk estimates below HED’s level of concern. In this

assessment, the most highly exposed subpopulation was children 1-2 years, with exposure comprising

2.0% of the cPAD.

Short term aggregate risk could not be estimated for NAA because the toxicity endpoints

selected for the chronic dietary/drinking water routes of exposure and those selected for

inhalation and dermal routes of exposure are not based on common effects. Residential handler

exposures did not fall below HED’s level of concern (LOC) and were not of risk concern. The

aggregate risk index (ARI) approach to risk was used to combine routes of exposure since the

LOC for inhalation was 1000 and the LOC for dermal was 100.

Residential handler exposures were updated for the last risk assessment. Residential postapplication exposure was not expected based on the registered use pattern. Occupational

exposures were assessed for handler and post-application activities; risk estimates indicate that

handler and post-application exposures were not of concern at the maximum proposed

application rate. Dermal and inhalation exposures were combined for NAA because the toxicity

endpoints for these exposure routes were based on common toxicological endpoints. 

Chemical Use Profile

1-Naphthaleneacetic acid (NAA), its salts, ester, and acetamide are plant growth regulators

which are collectively referred to as naphthalene acetates. They are currently registered for use

on various orchard and fruit crops and ornamentals at application rates up to 0.33 lb ai/A. 

Naphthalene acetates currently have tolerances in/on a number fruit commodities ranging from

0.05 ppm to 0.15 ppm (40 CFR§180.155). NAA is 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 NAA 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. NAA 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
Page 4 of 26

inhibition applications on ornamental plants. The plant growth regulating activity of NAA 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. 

The nomenclature and physiochemical properties of NAA are presented in Tables 1 and 2 of

Attachment 1. 

Hazard Identification/Toxicology

Based on structural activity relationships and metabolism data, all forms of NAA are expected to

exhibit similar toxicological effects. Therefore, the Agency concluded that required toxicity

testing on any form should apply to all members of this group of chemicals. The toxicity

database for naphthalene acetates is sufficient for a full hazard evaluation and is considered

adequate to evaluate risks to infants and children. Acceptable developmental toxicity studies in

the rat and rabbit and an acceptable reproduction study in the rat are available. Based on the

results of the available toxicity studies, there is no evidence for neurotoxicity or immunotoxicity.

Therefore, Hazard and Science Policy Council (HASPOC) has waived the requirement for

acute and subchronic neurotoxicity at the present time (TXR 0056465). A subchronic inhalation

toxicity study is not available and is required based on weight of evidence considerations by the

HASPOC (K. Rury, 10/16/12, TXR 0056465). At this time, HASPOC has waived the

requirement for an immunotoxicity study for the NAA and its salts (TXR 0056968).

The acute, subchronic, and chronic toxicity profile tables for NAA are included in Attachment 2. 

Toxicity endpoints, points of departure (PODs), and uncertainty/safety factors (UF/SFs) were

selected for oral, dermal, and inhalation exposure pathways for the Human Health Risk

Assessment conducted in 2013 (D397387), and these are shown in Attachment 3.

Upon review of the toxicology data and consideration of all available data including the open

literature, the endpoints for risk assessment and all uncertainty factors may be re-evaluated

during Registration Review to reflect current HED policies.

Conclusions: The toxicity data base for NAA is considered incomplete. A subchronic

inhalation toxicity study is needed for registration review. During registration review, the

endpoints and safety factors for risk assessment may be updated to reflect current policies.

Residue Chemistry

Residues of concern were determined by the HED risk assessment team for NAA. The residues

of concern in plants, ruminants, and drinking water are the parent compounds, NAA and its

conjugates, based on apple, olive, and goat metabolism studies. (D293239, G. Otakie, November

18, 2003). 
Page 5 of 26

NAA Residues of Concern in Plants, Ruminants and Drinking Water.

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

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 limit

of quantification (LOQ) of 0.01 ppm and at 1.0 ppm. This method is suitable for enforcement.

At the time of reregistration, data were required for storage stability of NAA in/on the processed

commodities of apple, citrus, and olive1. In addition a citrus processing study2 was required at

the time of reregistration. These data have not been submitted. No analytical reference

standards

3

for NAA are available at the EPA National Pesticide Standards Repository (personal

communication Theresa Cole, 8/4/14).

Conclusions: No storage stability data on the processed commodities of apples (or citrus fruits)

and olives are available, and these data are required for Registration Review. The requested

storage stability data for apple and olive processed commodities should reflect up to 143 and 283

days of freezer storage, respectively, since these were the maximum storage intervals of samples

in the respective processing studies. In addition, a citrus processing study is required for

registration review. The tolerance expression has been updated to reflect current guidance

(Knizner, 5/27/09). Analytical reference standards are also required and should be replenished

as needed. 

Dietary Exposure and Risk Assessment

The last NAA chronic dietary exposure assessment was conducted in 2012 (T. Morton,

D404399, 10/31/2012) using the Dietary Exposure Evaluation Model software with the Food

Commodity Intake Database DEEM-FCIDTM, 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. 

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. A chronic dietary assessment was conducted to support a petition for use

 

1 Storage stability data were required in data call-in (DCI) notices issued on December 12, 2007.

2 Citrus processing studies were required in the DCIs issued on December 12, 2007.

3 Analytical reference standards were required in the December 20017 DCIs. 
Page 6 of 26

of NAA on avocado and tropical fruits. The proposed use resulted in chronic dietary risk estimates

below HED’s level of concern. The most highly exposed subpopulation was children 1-2 years, with

2.0% of the cPAD.

