UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

March 14, 2012

SUBJECT: Naphthalene Acetates 

Potato Seed Pieces 

PC Code: 056003 (NAA potassium salt)

Decision No.: 427532

Petition No.: 0F7687

Risk Assessment Type: Single Chemical Aggregate

TXR No.: NA

MRID No.: NA

FROM: Becky Daiss, Biologist 

Susan Hummel, Chemist

Abdallah Khasawinah, Toxicologist

Ivan Nieves, Chemist

Risk Assessment Branch 4

Health Effects Division (7509P)

THROUGH: Elissa Reaves, PhD., Chief

Risk Assessment Branch 4, HED (7509P)

Health Effects Division (7509P)

TO: Tony Kish, Chemical Review Manager

Fungicide Branch

Registration Division (7505P)

Attached is Health Effects Division’s (HED’s) risk assessment of naphthalene acetates for 

purposes of issuing a Section 3 new use as a seed piece treatment on potatoes. 

Page 1 of 52

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

Naphthalene Acetates HED Risk Assessment for Section 3 Proposed New Use on 

Potato Seed Pieces 

056003 (NAA potassium salt) DP Barcode: D397387

Registration No.: 87320-E

Regulatory Action: Section 3

Single Chemical Aggregate Case No.: 0379

CAS No.: 15165-79-4 (NAA, potassium salt)

40 CFR: §180. 155

Becky Daiss, Biologist 

Susan Hummel, Chemist

Abdallah Khasawinah, Toxicologist

Nieves, Chemist

Risk Assessment Branch 4

Health Effects Division (7509P)

Elissa Reaves, PhD., Chief

Risk Assessment Branch 4, HED (7509P)

Health Effects Division (7509P)

Tony Kish, Chemical Review Manager

Fungicide Branch

ision (7505P)

Attached is Health Effects Division’s (HED’s) risk assessment of naphthalene acetates for 

purposes of issuing a Section 3 new use as a seed piece treatment on potatoes. 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

HED Risk Assessment for Section 3 Proposed New Use on 

4 (NAA, potassium salt)

Attached is Health Effects Division’s (HED’s) risk assessment of naphthalene acetates for 
Page 2 of 52

1.0 EXECUTIVE SUMMARY .................................................................................................4

2.0 HED RECOMMENDATIONS............................................................................................6

2.1 Data Deficiencies.................................................................................................................6

2.2 Tolerance Considerations.....................................................................................................6

2.2.1 Enforcement Considerations ...................................................................................6

2.2.2 International Harmonization ...................................................................................7

2.2.3 Recommended Tolerances.......................................................................................7

2.2.4 Revisions to Petitioned-For Tolerances...................................................................7

3.0 INGREDIENT PROFILE....................................................................................................7

3.1 Chemical Identity ................................................................................................................7

3.2 Physical/Chemical Characteristics.......................................................................................9

3.3 Pesticide Use Pattern............................................................................................................9

3.4 Anticipated Exposure Pathways ..........................................................................................9

3.5 Environmental Justice..........................................................................................................9

4.0 HAZARD CHARACTERIZATION/ASSESSMENT.......................................................10

4.1 Toxicology Studies Available for Analysis.......................................................................10

4.2 Absorption, Distribution, Metabolism, & Elimination ......................................................10

4.3 Toxicological Effects.........................................................................................................11

4.4 Safety Factor for Infants and Children...............................................................................12

4.4.1 Completeness of the Toxicology Database............................................................12

4.4.2 Evidence of Neurotoxicity .....................................................................................13

4.4.3 Evidence of Sensitivity/susceptibility in the Developing or Young......................13

4.4.4 Residual Uncertainty in the Exposure Data Base ..................................................13

4.5 Toxicity Endpoint and Point of Departure.........................................................................13

4.5.1 Dose-Response Assessment...................................................................................13

4.5.2 Recommendation for Combining Exposure Routes ..............................................14

4.5.3 Cancer Classification ............................................................................................14

4.5.4 Summary of Points of Departure Used in Risk Assessment..................................14

5.0 DIETARY AND DRINKING WATER RISK ASSESSMENT........................................15

5.1 Metabolite/Degradate Residue Profile...............................................................................15

5.1.1 Summary of Plant and Animal Metabolism Studies..............................................15

5.1.2 Summary of Environmental Degradation ..............................................................15

5.1.3 Comparison of Metabolic Pathways......................................................................16

5.1.4 Residues of Concern Summary and Rationale.......................................................16

5.2 Food Residue Profile..........................................................................................................16

5.2.1 Residues in Crops, Livestock and Poultry .............................................................16

5.2.2 Residues in Processed Commodities .....................................................................17

5.3 Water Residue Profile ........................................................................................................17

5.4 Dietary and Drinking Water Exposure and Risk ...............................................................17

6.0 RESIDENTIAL EXPOSURE AND RISK........................................................................18
Page 3 of 52

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT...............................................19

8.0 CUMULATIVE RISK.......................................................................................................19

9.0 OCCUPATIONAL EXPOSURE AND RISK...................................................................19

9.1 Exposure Scenarios............................................................................................................19

9.2 Handler Exposure...............................................................................................................20

9.2.1 Handler Exposure Scenarios..................................................................................20

9.2.2 Handler Exposure Data ..........................................................................................21

9.2.3 Handler Exposure Assumptions.............................................................................21

9.2.4 Handler Exposure and Risk Estimates...................................................................21

9.3 Post Application Exposure.................................................................................................22

9.3.1 Post Application Exposure Scenarios....................................................................22

9.3.2 Post Application Exposure Assumptions...............................................................22

10.0 REFERENCES ..................................................................................................................23

Appendix A. Toxicity Profile and Executive Summaries..............................................................24

A.1 Toxicity Data Requirements..................................................................................24

A.2 Toxicity Profiles.....................................................................................................30

A.3 Hazard Identification and Endpoint Selection .......................................................33

A.4 Executive Summaries.............................................................................................35

Appendix B. Physical/Chemical Properties...................................................................................51

Appendix C. Review of Human Research .....................................................................................52
Page 4 of 52

1.0 EXECUTIVE SUMMARY

This assessment provides information to support the issuance of a Section 3 proposed new 

use of 1-naphthaleneacetic acid, potassium salts in/on potatoes. The risk assessment process 

considers the human health effects of pesticides and incorporates a reassessment of tolerances 

(pesticide residue limits in food) to ensure that they meet the safety standard established by the 

Food Quality Protection Act (FQPA) of 1996. 

Use Profile 

Registered Uses

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

are collectively referred to as naphthalene acetates (NAA). They are currently registered for use 

on various orchard and fruit crops and ornamentals. Naphthalene acetates currently have 

tolerances in/on a number fruit commodities ranging from 0.05 ppm to 0.15 ppm 40CFR§180.155. 

Naphthalene acetates are used to stimulate growth, delay flower induction and leaf drop, prevent 

preharvest fruit drop, thin fruit, and control sprout formation. Registered formulations include 

dust, wettable powder, flowable concentrate, emulsifiable concentrate, soluble concentrate, and 

liquid ready-to-use. Thinning and stop drop formulations containing 1- naphthaleneacetic acid or 

its ammonium, potassium, or sodium salts 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. 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. Homeowner applications are limited use on ornamental plants.

Proposed New Use

Stehekin, LLC requested a Section 3 registration of RejuvenateTM Seed Treatment for use 

as a seed piece treatment on potatoes. RenewTM Concentrate is a soluble concentrate formulation 

containing 6.25% NAA, potassium salt. The maximum seed piece treatment rate Stehekin, LLC is 

0.25 g ai/A on seed. The proposed application rate is based on the registrant’s theoretical 

calculation of maximum potential residues at this rate showing residues less than the LOQ, in lieu 

of residue chemistry data. The proposed potato use does not include homeowner use or application 

to residential areas.

Hazard Identification

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

acetates. All six chemicals that comprise the naphthalene acetates are combined for the toxicity

assessment for this RED because they are structurally related and are metabolized to the acid form 

and eliminated from the body as glycine and glucuronic acid conjugates within 48 hours after 

exposure. Naphthalene acetates have low acute toxicity via the oral, inhalation and dermal routes 
Page 5 of 52

of exposure. NAA is not a skin irritant or a dermal sensitizer. The NAA acid and its sodium salt 

were found to be irritating to the eye, but the NAA ethyl ester was not an eye irritant. The NAA 

acetamide was found to be an eye irritant in one old test and a non-eye irritant in another study

conducted on the currently produced material.

Repeated exposure oral toxicity studies in rats and dogs resulted in decreased body weights 

and body weight gains accompanied by decreased food consumption. The major target organs of 

subchronic and chronic oral exposure were the liver, stomach and lung. Repeated oral exposure 

also resulted in decreased hematocrit and hemoglobin along with reduced RBC count in rats and 

dogs and hypocellularity of the bone marrow in dogs. There was no developmental toxicity at 

highest doses of NAA tested in the rat or in the rabbit, but developmental toxicity (decreased fetal 

weight and minor skeletal changes) were seen in rats orally gavaged with the sodium salt. 

Reproductive effects of NAA sodium salt occurred at relatively high doses and were limited to 

reduced litter survival and pup weight throughout lactation in both generations of offspring in a 

two generation reproduction study. Carcinogencity studies of NAA acetamide in mice and NAA 

sodium salt in rats and mice are considered adequate for the evaluation of the oncogenicity of the 

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

rats. 

Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water and occupational 

exposure scenarios. There were no toxicological effects attributable to a single exposure of NAA 

observed in oral toxicity studies. Therefore, a POD for acute dietary exposure was not selected. A 

chronic RfD was selected from a chronic toxicity study in dogs based on stomach lesions and liver 

effects in males. A toxicological point of departure (POD) for dermal exposures was selected from 

a dermal toxicity study in rats based on reduced body weight gain and food efficiency at the 

highest dose tested. A short-term inhalation exposure POD was selected from a developmental 

toxicity study in rats based on decreased body weight gain. An intermediate-term inhalation 

exposure POD was selected from a subchronic oral dog study based on based on GI tract and bone 

marrow effects. An uncertainty factor of 100X was applied to endpoints selected for exposure 

routes (10x for interspecies extrapolation, 10x for intraspecies variation). 

Exposure/Risk Assessment and Risk Characterization

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

pathways based on registered uses and requests for a new use of NAA salts on potato seed pieces. 

Screening level acute and chronic dietary and drinking water risk assessments for naphthalene 

acetates conclude that dietary and drinking water exposure estimates are below HED’s level of 

concern the general population and all population subgroups. Worker exposures were assessed for 

handler and post-application activities. Occupational exposure and risk estimates indicate that 

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

application rate for the proposed new use.

Use of Human Studies
Page 6 of 52

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix 1.0, have 

been determined to require a review of their ethical conduct. Some of these studies are also subject 

to review by the Human Studies Review Board. All of the studies used have received the 

appropriate review.

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies

There are no residue chemistry issues that would preclude granting registration for the 

requested seed piece treatment use of NAA on potatoes. However, the following studies will be 

required if the registrant requests future uses at a higher application rate. 

- A metabolism study (preferably on a root crop) must be submitted if a higher rate or foliar 

use is later proposed.

- No processing study is required at the present time. Processing studies for potatoes must 

be submitted if a higher rate or foliar use is proposed. A 5x exaggerated rate is suggested.

- No confined rotational crop study is required at the present time. A confined rotational 

crop for potatoes must be submitted if a higher rate or foliar use is proposed. An 

exaggerated rate is recommended.

- Method NAA-AM-001 and Method NAA-AM-002 will be submitted to ACL/BEAD and 

to FDA for updating PAM II. 

- Immunotoxicity and acute and subchronic neurotoxicity studies are required as part of new 

40 CFR Part 158 data requirements for registration of a pesticide.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An acceptable enforcement method is available for residues of NAA and salts in potatoes. 

HPLC methods (Method NAA-AM-001 and Method NAA-AM-002) for determination of NAA in 

plant commodities have been submitted and reviewed. 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 quantitation (LOQ; 0.01 ppm) and at 

1.0 ppm. These methods will be submitted to ACL/BEAD and to FDA for updating PAM II. 

These methods are an improvement of the existing enforcement methods in PAM II. Samples of 

potato tuber from the submitted field trials were analyzed for residues of NAA using Method 

NAA-AM-002. Acceptable method validation and concurrent method recoveries were achieved 

with potato tubers fortified at 0.01 ppm and 0.50 ppm.

2.2.2 International Harmonization
Page 7 of 52

No Codex, Canadian, or Mexican maximum residue limits (MRLs) have been established 

for residues of NAA, its salts, ester, and acetamide on potatoes.

2.2.3 Recommended Tolerances

The petitioner has requested an exemption from the requirement of a tolerance for residues 

of NAA potassium salts in/on potatoes. However, a tolerance at the LOQ is needed because some 

available data suggest the potential for residues below the LOQ and toxicological endpoints have 

been selected for dietary exposure based on available toxicity data for NAA. HED recommends 

that a tolerance be established for NAA residues in/on potatoes at the LOQ of 0.01 ppm, providing 

the theoretical calculations are clarified and the label is changed as provided below. 

There are no residue chemistry issues that would preclude granting registration for the 

requested seed piece treatment use of NAA on potatoes or establishment of a tolerance for the 

combined residues of 1-naphthaleneacetic acid and its conjugates calculated as 

1-naphthaleneacetic acid from the application of 1-naphthaleneacetic acid, its ammonium, sodium, 

or potassium salts, ethyl ester, and acetamide in/on potatoes at 0.01 ppm. 

Table 1. Tolerance Recommendation

Crop Group or 

Commodity

Proposed Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity Definition

Potato Exemption 0.01

2.2.4 Revisions to Petitioned-For Tolerances

The registrant proposed an exemption from the requirement of a tolerance. HED 

recommends establishment of a tolerance of 0.01 ppm for potato. 

3.0 INGREDIENT PROFILE 

3.1 Chemical Identity

The nomenclature for NAAs is provided in Table 2.

Table 2. NAA Nomenclature
Page 8 of 52

Table 2. NAA Nomenclature

Chemical structure

Common name NAA acetamide NAA

Molecular Formula C12H11NO C12H10O2

Molecular Weight 185.23 186.20

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

CAS name 1-naphthaleneacetamide 1-naphthaleneacetic acid

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

PC Code 056001 056002

Chemical structure

Common name NAA potassium salt NAA ammonium salt

Molecular Formula C12H10O2K C12H13NO2

Molecular Weight 224.31 203.24

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

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

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

PC Code 056003 056004

Chemical structure

Common name NAA sodium salt NAA ethyl ester

Molecular Formula C12H10O2Na C14H14O2

Molecular Weight 208.2 214.26

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

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

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

O

NH2

O

OH

O

O K

+

O

O NH4

+

O

O Na

+

O

O CH3
Page 9 of 52

Table 2. NAA Nomenclature

PC Code 056007 056008

3.2 Physical/Chemical Characteristics

A detailed description of the physiciochemical properties of NAA is provided in Appendix 

C. Based on the limited available for data NAA exhibits relatively low solubility in water and 

higher solubility in solvents. It has a relatively high vapor pressure (0.3 mmHg). NAA is relatively 

mobile but short lived in terrestrial and aquatic environments. NAA does not present significant 

concerns for bioaccumulation based on measured bioconcentration factors. 

3.3 Pesticide Use Pattern 

Stehekin, LLC has submitted a Section 3 request for registration of RenewTM Concentrate 

for use as a seed piece treatment on potatoes. Rejuvenate Seed TreatmentTM is a soluble 

concentrate formulation containing 6.25% NAA, potassium salt. The use pattern for the proposed 

new use is provided in Table 3.

Table 3. Summary of Directions for Use of NAA, Potassium Salts

Application 

Type 

Formulation Applic. Rate 

(g ae1/A)

Max. No. Applic. 

per Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Russet Potatoes

Seed piece 

treament

6.25% NAA, potassium salt. 0.25 Not provided Not applicable Not applicable

Use Directions and Limitations: Apply in enough water to ensure adequate coverage, but without 

damaging the seed piece. 

