### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

MEMORANDUM

DATE: November 20,2014 OFFICE OF CHEMICAL SAFETY

AND I'OLLUTION PREVENTION

S U BJECT: 1-Naphthaleneacetic ac id (NAA): Human Health Risk Assessment Scop in g

Document in Support of Registration Review

PC Code: OS600 I

, OS6002

, OS6003, OS6004

, OS6007

, 0S6008

Decision No.: 

### 4%.111

Petit i on No.: NA

Risk Assessment Type: Single C h emical 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: Thurs ton Morton

, Senior Chem ist

Abdallah Khasawinah, PhD., Toxico l o g is t

Susan Hummel

, Senior Chemist

Ivan N ie ves, 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-Eva luation Division (7508P)Executive Summary

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

ester, and acetamide and its tox icity

, 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 Ri sk Assessment conducted January 16

, 2013

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

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

shown s i gnificant differences between th e six active ingredients.

1-Naphthalen eacetic acid (NAA), its salts, ester, and acetamide are plant growt h regulators

which are collectively referred to as naphthalene acetates and hereaft er 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 commod iti es ranging from 0.05 ppm to

0.15 ppm ( 40 CFR§ 180.155 ). NAA is used to st imul ate growth, delay flower induction and leaf

drop, prevent preharvest fruit drop

, thin fruit

, and control sprout formation. Reg i stere d

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 aer ial equipment. Formula tions for

contro l of sprout formation containing the ester and/or ace tamide of 1- naphthaleneacetic acid

are applied by hand h eld sprayer and paint brush. NAA co ntainin g products used to stim ula te

root growth are applied as a dilute root dip or so il drench. Residential uses are limi t ed to r oot di p

and sprout inhibition applications on ornamental plants. T h e plant growth regulating activity of

naphthalene acetates is due to structural simi l arity 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 i s considered incomplete. A

subchronic inhalation study is required. The study shou ld be conducted with th e sodium or

potassium sa l t. As part of registration review

, however, the endpoints, doses, a nd safety factors

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

according to current H E D po li cy. No storage stabi lit y data on the proce sse d commodities of

apples (or citrus fruits) and olives are availab l e

, 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 re l ationships (SAR) and metabolism data

, all forms ofNAA are

expected to exhibit s imilar toxicological effects. Therefore, the Agency concluded that required

toxicity testing on any form should serve for a ll members of this group of c hemicals. The most

prevale nt 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 of26Page 3 of 26

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

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 lact ation 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 re sulted in dietary risk estimates below HED’s level of concern. In this

assessment, t he 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 con cern ( 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

. R esidential post

application exposure was not expected based on the registered use pattern. Occupational

exposures were assessed for handler an d post

- application activities; risk estimates indicate that

handler and post

- application exposu res 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 a pplied 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 roo t growth

are applied as a dilute root dip or soil drench. Residential uses are limited to root dip and sproutPage 4 of 26

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

to structural similarity to the natural plant h ormone 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 propertie s of NAA are presented in Tables 1 and 2 of

Attachment 1.

Hazard Identification/Toxicology

Based on structural activity relationship s 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 immu notoxicity.

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 fo r 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 20 13 ( 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 in complete. 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 plant s

, 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 extrac tion

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 reregistratio n

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

commodities of apple, citrus, and olive 1

. In addition a citrus processing study 2 was required at

the time of re registration. These data have not been submitted. No analytical referen ce

standard s 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 availabl e, and these data are required for R egistration R eview. 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 o f 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). A nalytical 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 da ta 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 condu cted 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

residentia l exposure risk ass essment may be updated during r egistration r eview. 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 f rom 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, c hronic 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 effect s ; 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 r elated 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

assessmen t (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 N AA 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 p ants 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) M ixer / L oader aerial, (2)

A pplicator aerial, (3) M/L airblast, (4) A airblast, (5) M/L/A ma nually

- 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 glo ves 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 i ndividuals 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

Dislodgeab le 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 post

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

Agricultural Re

- en try 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

Gree nhouse ” (EPA MRID 45344501). As a result, the range of F AR 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 co nditions (e.g., humidity); or many other difficult

- to

- quantify

f actors. Although witnessed across multiple chemicals, this range in F AR values is not expected

when considering DFR data for a single chemical. T he 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 c hance that the F AR 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 a ssessing residential and occupational post

application 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

- ap plication 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 re ly 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 chemical

specific 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 inhalatio n 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 toPage 9 of 26

individuals performing post

- application activities in previously treated fields. These potential

sources include volatilization of p esticides 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 appropriat e, 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 r evisit 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 as sessment 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

to xicological 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 Occupationa l 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 incl uded in the A gricultural 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 inc idents 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 eff orts 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 procedur es 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 20 13 risk assessment relied in part on data from studies in which adult human

subjects we re 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 ethic s

review pursuant to 40 CFR § 26, (2) have received that review, and (3) are compliant with

applicable ethics requirements. For certain studies, the ethics review may have included review

by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their

use, can be found at the Agency website s 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

fruit s) 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.htmlPage 11 of 26

References

Table 1. Memoranda Relevant to Registration Review 1

.