Conclusions: A new dietary exposure and risk assessment may need to be conducted if there are

changes to the NAA toxicological PODs or UFs or significant changes to the EDWCs. The

assessment, if conducted, will use the newest version of DEEM and reflect updated food

consumption information.

Residential Exposure

An updated residential exposure assessment was conducted for the 2013 risk assessment.

Residential handler exposures were assessed and no risks of concern were identified; residential

post-application exposure is not expected, based on the registered use pattern (ornamental trees). 

Residential bystander exposures resulting from off-site transport (e.g., spray drift or

volatilization) may occur as a result of applications of NAA. 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. In terms of volatilization, the agency 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.

Conclusions: The residential exposure risk assessment did not identify risks of concern. The

residential exposure risk assessment may be updated during registration review. The need for

spray drift and volatilization risk assessment for NAA will be examined during registration

review.

Aggregate Risk Assessment

In accordance with the Food Quality Protection Act (FQPA), HED must consider and aggregate

pesticide exposures and risks from three major sources: food, drinking water, and residential

exposures. The aggregate risk assessment evaluates the combined risk from dietary exposure

(food and water) and any non-occupational (residential) uses. An aggregate risk assessment was

conducted for the 2013 new use petition (T. Morton, D397387, 1/16/2013).

Acute and Chronic

No acute aggregate risk assessment is required since no acute POD was identified.

Chronic aggregate exposures include food plus drinking water exposures. In the last risk

assessment, chronic aggregate risks were not of concern for NAA.
Page 7 of 26

Short-Term

Short term aggregate risk could not be estimated for NAA because the toxicity endpoints

selected for the chronic dietary/drinking water routes of exposure and those selected for

inhalation and dermal routes of exposure are not based on common effects; i.e., the chronic

dietary endpoint is based on stomach lesions and liver effects while the dermal and inhalation

endpoints are based on decreased body weight gain. Residential handler exposures did not fall

below HED’s LOC and were not of risk concern. The ARI approach to risk was used to combine

routes of exposure since the LOC for inhalation was 1000 and the LOC for dermal was 100.

Conclusions: During registration review, updated aggregate assessments may be conducted as

required to include any significant change that might occur for toxicological PODs, FQPA and

other uncertainty factors, dietary exposure estimates, or EDWCs. Emerging policies related to

pesticide drift and volatilization assessments may dictate further changes to the existing

aggregate risk assessment.

Occupational Exposure

Occupational handler and post-application exposure scenarios were assessed for the latest risk

assessment (S Hummel, D406255, 1/16/2013). Based on the product labels and information

provided by the registrant, short- and intermediate-term exposure was assessed for handlers and

post-application activities. Dermal and inhalation exposures were combined for NAA because

the toxicity endpoints for these exposure routes were based on common toxicological endpoints. 

Labels for NAA products require that applicators and other handlers wear personal protective

equipment (PPE) consisting of long-sleeved shirt, long pants and shoes with socks plus chemical

resistant gloves. 

Based on the anticipated use patterns and current labeling for NAA, e.g, types of equipment and

techniques that can potentially be used, occupational handler exposure are expected from the

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

in the last risk assessment was based on the following scenarios: (1) Mixer/Loader aerial, (2)

Applicator aerial, (3) M/L airblast, (4) A airblast, (5) M/L/A manually-pressurized handwands,

(5) M/L/A hose-end sprayers, (6) M/L/A backpacks, and (7) M/L/A paint brush/roller.

The combined dermal and inhalation exposure risks were not of concern (i.e., ARIs >1),

provided the mixer/loaders wear chemical-resistant gloves as directed on the label. The ARI

approach to risk was used to combine routes of exposure since the LOC for inhalation was 1000

and the LOC for dermal was 100.

Occupational Post-Application

Post-application exposure to NAA residues are expected for individuals involved in hand

weeding; scouting; thinning; hand harvesting, and irrigation. For all dermal post-application

exposure scenarios, risk estimates did not fall below HED’s LOC (Dermal LOC = 100), and

therefore not of concern to HED. 
Page 8 of 26

Dislodgeable Foliar Residue (DFR): In accordance with 40 CFR §158, DFR data are required 

for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and 

vegetable gardens, pick-your-own farms, retail tree farms) uses that could result in postapplication exposure to foliage. In the absence of chemical-specific DFR data, EPA uses default 

values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure 

Assessment includes an analysis of a number of DFR studies, which resulted in the selection of a 

revised default values for the fraction of the application rate available for transfer after a foliar 

application (FAR). These values are based on an analysis of 19 DFR studies. Since that time, the 

Agricultural Re-entry Task Force (ARTF) has submitted information (MRID 49299201) that 

corrects an application rate error made in the original submission of “ARF039 – Determination of 

Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a 

Greenhouse” (EPA MRID 45344501). As a result, the range of FAR values was revised from 2 -

89% to 2 - 47%. In the data, a large range of transferability is observed and this variability can 

potentially be attributable to many factors such as active ingredient; formulation; field conditions 

in the studies; weather conditions (e.g., humidity); or many other difficult-to-quantify 

factors. Although witnessed across multiple chemicals, this range in FAR values is not expected

when considering DFR data for a single chemical. The ARTF submission did not alter the 

selection of 25% as the reasonable, high-end default value. Because DFR data are not available 

for NAA, EPA is using the default value of 25%. Although there may be a small degree of 

uncertainty in the use of the default DFR value for NAA (i.e., there is a small chance that the FAR

value may exceed the applicable default value), it is likely that the health-protective aspects of 