Other Varieties of Potatoes

Seed piece 

treament

6.25% NAA, potassium salt. 0.18 Not provided Not applicable Not applicable

Use Directions and Limitations: Apply in enough water to ensure adequate coverage, but without 

damaging the seed piece. 

1

ae = acid equivalent

3.4 Anticipated Exposure Pathways

Dietary (food and water) and occupational exposures via dermal and inhalation pathways 

are expected based on proposed uses of NAA as a seed treatment and foliar spray on potatoes. 

There are no residential uses for NAA resulting in exposure to children via incidental oral 

activities. 

3.5 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered 

in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal 

Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).
Page 10 of 52

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates risks 

to population subgroups from pesticide exposures that are based on patterns of that subgroup’s 

food and water consumption, and activities in and around the home that involve pesticide use in a 

residential setting. Whenever appropriate, non-dietary exposures based on home use of pesticide 

products and associated risks for adult applicators and for toddlers, youths, and adults entering or 

playing on treated areas postapplication are evaluated. Further considerations are currently in 

development, as OPP has committed resources and expertise to the development of specialized 

software and models that consider exposure to bystanders and farm workers as well as lifestyle and 

traditional dietary patterns among specific subgroups. 

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

Based on structural activity relationship and metabolism data, all forms of NAA are 

expected to exhibit similar toxicological effects. Therefore the Agency concluded that required 

toxicity testing on any form should serve for all members of this group of chemicals. The toxicity 

database for NAA is sufficient for a full hazard evaluation and is considered adequate to evaluate 

risks to infants and children. Acceptable developmental toxicity studies in the rat and rabbit and 

an acceptable reproduction study in the rat are available. Based on the results of the available 

toxicity studies, there is no evidence for neurotoxicity or immunotoxicity. However, in 

accordance with the revised 40 CFR Part 158 Toxicology Data Requirements, a Neurotoxicity

Battery (870.6200a and b) and an Immunotoxicity study (870.7800) are required. A subchronic 

inhalation toxicity study is not available but is not required based on results of the occupational 

exposure assessment which indicates that use of an oral endpoint provides an ample margin of 

safety to account for any uncertainties in route to route extrapolation (i.e., MOEs > 650,000). 

4.2 Absorption, Distribution, Metabolism and Excretion

The absorption, distribution metabolism and excretion of NAA were studied in rats. In 

one study, rats were given either a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 

mg/kg/day) of [14C] ring labeled -1-naphthaleneacetamide. Recovery of administered 

radioactivity was 97-101%. 1-Naphthaleneacetamide was readily absorbed and excreted within 36 

hours. Urinary excretion accounted for 66-74% of the administered radioactivity for single and 

repeat doses. Repeat did not appreciably affect the absorption/excretion processes. Excretion via 

the feces accounted for the remainder of the administered radioactivity in all treatment groups. 

Urinary metabolism involved amide cleavage followed by glycine conjugation with the glycine 

conjugate being the major metabolite of the low and repeat doses (14-47%). The glucuronide 

conjugate was also a major metabolite at the low doses (4.5-7%). For feces, the major metabolite 

detected was the dihydrodiol of naphthaleneacetamide (4-11%). Parent compound was detected at 

low concentrations (1-2% of administered) only in feces. In another study, rats were given either a 

single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day) of [14C] ring labeled 

1-naphthaleneacetic acid, ethyl ester. Recovery of administered radioactivity was 99-101%. 
Page 11 of 52

1-Naphthaleneacetic acid, ethyl ester was readily absorbed and excreted within 36 - 48 hours 

following a single and repeat doses. Urinary excretion accounted for 68-85% of the administered 

radioactivity following single or multiple oral low doses and 62-78% following a single high dose. 

Excretion via the feces accounted for the remainder of the administered radioactivity excreted by 

all treatment groups. At the high dose, glucuronide conjugation appeared to play a more important 

role following ester cleavage. Parent compound was detected at low concentrations (0.5-5% of 

administered) only in feces. For both studies, excretory patterns exhibited no gender-related 

variability for the low dose groups and only minor gender difference at the high dose. Excretion 

patterns of the high-dose group reflected delayed absorption. Tissue burdens of parent and 

metabolites were very low at termination for both studies. Most components in the matrices 

examined (urine and feces) were adequately quantified and characterized. 

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

supporting evidence that the toxicity of these various forms of NAA would be similar since all are 

metabolized to the acid form and eliminated from the body as glycine and glucuronic acid 

conjugates within 36 to 48 hours of initial exposure.

4.3 Toxicological Effects

The major target organs of repeated oral exposure of NAA to rats, dogs and mice were the 

liver (enlarged liver, increased liver weight with histopathological changes: vacuolation of the 

periportal hepatocytes, pericholangitis, sinusoidal histiocytosis in dogs) stomach (mucosal gland 

dilation), lung (focal alveolar macrophages).the liver, stomach and lung. Repeated oral exposure 

also resulted in decreased hematocrit and hemoglobin along with reduced RBC count in rats and 

dogs and hypocellularity of the bone marrow in dogs. 

There was no developmental toxicity at highest doses of NAA tested in the rat or rabbit, but 

developmental toxicity (decreased fetal weight and minor skeletal changes) were seen in rats 

orally gavaged with the sodium salt. Reproductive effects of NAA sodium salts included reduced 

litter survival and pup weight throughout lactation in both generations of offspring in a two 

generation reproduction study. 

NAA and its acetamide and the ethyl ester were tested for mutagenic effects in a gene 

mutation bacterial assay, mouse lymphoma assay, and mouse erythrocyte micronucleus assay and 

were not mutagenic. Additionally NAA was tested for mitotic gene conversion and dominant 

lethality in rats and found to be negative. A published NCI carcinogenicity study of NAA 

acetamide in mice and a guideline chronic/oncogenicity study of NAA sodium salt in rats and mice 

are considered adequate for the evaluation of the oncogenicity of the NAA group. In these three 

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

Naphthalene acetates have low acute toxicity via the oral (Toxicity Category III), 

inhalation (Toxicity Category IV), and dermal (Toxicity Category III) routes of exposure. NAA is 

not a skin irritant (Toxicity Category IV). It is not a dermal sensitizer. The NAA acid and its 

sodium salt were found to be irritating to the eye, but not the NAA ethyl ester (Category IV). The 

NAA acetamide was found to be an eye irritant in one old test and a non-eye irritant in another 
Page 12 of 52

recent study conducted on the currently produced material.

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

The FQPA factor for increased susceptibility to infant and children is reduced to 1x based 

on the following considerations. The toxicology data base for NAA is nearly complete and 

adequate for assessing increased susceptibility under FQPA. In the recently submitted 

developmental toxicity study conducted with NAA sodium salt in rats (MRID 46685803) fetal 

toxicity (mainly decreased fetal weights and minor skeletal changes) was observed at a dose lower 

than the maternally toxic dose. However, there were clear NOAELs in this developmental study 

and the point of departures used in the chronic dietary assessment (15 mg/kg/day) are protective of 

the fetal effects observed in the developmental study. There are no residual uncertainties in the 

exposure database. The dietary risk assessment is conservative and will not underestimate dietary

exposure to NAA.

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

158 for conventional pesticide registration. However, the toxicology database for NAA does not 

show any evidence of treatment-related effects on the immune system and the overall weight of 

evidence suggests that this chemical does not directly target the immune system. Consequently, 

the Agency does not believe that conducting a functional immunotoxicity study will result in a 

lower POD than that currently used for overall risk assessment, and therefore, a database 

uncertainty factor (UFDB) is not needed to account for lack of this study.

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

in the 40 CFR Part 158 for conventional pesticide registration. However, the Agency does not 

believe that conducting a neurotoxicity battery will result in lower PODs than those currently used 

for overall risk assessment or that a database uncertainty factor (UFDB) is needed to account for 

lack of these studies based on the following considerations. The acute oral toxicity studies of the 

various salts are all Category III or IV. The toxicity database does not show any indications of 

neurotoxicity or neuropathology (the liver, stomach, lung, and hematological parameters are the 

target organs based on repeat toxicity studies in rats, mice, and dogs). A screening level 

assessment of acute dietary exposure, conducted using the chronic RfD as a highly conservative 

POD, indicates that acute dietary risks are not of concern.

4.4.1 Completeness of the Toxicology Database

The toxicity database for NAA is sufficient for a full hazard evaluation and is considered 

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

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

subchronic neurotoxicity and immunotoxicity studies are required as part of new 40 CFR Part 158 

data requirements for registration of a pesticide. 

4.4.2 Evidence of Neurotoxicity

There are no neurotoxicity studies available but the chronic and subchronic 

studies show no evidence of neurotoxicity or neuropathology. 
Page 13 of 52

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

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

resulting from exposure to the NAA group of chemicals. Although the rat developmental study

showed quantitative susceptibility with lower fetal NOAELs than maternal NOAELs, the chronic 

dietary point of departure is protective of this study. There was no indication of increased 

susceptibility (quantitative or qualitative) to rabbits to in utero exposure to naphthalene acetates or 

to pre and post-natal exposure in rat reproduction studies. 

4.4.4 Residual Uncertainty in the Exposure Database 

There are no residual uncertainties in the exposure database. The dietary risk assessment is 

conservative and will not underestimate dietary exposure to NAA.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose-Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water), 

occupational, and residential exposure scenarios are summarized below. A detailed description of 

the studies used as a basis for the selected endpoints are presented in Appendix A. 

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

oral toxicity studies. Therefore, a POD for acute dietary exposure was not selected. A chronic 

POD of 15 mg/kg/day (NOAEL) was selected from a chronic feeding study in dogs with 

1-Naphthaleneacetic acid, sodium salt oral feeding study in based on stomach lesions in 75% of 

the males and by slight sinusoidal histiocytosis in the liver of 50% of the males at the LOAEL of 

75 mg/kg/day. A UF 100x (10x to account for interspecies extrapolation and 10x for intraspecies 

variation) was applied to the dose to obtain a chronic reference dose (cRfD/cPAD) of 0.15 

mg/kg/day. 

A NOAEL of 300 mg/kg/day was selected for short-term and intermediate term dermal 

exposure POD based on a subchronic dermal toxicity in rats which showed reduced body weight 

gain and food efficiency at the LOAEL of 1000 mg/kg/day. Due to a lack of inhalation studies, a 

POD from an oral prenatal developmental study in rats was selected for inhalation risk 

assessments: a POD for maternal toxicity of 50 mg/kg/day (NOAEL) was selected for short-term 

inhalation exposure based on decreased body weight gain during the compound administration at 

250 mg/kg/day. A NOAEL of 25 mg/kg/day was selected for intermediate-term inhalation 

exposure from a subchronic dog study based on lesions of the GI tract and hypocellularity of the 

bone marrow. An absorption factor of 100% is applied for inhalation exposures. The level of 

concern (LOC) or margin of exposure (MOE) for dermal and inhalation exposures is 100 based on 

uncertainty factors of 10x for intraspecies variability and 10x for interspecies sensitivity. For 

short-term exposure risk assessments, the dermal and inhalation exposure routes can be combined 

due to the common toxicity endpoint (reduced body weight gain) via the dermal and inhalation 
Page 14 of 52

(oral equivalent) routes. 

4.5.2 Recommendations for Combining Exposure Routes

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

must consider exposures from three major sources: oral, dermal and inhalation exposures. 

Exposures via the oral, dermal and inhalation routes cannot be combined for short-term 

assessments because oral exposure endpoints are not based on toxicological effects common to 

either dermal or inhalation endpoints (i.e., the chronic oral endpoint is based stomach lesions and 

liver effects; short-term inhalation and dermal endpoints are based on body weight effects). 

4.5.3 Cancer Classification

A guideline study for the oncogenicity of NAA in mice is not available. However 

published NCI carcinogenicity study of NAA acetamide in mice, a guideline chronic/oncogenicity 

study of NAA sodium salt in rats, and a chronic/oncogenicity study of NAA sodium salt mice are 

considered adequate for the evaluation of the oncogenicity of the NAA group. In these three 

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

4.5.4 Summary of Points of Departure Used in Risk Assessment

A summary of the endpoints selected by HED toxicologists is provided below and in Tables 4 and 

5.

Table 4. Summary of Toxicological Endpoints for Naphthalene Acetates for Use in Dietary Human Health Risk Assessments

Exposure/Scenario Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC 

for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(General Population)

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

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

Chronic Dietary 

(All Populations)

NOAEL = 

15 

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.15

mg/kg/day

cPAD = 0.15 

mg/kg/day

Chronic Toxicity - Dog;

LOAEL = 75 mg/kg/day based on stomach 

lesions in 75% of the males and by slight 

sinusoidal histiocytosis in the liver of 50% of the 

males. 

Incidental Oral 

Dermal

Inhalation

There are no residential uses for or exposures to the proposed use of naphthalene acetic acid ethyl ester. 

Therefore exposure endpoints are not required and not selected for residential exposure assessment. 

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

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

extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential 

variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a 

short-term study for long-term risk assessment. UFDB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA 

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

concern. N/A = not applicable.

Table 5. Summary of Toxicological Doses and Endpoints for NAA for Use in Occupational Human Health Risk Assessments
Page 15 of 52

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal Short Term (1-30 

days) and Intermediate (1-6 

months) 

NOAEL= 

300 

mg/kg/day

UFA= 10x

UFH=10x

Occupational LOC 

for MOE = 100

Dermal Toxicity Study - Rat 

LOAEL = 1000 mg/kg/day based on reduced body 

weight gain and food efficiency

Inhalation Short Term 

(1-30 days) 

NOAEL= 

50 

mg/kg/day

UFA= 10x

UFH=10x

Occupational LOC 

for MOE = 100

Developmental Toxicity Study - Rat 

Maternal LOAEL = 250 mg/kg/day based on 

based on decreased body weight gain during the 

gestation period. 

Inhalation Intermediate 

Term (1-6 months) 

NOAEL= 

25 

mg/kg/day

UFA= 10x

UFH=10x

Occupational LOC 

for MOE = 100

Subchronic Study -Dog

LOAEL for systemic toxicity =150 mg/kg/day 

based on lesions of the GI tract and 

hypocellularity of the bone marrow.

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

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The qualitative nature of the residue in plants and ruminants resulting from registered uses 

of naphthalene acetates is adequately understood based on apple, olive, and goat metabolism 

studies. Based on guideline requirements, plant metabolism studies should be conducted for a 

minimum of three diverse crops to determine the qualitative metabolic fate of the active ingredient 

(OPPTS GLN 860.1300). Although metabolism data are not available to a commodity similar to 

potatoes, a 3rd diverse metabolism study will not be required for the current petition. However, if 

other uses are proposed on crops other than fruit crops, tree nuts, or fruiting vegetables or at a 

higher application rate on potatoes, a metabolism study (preferably on a root crop) will be needed. 

5.1.2 Summary of Environmental Degradation

NAA appears to be generally short lived, based on measured and modeled values. It should 

degrade by means of a combination of both biotic and abiotic processes. The reported half-life for 

NAA of 10 days was attributed to microbial degradation. NAA is mostly ionized in the 

environment so would partition preferentially with the water. The environmental fate 

characteristics of the salts of NAA are expected to be similar to those of the acid. In the 

environment, the NAA salts will rapidly dissociate to 1-naphthalene acetate anion and its 

corresponding cation. Based on its pKa, NAA is expected to exist mostly as the anion in normal 

environmental conditions. Anions generally do not adsorb to organic carbon and clay more 

strongly than their neutral counterparts. Volatility may be an important route of dissipation for 

NAA under various environmental conditions based on NAA’s relatively high measured and 

estimated vapor pressures (0.3 mmHg). NAA ethyl ester is susceptible to hydrolysis at high pHs. 

