2

Table of Contents

EXECUTIVE SUMMARY ................................................................................................... 3

I. BACKGROUND ................................................................................................................... 7

II. INERT INGREDIENT PROFILE ......................................................................................... 7

A. Summary of Uses....................................................................................................... 7

B. Physical Chemical Properties .................................................................................... 7

III. HUMAN HEALTH ASSESSMENT................................................................................... 11

A. Summary of Toxicity Data....................................................................................... 11

B. Toxicity Endpoint Selection .................................................................................... 18

C. Special Considerations for Infants and Children ..................................................... 20

IV. EXPOSURE ASSESSMENT .............................................................................................. 21

A. Dietary Exposure: .................................................................................................... 21

i. Acute exposure ..................................................................................................... 21

ii. Chronic exposure................................................................................................. 21

iii. Cancer exposure ................................................................................................. 23

B. Residential (Non-Occupational) Exposure: ............................................................. 23

i. From non-dietary exposure................................................................................... 24

V. AGGREGATE RISK ASSESSMENT ................................................................................ 25

i. Acute Dietary Risk................................................................................................ 26

ii. Chronic Dietary Risk. .......................................................................................... 26

iii. Aggregate Cancer Risk for U.S. Population....................................................... 26

iv. Short-term Aggregate Risk. ................................................................................ 26

v. Intermediate-Term Aggregate Risk. .................................................................... 27

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY.......................................................... 27

A. Occupational Handler Risk...................................................................................... 27

B. Occupational Post-Application Risk........................................................................ 30

VII. CUMULATIVE EXPOSURE ............................................................................................. 31

VIII. ENVIRONMENTAL JUSTICE STATEMENT.................................................................. 32

IX. ENVIRONMENTAL FATE CONSIDERATIONS ............................................................ 32

X. ECOTOXICITY................................................................................................................... 34

XI. RISK CHARACTERIZATION........................................................................................... 34

REFERENCES ................................................................................................................................ 38

APPENDIX...................................................................................................................................... 39
3

EXECUTIVE SUMMARY

Technology Sciences Group Inc. (TSG) on behalf of Huntsman Corporation. (8600 Gosling 

Rd., The Woodlands, Texas 77381, USA) is requesting that EPA establish an exemption from the 

requirement of a tolerance for ethanesulfonic acid, 2-hydroxy- (CAS Reg. No. 107-36-8) and the 

corresponding ammonium (CAS Reg. No. 57267-78-4), sodium (CAS Reg. No. 1562-00-1), 

potassium (CAS Reg. No. 1561-99-5), calcium (CAS Reg. No. 10550-47-7), magnesium (CAS 

Reg. No. 17345-56-1), and zinc (CAS Reg. No. 129756-32-7) salts, when used as inert ingredient 

(chelators, sequestrants and conditioning agents) in pesticide formulations applied to growing 

crops and raw agricultural commodities and applied to animals, in accordance with 40 CFR 

180.910 and 180.930, respectively.

Ethanesulfonic acid, 2-hydroxy-, (also referred to as isethionic acid) has been used for 

many years in personal care products. It is a common ingredient in bath soaps and detergent bars. 

A number of personal care products contain sodium isethionate and the majority of these are rinseoff products that contain 2% to 6% of isethionate salts. 

The acute oral toxicity of ammonium isethionate is low. The acute oral LD50s in rats were > 

1000 mg/kg-bw. The acute dermal toxicity in rats was > 1000 mg/kg-bw. Ammonium isethionate 

is a minimal eye irritant based on a primary eye irritation study in rabbits. Ammonium isethionate

is not dermally irritating based on a primary skin irritation study in rabbits. Ammonium 

isethionate has an acute inhalation LC50 > 6.295 mg/L and is not a dermal sensitizer.

In a 90-day oral toxicity study on rats via gavage with sodium isethionate, decreased mean 

corpuscular hemoglobin concentration, increased mean absolute and relative reticulocyte counts, 

increased spleen weights and microscopic changes in the liver, bile duct, and spleen were observed 

at 1000 mg/kg/day (LOAEL). Effects showed complete reversal after exposure was discontinued. 

The NOAEL for sodium isethionate was identified in this study as 200 mg/kg/day.

In a combined repeated dose toxicity study with the reproduction/developmental toxicity 

screening test, ammonium isethionate was administered to rats by gavage. The parental systemic 

LOAEL for ammonium isethionate is 500 mg/kg/day based on absolute and relative kidney 

weights and relative adrenal weights, and the parental systemic NOAEL is 250 mg/kg/day. The 

reproductive/developmental LOAEL for ammonium isethionate in rats was not identified, and the 

reproductive/developmental NOAEL is greater than or equal to 500 mg/kg/day.

Ammonium isethionate was negative for mutagenicity or chromosomal abberations in a 

battery of tests of genotoxicity including a reverse gene mutation assay in bacteria, an in vitro

mammalian cell gene mutation test using mouse lymphoma cells and an in vitro mammalian cell 

micronucleus test.

The OncoLogicTM structure-activity model was used to evaluate the likelihood that the 

isethionate salts may cause cancer. Structure-activity modeling using Oncologic indicates that 

isethionic acid does not contain structural alerts of potential concern for carcinogenicity. Based on 

the negative results for genotoxicity as well as the structure-activity model for carcinogenicity

there is a low concern for the salts of isethionate as potential carcinogens. 
4

No neurotoxicity studies were available in the database for isethionic acid and salts. 

However, a functional observational battery (FOB) and locomotor activity patterns were evaluated 

in the combined reproduction/developmental toxicity screening test and 90-day oral toxicity study.

No alterations in the FOB or locomotor activity patterns were observed.

No immunotoxicity studies on isethionic acid and its salts were available in the database.

Increased spleen weights and microscopic changes in the spleen were observed in the 90-day 

toxicity study in rats; however, the chronic reference dose (cRfD) is based on this study and is 

protective of these effects. 