EPA’s occupational post-application assessment methodology will more than compensate for 

this potential uncertainty. For example, when assessing residential and occupational postapplication exposure to gardens and ornamentals, EPA assumes the following: exposures occur 

to zero-day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., 

EPA assumes that no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform 

the same post-application activities performed in the transfer coefficient study day after day (e.g., 

weeding, harvesting, pruning, etc.); and individuals engage in these post-application activities for 

a high-end amount of time every day (represented by data reflecting time spent gardening based 

on survey data). Given the conservatisms discussed above and the potential compounding nature 

of these conservatisms, EPA is able to rely upon the calculated exposure estimates with 

confidence that exposure is not being underestimated. 

Since the highest estimated occupational post-application exposure using default DFR values for 

NAA is minimal in comparison to the LOC (i.e., the calculated MOE is greater than 2 times 

higher than the LOC, MOE = 120,000 compared to the LOC of 100); EPA is waiving the 40

CFR §158 DFR data requirement at this time. In this instance, it is unlikely that chemicalspecific DFR data would be needed to further refine exposure assessments or would add 

appreciably to our overall understanding of the availability of dislodgeable foliar pesticide 

residues for NAA.

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for NAA at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category IV), low vapor pressure for NAA salts and esters 

compared to NAA, and the maximum single application rate of 0.11 lb acid equivalents per acre

(ae/A). However, there are multiple potential sources of post-application inhalation exposure to 
Page 9 of 26

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 (FIFRA SAP) 

in December 2009, and received the SAP’s final report on March 2, 2010. The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the ARTF and may, as appropriate, develop policies and procedures, to 

identify the need for and, subsequently, the way to incorporate occupational post-application 

inhalation exposure into the Agency's risk assessments. If new policies or procedures are put 

into place, the Agency may revisit the need for a quantitative occupational post-application 

inhalation exposure assessment for the naphthalene acetates.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

Conclusions: The occupational exposure database is adequate to support the Registration

Review process for NAA. Previous occupational handler and post-application exposure

assessments did not identify risks of concern. Registration Review may include updated handler

and post application risk estimates based on current policies and potential changes to the NAA

toxicological PODs or UFs.

Public Health and Pesticide Epidemiology Data

For this evaluation, both the OPP Incident Data System (IDS) and the Sentinel Event

Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for

pesticide incident data on the active ingredient NAA. The purpose of the database search is to

identify potential patterns in the frequency and severity of the health effects attributed to NAA

exposure. NAA is not included in the Agricultural Health Study, and therefore this study does

not provide information for this report.

Conclusions: There does not appear to be a concern at this time that would warrant further

investigation, since there were only a few reported incidents involving NAA reported to IDS and

SENSOR-Pesticides. The Agency will continue to monitor the incident information and if a

concern is triggered, additional analysis will be included in the risk assessment.
Page 10 of 26

Tolerance Assessment and International Harmonization

U.S. permanent tolerances are established under 40 CFR §180.155 for the registered uses of

NAA in/on a number of commodities. There are no Codex and Canadian maximum residue

limits (MRLs) for residues of NAA. Therefore, there are no issues with harmonization. See

Appendix 4.

Cumulative Risk Assessment

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. For the purposes of this registration review, 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 Office of Pesticide Programs concerning common mechanism determinations

and procedures for cumulating effects from substances found to have a common mechanism on

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Human Studies

The RED and 2013 risk assessment relied 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 Pesticide Handler Exposure Database (PHED) 1.1; the Agricultural Handler

Exposure Task Force (AHETF) database; and the ARTF database; 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 websites

4

. 

Risk Assessment Updates and Data Deficiencies

 GLN 870.3465: Subchronic inhalation study.

 GLN 860.1380: Storage stability data on the processed commodities of apples (or citrus

fruits) and olives.

 GLN 860.1520: Data depicting residues of NAA and its conjugates in the processed

commodities of citrus (dried pulp, oil, and juice).

 GLN 860.1650: Analytical Reference Standards.

 

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
Page 11 of 26

References

Table 1. Memoranda Relevant to Registration Review1.

Author Barcode Date Title

E. Evans and S.

Recore D421705 7/23/2014 Napthalene Acetic Acid: Tier I Review of HumanIncidents

Morton, T.,

Hummel, S.,

Khasiwinah, A

D404398 01/16/13 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.

Otakie, G. D399621 10/03/12 1-Naphthaleneacetic acid (NAA), its salts, ester, and

acetamide. Expansions of Existing Crop

Group/Representative Commodity Uses to Fruit, Pome,

Group 11-10 and New Uses in/on Avocado, Mango,

Mamey Sapote, and Rambuttan. Summary of Analytical

Chemistry and Residue Data.

Morton, T. D404399 10/31/12 Naphthalene Acetates- Acute and Chronic Dietary and

Drinking Water Exposure and Risk Assessment for

Section 3 New Use of Naphthalene Acetic Acid-ester on

Avocado, Mango, Mamey Sapote, Rambuttan, and the

Expansion to Crop Subgroup 11-10.

Hummel, S. D406255 01/16/13 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.

Rury, K. TXR#

0056465

10/16/12 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.