The product of NAA ethyl ester hydrolysis is NAA. NAA in aqueous solution appears to be 

unstable to sunlight irradiation. Upon exposure to sunlight, gaseous phase NAA reaction with 
Page 16 of 52

hydroxyl (OH) radicals should proceed with a half-life of around 0.3 days. NAA is mobile to 

moderately mobile according to the FAO mobility classification. For NAA measured 

bioconcentration factors (BCFs) of only 0.15-0.59 and <1.7-4.2 were observed in carp (Cyprinus 

carpio) at test chemical concentrations of 0.5 and 0.05 mg/L, respectively. These values suggest a 

low potential of bioconcentration for NAA.

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

Most of the environmental fate characteristics available for NAA are derived from structure 

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

NAA.

5.1.3 Comparison of Metabolic Pathways

Metabolism studies in animals of the NAA, its acetamide, and the ethyl ester in animals 

indicate that all forms are metabolized to the acid form and eliminated from the body as glycine 

and glucuronic acid conjugates within 36 to 48 hours of initial exposure. Studies show that NAA 

salts and esters are converted to the acid form and conjugates of the acid form.

5.1.4 Residues of Concern Summary and Rationale

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

terminal residues of concern in plants and ruminants are the parent compounds, NAA and its 

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

18, 2003). 

Table 6. NAA Residues of Concern in Plants and Ruminants.

Matrix

Residues of Concern

For Risk Assessment For Tolerance Expression

Plants Primary and Rotational crops NAA and Conjugates NAA and Conjugates

Livestock Ruminant and Poultry NAA and Conjugates NAA and Conjugates

Drinking Water NAA and Conjugates NA

5.2 Food Residue Profile

5.2.1 Residues in Crops, Livestock and Poultry

In lieu of providing field trial data for their proposed seed piece treatment, Stehekin, LLC, 

, through their consultant, Spring Trading Company submitted a theoretical calculation to show 

that residues of NAA on potatoes will be less than the LOQ. The petitioner originally requested 

an application rate of 0.25 lb ai/A for all types of potatoes based on their theoretical calculation 

which assumed a potato yield of about 550 cwt/A. Statistical data in a National Potato Council 

(NPC) publication (at www.NationalPotatoCouncil.org) were submitted to support the yield 

assumption. However, based on EPA’s analysis of NCP yield data the petitioner’s theoretical 

calculation (based on a potato yield of about 550 cwt/A) will support use of NAA as a seed piece 
Page 17 of 52

treatment on potatoes in the Pacific Northwest only, or on Russet potatoes only (75% or more of 

the potatoes produced in the Pacific Northwest are Russets). An application rate for NAA of 0.25 

lb ae/A can be supported on Russet potatoes only. An application rate for NAA of 0.18 lb ae/A 

can be supported for all potatoes based on a theoretical calculation showing residues less than the 

LOQ.

Based on livestock feedstuffs associated with proposed and registered uses, the dietary

burdens to livestock are 0.25 ppm for beef cattle and 0.13 ppm for dairy cattle. These burdens are 

considered tentative, but conservative, because citrus and potato processing data are not available. 

At this time, the Agency has determined that NAA is in Category 6(a)(3) (i.e., no reasonable 

expectations of finite residues of concern in meat and milk). This tentative conclusion is reserved 

pending submission of the required processing studies and a determination of the magnitude of the 

residues in citrus and potato processed commodities. When the requested processing data are 

submitted, the Agency will re-evaluate NAA's Category 3 determination, and if necessary

re-calculate the estimated dietary burden for ruminants.

5.2.2 Residues in Processed Commodities

Residue data for processed commodities associated with potatoes are needed. Since 

residues in the available field trials using the maximum proposed rate are near the LOQ, the 

processing study should be conducted using field trials treated at an exaggerated application rate.

5.3 Water Residue Profile 

The Environmental Fate and Effects Division (EFED) calculated conservative, Tier I 

Estimated Drinking Water Concentrations (EDWCs) of naphthalene acetates in ground water and 

surface water for use in the human health risk assessment. EDWCs for 1-naphthaleneacetic acid 

were calculated using FIRST (surface water) and SCIGROW (ground water) drinking water 

models. These values generally represent upper-bound estimates of the concentrations of 

1-naphthaleneacetic acid equivalents that might be found in surface and ground water due to the 

use of 1-naphthaleneacetic acid on olives, which represents the highest single application rate. 

Both models provide estimates suitable for screening purposes. Modeled EDWCs for peak and 

average concentrations of naphthalene acetates in surface water are 0.02 and 0.003 ppm 

respectively. The modeled peak and average EDWCs for groundwater is 0.00002 ppm. 

5.4 Dietary and Drinking Water Exposure and Risk

A conservative chronic dietary and drinking water exposure and risk assessment was 

conducted using the Dietary Exposure Evaluation Model with the Food Commodity Intake 

Database (DEEM-FCIDTM). Dietary risk assessment incorporates both exposure and toxicity of a 

given pesticide. For dietary assessments, the risk is expressed as a percentage of a maximum 

acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse 

health effects). This dose is referred to as the population adjusted dose (PAD). The PAD is 

equivalent to the POD divided by the uncertainty factors. For acute and non-cancer chronic 
Page 18 of 52

exposures, HED is concerned when estimated dietary risk exceeds 100% of the PAD. 

Conservative chronic dietary naphthalene acetates exposure and risk estimates resulting 

from food intake were determined for the general U.S. population and various population 

subgroups. The naphthalene acetates chronic dietary and drinking water exposure assessment was 

conducted using the Dietary Exposure Evaluation Model software with the Food Commodity

Intake Database (DEEM-FCIDTM, Version 1.3), which incorporates consumption data from 

USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII), 1994-1996 and 1998. The 

dietary risk assessment incorporates both exposure and toxicity of naphthalene acetates. For acute 

and chronic assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., 

the dose which HED has concluded will result in no unreasonable adverse health effects). This 

dose is referred to as the population adjusted dose (PAD). The PAD is equivalent to the Reference 

Dose (RfD) divided by the special FQPA Safety Factor. HED is concerned when estimated dietary 

risk exceeds 100% of the PAD. 

The chronic dietary and drinking water exposure/risk analyses for all supported 

naphthalene acetates food uses was conducted using conservative, Tier 1 exposure assessments. 

The Tier I analyses assume tolerance level residues for all registered uses, 100% crop treated for 

all commodities with existing tolerances, and default processing factors. The chronic analysis 

incorporated the annual year average surface drinking water estimate of 0.003 ppm from 

application of NAA to olives. Based on analyses of estimated dietary risks for the general U.S. 

population and various population subgroups, the chronic dietary exposure estimates for 

naphthalene acetates are significantly below HED’s level of concern for all supported 

commodities (Table 7). 

Table 7. Summary of Chronic Dietary Exposure and Risk for NAA

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) % cPAD

General U.S. Population

0.15

0.000528 <1

All Infants (< 1 year old) 0.001637 1

Children 1-2 years old 0.002634 2

Children 3-5 years old 0.001724 1

Children 6-12 years old 0.000791 <1

Youth 13-19 years old 0.000417 <1

Adults 20-49 years old 0.000304 <1

Adults 50+ years old 0.000311 <1

Females 13-49 years old 0.000333 <1

6.0 RESIDENTIAL EXPOSURE AND RISK

A new residential assessment is not required for the proposed new use on potato 

commodities because there are no residential uses associated with the proposed new use. 

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT 

In accordance with the FQPA, when there are potential residential exposures to a pesticide, 
Page 19 of 52

aggregate risk assessment must consider exposures from three major routes: oral, dermal, and 

inhalation. There are three sources for these types of exposures: food, drinking water, and 

residential uses. In an aggregate assessment, exposures from relevant sources are added together 

and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves 

can be aggregated. When aggregating exposures and risks from various sources, HED considers 

both the route and duration of exposure. There is potential for short-term residential exposure to 

NAA from ornamental uses. Oral, dermal and inhalation exposures cannot be combined for 

short-term assessment, however, because oral exposure endpoints are not based on common 

toxicological effects with either dermal or inhalation endpoints. Therefore, the acute and chronic 

exposure estimates provided in the dietary and drinking water exposure section represent 

aggregate exposure. 

8.0 CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information” concerning the 

cumulative effects of a particular pesticide's residues and “other substances that have a common 

mechanism of toxicity.”

EPA does not have, at this time, available data to determine whether NAA has a common 

mechanism of toxicity with other substances. Unlike other pesticides for which EPA has followed 

a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a 

common mechanism of toxicity finding as to NAA and any other substances and, NAA does not 

appear to produce a toxic metabolite produced by other substances which have tolerances in the U. 

S. For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that 

NAA has a common mechanism of toxicity with other substances. For information regarding 

EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to 

evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s 

OPP concerning common mechanism determinations and procedures for cumulating effects from 

substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/.

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

9.1 Exposure Scenarios

Occupational handler exposure to NAA K salt is expected for potato handlers involved in 

commercial and on-farm potato seed piece treatment (not for direct use in a hopper-box, 

planter-box, or slurry-box). Only short term exposures from inhalation and dermal exposure routes 

were assessed for all exposure scenarios. Longer term MOEs were not calculated since exposure 

for more than 30 days is unlikely to occur based on use patterns. Occupational and exposure and 

risk estimates were conducted using maximum application rates and surrogate exposure data from 

the Pesticide Handlers Exposure Database and the Residential Exposure Assessment SOPs. 

Dermal and inhalation exposures to workers should be aggregated for naphthalene acetic acid 

ethyl ester because dermal and inhalation endpoints are based on decreased body weight gain. 
Page 20 of 52

Exposure from post-application activities is unlikely.

9.2 Handler Exposure 

Occupational exposures from treating and planting treated potato seed pieces were 

assessed for this use. 

9.2.1 Handler Exposure Scenarios

9.2.1.1 Seed Treatment

The occupational pesticide “handlers” for seed piece treatment are the individual who 

prepares the stock spray solution that is used in enclosed treatment systems (primary handlers) and 

the individuals who plant the treated seed (secondary handlers). The primary handler activities are 

essentially the same as those performed by a mixer/loader supporting conventional ground or 

aerial spray operations. HED assessed seed piece treatment conducted at large scale seed 

treatment facilities and also on-farm treatment using equipment similar to large commercial 

facilities. Potato seed piece operations on and off- farm are large enough to facilitate farm scale 

planting and utilize equipment that is similar in principle and in treatment capability. 

For assessing commercial seed treatment, unit exposure data were taken from a study titled 

“Determination of Dermal and Inhalation Exposure of Workers During On-Farm Seed Piece 

Treatment of Potatoes” submitted by Bayer CropScience (MRID 470547-02, DP Barcode:

D378750, Seyed Tadayon, June 23, 2010). The objective of this study was to determine the 

dermal and inhalation exposure of experienced agricultural workers performing on-farm liquid 

seed piece treatment to potatoes and the inhalation exposure of agricultural workers who were 

sorting and cutting the potato seed pieces near the treatment site. The potato seed pieces were 

treated with imidacloprid, formulated as ADMIRE 240F, containing 21.4% of the active 

ingredient. The study was conducted at eleven potato treating cooperator locations in the southern 

potato growing region of Manitoba, Canada and encompasses a range of personal protective 

equipment, treatment equipment, and other variables. The overall mean for total dermal exposure 

was 127.3 μg/lb ai or 0.1273 mg/lb ai handled. The overall mean for inhalation exposure was 6.4 

μg/lb ai or 0.0064 mg/lb ai handled. 

Chemical-specific data for assessing exposure during commercial seed planting were not 

submitted to the Agency in support of this Section 18 application. Unit exposures are from 

ExpoSAC Policy 14: SOPs for Seed Treatment (May 1, 2003). Unit exposure values from 

ExpoSAC Policy 14 are based on data for open mixing/loading/application systems. Potential 

occupational exposure scenarios from the use of NAA as a potato seed piece treatment include the 

following.

Treating Seed Pieces (Primary Handler)

 Mixing, loading, applying liquid formulations;
Page 21 of 52

Planting Treated Seed Pieces (Secondary Handler)

Potential occupational exposure scenarios from the use of NAA as a potato seed piece 

treatment include planting treated seed (secondary handler). Planting treated seed consists of the 

farmer purchasing bags of treated seed, placing the seed in the hopper and applying seed to fields 

(considered a secondary handler exposure scenario). 

The overall mean for total dermal exposure was 127.3 μg/lb ai or 0.1273 mg/lb ai handled. 

The overall mean for inhalation exposure was 6.4 μg/lb ai or 0.0064 mg/lb ai handled. 

9.2.2 Handler Exposure Data

No chemical-specific handler exposure data were submitted in support of this registration. 

It is HED’s policy to use data from the USEPA OPP Occupational Pesticide Handler Unit 

Exposure Surrogate Reference Table (5/4/11). 

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

9.2.3 Handler Exposure Assumptions 

• Average body weight of an adult handler is 80 kg.

• Exposure duration short-term (1- 30 days)

• Maximum label application rates for seed treatment is 0.00000028 lb ai/lb seed:

• Amount (pounds) of Seed Treated per Day (Primary Handler) 480,000

• Amount (pounds) of Seed Planted per Day (Secondary Handler) 480,000

9.2.4 Handler Exposure and Risk Estimates

9.2.4.1 Primary Handler Exposure and Risk Estimates

The risk from mixing/loading liquid for potato seed piece treatment resulted in a combined 

(dermal + inhalation) MOE greater than the level of concern (i.e., LOC =100) and not of concern to 

HED. Table x summarizes the calculations for potato seed piece treatment handler exposures and 

risks.

Table 8. Short-Term Occupational Handler Exposure and Risk for Mixing/Loading for Potato Seed Piece Treatment

Application 

Ratea

(lb ai/lb 

seed)

Amount 

Treated 

Per Dayc

(lb seed)

Unit Exposuresb Dosed (mg/kg/day) MOEs LOC = 100

Baseline 

Dermal

(mg/lb ai)

Baseline 

Inhalation

(mg/lb ai)

Absorbed 

Dermale Inhalationf Dermalg

Inhalationh

Baseline 

Dermal + 

Inhalationi

Mixer/Loader

0.00000025 480,000 0.1273 0.0064 0.00021 0.000011 1,400,000 4,700,000 1,100,000

a Application Rates based on proposed uses on label for Rejuvenate Seed Treatment.

b Unit Exposures based on study (MRID 470547-02, DP Barcode: D378750) mean exposure (mg/lb ai).

c Amount Treated Per Day was based on National Potato Council Data.
Page 22 of 52

d Baseline Dermal: Long-sleeved shirt, long pants, and no gloves; Baseline Inhalation: no respirator. 

e Absorbed Dermal Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated/day (lb seed/day) x dermal 

absorption factor (100%) / body weight (70 kg adult).

f Inhalation Dose (mg/kg/day) = daily unit exposure (μg/lb ai) x application rate (lb ai/lb seed) x amount treated /day (lb seed/day) x inhalation 

absorption factor (100%) / body weight (80 kg adult).

g Dermal MOE = short-term NOAEL (300 mg/kg/day) / absorbed dermal daily dose (mg/kg/day). Level of concern = 100.

h Inhalation MOE = short-term NOAEL (50 mg/kg/day) / inhalation daily dose (mg/kg/day). Level of concern = 100.

i Total MOE = 1 / [(1 / Dermal MOE) + (1 / Inhalation MOE)]. Level of concern = 100.

9.2.4.2 Secondary Handler (Planter) Exposure and Risk Estimates

Table x shows that the planter (secondary handler) combined (dermal + inhalation) 

short-term exposure risks do not exceed HED’s level of concern (i.e., LOC is an MOE = 100) for 

handlers planting potato-treated seed pieces.