No metabolism studies were available in the database for isethionic acid and its salts.

The chronic reference dose (cRfD) of 2.0 mg/kg/day was determined on the basis of the 

NOAEL from the 90-day oral toxicity study in rats. The LOAEL of 1000 mg/kg/day sodium 

isethionate is based on decreased body weight, changes in hematology parameters, increased

spleen weights and macroscopic changes in the liver. This study provided the lowest NOAEL in 

the database (most sensitive endpoint) and also provides the most protective limits for potential 

human effects. An uncertainity factor (UF) of 100X (10-fold for interspecies extrapolation and 10-

fold for intra species variability) was applied to the NOAEL of 200 mg/kg/day to derive the cRfD. 

This endpoint of concern was also used for all dermal and inhalation exposure scenarios. Both 

dermal and inhalation absorption were assumed to be 100%.

EPA has determined that reliable data show the safety of infants and children would be 

adequately protected if the FQPA SF were reduced to 1X. 

An acute dietary risk assessment was not conducted because no endpoint of concern 

following a single exposure was identified in the available studies. A chronic dietary exposure 

assessment was completed and performed using the Dietary Exposure Evaluation Model DEEMFCIDTM, Version 3.16. The chronic population-adjusted dose (cPAD) is the cRfD divided by the 

FQPA SF therefore the chronic population-adjusted dose (cPAD) is equal to the RfD of 2.0 

mg/kg/day.

Based on analyses of estimated dietary risks for the general U.S. population and various 

population subgroups, the chronic dietary exposure estimates for isethionic acid and its salts are 

significantly below the Agency’s level of concern for the general U.S. population and all 

population subgroups. The chronic dietary exposure estimate is 9.5% of the cPAD for the general 

population and 35.3% of the cPAD for the highest exposed population subgroup, children 1-2 

years old.

The Agency’s level of concern (LOC) for occupational and residential inhalation exposures 

to isethionic acid and its salts is 100 [i.e., a margin of exposure (MOE) greater than 100 is not of 

concern to EPA]. The LOC is based on a 10X uncertainty factor (UF) to account for interspecies 

extrapolation to humans from the animal test species and 10X UF to account for intra-species 

sensitivity.
5

Short-term aggregate exposure takes into account short-term residential exposure plus 

chronic exposure to food and water (considered to be a background exposure level). Isethionic acid 

and its salts may be used as an inert ingredient in pesticide products that could result in short-term 

residential exposure. The Agency has determined that it is appropriate to aggregate chronic 

exposure through food and water with short-term residential exposures. The adult short-term 

aggregate MOE was calculated to be 187 for both males and females. Adult aggregate MOE 

combines average food and water exposure from the chronic dietary exposure with high end

residential applicator exposure (liquid trigger sprayer). As the level of concern is for MOEs that 

are lower than 100, this MOE is not of concern. EPA has concluded the combined short-term 

aggregated food, water, and residential exposures results in an aggregate MOE of 123 for children. 

Children’s aggregate MOE combines average food and water exposure from the chronic dietary 

exposure with residential exposure associated with contact with threated lawns (dermal post-app, 

hand-to-mouth and object-to mouth). As the level of concern is for MOEs that are lower than 100, 

these MOEs are not of concern.

Intermediate -term aggregate exposure takes into account intermediate-term residential 

exposure plus chronic exposure to food and water (considered to be a background exposure level). 

Isethionic acid and its salts may be used as an inert ingredient in pesticide products that could 

result in intermediate-term residential exposure. The endpoint of concern selected for short- and 

intermediate-term exposure assessment is the same NOAEL, therefore intermediate term exposure

is not expected to exceed short term aggregate exposure and therefore there are no concerns for 

intermediate-term aggregate exposure. 

Occupational handler risks are not of concern for all scenarios. It is noted that this

occupational handler assessment assumes that mixer/loader/applicators are not wearing protective 

respirators when using open pour loading in support of aerial and groundboom application. The 

estimated MOEs are greater than 100 based on 100% dermal and inhalation absorption, except for 

the estimated combined MOE of 93 for liquid aerial application with gloves and no respirator on 

corn. Even though this estimated occupational MOE is slightly under 100, based on the nature of 

conservatism and uncertainty factors used in the estimation, this MOE and the other occupational 

MOEs are not of concern.

Occupational post-application risks are not of concern for all scenarios. It is noted that this 

occupational post-application assessment assumes default 20% dislodgeable foliar residue. The 

estimated MOEs are greater than 100 based on 100% dermal absorption. The lowest estimated 

MOE was 110, based on hand harvesting, leaf pulling, thinning, pruning, training/tying grapes. As 

the level of concern is for MOEs that are lower than 100, these MOEs are not of concern.

Isethionic acid and its salts are expected to have a minimal impact on the environment. The 

physical and chemical properties of isethionic acid and its salts indicate it is generally readily 

biodegradable and will degrade rapidly in the environment. Isethionic acid is expected to partition 

into the soil, but it may also remain in or enter the water where it may readily biodegrade. 

Isethionic acid is not expected to bioconcentrate in aquatic organisms. Isethionic acid is not 

volatile, and so it will not be released into the air. 
6

Based on the readily biodegradability of isethionic acid and its salts identified in the EPI 

Suite model, and the low toxicity to freshwater aquatic invertebrate, Daphnia magna, and the lack 

of inhibition on growth of the unicellular algae, Pseudokirchneriella subcapitata, effects of 

concern to nontarget aquatic species resulting from the use of isethionic acid and its salts as an 

inert ingredient are not anticipated. 

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.