Daiss, B. D293881 03/30/04 Naphthalene Acetates HED Risk Assessment for

Reregistration Eligibility Document (RED) PC Codes:0

56001, 056002, 056003, 056004, 056007, 056008; DP

Barcode No: 293881 Reregistration Case 0379

Otakie, G. D299296 03/10/04 1-Naphthaleneacetic Acid (NAA), its Salts, Ester, and

Acetamide. Residue Chemistry Considerations for

Reregistration Eligibility Decision. Case No. 0379.

Otakie, G D293239, 11/18/03 1-Naphthaleneacetic Acid (NAA), its Salts, Ester, and

Acetamide. Residue Chemistry Considerations for

Reregistration Eligibility Decision.
Page 12 of 26

Attachments:

Attachment 1: Chemical Identity and Physicochemical Properties

Attachment 2: NAA Acute, Subchronic, and Chronic Toxicity Profile

Attachment 3: NAA Toxicological Doses and Endpoints

Attachment 4: NAA International Residue Limits

Attachment 1. Chemical Identity and Physicochemical Properties

Table 1. NAA Nomenclature

Chemical structure

Common name NAA acetamide NAA

Molecular Formula C12H11NO C12H10O2

Molecular Weight 185.23 186.20

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

CAS name 1-naphthaleneacetamide 1-naphthaleneacetic acid

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

PC Code 056001 056002

Chemical structure

Common name NAA potassium salt NAA ammonium salt

Molecular Formula C12H10O2K C12H13NO2

Molecular Weight 224.31 203.24

IUPAC name potassium-2(1naphthyl)acetate ammonium-2(1naphthyl)acetate

CAS name 1-naphthalnene acetic acid, potassium salt 1-naphthaleneacetic acid, ammonium salt

CAS # 15165-79-4 25545-89-5

PC Code 056003 056004

O

NH2

O

OH

O

O K

+

O

O NH4

+
Page 13 of 26

Table 1. NAA Nomenclature

Chemical structure

Common name NAA sodium salt NAA ethyl ester

Molecular Formula C12H10O2Na C14H14O2

Molecular Weight 208.2 214.26

IUPAC name sodium-2(1naphthyl)acetate ethyl-2(1naphthyl)acetate

CAS name 1-Naphthaleneacetic acid, sodium salt 1-Naphthaleneacetic acid, ethyl ester

CAS # 61-31-4 2122-70-5

PC Code 056007 056008

Table 2. Physicochemical Properties of NAA1

Parameter Value Reference

Active Ingredient NAA acetamide

Melting point/range 182-184 C Farm Chemicals Handbook

pH of 1% aqueous suspension 5.1 Product CSF

Density or specific gravity 0.221 g/cm3 Product CSF

Water solubility (20̊C) not available

Solvent solubility (20̊C) not available

Vapor pressure at 20̊C not available

Dissociation constant (pKa) not available

Octanol/water partition coefficient (Kow) not available

UV/vis absorption spectrum not available

Active ingredient NAA

Melting point/range 130 C Farm Chemicals Handbook

pH of 1% aqueous suspension 3.45 RD D265117, 5/15/00, B. Kitchens

Density or specific gravity 0.45 g/mL CB Nos. 3468 and 3469, 6/3/88, F.

Suhre

Water solubility (26̊C) 0.042 g/100 mL CB Nos. 3468 and 3469, 6/3/88, F.

Suhre

Solvent solubility (26̊C) xylene 5.5 g/100 mL

CCl4 1.06 g/100 mL

freely soluble in acetone,

ether, and chloroform

CB Nos. 3468 and 3469, 6/3/88, F.

Suhre

Farm Chemicals Handbook

Vapor pressure at 20̊C 0.3 mm Hg at 26 C CB Nos. 3468 and 3469, 6/3/88, F.

Suhre

Dissociation constant (pKa) 3.16 x 10-4 CB Nos. 3970 and 3971, 7/5/88,

F. Suhre

Octanol/water partition coefficient (Kow) not applicable; polar

compound

UV/vis absorption spectrum not available

Active ingredient NAA sodium salt

O

O Na

+

O

O CH3
Page 14 of 26

Table 2. Physicochemical Properties of NAA1

Parameter Value Reference

Melting point/range >300 C CB Nos. 3468 and 3469, 6/3/88, F.

Suhre

pH of 1% aqueous suspension 9.1 CB Nos. 3468 and 3469, 6/3/88, F.

Suhre

Density or specific gravity 0.46 g/mL CB Nos. 3468 and 3469, 6/3/88, F.

Suhre

Water solubility (26̊C) 340 g/100 mL CB Nos. 3468 and 3469, 6/3/88, F.

Suhre

Solvent solubility (26̊C) insoluble in nonpolar

solvents

CB Nos. 3468 and 3469, 6/3/88, F.

Suhre

Vapor pressure at 20̊C not available

Dissociation constant (pKa) 3.16 x 10-4 CB Nos. 3970 and 3971, 7/5/88, F.