Table 9. Summary of Secondary Handler (Planter) Exposures and Risks for NAA K Salt LOC = 100

Seed 

Type

Dermal 

UEa

(mg/lb)

Inhal 

UEa

(mg/lb)

Max App 

Rateb

(lb ai/lb 

seed)

Amt of Seed 

Planted/Dayc

(lb seed/day)

Dermal 

Dosed

(mg/kg/day)

Dermal 

MOEf

LOC = 

100

Inhalatio

n Dosee

(mg/kg/d)

Inhalation 

MOEg

Total 

MOEh

Potato 

Pieces 0.25 0.0034 0.00000028 480,000 0.00043 720,000 0.0000056 8,900,000 670,000

a Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment. 

b Application Rates based on proposed label uses for NAA K salt.

c HED default for lb seed planted per day from on National Potato Council.

d Daily Dermal Dose (mg/kg/day) = daily dermal unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount planted (lb seed/day) x 

absorption factor (100%) / body weight (70 kg adult).

e Dermal MOE = NOAEL (300 mg/kg/day for short- and intermediate-term exposure) / Dermal Dose (mg/kg/day). Level of concern = 100.

f Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount planted (lb seed/day) x 

absorption factor (100%) / body weight (80 kg adult).

g Inhalation MOE = NOAEL (50 mg/kg/day for short- and intermediate-term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 100.

h Total MOE = 1 / [(1 / Dermal MOE) + (1 / Inhalation MOE)]. Level of concern = 100.

9.3 Post-Application Exposure 

A quantitative post-application assessment for exposure to treated seeds that have already 

been planted was not conducted as exposure to these activities is considered unlikely.

9.3.1 Dermal Post-Application Exposure/Risks

The potential for post-application exposures following the planting of NAA K salt-treated 

potato seed pieces is unlikely because sustained levels of contact with the treated seed piece after it 

has been placed in the soil or other planting media would not be expected because no routine 

cultural practice required for the production of agricultural commodities involves such an activity 

as defined in the no/low contact criteria in the Worker Protection Standard (WPS). 

9.3.2 Inhalation Post-Application Exposure/Risks

A post-application inhalation exposure assessment is not required as exposure is expected 

to be negligible. Seed treatment assessments provide quantitative inhalation exposure assessments 

for seed treaters and secondary handlers (i.e. planters). It is expected that these exposure estimates 

would be protective of most post-application inhalation exposure scenarios.
Page 23 of 52

10.0 REFERENCES

NAA HED Risk Assessment for Reregistration Eligibility, B. Daiss (D293881, 3/30/04)

NAA. Amendment to Petition for New Use on Potatoes and an Exemption from the Requirement 

of a Tolerance for Residues of 1-Naphthaleneacetic Acid, Potassium Salt in/on Potatoes -

PP#0F7687. Residue Chemistry Considerations., S. Hummel, (D396076, date...)

Napthaleneacetic Acid (NAA) Potassium Salt. Occupational and Residential Exposure 

Assessment for a Section 3 use as a potato seed piece treatment, I. Nieves, (D396943, date)

Naphthalene Acetates- Acute and Chronic Dietary and Drinking Water Exposure and Risk 

Assessment for Section 3 New Use of Naphthalene Acetic Acid-ester on Potatoes, B.Daiss 

(D397389, date)

Tier I Estimated Drinking Water Assessment for the Propose New Uses of Potassium Naphthalene 

Acetate on Potato Seed and/or Potato Foliage for the New Products Renew PGR and Renew 

Concentrate PGR, J.L. Melendez (D387171, 5/20/11) 

Toxicology Chapter, A. Khasawinah (D293237 TXR No. 0052407, 3/8/04)
Page 24 of 52

APPENDICES

A. TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements

Guideline 

No. Study Type Technical MRID 

Required Submitted No.

870.3100

870.3150

870.3200

870.3250

870.3465

Subchronic (Oral) Toxicity - Rodent................................

Subchronic (Oral) Toxicity - Non-Rodent ................................

21/28-Day Dermal Toxicity ................................

90-Day Dermal Toxicity ................................................................

90-Day Inhalation Toxicity ................................

Y

Y

N

N

N

Y

Y

Y

N

N

43896001 

00043624

42932601

43896002

43895901

00136446

42983801

43914901

43581001

43134701

43581002

870.3700a

870.3700b

870.3800

Prenatal Developmental Toxicity - Rodent................................

Prenatal Developmental Toxicity - Non-Rodent................................

Reproduction and Fertility Effects................................

Y

Y

Y

Y

Y

Y

00042765

00137821

00137822

43796301

870.4100a

870.4100b

870.4200a

870.4200b

870.4300

Chronic (Oral) Toxicity - Rodent................................

Chronic (Oral) Toxicity - Non-Rodent (Dog) ................................

Carcinogenicity - Rat..................................................

Carcinogenicity - Mouse ................................................................

Combined Chronic Toxicity /Carcinogenicity

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

44157501

43744201

44157501

Lit Study

44157501

870.6100a

870.6100b

870.6200a

870.6200b

870.6300

870.7800

Neurotoxicity - Acute Delayed Neurotox.- Hen................................

Neurotoxicity - Subchronic - Hen ................................

Neurotoxicity - Acute - Rat................................................................

Neurotoxicity -Subchronic - Rat ................................

Developmental Neurotoxicity..................

Immunotoxicity............................. ................................

N

N

Y

Y

N

Y

N

N

N

N

N

N

---

---
Page 25 of 52

A.2 Toxicity Profiles

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

Acute - oral MRID 43495901

LD50 > 5050 mg/kg

Category III

MRID 00103128

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

(2100-3021) .

MRID 00108829

LD50: Males 1.35 (1.12–1.64)

Females 0.933 g/kg (0.631-1.38 )

MRID 43494101

LD50 2186 (1907-2506) mg/kg

Category III

Acute - Dermal MRID 43495902

LD50 > 2020 mg/kg

Category III

MRID 00103129

LD50 is greater than 2 g/kg. 

Category III. 

MRID 00108829

dermal LD50 = > 2 g/kg. Category 

III

MRID 43494102

LD50 > 2020 mg/kg. Category III

Acute - Inhal. MRID 43495903

LC50 > 2.17 mg/L

Category IV

MRID 43494103

LC50 > 2.13 mg/L

Category IV

Eye Irritation MRID 00103051

corrosive Category I

MRID 43495904

minimally irritating

Category IV

MRID 00103127

corrosive Category I

MRID 00108829

corrosive Category I

MRID 43494104

minimally irritating

Category IV

Derm. Irritation MRID 00103127

Non-irritating Category IV

MRID 00108829

Non-irritating Category IV

MRID 00103053 & 00103218.

non-irritating Category IV

Sensitization MRID 43495905

not a skin sensitizer. No positive 

control. Unacceptable

MRID 00153217

not a skin sensitizer

MRID 43494105

not a skin sensitizer. No positive 

control. Unacceptable

90-day - rat MRID 43896001

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

19.1, 73.8, or 292.1 mg/kg/day for 

males and 0, 20.4, 81.5, or 313.5 

mg/kg/day for females). LOAEL is 

4,000 ppm (292.1 mg/kg/day) 

decreased bw , bw gain & food 

consumption, and increased relative 

liver weights with adaptive 

histopathological changes in both 

sexes. NOAEL is 1,000 ppm (73.8 

mg/kg/day)

MRID 00043624

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

rats (20/sex/dose)

LOAEL for toxic effects is 300 

mg/kg/day based on decreased body 

weight in both sexes and enlarged 

liver weights in females. The 

NOAEL is 150 mg/kg/day.

MRID 42932601

0, 200, 2000, or 8000 ppm (13.9, 

136.6, and 564.9 for males and 15.2, 

149.3, and 583.4 mg/kg/day for 

females). LOAEL for systemic 

toxicity = 2000 ppm (136.6 for 

males and 149.3 mg/kg/day for 

females) with a NOAEL for 

systemic toxicity of 200 ppm (13.9 

for males and 15.2 mg/kg/day for 

females) based on decreased 

hematocrit and hemoglobin, 

increased liver weights and 

MRID 43896002

0, 400, 2000 or 8000 ppm (Average 

doses at study end were 19-25; 

92-123 ; and 388 - 519 mg/kg/day 

for males- females). LOAEL= 

8000 ppm (594 mg/kg/day), based 

on lower bw, bw gain, and food 

consumption. males and females at 

this dose also exhibited increased 

total bilirubin (19-21% higher) in 

conjunction with reduced RBC 

counts, hemoglobin, and 

hematocrits. NOAEL= is 2000 
Page 26 of 52

A.2 Toxicity Profiles

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

vacuolation of the periportal 

hepatocytes along with hypertrophy 

of the cells of the adrenal cortex 

zona glomerulosa.

ppm (144mg/kg/day).

10-day range 

finding - rat

MRID 00043623

0, 250, 1000 or 4000 mg/kg bw/day 

by gavage for 10 days (3 

rats/sex/dose). Death of all high 

dose rats, one female in the mid 

dose and none in the low dose. 

Dose related depression in body 

weight gain and food consumption. 

Discoloration of lungs, liver and 

kidneys, distended bladder (high 

dose), blood and gas in the GI tract. 

The MTD would be 250 mg/kg/day.

90-day - dog MRID 43895901

0, 30, 100, or 300 mg/kg/day for 13 

weeks. LOAEL is 300 mg/kg/day, 

based on increased platelet count, 

decreased red cell parameters, and 

increased mean corpuscular volume 

which correlate with 

histopathological changes observed 

in the liver, spleen, and bone 

marrow in both sexes. The NOAEL

is 100 mg/kg/day.

MRID 00136446

0, 50, 150, or 300 mg/kg/day for 6 

months to beagle dogs (4/sex/dose) 

by gelatin capsules. 

The LOAEL was 50 mg/kg/day, the 

lowest dose tested, based on hepatic 

liver changes (pericholangistis). No 

NOAEL derived from this study. 

MRID 42983801

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

LOAEL for systemic toxicity =150 

mg/kg/day based on lesions of the 

GI tract and hypocellularity of the 

bone marrow. NOAEL for systemic 

toxicity is 25 mg/kg/day .

MRID 43914901

0, 40, 125, or 400 mg/kg/day for 13 

weeks. LOAEL= 400 mg/kg/day, 

based on soft/liquid feces and 

depressed body weight gains of 

male and female dogs. Blood 

parameters (RBC, hemoglobin, 

hematocrit and mean platelet 

volume) were all depressed in the 

male dogs at this level. NOAEL = 

125 mg/kg/day.

21-day - dermal MRID 43581001

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

6-6.5 hours/day, 5 days/week, for 3 

weeks. No LOAEL was 

established. The NOAEL was the 

highest treatment level, 1000 mg/kg 

body weight.

MRID 43134701

0, 100, 300, or 1000 mg/kg for 6-6.5 

hours/day, 5 days/week, for 3 

weeks. LOAEL for systemic 

toxicity is 1000 and NOAEL = 300 

mg/kg/day based on reduced bw 

gain and food efficiency. LOAEL

for dermal toxicity = 1000 mg/kg 

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 
Page 27 of 52

A.2 Toxicity Profiles

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

Dermal Toxicity NOAEL = 300 

mg/kg based on microscopic 

changes in the skin.

treatment-related dermal irritation 

in the treated ski. No NOAEL for 

dermal irritation was established.

28-day inhal. Not available

Develop.- rat MRID 00042765

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

intubation to pregnant rats 

(24/group). Developmental 

LOAEL is >250 mg/k/day and the 

NOAEL is 250 mg/kg/day. 

Maternal toxicity LOAEL 250 

mg/kg/day based on decreased body 

weight gain during the compound 

administration and the NOAEL is 

50 mg/kg/day.

MRID 46685803

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

days 5 through 21 (inclusive) of 

gestation.

maternal LOAEL is >150 mg/kg 

bw/day, and the maternal NOAEL

is 150 mg/kg bw/day

Developmental LOAEL is 150 

mg/kg/day based on decreased fetal 

weight and minor skeletal changes 

(centrum 5 not ossified, cervical 

arch 7 cartilage fused to arch 6 

cartilage, shortened 7th cervical rib),

compound administration and the 

NOAEL is 50 mg/kg/day.

Develop. - Rabbit MRID 00137821, 00137822

doses 0, 37.5, 75 or 150 mg/kg/day

maternal toxicity NOAEL = 75 

mg/kg/day based on lethality at the 

LOAEL of 150 mg/kg/day. The 

teratogenic and fetotoxic LOAEL = 

>150 mg/kg/day and NOAEL = 150 

mg/kg/day.

MRID 46685801

dose levels of 0, 30, 100 or 300 

mg/kg bw/day from days 5 through 

29 (inclusive) of gestation

maternal LOAEL is 300 mg/kg/day 

based on reduced body weight, 

body weight gain and reduced food 

consumption, clinical signs (few/no 

feces) and stomach irritation 

(red/black spots/areas in the 

glandular mucosa of the stomach) 

and NOAEL = 100 mg/kg/day .

Developmental LOAEL is 300 

mg/kg/day based on an increase in 
Page 28 of 52

A.2 Toxicity Profiles

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

the overall incidences of fetuses 

with minor skeletal defects and 

variants (dumbell ossification of the 

7

th thoracic centrum, extra 

thoracolumbar ribs and 27 

pre-pelvic vertebrae) and a decrease 

in ossification of the manus and 

NOAEL = 100 mg/kg/day.

Reproduction MRID 43796301

0, 100, 1000 or 3000 ppm [0, 7, 69 

or 210 and 0, 8, 81 or 239 

mg/kg/day for males and females]. 

Systemic and repro./develop. 

LOAEL = 3000 ppm (210 & 239 

mg/kg/day for males & females), 

based upon reduced bw gain and 

food consum. in parental animals 

and reduced litter survival, and pup 

weight throughout lactation in both 

generations of offspring. Systemic 

and repro./develop. NOAEL = 

1000 ppm (69 & 81 mg/kg/day for 

males & females)

Chronic/Onco - rat MRID 44157501

0, 100, 1000, or 5000 ppm (0, 4.4, 

43.8, and 224.5 mg/kg/day for 

males and 0, 5.6, 55.8, and 303.6 

mg/kg/day for females). LOAEL = 

5000 ppm (224.5 mg/kg/day for 

males and 303.6 mg/kg/day for 

females), based on an increased 

incidence of stomach (mucosal 

gland dilation) and lung lesions 

(focal alveolar macrophages) in 

both sexes, and on lowered bw gain 

and food efficiency in females. 
Page 29 of 52

A.2 Toxicity Profiles

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

NOAEL= 1000 ppm (43.8 

mg/kg/day for males and 55.8 

mg/kg/day for females). Increased 

incidence (p  0.01) of uterine 

endometrial stromal polyps in 

high-dose females (2/60, 1/60, 3/60, 

13/60 at 0, 100, 1000, 5000 ppm, 

respectively).

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

NAA acetamide was tested at one 

dose (MTD according to the 

published article) as part of a testing 

program of 120 chemicals. Only the 

preliminary results were published. 

The test materials were 

administered to two hybrid strains 

of mice : C57BL/6 x C3H/Anf and 

C57BL/6 x AKR (18/sex/hybrid 

strain). The mice were 

administered NAA acetamide at one 

week of age by stomach intubation 

at 464 mg/kg/day until weaning at 4 

weeks of age and administered the 

NAA acetamide in the diet at 1298 

ppm for approx. 18 months. Gross 

and hostopath. examination of the 

mice at the end of the feeding period 

did not reveal a significant increase 

in tumors over the controls.

MRID 46685802

0, 100, 500, or 2500 ppm [0, 10.8, 

53.3, 276.0 / 0, 14.3, 70.9, 348.7 

mg/kg bw/day M/F, respectively] 

for at least 80 weeks.

LOAEL = 2500 ppm [276 (M), 

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

↓body weight, food consumption, 

↑liver and kidney weights in both 

sexes and epididymis in males, 

↓brain weights in males, 

hepato-cellular vacuolation in 

males, adenomas of the liver and 

lung in males, ↑in the incidence of 

multiple tumors in females. The 

NOAEL is 500 ppm [53.3 (M), 70.9 

(F)] mg/kg/day. 