Taking into consideration all available information on isethionic acid and its salts, EPA 

concludes that there is a reasonable certainty that no harm to any population subgroup will result 

from aggregate exposure to isethionic acid and its salts when considering residential, occupational, 

dietary exposure and all other non-occupational sources of pesticide exposure for which there is 

reliable information. Therefore, the establishment of an exemption from the requirement of a 

tolerance under 40 CFR 180.910 and 180.930 for residues of ethanesulfonic acid, 2-hydroxy-

(CAS Reg. No. 107-36-8), and the corresponding ammonium (CAS Reg. No 57267-78-4), sodium 

(CAS Reg. No. 1562-00-1), potassium (CAS Reg. No. 1561-99-5), calcium (CAS Reg. No. 10550-

47-7), magnesium (CAS Reg. No. 17345-56-1), zinc (CAS Reg. No 129756-32-7), salts when used 

as a pesticide inert ingredient applied to growing crops, raw agricultural commodities after harvest 

and animals can be considered assessed as safe under section 408(q) of the FFDCA.
7

I. BACKGROUND

Technology Sciences Group Inc. (TSG) on behalf of Huntsman Corporation. (8600 Gosling 

Rd., The Woodlands, Texas 77381, USA) is requesting that EPA establish an exemption from 

tolerance for ethanesulfonic acid, 2-hydroxy- (CAS Reg. No. 107-36-8) and the corresponding 

ammonium (CAS Reg. No. 57267-78-4), sodium (CAS Reg. No. 1562-00-1), potassium (CAS 

Reg. No. 1561-99-5), calcium (CAS Reg. No. 10550-47-7), magnesium (CAS Reg. No. 17345-56-

1), and zinc (CAS Reg. No. 129756-32-7) salts when used as (chelators, sequestrants and

conditioning agents) in pesticide formulations applied to growing crops, raw agricultural 

commodities after harvest and application to animals in accordance with 40 CFR 180.910 and 

180.930, respectively. 

II. INERT INGREDIENT PROFILE

A. Summary of Uses

Isethionic acid and its salts have been used for many years in personal care products. It is a 

common ingredient in bath soaps and detergent bars (NLM, HPDC; CIR, 2013). 

Approximately 77 personal care products contain sodium isethionate and the majority of 

these are rinse-off products that contain 2 to 6% of the isethionate (CIR, 2013). 

Approximately 61 of the products may be applied to mucus membranes, and these contain 

a maximum of 6% sodium isethionate. One leave-on product contains 0.8% of sodium 

isethionate (CIR, 2013).

B. Physical Chemical Properties

Some of the physical and chemical characteristics of isethionic acid and its salts, along with 

its structure and nomenclature, are found in Table 1a and 1b. The physical-chemical 

properties and environmental fate characteristics of ethanesulfonic acid, 2-hydroxy-

(isethionic acid), ethanesulfonic acid, 2-hydroxy, ammonium salt (ammonium isethionate),

ethanesulfonic acid, 2-hydroxy-, monopotassium salt (Potassium isethionate), and 

ehtanesulfonic acid, 2-hydroxy-, zinc salt (zinc isethionate) were estimated using EPI Suite. 

EPI Suite is a screening-level tool used to estimate the physical chemical properties and 

environmental fate of compounds when measured values are not available.

Table 1a. Physical and Chemical Properties of Ethanesulfonic acid, 2-hydroxy- (Isethionic Acid) 

Parameter Value Source

Structure

CAS # 107-36-8 EPI Suite

Molecular Formula C2H6SO4 EPI Suite

Molecular Weight (g/mol) 126.1 EPI Suite

Common Names Isethionic acid EPI Suite

Melting Point (°C) 76.88 EPI Suite

Boiling Point (°C) 297.3 EPI Suite

Octanol/water Partition Coefficient 

(Log Kow)

-3.36 EPI Suite

Soil organic carbon/water Partition 

coefficient (Log Koc)

0

c

-1.345d EPI Suite

Solubility 1.0E+6a EPI Suite
8

Table 1a. Physical and Chemical Properties of Ethanesulfonic acid, 2-hydroxy- (Isethionic Acid) 

Parameter Value Source

1.0E+6b

Vapor Pressure (mmHg at 25°C) 8.8E-5 EPI Suite

Henry's Law Constant (atm*m3/mole 

at 25°C) 6.11E-13 EPI Suite
Table 1b. Physical and Chemical Properties of Ethanesulfonic acid, 2-hydroxy- (Isethionic Acid) and Representative Corresponding Salts.

Parameter Isethionic Acid Ammonium Isethionate Potassium Isethionate Zinc Isethionate

Structure

CAS # 107-36-8 57267-78-4 1561-99-5 129756-32-7

Molecular Formula C2H6SO4 C2H5SO4NH4 C2H5SO4K C4H10S2O8Zn

Molecular Weight (g/mol) 126.1 143.13 164.22 315.63

Melting Point (°C) 76.88 178.61 214.41 233.13

Boiling Point (°C) 297.3 427.23 503.8 543.96

Octanol/water Partition Coefficient (Log Kow) -3.36 -2.65 -5.5 -2.37

Soil organic carbon/water Partition coefficient (Log Koc) 0

c

-1.345d

0

c

-0.791d

0

c

-2.529d

0

c

-0.886d

Solubility 1.0E+6a

1.0E+6b

1.0E+6a

8.55E+5b

1.0E+6a

9.814E+5b

1.0E+6a

1.0E+6b

Vapor Pressure (mmHg at 25°C) 8.8E-5 7.36 E-10 1.37 E-12 1.36E-14

Henry's Law Constant (atm*m3/mole at 25°C) 6.11E-13 1.386E-16 2.96 E-19 5.648 E-21

Probability of Rapid Biodegradation (BIOWIN)

0.9546e

0.9999f

3.273 days-weeksg

0.5969h

0.6787i

0.8381e

0.8903f

3.04 days-weeksg

0.5370h

0.6250i

0.9546e

0.9999f

3.273 days-weeksg

0.5969h

0.6787i

0.97147e

0.6819f

2.8216 weeksg

0.2931h

0.0542i

Ready Biodegradability Yes Yes Yes No

BCF (L/kg wet-wt) 3.162 3.162 3.162 3.162

Volatilization from Water Half Life (hr) 1.076 E+9j

1.174 E+10k

2.38 E+17j

2.39 2.6 E+18k

2.535 E+15j

2.765 E+16k

1.842 E+17j

2.009 E+18k

Fugacity Model Compartment/ Mass Amount (%)