Suhre

Octanol/water partition coefficient (Kow) not applicable; polar

compound

UV/vis absorption spectrum not available

Active ingredient NAA ethyl ester

Boiling point/range >150 C Old unreviewed Union Carbide data

pH of 1% aqueous suspension not available

Density or specific gravity 1.11 at 20 C Old unreviewed Union Carbide data

Water solubility (26̊C) Insoluble Old unreviewed Union Carbide data

Solvent solubility soluble in xylene, toluene,

ethanol, acetone, and methyl

ethyl ketone

Old unreviewed Union Carbide data

Vapor pressure at 20̊C not available

Dissociation constant (pKa) not available

Octanol/water partition coefficient (Kow) not available

UV/vis absorption spectrum not available
Attachment 2. NAA Acute, Subchronic, and Chronic Toxicity Profile

A.2 Toxicity Profiles

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

Acute - oral MRID 43495901

LD50 > 5050 mg/kg

Category III

MRID 00103128

LD50 (95% C.I.) = 2520 mg/kg 

(2100-3021).

MRID 00108829

LD50: Males 1.35 (1.12–1.64)

Females 0.933 g/kg (0.631-1.38 

)

MRID 43494101

LD50 2186 (1907-2506) mg/kg

Category III

Acute - Dermal MRID 43495902

LD50 > 2020 mg/kg

Category III

MRID 00103129

LD50 is greater than 2 g/kg. 

Category III. 

MRID 00108829

Dermal LD50 = > 2 g/kg. 

Category III

MRID 43494102

LD50 > 2020 mg/kg. Category 

III

Acute - Inhal. MRID 43495903

LC50 > 2.17 mg/L

Category IV

MRID 43494103

LC50 > 2.13 mg/L

Category IV

Eye Irritation MRID 00103051

corrosive Category I

MRID 43495904

minimally irritating

Category IV

MRID 00103127

corrosive Category I

MRID 00108829

corrosive Category I

MRID 43494104

minimally irritating

Category IV

Derm. Irritation MRID 00103127

Non-irritating Category IV

MRID 00108829

Non-irritating Category IV

MRID 00103053 & 00103218.

non-irritating Category IV

Sensitization MRID 43495905

not a skin sensitizer. No 

positive control. Unacceptable

MRID 00153217

not a skin sensitizer

MRID 43494105

not a skin sensitizer. No 

positive control. Unacceptable

90-day - rat MRID 43896001

0, 250, 1,000, or 4,000 ppm (0, 

19.1, 73.8, or 292.1 mg/kg/day 

for males and 0, 20.4, 81.5, or 

313.5 mg/kg/day for females). 

LOAEL is 4,000 ppm (292.1 

MRID 00043624

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

SD rats (20/sex/dose)

LOAEL for toxic effects is 300 

mg/kg/day based on decreased 

body weight in both sexes and 

MRID 42932601

0, 200, 2000, or 8000 ppm 

(13.9, 136.6, and 564.9 for 

males and 15.2, 149.3, and 

583.4 mg/kg/day for females). 

LOAEL for systemic toxicity = 

MRID 43896002

0, 400, 2000 or 8000 ppm 

(Average doses at study end 

were 19-25; 92-123 ; and 388 -

519 mg/kg/day for malesfemales). LOAEL= 8000 ppm 
Page 16 of 26

A.2 Toxicity Profiles

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

mg/kg/day) decreased bw, bw

gain & food consumption, and 

increased relative liver weights 

with adaptive histopathological 

changes in both sexes. 

NOAEL is 1,000 ppm (73.8 

mg/kg/day)

enlarged liver weights in 

females. The NOAEL is 150 

mg/kg/day.

2000 ppm (136.6 for males and 

149.3 mg/kg/day for females) 

with a NOAEL for systemic 

toxicity of 200 ppm (13.9 for

males and 15.2 mg/kg/day for 

females) based on decreased 

hematocrit and hemoglobin, 

increased liver weights and 

vacuolation of the periportal 

hepatocytes along with 

hypertrophy of the cells of the 

adrenal cortex zona 

glomerulosa.

(594 mg/kg/day), based on 

lower bw, bw gain, and food 

consumption. Males and 

females at this dose also 

exhibited increased total 

bilirubin (19-21% higher) in 

conjunction with reduced RBC 

counts, hemoglobin, and 

hematocrits. NOAEL= is 2000 

ppm (144mg/kg/day).

10-day range 

finding - rat

MRID 00043623

0, 250, 1000 or 4000 mg/kg 

bw/day by gavage for 10 days 

(3 rats/sex/dose). Death of all 

high dose rats, one female in the 

mid dose and none in the low 

dose. Dose related depression 

in body weight gain and food 

consumption. Discoloration of 

lungs, liver and kidneys, 

distended bladder (high dose), 

blood and gas in the GI tract. 

The MTD would be 250 

mg/kg/day.

90-day - dog MRID 43895901

0, 30, 100, or 300 mg/kg/day 

for 13 weeks. LOAEL is 300 

mg/kg/day, based on increased 

platelet count, decreased red 

cell parameters, and increased 

mean corpuscular volume

MRID 00136446

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

for 6 months to beagle dogs 

(4/sex/dose) by gelatin 

capsules. 

The LOAEL was 50 

mg/kg/day, the lowest dose 

MRID 42983801

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

LOAEL for systemic toxicity 

=150 mg/kg/day based on 

lesions of the GI tract and

hypocellularity of the bone 

marrow. NOAEL for systemic 

MRID 43914901

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

for 13 weeks. LOAEL= 400 

mg/kg/day, based on soft/liquid 

feces and depressed body 

weight gains of male and 

female dogs. Blood parameters 
Page 17 of 26

A.2 Toxicity Profiles

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

which correlate with 

histopathological changes 

observed in the liver, spleen, 

and bone marrow in both sexes. 