There was no treatment related 

increase in tumor incidence when 

compared to controls. Dosing was 

considered adequate based on the 

effects observed on the top dose 

(2500 ppm/kg/day).

Chronic - dog MRID 43744201

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

LOAEL= 75 mg/kg/day in males 

and 225 mg/kg/day in females, 
Page 30 of 52

A.2 Toxicity Profiles

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

based on emesis, capsular 

regurgitation incidences, gross and 

histopathologic changes in 

stomachs, and sinusoidal 

histiocytosis in livers. NOAEL= 15 

mg/kg/day in males and 75 

mg/kg/day in females.

Gene 

mutation-bacterial

MRID 43581006

Salmonella five doses 100-5000 

ug/plate. No mutagenic effect with 

or without S9 activation

MRID 00042761

Escherichia coli polA. Strains 

W3110 and p3478 at 1, 2 or mg/ml. 

Not mutagenic. 

MRID 00042762

Salmonella. At 0.5-5000 ug/plate. 

Not mutagenic:

MRID 43581004

five doses 33-5000 ug/plate. No 

mutagenic effect with or without S9 

activation

Gene mutation -

mammalian: 

mouse lymphoma 

cells

MRID 43580202

-S9: not mutagenic.

+S9 mutagenic at 100 ug/mL and 

above 

MRID 43580201

-S9: not mutagenic.

+S9 mutagenic at 300 ug/mL and 

above

erythrocyte 

micronuleus mice

MRID 43581005

ip injections 250, 500 or 1000 

mg/kg to 5 mice/sex. Lethargy and 

death at high dose. Did not induce a 

clastogenic or aneurogenic effect.

MRID 00042763

ip injections 60 or 125 mg/kg to 4 

mice/sex. No overt aymptoms at 

high dose. Negative.

MRID 43581003

ip injections 305, 610, or 1220 

mg/kg to 5 mice/sex. Lethargy and 

death (48%) at high dose. Did not 

induce a clastogenic or aneurogenic 

effect

Mitotic gene 

conversion: 

Saccharomyces 

cervisiae

MRID 00042758, 00042759, 

00042760

NAA was tested at 10-2, 10-3, 10-4, 

10-5, 10-6 M.. NAA was not 

mutagenic in this test system. 

Unacceptable. No purity, not run 

at toxic dose, no S9 activation

Rodent dominant 

lethal assay

MRID 00042764

oral doses of 125, 250, or 500 

mg/kg/day to 10 male rats/dose for 
Page 31 of 52

A.2 Toxicity Profiles

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

5 days. NAA did not produce 

dominant lethal effects as measured 

by pre implantation and post 

implantation losses. 

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

major urinary metabolite in man, rhesus monkey, marmoset, rabbit, rat, and fruit bat. In th cat, no GAC was detected; but turine and glycine conjugates The

glycine conjugate was a major urinary metabolite (>20%) in the cat, squirrel and bushbaby monkey and a minor metabolite in rabbit, rat, capuchia and 

marmoset monkey. 1-NAA glutamine conjugate was formed only in the cynomolgus , squirrel and capuchin monkeys and marmoset in amounts not 

exceeding 3% of the AD. 1-NAA turine was excreted by all species except the rabbit, rat and the fruit bat. It was a major excretion product (>6%) in the 

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

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

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

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

Lethco and Brouwer, 1966. carboxy -

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

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

second day. Fecal excretion was 3-10% at the 0.1-1.0 mg/kg doses and 14-21% of the AD at the 100 and 250 mg/kg doses. After the third day, no 

radioactivity was detected in the feces or urine at any dose. 70-93% of the urinary radioactivity was NAA glycine conjugate and NAA GAC. The GAC 

predominated at the two high doses and the glycine conjugate predominated at the lower dose. Minor amounts of NAA and two other minor unidentified 

metabolites were detected in the urine. Bile cannulation experiments demonstrated biliary metabolism and excretion of the test material. At the high dose 

a maximum of 29% of the AD was recovered at 6 hours, while a maximum of 54% was recovered at the low dose at 2 hours. At the low dose, the NAA 

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

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

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

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

repeated dose (1 mg/kg/day) of unlabeled material followed by a single dose of the labeled material. Overall recovery of AD was 98.6-101.8%. NAA ethyl 

ester was readily absorbed and excreted within 36 - 48 hours following all exposure regimens (urinary excretion: 67.6-85.3% of the AD at the low dose and 

61.8-78% of the AD at the high dose). Fecal excretion was 12.3-35.2% of the AD. Tissue radioactivity was very low. The major pathway of metabolism 

involved ester cleavage followed by glycine and glucuronide conjugation at the low and low repeat doses. At the high dose, glucuronide conjugation 

appeared to play a more important role following ester cleavage. Parent compound was detected at low concentrations (0.5-4.7% of administered) only in 

feces. 

MRID 43963301. Rrats (5/sex) were given either a single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day) using [

14C] ring labeled 

-1-naphthaleneacetamide (NAAD). Overall recovery of the AD was 97.2-101%. NAAD was readily absorbed and excreted within 36 hours (urinary 

excretion: 70.8-74.1% of the AD at the low dose, single or multiple, 66.2-69.5% of the AD excreted in urine at the high dose). Fecal excretion was 

21.6-26.2% of the AD. Tissue radioactivity was very low (<0,5% of the AD). Metabolism involved amide cleavage followed by glycine conjugation 
Page 32 of 52

A.2 Toxicity Profiles

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

(13.7-47.3% of the AD) glucuronide conjugation (4.5-7.0% of the AD at the low dose and 12.8-18.1% of the AD at the high dose inthe urine). For feces, the 

major metabolite detected was the dihydrodiol of naphthaleneacetamide (3.6-11.3% of the AD). Parent compound was detected at low concentrations 

(0.7-1.9% of administered) only in feces. 
Page 33 of 52

APPENDIX A.3 HAZARD IDENTIFICATION AND ENDPOINT SELECTION 

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

Selected Study: Developmental Toxicity Study in Rats 

MRID 46685803

Dose and Endpoint for Establishing an aPAD: On the basis of this study, the dose selected is 50 

mg/kg/day based on decreased body weight gain at 250 mg/kg/day during the gestation period. 

This dose and endpoint is protective of the general population and is representative of the exposure 

duration of concern (effects occurred during administration of NAA during short period of 

exposure). This was also the only available study on NAA with short exposure duration. 

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

intraspecies variation.

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

Selected Study: Chronic/Oncogenicity Study in Dogs 

MRID 43744201

Dose and Endpoint for Establishing an cPAD: On the basis of this study, the dose selected is 15 

mg/kg/day based on stomach lesions in 75% of the males consisting of necrosis of the fundic or 

pyloric epithelium and by slight sinusoidal histiocytosis in the liver of 50% of the males occurring 

at 75 mg/kg/day of oral feeding of the NAA sodium salt. The sodium salt also appeared to be the 

more toxic in subchronic testing among the NAA group of chemicals. A chronic study in rats with 

NAA sodium salt showed a NOAEL of 44-56 mg/kg/day based on increased incidence of stomach 

(mucosal gland dilation) and lung lesions (focal alveolar macrophages) in both sexes, and on 

lowered body weight gain and food efficiency in female rats at 224 - 303 mg/kg/day. Therefore, 

this dose and endpoint is appropriate for protecting the general population from dietary chronic 

exposure to NAA group of chemicals. 

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

intraspecies variation.

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

 (UF) 100

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

 (UF) 100
Page 34 of 52

A.3.4 Dermal Absorption

A dermal absorption factor (DAF) is applied when dermal exposure endpoints are selected 

from oral toxicity studies. The dermal factor converts the oral dose to an equivalent dermal dose 

for the risk assessment. A DAF of 6% was selected for use in risk assessment based on available in 

vivo dermal absorption studies in rat and in vitro dermal absorption studies conducted with rat and 

human skin. The DAF was selected by a special working group of the Antimicrobials Division 

Toxicity Endpoint Selection Committee (12/18/08 memorandum from J. Chen to M. Swindell –

Attachment A.3).

4.3.5 Dermal Exposure (Short and Intermediate-Term)

Selected Study: 21-day dermal toxicity study

MRID 42090018

Dose and Endpoint for Establishing POD: In this study, the systemic NOAEL was 300 mg/kg/day 

based on reduced body weight gain and food efficiency at the LOAEL of 1000 mg/kg/day. 

Therefore, the dermal dose for risk assessment is 300 mg/kg/day. A margin of Exposure (MOE) of 

100 is applied.

Uncertainty Factor (UF): An MOE 100 is required for the short- and intermediate-term scenarios 

for dermal exposure is based on the conventional uncertainty factor of 100. This includes 10x for 

interspecies extrapolation and 10x for intraspecies variation..

A.3.6 Inhalation Exposure (Short- and Term) 

Selected Study: Developmental Toxicity Study in Rats

See Section A.3.1

A.3.6 Inhalation Exposure (Intermediate Term)

Selected Study: 90 day oral toxicity study in dogs 

MRID 42983801

Dose and Endpoint for Establishing POD: In this study, the systemic NOAEL was 25 mg/kg/day

based on lesions of the GI tract and hypocellularity of the bone marrow at the LOAEL of 150 

mg/kg day. Therefore, the dose for risk assessment is 25 mg/kg/day. 

Uncertainty Factor (UF): An MOE 100 is required for the intermediate-term scenarios for dermal 

exposure is based on the conventional uncertainty factor of 100. This includes 10x for interspecies 

extrapolation and 10x for intraspecies variation..
Page 35 of 52

A.4 EXECUTIVE SUMMARIES FOR SUPPORTING TOXICITY STUDIES 

A.4.1 Subchronic Toxicity

870.3100: 90-Day Oral Toxicity - Rat

In a subchronic oral toxicity study (MRID 00043624), 1-naphthaleneacetic acid, technical (Lot 

# not reported; purity not reported) was administered, in the diet, to Sprague Dawley rats 

(20/sex/dose) at dose levels of 0, 50, 150 or 300 mg/kg bw/day for 13 weeks. Two additional 

group of 10 rats/sex were administered 0 or 300 mg/kg bw/day and sacrificed after 30 days and 

necropsied. All rats survived except for one death in the control group. No abnormal behavior or 

toxic effects were observed in the treated rats. Fluctuations in food consumption occurred in 

control and treated groups. Body weights in males and females of the high dose group were 

depressed particularly in the females where they gained only one third of the body weight achieved 

by the controls. All hematologic values were within the reference limits. Hematocrit, 

hemoglobin, and/or RBC values in the mid and high dose males and females were slightly reduced, 

but considered not compound related. Alkaline phosphatase in the high dose group was elevated, 

probably associated with the rate of body growth. Urinalysis values were comparable in all 

groups. There were no visible macroscopic lesions in male rats except for one control male with 

enlarged spleen and liver and red, depressed areas in the stomach. In the females, clear fluid in the 

uterus (hydrometra) was noted in 3 controls, 2 low dose, 7 mid dose and 5 high dose. These and 

other lesions (ovarian cyst in one mid dose female, focal omental fat necrosis in one high dose 

female, one nenocortical cyst in another high dose female) observed were considered not be 

compound induced. The absolute and relative liver weight in the high dose females appeared to be 

significantly increased with no histopathological findings. It was concluded that the LOAEL for 

toxic effects in this study is 300 mg/kg/day based on decreased body weight in both sexes and 

enlarged liver weights in females. The NOAEL is 150 mg/kg/day. This subchronic toxicity study 

in the rat was conducted prior to the current testing guidelines. 

In a subchronic toxicity study (MRID 43896001), 1-Naphthaleneacetamide (Lot # I940415; 

98.7% a.i.) was administered to CRL:CD BR rats (10/sex/dose) by feeding at dose levels of 0, 250, 

1,000, or 4,000 ppm (mean measured concentrations of 0, 19.1, 73.8, or 292.1 mg/kg/day for males 

and 0, 20.4, 81.5, or 313.5 mg/kg/day for females) for 90 days. In the 4,000 ppm treatment groups, 

mean body weights were lower for males (10-15%) and females (9-12%) throughout the study, 

compared to controls. Final mean body weight gains were lower for males (14%) and females 

(20%). In addition, food consumption was consistently reduced for males (11-28%) and females 
Page 36 of 52

(2-20%) throughout the study. Mean relative liver weights were significantly increased in both 

4,000 ppm males (14%; p0.05) and females (32%; p0.01) with accompanying histopathological 

changes consisting of enlarged (hypertrophied) centrilobular hepatocytes with an abundance of 

fine granular eosinophilic cytoplasm. No rats died during the study. No treatment-related 

differences in clinical appearance, ophthalmology, hematology, clinical blood chemistry or 

urinalysis parameter or gross pathology were observed in any treatment group. No neoplastic 

tissue was observed in any of the treatment groups. The LOAEL is 4,000 ppm (292.1 mg/kg/day), 

based on decreased body weight, reduced body weight gain, reduced food consumption, and 

increased relative liver weights with histopathological changes in both sexes. The NOAEL is 

1,000 ppm (73.8 mg/kg/day).

In a 90 day oral (diet) toxicity study (MRID 42932601), male and female Crl:CDBR 

(Sprague-Dawley) rats (10/group/sex) received 1-Napthaleneacetic Acid Sodium Salt (Lot # 

214001; 96.44% purity) either 0, 200, 2000, or 8000 ppm (equivalent to 13.9, 136.6, and 564.9 

mg/kg/day for males and 15.2, 149.3, and 583.4 mg/kg/day for females, respectively) for 13 

weeks. Dose levels were based on a 14-day dietary study with 1-Na-NAA, no information was 

provided. No clinical toxicity or mortality related to the treatment was reported in any of the 

groups. The absolute body weights for both sexes in the high dose groups were statistically 

significantly different from control from day 7 for males and day 14 for females, approximately 18 

to 20 % lower than control for both sexes at the end of 90 days. Systemic toxicity was noted at 

2000 ppm and above based on statistically significant (p<0.05 -p<0.01) decreased hematocrit and 

hemoglobin, increased liver weights and vacuolation of the periportal hepatocytes along with 

hypertrophy of the cells of the adrenal cortex zona glomerulosa in females and increased kidney

weights in males. Further, at the 8000 ppm dose group there were decreased body weight gains 

(25-30% decrease), decreased food consumption and decreased food efficiency along with 

decreased red blood cell parameters, platelet counts, total serum protein and albumin. The liver 

and kidney weights (absolute and relative to body weight) were increased in high dose males and 

females along with hepatocellular hypertrophy (4/10 in high dose males and females) and 

vacuolation of the periportal hepatocytes (10/10 in mid and high dose females) and hypertrophy of 

the cells of the adrenal cortex zona glomerulosa (6/10 in the mid dose females and 7/10 in the high 

dose females, and 3/10 in high dose males) and urinary bladder mucosa (9/10 in high dose males 

and 7/10 in high dose females). The LOAEL for systemic toxicity is 2000 ppm (136.6 mg/kg/day 

for males and 149.3 mg/kg/day for females) with a NOAEL for systemic toxicity of 200 ppm (13.9 

mg/kg/day for males and 15.2 mg/kg/day for females) based on decreased hematocrit and 

hemoglobin, increased liver weights and vacuolation of the periportal hepatocytes along with 

hypertrophy of the cells of the adrenal cortex zona glomerulosa. 