Air: 2.14 E-5

Water: 33.5

Soil: 66.5

Sediment: 0.0592

Air: 2.6E-12

Water: 37.7

Soil: 62.2

Sediment: 0.0706

Air: 9.08 E-8

Water: 33.5

Soil: 66.5

Sediment: 0.0592

Air: 6.96 E-8

Water: 30.6

Soil: 69.4

Sediment: 0.0688

Fugacity Model Compartment/ Hal fife (hr)

Air: 47.1

Water: 208

Soil: 416

Sediment: 1.87 E+3

Air: 48.3

Water: 360

Soil: 720

Sediment: 3.24 E+3

Air: 48.3

Water: 208

Soil: 416

Sediment: 1.87 E+3

Air: 24.2

Water 360

Soil: 720

Sediment: 3.24 E+3

a WSKOW result; not appropriate for estimation of water solubility of dispersible compounds, including surfactants

b Fragment results

c MCI method results
10

d Kow method results

e Biowin1 (linear model)

f Biowin2 (non-linear model)

g Biowin3 (Ultimate survey model)

h Biowin5 (MITI linear model)

i Biowin6 (MITI non-linear model)

j Model River

k Model Lake
III. HUMAN HEALTH ASSESSMENT

A. Summary of Toxicity Data 

Acute Oral Toxicity

In an acute oral toxicity study (MRID 49285804), four fasted, young adult female SpragueDawley rats were given a single dose of 550 or 2000 mg/kg ammonium isethionate (purity 

50%) by gavage. Initially, a single animal was dosed at 550 mg/kg. Since this animal 

survived, the second animal was dosed at 2000 mg/kg. Two additional animals were dosed 

at 2000 mg/kg. Individual body weights were recorded prior to dosing on day 1 and on 

days 8 and 15. The animals were observed for mortality and clinical signs of toxicity 

approximately 30 minutes and 4 hours post-dosing and once daily thereafter for the 

remainder of the 14-day study period. All animals were necropsied at the end of the study.

All animals appeared normal, gained weight, and survived the study. No visible lesions 

were noted from any animal at necropsy.

Oral LD50 females > 2000 (1000 corrected for purity) mg/kg.

Based on the observed LD50 in females, ammonium isethionate is classified as EPA 

Toxicity Category III.

This study is classified as acceptable. It does satisfy the guideline requirements for an 

acute oral study (OCSPP 870.1100; OECD 425) in the rat.

Acute Dermal Toxicity

In an acute dermal toxicity study (MRID 49285806), young adult Sprague-Dawley, 

Hsd:SD rats (5 males and 10 females) were dermally exposed for 24 hours on an area of 

approximately 10% of the total body surface area on the clipped dorsal trunk to 2000 

mg/kg ammonium isethionate (purity 50%) as received. The test material was applied 

evenly over the dose area and covered with a gauze patch/dental dam. The gauze and the 

trunk were wrapped with an elastic bandage and secured with non-irritating tape. The 

animals were observed immediately after the 24 hours post dose unwrap and daily for 14 

days. Body weight was recorded prior to dosing on day 1 and on days 8 and 15.

All animals appeared normal, gained weight, and survived the study. No visible lesions 

were noted from any animal at necropsy.

LD50 Males > 2000 (1000 corrected for purity) mg/kg.

LD50 Females > 2000 (1000 corrected for purity) mg/kg.

LD50 Combined > 2000 (1000 corrected for purity) mg/kg.
12

Based on the observed LD50, ammonium isethionate is classified as EPA Toxicity Category 

III. 

This study is classified as acceptable. It does satisfy the guideline requirements for an 

acute dermal study (OCSPP 870.1200; OECD 402) in the rat.

Inhalation Toxicity

In an acute inhalation toxicity study (MRID 49285805), young adult Wistar Hannover rats 

(5/sex/group; age: 10 weeks; body weight: males: 291-348 g and females: 196-214 g; 

source: BIOAGRI’S (DF) rearing house) were exposed by nose-only inhalation to 55% 

ammonium isethionate (Batch No.: 8781-14-38) for 4 hours at a concentration of 6.295 

mg/L. The animals were observed frequently during exposure, immediately after exposure, 

twice during the first 24 hours post-exposure, then daily for 14 days. The animals were 

weighed on days 0, 1, 3, 7, and 14 and were necropsied at the end of the study. The mass 

median aerodynamic diameter (MMADs) were 4.0 and 3.84 m and the geometric standard 

deviation (GSD) 2.07 and 2.08, respectively.

All animals survived until study termination. Piloerection, kyphosis, epistaxis, and/or 

chromodacryorrhea were noted on all animals after removal from exposure with recovery 

by the next day. With the exception of one male that lost weight during the first week, all 

animals gained weight during the study. No macroscopic findings were noted at necropsy.

LC50 Males > 6.295 mg/L

LC50 Females > 6.295 mg/L 

LC50 Combined > 6.295 mg/L

Based on the observed LC50, ammonium isethionate is classified as EPA Toxicity Category 

IV.

This study is classified as acceptable. It does satisfy the guideline requirements for an 

acute inhalation study (OCSPP 870.1300; OECD 403) in the rat.

Primary Eye Irritation

In a primary eye irritation study (MRID 49285807), 0.1 mL of undiluted ammonium 

isethionate (purity 50%) was instilled as received into the conjunctival sac of the right eye 

of three male young adult New Zealand White rabbits (age: 16 weeks; body weight: 2.8-3.2 

kg; source: Harlan). The untreated eye served as a control. The animals were observed at 

1, 24, 48, and 72 hours post-instillation.