The NOAEL is 100 mg/kg/day.

tested, based on hepatic liver 

changes (pericholangistis). No 

NOAEL derived from this 

study. 

toxicity is 25 mg/kg/day. (RBC, hemoglobin, hematocrit 

and mean platelet volume) were 

all depressed in the male dogs 

at this level. NOAEL = 125 

mg/kg/day.

21-day - dermal MRID 43581001

0, 100, 300, or 1000 mg/kg for 

6-6.5 hours/day, 5 days/week, 

for 3 weeks. No LOAEL was 

established. The NOAEL was 

the highest treatment level, 

1000 mg/kg body weight.

MRID 43134701

0, 100, 300, or 1000 mg/kg for 

6-6.5 hours/day, 5 days/week, 

for 3 weeks. LOAEL for 

systemic toxicity is 1000 and 

NOAEL = 300 mg/kg/day 

based on reduced bw gain and 

food efficiency. LOAEL for 

dermal toxicity = 1000 mg/kg 

Dermal Toxicity NOAEL = 

300 mg/kg based on 

microscopic changes in the 

skin.

MRID 43581002

0, 100, 300, or 1000 mg/kg for 

6-6.5 hours/day, 5 days/week, 

for 3 weeks. LOAEL for 

systemic toxicity is >1000 

mg/kg/day and NOAEL =1000 

mg/kg/day. LOAEL for 

dermal irritation = 100 mg/kg, 

based on the presence of 

treatment-related dermal 

irritation in the treated ski. No 

NOAEL for dermal irritation 

was established.

28-day 

inhalation

Not available (Required: HASPOC TXR 0056465)

Develop.- rat MRID 00042765

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

gastric intubation to pregnant 

rats (24/group). Developmental 

LOAEL is >250 mg/k/day and 

the NOAEL is 250 mg/kg/day. 

Maternal toxicity LOAEL 250 

mg/kg/day based on decreased 

body weight gain during the 

compound administration and 

the NOAEL is 50 mg/kg/day.

MRID 46685803

0, 15, 50 or 150 mg/kg bw/day 

from days 5 through 21 

(inclusive) of gestation.

maternal LOAEL is >150 

mg/kg bw/day, and the maternal 

NOAEL is 150 mg/kg bw/day

Developmental LOAEL is 150 

mg/kg/day based on decreased 

fetal weight and minor skeletal 

changes (centrum 5 not ossified, 

cervical arch 7 cartilage fused 

to arch 6 cartilage, shortened 7th
Page 18 of 26

A.2 Toxicity Profiles

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

cervical rib), the NOAEL is 50 

mg/kg/day.

Develop. -

Rabbit

MRID 00137821, 00137822

doses 0, 37.5, 75 or 150 

mg/kg/day

Maternal toxicity NOAEL = 75 

mg/kg/day based on lethality at 

the LOAEL of 150 mg/kg/day. 

The teratogenic and fetotoxic 

LOAEL = >150 mg/kg/day and 

NOAEL = 150 mg/kg/day.

MRID 46685801

dose levels of 0, 30, 100 or 300 

mg/kg bw/day from days 5 

through 29 (inclusive) of 

gestation

maternal LOAEL is 300 

mg/kg/day based on reduced 

body weight, body weight gain 

and reduced food consumption, 

clinical signs (few/no feces) and 

stomach irritation (red/black 

spots/areas in the glandular 

mucosa of the stomach) and 

NOAEL = 100 mg/kg/day .

Developmental LOAEL is 300 

mg/kg/day based on an increase 

in the overall incidences of 

fetuses with minor skeletal 

defects and variants (dumbell 

ossification of the 7th thoracic 

centrum, extra thoracolumbar 

ribs and 27 pre-pelvic 

vertebrae) and a decrease in 

ossification of the manus and 

NOAEL = 100 mg/kg/day.

Reproduction MRID 43796301

0, 100, 1000 or 3000 ppm [0, 7, 

69 or 210 and 0, 8, 81 or 239 

mg/kg/day for males and 

females]. Systemic and 

repro./develop. LOAEL = 

3000 ppm (210 & 239 
Page 19 of 26

A.2 Toxicity Profiles

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

mg/kg/day for males & 

females), based upon reduced 

bw gain and food consum. In 

parental animals and reduced 

litter survival, and pup weight 

throughout lactation in both 

generations of offspring. 

Systemic and repro./develop. 

NOAEL = 1000 ppm (69 & 81 

mg/kg/day for males & 

females)

Chronic/Onco -

rat

MRID 44157501

0, 100, 1000, or 5000 ppm (0, 

4.4, 43.8, and 224.5 mg/kg/day 

for males and 0, 5.6, 55.8, and 

303.6 mg/kg/day for females). 

LOAEL = 5000 ppm (224.5 

mg/kg/day for males and 303.6 

mg/kg/day for females), based 

on an increased incidence of 

stomach (mucosal gland 

dilation) and lung lesions (focal 

alveolar macrophages) in both 

sexes, and on lowered bw gain 

and food efficiency in females. 

NOAEL= 1000 ppm (43.8 

mg/kg/day for males and 55.8 

mg/kg/day for females). 

Increased incidence (p  0.01) 

of uterine endometrial stromal 

polyps in high-dose females 

(2/60, 1/60, 3/60, 13/60 at 0, 

100, 1000, 5000 ppm, 

respectively).
Page 20 of 26

A.2 Toxicity Profiles

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

Chronic - mouse NCI study. (Innes et al 1969). 