Author Barcode Date Title

E. Evans and S.

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

Incidents

Morton, T.,

Hummel, S.,

Khasiwinah, A D 404398 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 a nd 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 N aphthalene 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 C 12 H 11 NO C 12 H 10 O 2

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 C 12 H 10 O 2 K C 12 H 13 NO 2

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 056004Page 13 of 26

Table 1. NAA Nomenclature

Chemical structure

Common name NAA sodium salt NAA ethyl ester

Molecular Formula C 12 H 10 O 2 Na C 14 H 14 O 2

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 NAA 1

Parameter Value Reference

Active Ingredient NAA acetamide

Melting point/range 182

- 184 C Farm Chemicals Handbook

pH of 1% aqueous suspension 5.1 Product CSF

Density or specific gravity 0.221 g/cm 3 Product CSF

Water solubility (20

̊ C) not available

Solvent solubility (20

̊ C) not available

Vapor pressure at 20

̊ C not available

Dissociation constant (pK

a ) not available

Octanol/water partition coefficient (K

ow ) 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

CCl 4 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 (pK

a ) 3.16 x 10

- 4 CB Nos. 3970 and 3971, 7/5/88,

F. Suhre

Octanol/water partition coefficient (K

ow ) not applicable; polar

compound

UV/vis absorption spectrum not available

Active ingredient NAA sodium saltPage 14 of 26

Table 2. Physicochemical Properties of NAA 1

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 (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 (pK

a ) 3.16 x 10

- 4 CB Nos. 3970 and 3971, 7/5/88, F.

Suhre

Octanol/water partition coefficient (K

ow ) 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 (26

̊ C) I nsoluble 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 20

̊ C not available

Dissociation constant (pK

a ) not available

Octanol/water partition coefficient (K

ow ) not available

UV/vis absorption spectrum not availableAttachment 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

LD 50 > 5050 mg/kg

Category III MRID 00103128

LD 50 (95% C.I.) = 2520 mg/kg

(2100

- 3021). MRID 00108829

LD 50 : Males 1.35 (1.12

– 1.64)

Females 0.933 g/kg (0.631

- 1.38

) MRID 43494101

LD 50 2186 (1907

- 2506) mg/kg

Category III

Acute

- Dermal MRID 43495902

LD 50 > 2020 mg/kg

Category III MRID 00103129

LD 50 is greater than 2 g/kg.

Category III. MRID 00108829

Dermal LD 50 = > 2 g/kg.

Category III MRID 43494102

LD 50 > 2020 mg/kg. Category

III

Acute

- Inhal. MRID 43495903

LC 50 > 2.17 mg/L

Category IV MRID 43494103

LC 50 > 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 males

females). LOAEL = 8000 ppmPage 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. M ales and

females at this dose also

exhibited incre ased 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 i n 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 parametersPage 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 h ours/day, 5 days/week,

for 3 weeks. LOAEL for

systemic toxicity is 1000 and

NOAEL = 300 mg/kg/day

based on reduced bw gain and

food efficiency. LOAEL for

dermal toxicity = 1000 mg/kg

Dermal Toxicity NOAEL = 300 mg/kg based on

microscopic changes in the

skin. MRID 43581002

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

6

- 6.5 hours/day, 5 days/week,

for 3 weeks. LOAEL for

systemic toxicity is >1000

mg/kg/day and NOAEL =1000

mg/kg/day. LOAEL for

dermal irritation = 100 mg/kg,

based on the presence of

treatment

- related dermal

irritation in the treated ski. No

NOAEL for dermal irritation

was established.

28

- day

inhal ation 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 7 thPage 18 of 26

A.2 Toxicity Profiles

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

cervical rib), t he NOAEL is 50

mg/kg/day.

Develop.

-

Rabbit MRID 00137821, 00137822

doses 0, 37.5, 75 or 150

mg/kg/day

M aternal 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 th e glandular

mucosa of the stomach) and

NOAEL = 100 mg/kg/day .

Developmental LOAEL is 300

mg/kg/day based on an increase

in the overall incidences of

fetuses with minor skeletal

defects and variants (dumbell

ossification of the 7 th thoracic

centrum, extra thoracolumbar

ribs and 27 pre

- pelvic

vertebrae) and a decrease in

ossification of the manus and

NOAEL = 100 mg/kg/day.