No corneal opacity was noted on any animal during the study. Iritis was noted on two 

treated rabbits one hour after test material instillation with clearance by 24 hours. Positive 

conjunctival irritation (chemosis) was noted on all treated rabbits one hour after test 

material instillation with clearance by 24 hours. The highest maximum mean total score 

was 14.7, recorded one hour after test material instillation.
13

Based on no “positive” irritation by 72 hours, ammonium isethionate was minimally 

irritating and is classified as EPA toxicity category III for primary eye irritation.

This study is classified as acceptable. It does satisfy the guideline requirements for a 

primary eye irritation study (OCSPP 870.2400; OECD 405) in the rabbit.

Primary Skin Irritation

In a primary dermal irritation study (MRID 49285808), three female young adult New 

Zealand White rabbits were dermally exposed to 0.5 mL of undiluted ammonium 

isethionate (purity 50) for 4 hours on a ~ 5 cm x 5 cm area of the clipped dorsal skin that 

was covered loosely with a gauze patch. The patch and trunk were wrapped with elastic 

bandage dressing and secured with non-irritating tape. The animals were observed and 

irritation was scored at 30-60 minutes, and 24, 48, and 72 hours after patch removal. 

Before the study, one animal was exposed to the same amount test material for three 

minutes on one site and for 60 minutes at another site. No serious irritation was observed, 

so the four-hour exposure was used. 

All animals survived and no dermal irritation was noted on any animal during the study.

In this study, the test material was not irritating and the primary irritation index (PII) was 

0.0, based on the non-irritation at 72 hours. Ammonium isethionate is classified as EPA 

toxicity category IV for primary dermal irritation. 

This study is classified as acceptable. It does satisfy the guideline requirements for a 

primary dermal irritation study (OCSPP 870.2500; OECD 404) in the rabbit.

Dermal Sensitization

In a dermal sensitization study (MRID 49285809) with ammonium isethionate, 20 male 

and 20 female young adult Hartley guinea pigs; were tested using the Buehler Method. 

Dose levels were based on the range dose finding results with 100% test material. The test 

animals (ten males and ten females) were induced with undiluted test material for six hours 

using 25 mm Hilltop chambers that were occluded with a rubber dental dam and secured 

with restrainer and binder clip. The procedure was repeated once each week for three 

consecutive weeks. Fourteen days after the last induction, the test animals were challenged 

with undiluted test material (left flank) and mineral oil (right flank) under occlusion to 

naive sites. The vehicle control animals (five males and five females) were treated with 

mineral oil at induction and the positive control animals (three males and three females) 

were treated with 0.3% 1-chloro-2,4-dinitrobenzene (DNCB) in 80% ethanol at induction. 

The vehicle control animals were challenged with undiluted test material (right flank) and 

mineral oil (left flank). The positive control animals were challenged with 0.2% DNCB in 

acetone. Reactions were scored 24 and 48 hours following induction and challenge.

After three consecutive inductions and challenge, no dermal reactions were noted on any 

vehicle control or test animal. The positive control animals showed appropriate results.
14

Based on the results of this study, ammonium isethionate was not a dermal sensitizer. The 

mean challenge scores were 0.0 for control and test animals at 24 hours and 48 hours.

This study is classified as acceptable. It does satisfy the guideline requirements for a 

dermal sensitization study (OCSPP 870.2600; OECD 406) in the guinea pigs.

Acute Toxicity

Table 2. Acute Toxicity Profile of Isethionic Acid and Salts

Study Type Results MRIDs # /Reference

Acute Oral – rat

OCSPP 870.1100

OECD 425

LD50 (female) > 1000 mg/kg MRID 49285804

Vasquez, R. 2011

Acute Dermal – rat

OCSPP 870.1200

OECD 402

LD50 >1000 mg/kg MRID 49285806

Vasquez, R. 2011

Acute Inhalation – rat

OCSPP 870.1300

OECD 403

LC50 >6.295 mg/L MRID 49285805

Ferreira, T. 2012

Primary Eye Irritation – rabbit

OCSPP 870.2400

OECD 405

Minimally irritating MRID 49285807

Vasquez, R. 2011

Primary Skin Irritation – rabbit

OCSPP 870.2500

OECD 404

Not irritating MRID 49285808

Vasquez, R. 2011

Dermal Sensitization – guinea pig

OCSPP 870.2600

OECD 406

Not a dermal sensitizer MRID 49285809

Vasquez, R. 2011

Subchronic Toxicity –

A 90-day oral dose toxicity study was conducted on male and female Wistar rats that 

received sodium isethionate at doses of 50, 200 or 1000 mg/kg body weight/day via gavage 

(CIR, 2013). The control group and the high dose group consisted of 15 animals of each 

sex, and the low and mid dose groups had 10 animals per group. Five animals from the 

control group and high dose group were kept on regular diet for 28 days to assess 

reversibility of effects. All rats survived until study end. No clinical signs of toxicity were 

observed during daily or weekly observations. There were also no toxicologically relevant 

ophthalmoscopic changes, no differences in the mean feed consumption, no changes in 

hematology parameters at 50 mg/kg/day or 200 mg/kg/day, and no changes in urinalysis 

parameters at 50 mg/kg/day. A statistically significant difference was identified in the mean 

hindlimb grip strength of males dosed with 1000 mg/kg/day compared with controls, but 

this was considered secondary to a decrease in body weight. No clinical signs were evident 

at any dose level during the fictional observation battery. There were no test item-related 

effects on the mean locomotor activity. Changes in the hematology parameters were 

reported in the 1000 mg/kg/day group which included a decrease in mean corpuscular 

hemoglobin concentration and an increase in mean absolute and relative reticulocyte 

counts. Gross pathology findings included increased spleen weights and macroscopic 

changes in the liver in rats at 1000 mg/kg/day. Histopathology findings included 
15

microscopic changes in the liver, bile duct, and spleen. Effects showed complete reversal 

after exposure was discontinued. The LOAEL was 1000 mg/kg/day based on decreased 

mean corpuscular hemoglobin concentration and increased mean absolute and relative 

reticulocyte counts, increased spleen weights and macroscopic changes in the liver and 

microscopic changes in the liver, bile duct, and spleen. The NOAEL for sodium 

isethionate was identified in this study as 200 mg/kg/day.