NAA acetamide was tested at 

one dose (MTD according to 

the published article) as part of 

a testing program of 120 

chemicals. Only the 

preliminary results were 

published. The test materials 

were administered to two

hybrid strains of mice: 

C57BL/6 x C3H/Anf and 

C57BL/6 x AKR (18/sex/hybrid 

strain). The mice were 

administered NAA acetamide at 

one week of age by stomach 

intubation at 464 mg/kg/day 

until weaning at 4 weeks of age 

and administered the NAA 

acetamide in the diet at 1298 

ppm for approx. 18 months. 

Gross and histopath

examination of the mice at the 

end of the feeding period did 

not reveal a significant increase 

in tumors over the controls.

MRID 46685802

0, 100, 500, or 2500 ppm [0, 

10.8, 53.3, 276.0 / 0, 14.3, 70.9, 

348.7 mg/kg bw/day M/F, 

respectively] for at least 80 

weeks.

LOAEL = 2500 ppm [276 (M), 

348.7 (F) mg/kg/day], based on 

↓body weight, food 

consumption, ↑liver and kidney 

weights in both sexes and 

epididymis in males, ↓brain 

weights in males, hepatocellular vacuolation in males, 

adenomas of the liver and lung 

in males, ↑in the incidence of 

multiple tumors in females. The 

NOAEL is 500 ppm [53.3 (M), 

70.9 (F)] mg/kg/day. 

There was no treatment related 

increase in tumor incidence 

when compared to controls. 

Dosing was considered 

adequate based on the effects 

observed on the top dose (2500 

ppm/kg/day).

Chronic - dog MRID 43744201

0, 15, 75, or 225 mg/kg/day. 

LOAEL= 75 mg/kg/day in 

males and 225 mg/kg/day in 

females, based on emesis, 

capsular regurgitation 

incidences, gross and 

histopathologic changes in 

stomachs, and sinusoidal 
Page 21 of 26

A.2 Toxicity Profiles

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

histiocytosis in livers. 

NOAEL= 15 mg/kg/day in 

males and 75 mg/kg/day in 

females.

Gene mutationbacterial

MRID 43581006

Salmonella five doses 100-

5000 ug/plate. No mutagenic 

effect with or without S9 

activation

MRID 00042761

Escherichia coli polA. Strains 

W3110 and p3478 at 1, 2 or 

mg/ml. Not mutagenic. 

MRID 00042762

Salmonella. At 0.5-5000 

ug/plate. Not mutagenic:

MRID 43581004

five doses 33-5000 ug/plate. 

No mutagenic effect with or 

without S9 activation

Gene mutation -

mammalian: 

mouse 

lymphoma cells

MRID 43580202

-S9: not mutagenic.

+S9 mutagenic at 100 ug/mL 

and above 

MRID 43580201

-S9: not mutagenic.

+S9 mutagenic at 300 ug/mL 

and above

erythrocyte 

micronuleus 

mice

MRID 43581005

ip injections 250, 500 or 1000 

mg/kg to 5 mice/sex. Lethargy 

and death at high dose. Did not 

induce a clastogenic or 

aneurogenic effect.

MRID 00042763

ip injections 60 or 125 mg/kg to 

4 mice/sex. No overt symptoms 

at high dose. Negative.

MRID 43581003

ip injections 305, 610, or 1220 

mg/kg to 5 mice/sex. Lethargy 

and death (48%) at high dose. 

Did not induce a clastogenic or 

aneurogenic effect

Mitotic gene 

conversion: 

Saccharomyces 

cervisiae

MRID 00042758, 00042759, 

00042760

NAA was tested at 10-2, 10-3, 

10-4, 10-5, 10-6 M.. NAA was 

not mutagenic in this test 

system. Unacceptable. No 

purity, not run at toxic dose, no 

S9 activation

Rodent 

dominant lethal 

MRID 00042764

oral doses of 125, 250, or 500 
Page 22 of 26

A.2 Toxicity Profiles

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

assay mg/kg/day to 10 male rats/dose 

for 5 days. NAA did not 

produce dominant lethal effects 

as measured by pre 

implantation and post 

implantation losses. 

Metabolism Dixon et al.1977. NAA 14C as Na salt. 60-100% of the AD was excreted in the urine by the end of 48 hours. The glucuronic acid 

conjugate (GAC): major urinary metabolite in man, rhesus monkey, marmoset, rabbit, rat, and fruit bat. In the cat, no GAC was 

detected; but turine and glycine conjugates. The glycine conjugate was a major urinary metabolite (>20%) in the cat, squirrel and 

bushbaby monkey and a minor metabolite in rabbit, rat, capuchia and marmoset monkey. 1-NAA glutamine conjugate was formed only 

in the cynomolgus, squirrel and capuchin monkeys and marmoset in amounts not exceeding 3% of the AD. 1-NAA turine was excreted 

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

marmoset and the cat. When female rats were given ip doses of 5-500 mg/kg, bile duct cannulation showed that 10-44% of the 

radioactivity was present in the bile 3 hours after injection, while 0.6-32% was present in the urine. At the higher doses urinary GAC 

predominated whereas at the lower doses the glycine conjugates predominated. In the bile the GAC was the major metabolite (>80% of 

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

fecal radioactivity.

Lethco and Brouwer, 1966. carboxy -

14C-1- NAA as NA salt in male rats. Within 3 days, 71-90% of the AD was excreted in the urine. 