Reproduction MRID 43796301

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

69 or 210 and 0, 8, 81 or 239

mg/kg/day for males and

females]. Systemic and

repro./develop. LOAEL = 3000 ppm (210 & 239Page 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. I n

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 fe males.

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 t he 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, he pato

cellular vacuolation in males,

adenomas of the liver and lung

in males, ↑in the incidence of

multiple tumors in females. The

NOAEL is 500 ppm [53.3 (M),

70.9 (F)] mg/kg/day.

There was no treatment related

increase in tumor incidence

when compared to controls.

Dosing was considered

adequate based on the effects

observed on the top dose (2500

ppm/kg/day).

Chronic

- dog MRID 43744201

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

LOAEL = 75 mg/kg/day in

males and 225 mg/kg/day in

females, based on emesis,

capsular regurgitation

incidences, gross and

histopathologic changes in

stomachs, and sinusoidalPage 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 mutation

bacterial MRID 43581006

Salmonella five doses 100

- 5000 ug/plate. No mutagenic

effect with or without S9

activation MRID 00042761

Escherichia coli polA . Strains

W3110 and p3478 at 1, 2 or

mg/ml. Not mutagenic.

MRID 00042762

Salmonella. At 0.5

- 5000

ug/plate. Not mutagenic: MRID 43581004

five doses 33

- 5000 ug/plate.

No mutagenic effect with or

without S9 activation

Gene mutation

-

mammalian:

mouse

lymphoma cells MRID 43580202

- S9: not mutagenic.

+S9 mutagenic at 100 ug/mL

and above MRID 43580201

- S9: not mutagenic.

+S9 mutagenic at 300 ug/mL

and above

erythrocyte

micronuleus

mice MRID 43581005

ip injections 250, 500 or 1000

mg/kg to 5 mice/sex. Lethargy

and death at high dose. Did not

induce a clastogenic or

aneurogenic effect. MRID 00042763

ip injections 60 or 125 mg/kg to

4 mice/sex. No overt s ymptoms

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 500Page 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 14 C as Na salt . 60

- 100% of the AD was excreted in the urine by the end of 48 hours. The glucuronic acid

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

detected; but turine and glycine conj ugates

. 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 ca puchin 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 wherea s 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 analy sis of the

fecal r adioactivity.

Lethco and Brouwer, 1966. carboxy

- 14 C

- 1

- NAA as NA salt in male rats. Within 3 days, 71

- 90% of the AD was excreted in the urine.

At the lower doses (0.1

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

excretion was highest on the second day. Fecal excretion was 3

- 10% at the 0.1

- 1.0 mg/kg doses and 14

- 21% of the AD at the 100 and

250 mg/kg doses. After the third day, no radioactivity was detected in the feces or urine at a ny 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 w ere 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 h ours. 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 met abolites

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

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

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

- 1

- napht haleneacetic 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 hour s 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 es ter cleavage followed by glycine andPage 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 i mportant

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

[ 14 C] ring labeled

- 1

- naphthaleneacetamide (NAAD). Overall recovery of the AD was 97.2

- 101%. NAAD was readily absorbed and

excreted within 36 hours (urinary excretion: 70.8

- 74.1% of the AD at the low dose, single or multiple, 66.2

- 69.5% of the AD excreted in

urine at the high dose). Fecal excretion was 21.6

- 26.2% of the AD. Tissue radioactivity was very low (<0

. 5% of the AD). Metabolism

involved amide cleavage followed by glycine conjugation (13.7

- 47.3% of the AD) glucuronide conjugation (4.5

- 7.0% of the AD at the

low dose and 12.8

- 18.1% of the AD at the high dose 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 UF A = 10x

UF H =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 exposu re 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. UF A = extrapolation from animal to human (interspecies). UF H = potential v ariation in sensitivity among members of the human

population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S

= use of a short

- term study for long

- term risk

assessment. UF DB = to account for the absence of key date (i.e., lack of a crit ical 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 UF A = 10x

UF H =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 * UF A = 10x

UF H =10x

UF DB = 10x LOC = 1000 Developmental

- Rat: NAA MRID

00042765,

LOAEL = 2 50 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 o bserved adverse effect level. UF

= uncertainty factor. UF A = extrapolation from

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

UF DB = 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 assume d to be equivalent to oral absorptionPage 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 Mexico 3 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

equivale nt of 1

- naphthaleneacetic acid

Livestock: NA None None

Commodity 2 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 3 Codex

Avocado 0.05

Cherry, sweet 0.1

Fruit, pome, group 11

- 10 0.15

Mango 0.05

Olive 0.7

Orange 0.1

Pineapple 1 0.05

Potato 0.01

Rambutan 2.0

Sapote, mamey 0.05

Tangerine 0.1

Completed: M. Negussie; 07/24/14

1 There 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.