Developmental Toxicity -

In a combined reproduction/developmental toxicity screening test (MRID 49285810),

ammonium isethionate (purity 50%) was administered to twelve Wistar Hannover 

rats/sex/dose by gavage in deionized water at dose levels of 0, 250, 500, or 1000 

mg/kg bw/day (0, 125, 250 or 500 mg/kg/day corrected for purity) for at least 14 days prior 

to mating, throughout mating, and after mating, up to and including the day prior to 

sacrifice. Terminal sacrifices took place following at least 28 days of treatment for males, 

on lactation day (LD) 4 for females that littered, on or after presumptive gestation day 

(GD) 26 for mated females that did not litter, or 24-26 days after the last day of the mating 

interval for females without evidence of mating. Evaluated parameters in the parental 

animals included functional observational battery (FOB), hematology, clinical chemistry, 

organ weights, and histopathology (in 5 animals/sex/day); grip strength and motor activity 

were not assessed. Two additional satellite groups of five unmated animals per sex were 

treated with 0 or 500 mg/kg/day ammonium isethionate for at least 28 days, then 

maintained untreated and observed for the reversibility, persistence, or delayed occurrence 

of systemic toxic effects for at least 14 days post treatment. 

There were no treatment-related effects on mortality, clinical signs, body weight, body 

weight gain, or food consumption. Toxicity was evident in mid- and high-dose males as 

reversible decreases in serum sodium concentration (146.6-149.0 mEq/L vs. 165.0 mEq/L 

for controls; p<0.05) and serum protein (5.9-6.1 g/dL vs. 7.4 g/dL for controls; p<0.05) 

with both albumin and globulins decreased. High-dose males also had reversible decreases 

in erythrocyte count (5.22 vs. 8.21 106/mL), hemoglobin (10.50 vs. 16.24 g/dL), and 

hematocrit (30.24 vs. 45.12%) without alteration in mean cell volume (MCV), mean 

corpuscular hemoglobin (MCH), or mean corpuscular hemoglobin concentration (MCHC). 

Slight dilatation of the renal pelvis was noted unilaterally or bilaterally in 4/5 of the 

evaluated high-dose main-study females and 1/5 high-dose main-study males but was not 

noted in any main-study control animal of either sex. It is unknown why histopathological 

evaluation of the kidneys was not extended to include additional treated main-study groups 

and the satellite/recovery animals. Absolute and relative-to-body adrenal weights were 

increased in main-study high-dose males (36-43% greater than controls; p<0.05). Absolute 

and relative-to-body kidney weights were increased in high-dose main-study males and 

females (absolute weights of right and left kidneys: +10-15% and +14% in males and 

females, respectively) and remained increased in the high-dose satellite/recovery males and 

females (absolute weights of right and left kidneys: +9-10% and +12-16%, respectively). 

The increased organ weights in the high-dose animals are considered adverse in light of the 

clinical chemistry abnormalities (in males) and histopathology findings (females); the 

effect on the adrenal weights was reversible, but the effect on the kidney weights did not 

appear to be reversible within two weeks. Therefore, the parental systemic LOAEL for 
16

ammonium isethionate in male rats is 500 mg/kg/day, based on absolute and relative 

kidney weights and relative adrenal weights, and the parental systemic NOAEL in male 

rats is 250 mg/kg/day. 

There were no clear treatment-related effects on the reproductive indices, the mean 

numbers of corpora lutea and implantation sites, precoital intervals, gestation lengths, or 

pre- or postimplantation losses. Numbers of stillborn pups, live litter sizes, pup survival to 

PND 4, pup clinical signs and macroscopic findings, and pup weight and growth were not 

affected by treatment. An increased percentage of male pups seen in the high-dose litters 

on both PNDs 0 and 4 was not considered treatment-related because there were no 

correlated changes in other endpoints (e.g. live litter size, numbers of dead pups, increased 

postimplantation loss) to definitively indicate decreased survival of female embryos or 

fetuses. Under the conditions of this study, the reproductive/developmental LOAEL for 

ammonium isethionate in rats was not identified, and the reproductive/developmental 

NOAEL was greater than or equal to 500 mg/kg/day. However, the negative findings must 

be interpreted with caution because only seven high-dose litters were available for 

evaluation, while preimplantation losses in all groups were unusually high (>42%), and 

there were more total litter resorptions seen (across groups and including the control group) 

than one would normally expect in a study with twelve females per group. 

This study is classified as acceptable / guideline and satisfies the guideline requirement for 

a combined reproduction/developmental toxicity screening test (OCSPP 870.3650; OECD 

422) in the rat. The study was of adequate quality to identify the kidney and adrenals as 

potential target organs. It must be noted that the study did not adequately screen for 

functional neurological effects, and the negative developmental/reproductive findings are 

of limited usefulness and must be interpreted with caution. 

Mutagenicity and Genotoxicity

In a reverse gene mutation assay in bacteria (MRID 49285811), Salmonella typhimurium

strains TA98, TA100, TA1535, and TA1537 and Escherichia coli strain WP2 uvrA were 

exposed to test article ammonium isethionate dissolved in water, without and with S9 

activation, in two independent plate incorporation tests. In the first test the concentrations 

were: 0, 1.5, 5.0, 15, 50, 150, 500, 1500, and 5000 μg/plate, without and with activation, in 

all strains, using two plates/concentration. Due to an initial unacceptable positive control 

value for tester strain WP2 uvrA with activation, the tester strain was retested based on the 

precipitate and toxicity profiles observed. In the re-test of tester strain WP2 uvrA in the 

presence of S9 activation, the concentrations of the test article were 50, 150, 500, 1500 and 

5000 μg/plate. In the repeat experiment the concentrations were: 0, 50, 150, 500, 1500, and 

5000 μg/plate with all tester strains, without or with activation. Triplicate plating was used 

in all cases in the repeat experiment. The S9 fraction was obtained from Aroclor 1254-

induced male Sprague-Dawley rat liver.