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

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

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

were 19-25 mg/kg/day for the 400 ppm group, 92-123 mg/kg/day for the 2000 ppm group, and 388 

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

body weight gain, food consumption and food efficiency were observed for the 8000 ppm males 

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

females were 9-21% lower than the corresponding controls throughout the study. Body weight 
Page 37 of 52

gains were significantly reduced for both sexes at various weekly intervals throughout the study, 

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

control gains. Mean food consumption by the males and females was 5-11 and 15-22 lower, 

respectively, than the control values for most weekly intervals; decreased food efficiency for both 

sexes was observed at most weekly intervals. Increased relative and/or absolute liver and kidney 

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

21% higher for the 2000 ppm females and 20 and 58% higher for the 8000 ppm males and females, 

respectively, compared to the control weights. Absolute liver weights were 13 and 24% higher for 

the 2000 and 8000 ppm females, respectively, compared to the controls. Relative kidney weights 

were higher for both sexes from the 2000 ppm (11% higher) and 8000 ppm (17-23% higher) 

treatment groups. Absolute kidney weight for the 2000 ppm males was 16% higher than the 

controls but was not increased for the 8000 ppm males. No associated macroscopic or microscopic 

changes were observed in the livers and kidneys of rats from any treatment group. Decreased red 

blood cell counts, hemoglobin, and hematocrits for both sexes from the 2000 and 8000 ppm groups 

were not considered clinically significant, but appeared to be treatment-related since they were 

dose-dependent. The 8000 ppm males and females also exhibited increased total bilirubin 

(19-21% higher) in conjunction with reduced red blood cell counts, hemoglobin, and hematocrits. 

No other treatment-related effects were observed during the study. No rats died during the study. 

No differences in clinical signs, ophthalmology, macroscopic or microscopic pathology were 

observed between any of the treatment and control groups. Decreased urine protein in the 2000 

and 8000 ppm males was not observed in the corresponding females. The LOAEL for this study is 

8000 ppm (594 mg/kg/day) for male and female rats, based on lower body weight, suppressed 

body weight gain, and reduced food consumption as compared to the controls. Absolute and/or 

relative liver and kidney weights for both sexes were seen at this dose but were not accompanied 

by any macroscopic or microscopic changes, however, males and females at this dose also 

exhibited increased total bilirubin (19-21% higher) in conjunction with reduced red blood cell 

counts, hemoglobin, and hematocrits. The NOAEL is 2000 ppm (144 mg/kg/day) for both sexes. 

870.3150: 90-Day Oral Toxicity - Dog

In a subchronic oral toxicity study (MRID 00136446), 1-naphthaleneacetic acid, technical (Lot # 

16388; purity not reported) was fed (gelatin capsules) to beagle dogs (4/sex/dose) at dose levels of 

0, 50, 150, or 300 mg/kg/day for 180 consecutive days. Clinical signs of toxicity were evident in 

the high dose group. These included anorexia lasting several days, tenderness in the mouth while 

dosing, icteric and pale mucous membranes, steady loss in weight, lethargy, an uncoordinated gait, 

dark urine, and dark stools. Two of four males and all the females showed some or all of these 

effects at the end of the study. One dog had a great amount of edema in the hind legs progressing 

over 3 days until its legs were swollen to approximately the coxo femoral joint. This dog was 

sacrificed on day 126 of the study. Urine collected from this dog prior to sacrifice showed large 

amounts of bilirubin, urobilinogen and a small amount of RBC and blood. These effects are 

considered to treatment-related. The mean body weight and body weight gain was significantly 

depressed in the high dose females (p<0.01) at 2, 3, 4,5 and 6 months in comparison to the control 

dogs. The male dogs had also reduced body weight and body weight gain during the last two 

months of the study. Hematological parameters were within reference limits for the four groups. 

The hematology of the dog that was sacrificed showed slightly increased WBC count with a 
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relative and absolute neutrophilia and lymphopenia which may be compound related. The clinical 

chemistry analysis showed that alanine amino transferase (SGPT) were elevated at 4 months 

(slightly) and 6 months (2x the normal value) for the high dose females. The clinical chemistry of 

the male dog that was sacrificed in moribund condition showed lower protein, cholesterol and 

glucose and greatly elevated levels of total bilirubin, direct bilirubin, alkaline phosphatase, 

aspartate amino transferase (SGOT) and SGPT. Dose-related increases in relative weights of 

kidneys occurred in both males and females of the high dose group. Dose-related weight increases 

in liver, adrenals, brain and heart occurred in high dose females. The low dose group males had 

increased relative kidney weights and the mid dose group females had an increase in relative heart 

weights. Histopathologisal examination revealed very slight evidence of pericholangistis in the 

low dose group (2/8), very slight to moderate degree of hepatic insult in the mid dose group 

(7/8)and slight to severe degree of hepatic insult in the high dose group (8/8). This hepatic insult 

was characterized by pericholangistis, toxic degeneration of hepatocytes and hepatocellular 

hypertrophy in the mid dose group and additionally centrilobular necrosis, periportal fibrosis in the 

high dose group and hyperplastic nodule in the male dog that was sacrificed moribund. There was 

also evidence of squamoid metaplasi in the tracheal epithelium of 2/8 dogs and a slight degree of 

myocarditis (1/8) in the high dose group. Hyperkeratosis of the skin at the thoroacolumbar 

junction was seen in 2/8 dogs of the mid dose and 4/8 dogs of the high dose groups. It was 

concluded that there was no NOAEL derived from this study. The LOAEL was 50 mg/kg/day, 

the lowest dose tested, based on hepatic liver changes (pericholangistis). This subchronic toxicity

study in the dog was conducted prior to the current testing guidelines. 

In a subchronic toxicity study (MRID 43895901), 1-Naphthaleneacetamide (Lot/Batch # 

I940415; 98.7% a.i.) was administered via capsule to four beagle dogs/sex/dose at dose levels of 

0, 30, 100, or 300 mg/kg/day for 13 weeks. In the 300 mg/kg/day treatment group, all livers 

contained accumulations of a hemosiderin-containing pigment in the reticuloendothelial cells and 

bilirubin in the intracanicular spaces. The spleens of 3/4 males and 2/4 females also contained 

hemosiderin and hematopoiesis was increased in the bone marrow in 3/4 animals of both sexes. 

Decreases in red blood cell counts, hematocrit, and hemoglobin occurred in both sexes. Platelet 

counts and mean corpuscular volumes were increased in both sexes. Total bilirubin was increased 

in 1/4 males and 3/4 females, but the increases were significant (p<0.05 or 0.01) only for females. 

Body weights were reduced in males only. Clinical signs of toxicity in both sexes were soft or 

liquid feces. No treatment-related effects were observed in the 30 or 100 mg/kg/day treatment 

groups. No dogs died during the study. No treatment-related differences in clinical appearance, 

food consumption, ophthalmology, urinalysis parameters, organ weights, or gross pathology were 

observed in any treatment group. No neoplastic tissue was observed in any of the treatment 

groups. The LOAEL is 300 mg/kg/day, based on increased platelet count, decreased red cell 

parameters, and increased mean corpuscular volume which correlate with histopathological 

changes observed in the liver, spleen, and bone marrow in both sexes.

In a 13 week oral toxicity study (MRID 42983801), 6-month old beagle dogs (4/group/sex) 

received by capsule either 0, 25, 150, or 450 mg/kg/day 1-Naphthaleneacetic Acid Sodium Salt 

(Lot# 214001, Purity - 96.44% 1-NAA & 1.79% 2-NAA). Due to inappetence at the high dose, the 

feeding regimen was altered for several high dose animals to reduce excessive weight loss. Dose 

levels were based on a previous 6 month study with Naphthalene Acetic Acid (MRID 00136446) 
Page 39 of 52

where male and female dogs receiving 50, 150, or 300 mg/kg/day experienced severe toxicity at 

the 300 mg/kg/day dose. These included depressed body weight and body weight gain, 

histopathological changes and mortality. In the current study with NAA sodium salt, none of the 

animals died. Regurgitation of intact or partially digested capsules and emesis were the most 

common treatment- related clinical sign and was toxicologically significant at the high dose. Body

weight gain was significantly reduced in the high dose males (15% of controls, p<0.05) and 

females (29% of controls, p<0.05) accompanied by decreased food consumption and food 

efficiency. There were statistically significant increases in relative organ weight for the liver, 

adrenals, thyroids/parathyroids, kidneys and brain and a decrease in gonad absolute and relative 

weights for the high dose males. The high dose females only showed a statistically significant 

increase in relative kidney weights, although the relative weights for other organs did show a 

tendency towards an increase. Gross examination of the genital tract revealed small prostates, 

small testes and epididymides in all high dose males. Microscopic examination in these males 

revealed an increased incidence of hypospermatogenesis, characterized by less spermatogonia and 

spermatocytes and were associated with aspermia in the epididymides. These may be secondary

effects to the condition of the animals, but deserve further examination. Systemic toxicity was 

noted at 150 mg/kg/day and above based on lesions of the gastrointestinal tract (ulcerative 

duodenitis and acute or erosive gastritis), hypocellularity of the bone marrow along with changes 

in liver enzymes (increased alkaline phosphatase in the high dose group), increased relative liver 

weights, histopathological changes of the liver (single cell necrosis, centrilobular necrosis, 

pigment accumulation, extramedullary hematopoiesis and mononuclear or mixed cell infiltration), 

depression in erythrocyte parameters (red blood cell count, hemoglobin and hematocrit levels in 

high dose females with a slight similar effect in males), decreased body weight gains, food 

consumption and food efficiency, inappetence and emesis in the high dose group. The NOAEL 

for systemic toxicity is 25 mg/kg/day with a LOAEL for systemic toxicity of 150 mg/kg/day

based on lesions of the gastrointestinal tract and hypocellularity of the bone marrow.

In a subchronic oral toxicity study (MRID 43914901), 1-naphthaleneacetic acid, ethyl ester

(Lot/Batch # AM 315002; 97.75% ai) was fed (gelatin capsules) to beagle dogs (4/sex/dose) at 

dose levels of 0, 40, 125, or 400 mg/kg/day for 13 weeks. All dogs survived the treatment. 

Treatment-related clinical signs were limited to soft or liquid feces particularly in males and to a 

lesser extent in females at the high dose of 400 mg/kg/day. Male dogs in the 40, 125, or 400 

mg/kg/day treatment groups had a 4- to 5.5-fold increase in soft/liquid feces (maximum 65 

instances during 13 weeks in the 400 mg/kg/day group) compared to the control group. For 

females, there was one incident of soft/liquid feces in the control group, five in the 40 mg/kg/day

group, eight in the 125 mg/kg/day group, and 19 in the 400 mg/kg/day group during the 13-week 

study. A treatment-related lower body weight gain (20% less than the control) was seen in the 

males and females of the high dose group. Males in the 40 or 125 mg/kg/day treatment group were 

25-29% heavier, and males in the 400 mg/kg/day treatment group were 20% lighter than males in 

the control group; all three groups consumed 19% more food than the control during the study. 

Female dogs in the 400 mg/kg/day treatment groups consumed 11% less food over the course of 

the study. Male dogs in the 40, 125, or 400 mg/kg/day treatment groups had significantly (p <0.05 

or 0.01) lower red blood cell, hemoglobin, and hematocrit levels, and lower mean platelet volumes 

(MPV) than the controls throughout the study. In the high dose males at 12 weeks, these were 

18%, 17%, 17% and 22% lower than the controls for RBC, hemoglobin, hematocrit and MPV 
Page 40 of 52

levels, respectively. Although , these parameters were within the historical range values for this 

dog type, they were at the lower end of the range and may suggest anemic affects caused by the 

administration of this material at this dose. Low white blood cell counts in female dogs in the 125 

or 400 mg/kg/day treatment groups after 12 weeks of treatment were also within expected 

biological ranges. No other treatment-related responses were observed during the study. No 

differences were observed in clinical blood chemistry, ophthalmology, urine volume or chemistry, 

organ weights, or macroscopic or microscopic organ morphology between dogs in the treated and 

the control groups. No neoplastic tissue was observed. The LOAEL for this study is 400 

mg/kg/day, based on soft/liquid feces and the depressed body weight gains of male and female 

dogs at this treatment level. Additionally some blood parameters (RBC, hemoglobin, hematocrit 

and mean platelet volume) were all depressed in the male dogs at this level. The NOAEL was 125 

mg/kg/day. 

A.4.2 Prenatal Developmental Toxicity

870.3700a: Prenatal Developmental Toxicity Study - Rat

In a prenatal developmental study (MRID 00042765), NAA technical (Lot # NAA 73323G; purity 

not reported, white powder) was administered by gastric intubation to groups (24/group) of 

healthy timed pregnant albino CD rats at dose levels of 0, 10, 50 or 250 mg/kg/day in 0.05% 

sodium carboxymethylcellulose from days 6 through 15 of gestation. The dams were observed 

daily for signs of toxicity and weighed on day 1, 3, 6-15, 17 and 20 of gestation. On day 20 of 

gestation the dams were euthanized with ether and the ovaries and uterine contents were 

immediately examined for viable and nonviable fetuses, resorptions, number of implantations, and 

number of corpora lutea. Fetuses were examined for visceral and skeletal anomalies using proper 

techniques. No deaths or toxic symptoms were reported at any dose level. There was a 

statistically significant decrease in the mean body weight gain in the 250 mg/kg/day rats with the 

onset of the compound administration. The dams in the 10 and 50 mg/kg/day groups did not show 

significant decrease in body weight gain during compound administration but showed a decrease 

compared to the controls from days 17-20. Litter size and fetal loss were not affected by the 

treatment. A slight decrease (statistically insignificant) in mean litter size (9.3, 9.3, 8.8 and 7.9 in 

the control, low-, mid-, and high-dose groups, respectively) was considered unrelated to treatment. 

There was a statistically increased (p<0.05) mean preimplantation loss in the mid- and high dose 

groups (38.1-42.6%) in comparison to the control animals (20.6%). However the means were 

within the range of the individual values of the control animals and were considered not treatment 

related. The incidence of major malformations and minor anomalies were comparable in all 

groups. It was concluded that NAA is not teratogenic in pregnant rats at 250 mg/kg/day, the 

highest dose tested. Therefor the developmental LOAEL is >250 mg/k/day and the NOAEL is 

250 mg/kg/day. The maternal toxicity LOAEL 250 mg/kg/day based on decreased body weight 

gain during the compound administration and the NOAEL for maternal toxicity is 50 mg/kg/day.

In another developmental toxicity study (MRID 46685803), 1-Naphthaleneacetic acid sodium salt 

(97.4% a.i., batch/lot # 014-S0401-001) was administered to 24 female SD (Wistar-derived) 

rats/dose by gavage at dose levels of 0, 15, 50 or 150 mg/kg bw/day from days 5 through 21 
Page 41 of 52

(inclusive) of gestation. All animals survived the duration of the study and all were pregnant with 

live fetuses in utero at scheduled termination on day 22 of gestation. There were no 

treatment-related clinical signs. Cesarean section data did not reveal any differences among all 

groups including the controls. Maternal body weights of the 150 mg/kg/day females adjusted for 

initial weight were statistically significantly (p<0.01) lower than the control group from day 6 

through day 17. For the 50 mg/kg/day females body weights were lower during the first 4 days 

following the test material administration. Females in the low dose groups were not affected. Body 

weight gains were lower following the first day of treatment and recovered completely on the 

second day (low-dose group) and third day of treatment for the mid-and high-dose groups. 

Sporadic lower food consumption occurred in the mid- and high-dose groups. Although the lower 

body weights seen in the high and mid dose groups were statistically significant, these are 

considered not to be biologically significant or adverse since these changes were only 1-4% lower 

than the controls. Therefore, the maternal LOAEL is >150 mg/kg bw/day, and the maternal 

NOAEL is 150 mg/kg bw/day.

A treatment-related effect at the high dose resulted in reduced mean fetal weights of male and 

female fetuses. The only notable visceral anomaly was increased slightly dilated ureters with 

statistical significance in the mid (p<0.05) and the high doses (p<0.01). There were no 

treatment-related external malformations or variations of the fetuses. Minor treatment-related 

skeletal malformations were seen at the high dose of 150 mg/kg/day. These included an increased 

number of unossified centrum 5, increased number of cervical arch 7 cartilage fused to arch 6 

cartilage, increased interruptions of thoracic rib 10 costal cartilage, increased number of long 

length cervical rib. A treatment-related increased incidence of fetuses but not litters with a 

shortened 7

th cervical rib was observed in the 50 and 150 mg/kg/day groups. The incidence of both 

fetuses and litters with an ossified calcaneum was lower than in the control group and indicated a 

reduction in ossification, in the 150 mg/kg/day group. Reduced ossification of the mania and pes 

was seen at the high dose. A statistically significant higher mean score for the pes was reported for 

the 50 mg/kg/day group, but the difference from the control mean was minimal. The 

developmental LOAEL is 150 mg/kg bw/day, based on decreased fetal weight and minor 

skeletal changes (centrum 5 not ossified, cervical arch 7 cartilage fused to arch 6 cartilage, 

shortened 7th cervical rib). The developmental NOAEL is 50 mg/kg bw/day.