At the lower doses (0.1-100 mg/kg) most of the radioactivity was excreted during the first 24 hours, while at the higher dose (250 mg/kg), 

excretion was highest on the second day. Fecal excretion was 3-10% at the 0.1-1.0 mg/kg doses and 14-21% of the AD at the 100 and 

250 mg/kg doses. After the third day, no radioactivity was detected in the feces or urine at any dose. 70-93% of the urinary radioactivity 

was NAA glycine conjugate and NAA GAC. The GAC predominated at the two high doses and the glycine conjugate predominated at 

the lower dose. Minor amounts of NAA and two other minor unidentified metabolites were detected in the urine. Bile cannulation 

experiments demonstrated biliary metabolism and excretion of the test material. At the high dose a maximum of 29% of the AD was 

recovered at 6 hours, while a maximum of 54% was recovered at the low dose at 2 hours. At the low dose, the NAA glycine conjugate 

was the major urinary metabolite and the NAA GAC was a minor metabolite, while in the bile the preponderance of these two metabolites 

was reversed. Unchanged NAA was detected in the bile but not in the urine at both doses. At the high dose the NAA GAC was the major 

metabolite in both urine and bile while the glycine conjugate was a minor metabolite.

MRID 43961701. Rats (5/sex) were given a single 1 or 100 mg/kg bw oral dose of [14C] ring labeled -1-naphthaleneacetic acid, ethyl 

ester, or a 14-day repeated dose (1 mg/kg/day) of unlabeled material followed by a single dose of the labeled material. Overall recovery 

of AD was 98.6-101.8%. NAA ethyl ester was readily absorbed and excreted within 36 - 48 hours following all exposure regimens 

(urinary excretion: 67.6-85.3% of the AD at the low dose and 61.8-78% of the AD at the high dose). Fecal excretion was 12.3-35.2% of 

the AD. Tissue radioactivity was very low. The major pathway of metabolism involved ester cleavage followed by glycine and 
Page 23 of 26

A.2 Toxicity Profiles

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

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. 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. 
Attachment 3. Toxicological Doses and Endpoints

Summary of Toxicological Endpoints for Naphthalene Acetates for Use in Dietary Human Health Risk Assessments

Exposure/Scenario Point of

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD,

LOC for Risk

Assessment

Study and Toxicological Effects

Acute Dietary

(General Population)

An acute RfD for the general population or any population subgroups was not selected because no effect

attributable to a single (or few) day(s) oral exposure was observed in animal studies.

Chronic Dietary

(All Populations)

NOAEL =

15

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD =

0.15

mg/kg/day

cPAD = 0.15

mg/kg/day

Chronic Toxicity - Dog, MRID 43744201;

LOAEL = 75 mg/kg/day based on stomach

lesions in 75% of the males and by slight

sinusoidal histiocytosis in the liver of 50% of

the males. 

Incidental Oral

Dermal

Inhalation

There are no post-application residential uses for or exposures to the proposed use of naphthalene acetic

acid ethyl ester that would result in incidental oral exposure. Therefore exposure endpoints are not

required and not selected for residential exposure assessment. 

Cancer (all routes) A “not likely” human carcinogen

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

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL

= no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA =

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human

population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term risk

assessment. UFDB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD

= population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. 

N/A = not applicable.
Page 25 of 26

Endpoints selected for Assessing Occupational and Residential Risks for Naphthalene Acetates

Exposure

Scenario

Dose Used in Risk 

Assessment, UF 

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC 

for Risk 

Assessment

Study and Toxicological Effects

Dermal 

Short-Term 

(1 - 30 days)

Dermal study 

NOAEL= 300

mg/kg/day

UFA= 10x

UFH=10x LOC = 100

21- day dermal: NAA Na salt, MRID 

43134701

LOAEL = 1000 mg/kg/day based on

reduced body weight gain and food 

efficiency

Inhalation

Short-Term 

(1 - 30 days)

Oral study NOAEL=

50 mg/kg/day *

UFA= 10x

UFH=10x

UFDB= 10x

LOC = 1000 Developmental - Rat: NAA MRID 

00042765,

LOAEL = 250 mg/kg/day based on 

decreased BW gain during gestation 

period.

Cancer Bioassay in rats and mice not carcinogenic. Not mutagenic.

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

the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from

animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). 

UFDB= database uncertainty factor: lack of an inhalation specific study. FQPA SF = FQPA Safety Factor. MOE = margin of

exposure. LOC = level of concern. 

* Incidental oral, intermediate and long term exposure duration scenarios are not assessed based on use patterns; inhalation 

absorption is assumed to be equivalent to oral absorption
Page 26 of 26

Attachment 4. International Residue Limits

NAA (056002; 7/24/14)

Summary of US and International Tolerances and Maximum Residue Limits

Residue Definition:

US Canada Mexico3 Codex

40 CFR 180.155:

Plant: 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

Livestock: NA

None None

Commodity2

Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico3 Codex

Avocado 0.05

Cherry, sweet 0.1

Fruit, pome, group 11-10 0.15

Mango 0.05

Olive 0.7

Orange 0.1

Pineapple1 0.05

Potato 0.01

Rambutan 2.0

Sapote, mamey 0.05

Tangerine 0.1

Completed: M. Negussie; 07/24/14

1There are no U.S. registrations since 1988.

2

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations 

and not those proposed by the applicant.

3 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.