In both experiments the test article was soluble under all experimental conditions. The test 

article was tested up to the limit concentration of the assay with no evidence of cytotoxicity

at any concentration, without or with activation. The number of revertants per plate was not 

increased over the concurrent solvent control value at any test article concentration, up to 
17

the limit concentration of 5000 μg/plate, without or with S9-mix, in any tester strain, in 

either experiment. The solvent and positive controls induced the appropriate responses in 

the corresponding strains and were in agreement with the historical control data from this 

laboratory. There was no evidence of induced mutant colonies over background.

This study is classified as acceptable/guideline and does satisfy the guideline requirement 

for Test Guideline OCSPP 870.51001; OECD 471 for in vitro mutagenicity (bacterial 

reverse gene mutation) data. 

In an in vitro mammalian cell gene mutation test using mouse lymphoma cells (CIR, 2013), 

the potential for sodium isethionate to induce mutations was evaluated. Two assays were 

performed, one had a 4 hour treatment both with and without metabolic activation, and the 

second had a 24 hour treatment without metabolic activation and a 4 hour treatment with 

activation. Sodium isethionate did not induce mutations in the mouse lymphoma thymidine 

kinase locus L5178Y assay either with or without metabolic activation.

The potential for sodium isethionate to induce micronuclei was evaluated in human 

lymphocytes with and without metabolic activation (CIR, 2013). Two experiments were 

performed, one had a 4 hour exposure period both with and without metabolic activation, 

and the second had a 24 hour exposure period without metabolic activation and a 4 hour 

exposure period with activation. Sodium isethionate did not induce micronuclei in human

lymphocytes in the in vitro mammalian cell micronucleus test with or without metabolic 

activation.

Carcinogenicity

In the absence of data from an animal bioassay to evaluate the potential for the salts of 

isethionate to stimulate development of cancer, the OncoLogic structure activity model was 

used to evaluate the likelihood that the isethionate salts may cause cancer. Structureactivity modeling using Oncologic indicates no specific structural alerts for carcinogenicity 

suggesting that there is a low concern for potential carcinogenicity from exposure to 

isethionic acid. Based on the negative results for genotoxicity in bacterial and mammalian 

cell assays, and lack of structural alerts in the OncoLogic, there is a low concern for the 

salts of isethionate as potential carcinogens. 

Reproductive Toxicity

See Developmental Toxicity section.

Immunotoxicity

No immunotoxicity studies were available in the database for isethionic acid or salts.

Increased spleen weights and microscopic changes in the spleen were observed in the 90-

day toxicity study in rats. The increased weights were due to accumulation of iron. 

Neurotoxicity

No neurotoxicity studies were available in the database for isethionic acid and salts.

However, neurotoxicity was evaluated in the combined repeated dose toxicity study with 
18

the reproduction/developmental toxicity screening test (MRID 49285810) and also in the 

90 day study. No alterations in the FOB or locomotor activity patterns were reported in 

male or female treated groups compared to control.

Metabolism and Pharmacokinetics

No metabolism studies were available in the database for isethionic acid and salts.

Table 3. Toxicology Profile of Isethionic Acid and Salts

Guideline No./ Study Type Doses Levels Results MRID No. 

(year)/References

Combined Repeated Dose Toxicity 

Study with 

Reproduction/Developmental 

Toxicity Screening Test

Ammonium isethionate

OCSPP 870.3650

OECD 422

0, 250, 500, or 

1000 mg/kg/day

0, 125, 250, or 

500 mg/kg/day 

(adjusted for 

50% purity)

NOAEL (parental) 250 mg/kg/day

(corrected for purity)

LOAEL (parental) 500 mg/kg/day 

(corrected for purity) based on 

decreased serum sodium and protein 

concentrations (albumin and 

globulin)

NOAEL (repro/developmental) > 

500 mg/kg/day (corrected for purity)

LOAEL (repro/developmental) was 

not established.

MRID 49285810

Martell, A. 2013

90 Day oral toxicity study – rats 

(gavage)

Sodium isethionate

50, 200 or 1000 

mg/kg bw/day

NOAEL 200 mg/kg bw/day

LOAEL 1000 mg/kg bw/day based 

on decrease body weight, changes in 

hematology parameters, increase 

spleen weights, macroscopic changes 

in liver and microscopic changes in 

the liver, bile duct and spleen.

CIR 2013

In vitro Bacterial Gene Mutation

Ammonium isethionate

OCSPP 870.5100

OECD 471

0, 1.5, 5.0, 15, 

50, 150, 500, 

1500, and 5000 

μg/plate with 

and without 

metabolic 

activation

Negative MRID 49285811

Wagner, V.O. (III) 

and Divi, K. 2011

B. Toxicity Endpoint Selection

The 90-day oral dose toxicity study in rats was selected for dietary, dermal and inhalation 

exposure scenarios (all durations) for this risk assessment. The NOAEL in this study was 

200 mg/kg/day. The LOAEL was 1000 mg/kg/day based on decrease body weight, 

changes in hematology parameters, increase spleen weights and macroscopic changes in 

the liver and microscopic changes in the liver, bile duct and spleen. The rationale for 

selecting this study for the dietary, dermal and inhalation exposure scenario is based on the 

fact that this study provided the lowest and most conservative toxicity endpoint in the most 

sensitive species. Uncertainty Factor of 100x was applied, 10x for interspecies variability 

and 10x for intraspecies variability. A default value of 100% absorption will be used for

dermal and inhalation exposure scenarios. 
19

Table 4. Summary of Toxicological Doses and Endpoints of Isethionic Acid and Salts for Use in Human 

Health Risk Assessment

Exposure/Scenario Point of Departure and 

Uncertainty/Safety 

Factors

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects

Acute dietary 

(General population 

including infants and 

children)

An acute effect was not found in the database therefore an acute dietary assessment is not 

necessary.