870.3700b: Prenatal Developmental Toxicity Study - Rabbit

In a prenatal developmental study (MRID 00137822), NAA (Lot # RTS2846AC; 98.55% purity) 

was administered by oral gavage to groups (16/group) of artificially inseminated Dutch Belted 

rabbits (4 1⁄2 to 5 months old) at dose levels of 0, 37.5, 75, or 150 mg/kg/day from days 6 through 

27 of gestation. These doses were selected on the basis of a range finding study (MRID 

00137821) where groups (5 rabbits/group) were dosed NAA once daily by gavage at dose levels of 

0, 28, 80 or 240 mg/kg/day from days 6 through 27 of gestation. Animals were observed twice 

daily for mortality and once daily for toxic signs during the dosing period. Animals that died were 

necropsied. Body weights were taken on days 0, 6, 12, 18, 24 and 28. Surviving animals were 

sacrificed on day 28 and the uterus and ovaries were examined for viable and nonviable fetuses, 

resorptions, number of implantations, and number of corpora lutea. One animal in the range 

finding study dosed at 240 mg/kg/day aborted on GD 28 following signs of toxicity consisting of 
Page 42 of 52

hair loss, decreased feces and significant weight loss. In the main study, one low dose animal died 

on GD 25 and three high dose gravid animals died during the study on GD 20, 22 and 27. Only two 

of the high dose animals showed signs of toxicity (hair loss on the forelimbs, clear or white nasal 

discharge with dried material around the nose, decreased defecation and dry red material, 

presumably died blood, beneath the cage) prior to death. Necropsy observations of the dead 

animals showed foamy fluid or congested lining in the trachea, congested lungs, fluid in the 

thoracic and/or abdominal cavities., reddening and/or erosions on the stomach mucosa, mucoid 

material or fluid in the intestines and pale liver or pitted kidneys. Weights of the pregnant animals 

varied over the gestation period with some indication of treatment related loss in the high dose. No 

compound-related abnormalities were observed in the pregnant animals at necropsy. No 

compound-related effect was observed on implantation or fetal viability. However, in the range 

finding study, an increase in the mean preimplantaion loss (23.2% at the low dose to 42.1% at the 

high dose compared to 11.4% in the concurrent control) occurred at all doses in the treated animals 

and appeared to be treatment related. However, this increased preimplantation loss was 

considered problematic by the EPA reviewer since historical control data on 343 animals showed a 

preimplantaion loss of 30.8%. Examination of the fetuses derived from the main study did not 

reveal any teratogenic effects. It was concluded that the maternal toxicity NOAEL is 75 

mg/kg/day based on lethality at the LOAEL of 150 mg/kg/day. The teratogenic and fetotoxic 

NOAEL was 150 mg/kg/day based on lack of developmental and fetoxic effects at the highest 

dose of 150 mg/kg/day tested.

In another developmental toxicity study (MRID 46685801) 1-Naphthaleneacetic acid sodium 

salt (97.4% a.i., batch/lot # 014-S0401-001) was administered to 24 female New Zealand 

White rabbits/dose in water by gavage at dose levels of 0, 30, 100 or 300 mg/kg bw/day 

from days 5 through 29 (inclusive) of gestation. All animals survived the duration of the study

except for one rabbit at the high dose which died on GD 22 due to a dosing error and one control 

rabbit was sacrificed on GD 24 following accidentally biting the dosing catheter into its 

esophagus. A treatment related reduction in body weight and body weight gain was noted 

following the initial oral administration of 1-NAA Na salt to pregnant rabbits at the high 

dose of 300 mg/kg/day. This was accompanied by initial reduction in food consumption. 

Final body weights were comparable in all treatment groups. Several dams receiving this 

dose were observed with few/no feces during the study. Post mortem examination 

revealed red/black spots/areas in the glandular mucosa of the stomach in several of 

these dams indicating local irritation by the test material. No adverse effects were noted 

in the dams at the lower dose of 30 and 100 mg 1-NAA Na salt /kg/day. Cesarean section 

data did not reveal any statistically significant differences among all groups including the controls. 

The LOAEL for maternal toxicity is 300 mg/kg/day based on reduced body weight, body 

weight gain and reduced food consumption, clinical signs (few/no feces) and stomach 

irritation (red/black spots/areas in the glandular mucosa of the stomach). The 

maternal toxicity NOAEL of 1-NAA Na in pregnant rabbits derived from this study is 100 

mg/kg/day. 

Developmental Toxicity. The oral administration of 1-NAA Na salt during gestation to rabbits 

resulted in decreased mean fetal weights (males and females) at the high dose of 300 mg/kg/day. 
Page 43 of 52

Mean fetal weights at the low- and mid-dose were comparable to the control group. There was no 

effect by l-NAA-Na salt administration on the overall incidence of major external/visceral, 

skeletal or Bouin’s head defects or on the incidence of any specific major fetal abnormalities. The 

defects were considered to be spontaneous in origin. Fetuses with minor defects of the head 

following Bouin’s fixation and sectioning, and fetuses with minor external/visceral defects were 

comparable in all groups including the control. There was no indication that any of the specific 

effects were attributable to the test material. Fetuses with minor skeletal defects were statistically 

significantly higher in the 300 mg/kg/day. However, only one specific defect (dumbbell shaped 

ossification of the 7th thoracic centrum) was statistically significantly higher (p<0.01) in the 300 

mg/kg/day group in comparison with the control group. No variants were detected in the heads of 

the fetuses following Bouin’s fixation and serial sectioning and no external/visceral findings were 

detected in any fetus. The overall proportion of fetuses with skeletal variants was statistically

significantly higher in the 30, 100 and 300 mg/kg/day groups in comparison with the control 

group, but there was no specific increase in any specific variant and is not attributable to the test 

material administration. The incidence of lengthened costal cartilage of the 10th thoracic rib was 

statistically significantly higher in all groups administered 1-NAA-Na in comparison with the 

control group, although there was no evidence of a dose-related trend. However, the incidences of 

fetuses with shortened or lengthened 13th thoracolumbar ribs (i.e. extra ribs) and with 27 bilateral 

pre-pelvic vertebrae were statistically significantly increased in the 300 mg/kg/day group in 

comparison with the control group and were considered to be attributable to 1-NAA-Na 

administration. The LOAEL for developmental toxicity is 300 mg/kg/day based on an 

increase in the overall incidences of fetuses with minor skeletal defects and 

variants (dumbell ossification of the 7

th

thoracic centrum, extra thoracolumbar ribs 

and 27 pre-pelvic vertebrae) and a decrease in ossification of the manus. The 

NOAEL is 100 mg/kg/day.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat MRID 42090018

870.3800: Reproduction and Fertility Effects - Rat

In a 2-generation reproduction study (MRID 43796301) 1-Na-NAA (Lot # 214001; 96.44% a.i.) 

was administered to 35 Crl:CD®BR, rats/sex/group in diet at dose levels of 0, 100, 1000 and 3000 

ppm [0, 7, 69 and 210 mg/kg/day for males and 0, 8, 81 and 239 mg/kg/day for females, 

respectively]. The dose levels were selected on the basis of previous toxicity studies in rats. At 

3000 ppm (HDT), treatment-related decreases in body weight gain and food consumption were 

observed in the P1 and P2 females during premating and gestation periods and decrease in body 

weight gain in P2 males during the premating period. Reductions in P2 male and female premating 

body weight gain, although appearing systemic in nature, may have been secondary to 

developmental toxicity in these animals. Reduced survival and growth were observed in both F1

and F2 offspring. No adverse effects were noted at 1000 ppm. Systemic and 

reproductive/developmental LOAEL = 3000 ppm (210 mg/kg/day for males, 239 mg/kg/day for 

females), based upon reduced body weight gain and food consumption in parental animals and 

reduced litter survival, and pup weight throughout lactation in both generations of offspring. 
Page 44 of 52

Systemic and reproductive/developmental NOAEL = 1000 ppm (69 mg/kg/day for males, 81 

mg/kg/day for females).

A.4.4 Chronic Toxicity

870.4100a: Chronic Toxicity – Rat

In a combined chronic toxicity/oncogenicity study (MRID 44157501), 1- Naphthaleneacetic acid 

sodium salt (1-Na-NAA) (96.44% 1-NAA; 1.79% 2-NAA w/w; Lot no. 214001) was 

administered to Crl:CD® BR rats (80/sex/dose) in the diet at concentrations of 0, 100, 1000, or 

5000 ppm (corresponding to 0, 4.4, 43.8, and 224.5 mg/kg/day for males and 0, 5.6, 55.8, and 

303.6 mg/kg/day for females). An interim sacrifice was performed at 12 months on 20 

rats/sex/dose; terminal sacrifice (main study) was after 20.5-23 months due to the high mortality 

and poor health in the treated and control groups. There were no treatment-related effects on 

survival or clinical observations. High-dose females had lower mortality than the controls (p 

0.05). Weekly body weights of the high-dose males were significantly lower for days 14-119 and 

238-259 ( 8.8%; p  0.05 or 0.01), but their overall weight gain was similar to that of the controls. 

The low- and mid-dose females’ weekly body weights and overall weight gains were within 7.4% 

and 14% of controls, respectively (p  0.05 or 0.01). High-dose females, however, had lowered 

weekly body weights ( 35%; p  0.01), total weight gain (61% of controls), and overall food 

consumption and efficiency (15% and 36% lower than controls, respectively). Serum triglyceride 

levels were about 50% lower than control levels at 6 and 12 months in high-dose males, and were 

66-78% lower at 12 and 18 months in high-dose females (p  0.05 or 0.01). The urine protein 

content of high-dose females was decreased from 12 months to terminal sacrifice to only 4.1-6.1% 

of control values (p  0.05 or 0.01). These clinical chemistry changes had no histopathological 

correlates and their toxicological significance is unknown. High-dose males and females had a 

significantly increased incidence and severity of stomach mucosal gland dilation (p  0.05). The 

incidence of focal alveolar macrophages (in some cases accompanied by focal chronic 

inflammation) was increased in mid- and high-dose females, and was correlated at the high dose 

with an increased incidence of grossly observed lung nodules (p  0.05 or 0.01). The incidence of 

focal alveolar macrophages was also slightly increased in high-dose males (p = 0.071). The 

LOAEL is 5000 ppm (224.5 mg/kg/day for males and 303.6 mg/kg/day for females), based on an 

increased incidence of stomach (mucosal gland dilation) and lung lesions (focal alveolar 

macrophages) in both sexes of rats, and on lowered body weight gain and food efficiency in 

females. The corresponding NOAEL is 1000 ppm (43.8 mg/kg/day for males and 55.8 mg/kg/day

for females). The only neoplastic finding (p  0.01) was an increased incidence of uterine 

endometrial stromal polyps in high-dose females (2/60, 1/60, 3/60, 13/60 at 0, 100, 1000, 5000 

ppm, respectively). The longer survival time of the high-dose females (about 88 days) did not 

account for the greater incidence of these benign neoplasms. The rats were dosed adequately, 

judging by the toxicologic findings in both sexes of high-dose rats.

870.4100b: Chronic Toxicity - Dog

In a chronic toxicity study (MRID 43744201), 1-napthaleneacetic acid, sodium salt (Lot # 
Page 45 of 52

214001; 96.44% ai) was administered (gelatin capsules) to beagle dogs (4/sex/dose) at dose levels 

of 0, 15, 75, or 225 mg/kg/day for 52 weeks. At 225 mg/kg/day, Na-NAA administration resulted 

in gross pathological changes in the stomach of one male and one female and histopathological 

changes in the stomachs of four males and one female. The latter were characterized by mucosal 

atrophy (3) and congestion (1) in males and hemorrhaging in the female. Slight sinusoidal 

histiocytosis was observed in the livers of four males and three females. Both males and females 

exhibited a high incidence of emesis and capsule regurgitation at the 225 mg/kg/day dose level. At 

75 mg/kg only males exhibited dose-related toxic response to Na-NAA as characterized by

stomach lesions in three animals consisting of necrosis of the fundic or pyloric epithelium and by 

slight sinusoidal histiocytosis in the liver of two males. No other definitive treatment-related 

changes were noted in organ weights or gross pathological changes. All microscopic tissue 

abnormalities, other than those mentioned, occurred randomly and sporadically in all study

groups. No neoplastic tissue was observed in beagles in the treatment or control groups. No dogs 

died during the study. No treatment-related differences were observed between the clinical 

appearance, body weights, food consumption, biochemistry, hematology, urinalysis, or 

ophthalmology of the treated and control animals. The LOAEL is 75 mg/kg/day in males and 225 

mg/kg/day in females, based on emesis, capsular regurgitation incidences, gross and 

histopathologic changes in stomachs, and sinusoidal histiocytosis in livers. The NOAEL is 15 

mg/kg/day in males and 75 mg/kg/day in females.

 

A.4.5 Carcinogenicity

870.4200a: Carcinogenicity Study - Rat

This study is described above in the chronic studies section. An increased incidence of uterine 

endometrial stromal polyps occurred in female rats at 303 mg/kg/day dietary feeding of Na NAA 

for two years. According to HED consulting pathologist, Dr. John Pletcher these are considered 

to be benign proliferative lesions of no carcinogenic concern (email to Dr. William Burnam of 

HED on 04/04/2002). Na NAA was not carcinogenic in the rat. 

870.4200b: Carcinogenicity (feeding) - Mouse

There is an NCI study published in 1969 where NAA acetamide was tested at one dose (maximum 

tolerated dose: according to the published article) as part of a testing program of 120 compounds. 

Only the preliminary results were published (Innes et al, Innes JR, Ulland BM, Valerio MG, 

Petrucelli L, Fishbein L, Hart ER, Pallotta AJ, Bates RR, Falk HL, Gart JJ, Klein M, Mitchell I, 

Peters J. 1969. Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: a 

preliminary note. J. Natl Cancer Inst. 42: 1101-1114). The test materials were administered to 

two hybrid strains of mice : C57BL/6 x C3H/Anf and C57BL/6 x AKR (18/sex/hybrid strain). The 

mice were administered NAA acetamide at one week of age by stomach intubation at 464 

mg/kg/day until weaning at 4 weeks of age and administered the NAA acetamide in the diet at 

1298 ppm (equivalent to 195 mg/kg/day at the conversion rate of 0.15 mg/kg for 1ppm) for 

approximately 18 months. Gross and hostopathologic examination of the mice at the end of the 

feeding period did not reveal a significant increase in tumors over the controls.
Page 46 of 52

In a carcinogenicity study (MRID # 46685802), Naphthaleneacetic Acid Sodium Salt (97.4%, 

batch/lot # 014-S0401-001) was administered to 50 C57BI/10JfCD-1 Alpk mice/sex/dose in the 

diet at dose levels of 0, 100, 500, or 2500 ppm [equivalent to 0, 10.8, 53.3, 276.0 / 0, 14.3, 70.9, 

348.7 mg/kg bw/day M/F, respectively] for at least 80 weeks. There were no statistically

significant differences in survival or clinical signs between treated groups and controls in either 

sex. At the top dose (2500 ppm), bodyweights in males and females were statistically significantly 

lower than controls throughout the study with a maximum effect of 11% at week 77 in males, and 

5% in females at week 41. Food consumption in males and females at this dose level was 

statistically significantly lower than controls at some time points throughout the study while food 

utilization in males was statistically significantly lower than controls in weeks 1-4 and overall in 

weeks 1-13. Total white blood cell, monocytes and large unstained cell counts were statistically 

significantly higher than controls in females at the top dose. This apparent elevation is due to 

higher counts in 2 individual animals and is considered to reflect animals with lymphomas in 

which there is also a leukaemic response. This effect was not compound-related. Also, at the top 

dose, liver and kidney weights in both sexes and epididymis in males were statistically higher than 

controls while brain weights in males were statistically lower. Masses in the liver were identified 

in 3 male rats at the top dose, and in one female at 100 ppm. Pancreatic masses were also identified 

in 2 females at 2500 ppm and in 1 female at 500 ppm. A four-fold increase, compared to controls, 

in the incidence of hepato-cellular vacuolation in the liver was observed in males dosed at 2500 

ppm. A slight increase in the presence of mononuclear cell infiltration in the liver was also 

observed in both males and females at this dose level. An increase in the incidence of intratubular 

microlithiasis and tubular basophilia within the kidney was observed in females and an increase in 

interstitial mononuclear cell infiltration in the kidney of males at 2500 ppm. There was an increase 

in the incidence of marked degeneration in the testes in males dosed with 2500 ppm of compound. 

Associated with this change, there was an increase in the incidence of decreased spermatozoa 

within the epididymis and dilated rete within the testis. At 2500 ppm, adenomas of the liver were 

observed in one male rat, and adenomas of the lung were observed two males. Adenocarcinomas 

of the liver were observed in one control male and two males given 2500 ppm. None of these 

changes achieved statistical significance. There was a statistically significant increase in the 

incidence of histiocytic sarcoma in females at 2500 ppm but it was within historical control levels. 

There was a statistically significant increase (overall) in the incidence of multiple tumors in 

females given 2500 ppm. However there was no statistically significant increase in any individual 

tumor type, the incidence was low, and there was no dose-response relationship. Therefore this 

difference was considered not to be compound related. The LOAEL is 2500 ppm [276 (M), 

348.7 (F) mg/kg/day], based on lower body weight, food consumption, increased liver and 

kidney weights in both sexes and epididymis in males, lower brain weights in males, 

hepato-cellular vacuolation in males, adenomas of the liver and lung in males, increase in the 

incidence of multiple tumors in females. 

The NOAEL is 500 ppm [53.3 (M), 70.9 (F)] mg/kg/day. At the doses tested, there was no 

treatment related increase in tumor incidence when compared to controls. Dosing was considered 

adequate based on the effects observed on the top dose (2500 ppm/kg/day).

A.4.6 Mutagenicity

Gene Mutation
Page 47 of 52

GLN 870.5100, 

MRID 43581006: NAA Acetamide

MRID 00042761: NAA

MRID 43581004: NAA Ethyl Ester

No mutagenic effect was noted with or without microsomal activation at 

concentrations up to the toxic range of 5000 micrograms/plate in the 

initial tests or in the confirmatory assay.

Chromosomal Aberrations

GLN 870.5395

MRID 43581005 NAA Acetamide

MRID 00042763 NAA

MRID 43581003 NAA Ethyl Ester

In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay in 

Mice. There was no indication that NAA technical or the acetamide or the 

ethyl ester induced a clastogenic or aneugenic effect in either sex at any 

dose or sacrifice time. 

GLN 870.5300

MRID 43580202: NAA Acetamide

MRID 43580201: NAA Ethyl Ester

In Vitro mammalian cell gene mutation - L5178Y TK+/- Mouse 

Lymphoma Mutagenesis Assay. NAA acetamide was tested up to 

cytotoxic levels (1250 μg/mL -S9 and 150 μg/mL +S9). NAA Ethyl 

ester was tested up to cytotoxic levels (100 μg/mL -S9 and 300 μg/mL 

+S9). Both were non mutagenic without S9 activation system, but 

positive with S9 activation system at or above 100 ug/mL for the 

acetamide and 300 ug/mL for the ethyl ester.

GLN 870.5450

MRID 00042764 NAA

Rodent Dominant Lethal Assay. NAA did not produce dominant lethal 

effects in mice at oral doses of 125, 250 or 500 mg/kg/day as measured by 

pre implantation and post implantation losses

A.4.7 Neurotoxicity

A neurotoxicity screening battery is required. The registrant has committed to either develop new 

data or submit existing data to satisfy this requirement by early 2014. AMVAC is in the process of 

determining the value of certain acute neurotoxicity data that have successfully supported foreign 

registrations. If applicable to EPA standards these data could be submitted this year.

A.4.8 Metabolism

870.7485 Metabolism – Rat 

In a study (MRID 43963301) conducted to examine the metabolism and disposition of

1-naphthaleneacetamide, five male and five female Sprague-Dawley rats were given either a 

single 1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day). Groups of male and 

female rats were subjected to the dosing regimens above using [14C] ring labeled 

-1-naphthaleneacetamide (Batch No. 94-516-38-10; 99.7% radiochemical purity, specific activity

55.5 mCi/mmol), and nonlabeled test article (Batch No. KP 0100487, chemical purity not 

available). Excretion, tissue distribution, and metabolite profiles were determined. There were no 

biologically significant treatment-related effects noted during the course of the study. Overall 

recovery of administered radioactivity was an excellent 97.2-101%. 1-Naphthaleneacetamide was 

readily absorbed and excreted within 36 hours following a single 1 mg/kg bw, a 14-day repeat oral 
Page 48 of 52

dose of 1 mg/kg bw, or a single 100 mg/kg bw oral dose. Following single or multiple oral low 

doses (1 mg/kg bw) of [C14]-1-naphthaleneacetamide, urinary excretion accounted for 70.8-74.1% 

of the administered radioactivity suggesting that a multiple exposure regimen did not affect the 

absorption/excretion processes. Urinary excretion was unaffected following a single 100 mg/kg 

dose with 66.2-69.5% of the administered radioactivity excreted in urine. Excretion via the feces 

accounted for the remainder of the administered radioactivity in all treatment groups 

(21.6-26.2%). Excretory patterns did not exhibit gender-related variability but reflected delayed 

absorption in the high-dose group. Because tissue burdens were very low at termination, neither 

1-naphthaleneacetamide nor its metabolites appear to undergo significant sequestration. Both 

urinary and fecal metabolites were quantified by HPLC and most were identified using HPLC and 

HPLC/MS in conjunction with known standards. Urinary metabolism involved amide cleavage 

followed by glycine conjugation with the glycine conjugate being the major metabolite of the low 

and repeat doses (13.7-47.3% of the administered radioactivity). The glucuronide conjugate was 

also a major metabolite at the low doses (4.5-7.0% of administered). For feces, the major 

metabolite detected was the dihydrodiol of naphthaleneacetamide (3.6-11.3% of administered. 

Parent compound was detected at low concentrations (0.7-1.9% of administered) only in feces. 

Extraction efficiencies appeared to be excellent and most components in the matrices examined 

(urine and feces) were adequately quantified and characterized. The available data, based upon 

studies using labeled 1-naphthaleneacetamide, affirmed the metabolism pathway proposed by the 

investigators.

In another study (MRID 43961701) conducted to examine the metabolism and disposition of

1-naphthaleneacetic acid, ethyl ester, male and female Sprague-Dawley rats were given a single 

1 or 100 mg/kg bw oral dose, or a 14-day repeated dose (1 mg/kg/day). Groups of male and female 

rats were subjected to the dosing regimens above using [14C] ring labeled -1-naphthaleneacetic 

acid, ethyl ester (Batch No. CSL-94-516-33-25, 99.3% radiochemical purity, specific acttivity

56.2 mCi/mmol), and nonlabeled test article (Batch No. GAB 69-34-02, chemical purity not 

available). Excretion, tissue distribution, pharmacokinetic parameters, and metabolite profiles 

were determined. There were no biologically significant treatment-related effects noted during the 

course of the study. Overall recovery of administered radioactivity was an excellent 98.6-101.8%. 

1-Naphthaleneacetic acid, ethyl ester was readily absorbed and excreted within 36 - 48 hours 

following a single 1 mg/kg bw, a 14-day repeat oral dose of 1 mg/kg bw, or a single 100 mg/kg bw 

oral dose. Following single or multiple oral low doses (1 mg/kg bw) of [C14]-1-naphthaleneacetic 

acid, ethyl ester, urinary excretion accounted for 67.6-85.3% of the administered radioactivity. 

Urinary excretion was unaffected following a single 100 mg/kg bw dose with 61.8-78% of the 

administered radioactivity excreted in urine. Excretion via the feces accounted for the remainder 

of the administered radioactivity excreted by all treatment groups (12.3-35.2%). Excretory

patterns did not exhibit gender-related variability for the low dose groups although a minor 

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

delayed absorption. Because tissue burdens were very low at termination, neither 

1-naphthaleneacetic acid, ethyl ester nor its metabolites appear to undergo significant 

sequestration. Both urinary and fecal metabolites were quantified by HPLC, TLC and most were 

identified using HPLC, GC/MS, and HPLC/MS in conjunction with known standards. The major 

pathway of metabolism involved ester cleavage followed by glycine and glucuronide conjugation 

at the low and low repeat doses. At the high dose, glucuronide conjugation appeared to play a 
Page 49 of 52

more important role following ester cleavage. Parent compound was detected at low 

concentrations (0.5-4.7% of administered) only in feces. Extraction efficiencies appeared to be 

excellent and most components in the matrices examined (urine and feces) were adequately

quantified and characterized. The available data, based upon studies using labeled 

1-naphthaleneacetic acid, ethyl ester, affirmed the metabolism pathway proposed by the 

investigators.

There are two published reports dealing with the metabolism of NAA in animals. In one study 

(Dixon et al, 1977), carboxy -

14C-1-naphthylacetic acid (aqueous equivalent NaOH solution) at 

100 mg/kg was administered intramuscularly to 6 primate species (rhesus monkey: 1M, 1F; 

cynomolgus monkey: 1F; squirrel monkey: 2F; capuchin: 2F; marmoset: 1M and bushbaby: 1M, 

1F), and intraperitoneally to cats (2F, 1M), rat (3F) and fruit bat (1F, 1M), orally to the rabbit (2F) 

and orally to 2 human males at 5 mg/individual. Urine was collected for 24 hours and analyzed for 

radioactivity and metabolites, by liquid scintillation counting, chromatography, 

radiochromatography scanning, and reverse isotope dilution. In most species tested, 60-100% of 

the administered radioactivity was excreted in the urine by the end of 48 hours. The glucuronic 

acid conjugate was the major urinary metabolite in man, rhesus monkey, marmoset, rabbit, rat, 

and fruit bat. In the cat, no glucuronic acid conjugate was detected; turine and glycine conjugates 

were the major excretion products. The 1-Naphthylacetyl glycine conjugate was a major urinary 

metabolite (>20%) in the cat, squirrel and bushbaby monkey and a minor metabolite in rabbit, rat, 

capuchia and marmoset monkey. 1-Naphthylacetylglutamine conjugate was formed only in the 

cynomolgus , squirrel and capuchin monkeys and marmoset in amounts not exceeding 3% of the 

administered dose. 1-Naphthylacetylturine was excreted by all species except the rabbit, rat and 

the fruit bat. It was a major excretion product (>6%) in the squirrel and capuchin monkeys, the 

marmoset and the cat. In addition, when female rats were administered intraperitoneally doses of 

5-500 mg/kg, bile duct cannulation showed that 10-44% of the radioactivity was present in the bile 

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

glucuronic acid predominated whereas at the lower doses the glycine conjugates predominated. In 

the bile, the glucuronic acid conjugate was the major metabolite (>80% of the bile radioactivity), 

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

analysis of the fecal radioactivity reported. 

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

14C-1-naphthylacetic acid metabolism was 

investigated in male rats. 14C-NAA (neutralized with NaOH) was administered orally by stomach 

intubation at 0.1, 1.0, 100 and 250 mg/rat (2 rats/dose, weighing 250-280 g). Urine and feces were 

collected for 3 days. For bile cannulation study, 

14C-NAA was administered orally to 8 and 7 rats 

(weighing 350-435 g) at 0.1 and 100 mg/ rat, respectively, and urine and bile were collected at 2 

and 6 hours after administration. Radioactivity was analyzed by liquid scintillation counting, 

column and paper chromatography and enzymatic analysis. Within 3 days, 71-90% of the 

administered 14C was excreted in the urine. At the lower doses (0.1-100 mg/kg) most of the 

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

excretion was highest on the second day. Fecal excretion accounted for 3-10% at the 0.1-1.0 

mg/kg doses and 14-21% of the administered dose at the 100 and 259 mg/kg doses. After the third 

day, no radioactivity was detected in the feces or urine at any dose. Fractionation of the urinary

radioactivity by column chromatography and subsequent paper chromatography, UV spectral 
Page 50 of 52

analysis and B-glucuronidase enzyme hydrolysis, revealed that 70-93% of the urinary

radioactivity was NAA glycine conjugate and NAA glucuronic acid conjugate. The glucuronic 

acid conjugate predominated at the two high doses and the glycine conjugate predominated at the 

lower dose. Minor amounts of unchanged NAA and two other minor unidentified metabolites 

were also detected in the urine. The fecal radioactivity was not characterized. In the bile 

cannulation experiment, excretion of radioactivity into the bile and urine varied by the 

administered dose. At the low dose of 0.1 mg/kg radioactivity in the urine was nearly four times 

the radioactivity detected in the bile after 2 hours, while at the higher dose of 100 mg/kg the ratio 

was reversed. At the high dose a maximum of 29% of the administered radioactivity was 

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

low dose, the NAA glycine conjugate was the major metabolite and the NAA glucuronic 

conjugate was a minor metabolite, while in the bile the preponderance of these two metabolites 

was reversed. Also unchanged NAA was detected in the bile but not in the urine at both doses. At 

the high dose the NAA glucuronic conjugate was the major metabolite in both urine and bile 

while the glycine conjugate was a minor metabolite. 

A.4.9 Immunotoxicity

870.7800 Immunotoxicity – Rat

An immunotoxicity study is required. The registrant has committed to begin this study in early 

2013 and submit to EPA in early 2014.
Page 51 of 52

B. PHYSICAL/CHEMICAL PROPERTIES

Table 2. Physicochemical Properties of NAA1

Parameter Value Reference

Active Ingredient NAA acetamide

Melting point/range 182-184 C Farm Chemicals Handbook

pH of 1% aqueous suspension 5.1 Product CSF

Density or specific gravity 0.221 g/cm3Product CSF

Water solubility (20̊C) not available

Solvent solubility (20̊C) not available

Vapor pressure at 20̊C not available

Dissociation constant (pKa) not available

Octanol/water partition coefficient (Kow) not available

UV/vis absorption spectrum not available

Active ingredient NAA

Melting point/range 130 C Farm Chemicals Handbook

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

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

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

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

CCl4 1.06 g/100 mL

freely soluble in acetone, ether, 

and chloroform

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

Farm Chemicals Handbook

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

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

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

UV/vis absorption spectrum not available

Active ingredient NAA sodium salt

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

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

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

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

Solvent solubility (26̊C) insoluble in nonpolar solvents CB Nos. 3468 and 3469, 6/3/88, F. Suhre

Vapor pressure at 20̊C not available

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

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

UV/vis absorption spectrum not available

Active ingredient NAA ethyl ester

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
Page 52 of 52

Table 2. Physicochemical Properties of NAA1

Parameter Value Reference

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

B. REVIEW OF HUMAN RESEARCH

Klonne, D. (1999) Integrated Report for Evaluation of Potential Exposures to Homeowners and 

Professional Lawn Care Operators Mixing, Loading, and Applying Granular and Liquid Pesticides 

to Residential Lawns: Lab Project Number: OMA005: OMA001: OMA002. Unpublished study

prepared by Riceerca, Inc., and Morse Laboratories. 2213 p. (MRID 44972201).

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task 

Force members Health Canada, U.S. Environmental Protection Agency, and the National 

Agricultural Chemicals Association, released February, 1995.