Chronic dietary 

(All populations)

NOAEL= 200 mg/kg/day 

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

Chronic RfD = 

200 mg/kg/day

cPAD = 2.0

mg/kg/day

[90-day oral toxicity-rat] LOAEL = 1000

mg/kg/day based on decrease body 

weight, changes in hematology 

parameters, increase spleen weights, 

macroscopic changes in the liver and 

microscopic changes in the liver, bile 

duct and spleen.

Incidental oral shortterm 

(1 to 30 days)

NOAEL= 200 mg/kg/day 

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE 

= 100

[90-day oral toxicity-rat] LOAEL = 1000

mg/kg/day based on decrease body 

weight, changes in hematology 

parameters, increase spleen weights, 

macroscopic changes in the liver and 

microscopic changes in the liver, bile 

duct and spleen.

Incidental oral 

intermediate-term 

(1 to 6 months)

NOAEL= 200 mg/kg/day

UFA= 10 x

UFH= 10 x

FQPA SF = 1 x

LOC for MOE 

= 100

[90-day oral toxicity-rat] LOAEL = 1000

mg/kg/day based on decrease body 

weight, changes in hematology 

parameters, increase spleen weights , 

macroscopic changes in the liver and 

microscopic changes in the liver, bile 

duct and spleen.

Dermal short- and 

intermediate term 

Oral study NOAEL= 200

mg/kg/day (dermal

absorption rate = 100%)

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE 

= 100

[90-day oral toxicity-rat] LOAEL = 1000

mg/kg/day based on decrease body 

weight, changes in hematology 

parameters, increase spleen weights , 

macroscopic changes in the liver and 

microscopic changes in the liver, bile 

duct and spleen.

Inhalation short- and 

intermediate term 

Oral study NOAEL= 200

mg/kg/day (inhalation 

absorption rate = 100%)

UFA = 10 x

UFH = 10 x

FQPA SF = 1 x

LOC for MOE 

= 100 

[90-day oral toxicity-rat] LOAEL = 1000

mg/kg/day based on decrease body 

weight, changes in hematology 

parameters, increase spleen weights , 

macroscopic changes in the liver and 

microscopic changes in the liver, bile 

duct and spleen.

Cancer (Oral, dermal, 

inhalation)

Based on Oncologic and the functional analysis endpoint of chronic inflammation that 

could be identified based on the high dose effects in the 90-day exposure to 1000 

mg/kg/day and on the negative results for genotoxicity in bacterial and mammalian cell 

assays, there is a low concern for the salts of isethionate and isethionic acid as potential 

carcinogens. 

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 data or other data deficiency. FQPA SF = Food 
20

Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. 

MOE = margin of exposure. LOC = level of concern.

C. Special Considerations for Infants and Children

FFDCA, as amended by FQPA, directs the Agency to use an additional 10X safety factor 

(SF), to account for potential pre- and postnatal toxicity and completeness of the data with

respect to exposure and toxicity to infants and children. FQPA authorizes the Agency to 

modify the 10X FQPA SF only if reliable data demonstrate that the resulting level of 

exposure would be safe for infants and children. EPA concludes that the FQPA safety 

factor could be reduced to 1X for isethionic acid and its salts for the following reasons:

i. The toxicity database for isethionic acid and its salts contains the following 

acceptable studies: subchronic, reproduction/developmental screening study, and a 

mutagenicity study. The database is considered as adequate for FQPA assessment.

ii. Fetal susceptibility was not observed in the combined developmental/reproduction 

toxicity screening test in rats. Neither offspring nor reproduction toxicity was observed in 

this study. Parental toxicity was observed at the highest dose of 500 mg/kg/day (corrected

dose) in rats. 

iii. There is no indication that isethionic acid and its salts are neurotoxic chemicals. 

Although no neurotoxicity studies were available in the database, no neurotoxicity 

parameters (FOB and motor activity) measurements were affected in the available 

reproductive/developmental screening study and 90-day toxicity study in rats. Therefore, 

there is no need for a developmental neurotoxicity study or additional UFs to account for 

neurotoxicity. 

iv. There is no indication that isethionic acid and its salts are immunotoxic chemicals. 

No immunotoxicity studies were available in the database for isethionic acid or its salts. 

Increased spleen weights and microscopic changes in the spleen were observed in the 90-

day toxicity study in rats. The increase in spleen weight and microscopic changes were due 

to red blood cell destruction and therefore, not considered as immunotoxicity. In addition, 

the cRfD is based on this study and is protective of these effects. Therefore, there is no 

need for an immunotoxicity study or additional UFs to account for immunotoxicity.

v. The dietary food exposure assessment utilizes proposed tolerance level or higher 

residues and 100% crop treated information for all commodities. By using these screeninglevel assessments, chronic exposures/risks will not be underestimated.

Taking into consideration the available information, EPA concludes the additional 10X 

FQPA safety factor can be reduced to 1X.
21

IV. EXPOSURE ASSESSMENT

The petitioner requested the ability to use isethionic acid and its salts in any type of 

pesticide i.e., insecticide, fungicide or herbicide on any application site i.e., agricultural 

crops, livestock, residential uses indoor and outdoor. The petitioner did not provide any 

exposure or risk assessments regarding human occupational or residential exposure. 

Resources constraints prohibit the Agency from conducting monographic, “all-inclusive” 

assessments of exposure for all possible or imaginable combinations of methods of 

application to all possible application sites.

Therefore, the Agency has conducted a “screening-level” assessment of a wide variety of 

sites and use patterns in an effort to obtain a qualitative idea of the possible results of 

human exposures that might result from such combinations of methods of application and 

sites of application. 

It should be noted again, as indicated from the earlier discussion of toxicological 

properties, that the data and information regarding toxicological effects are limited. Thus 

the “screening-level” assessment is based upon some conservative assumptions. 

A. Dietary Exposure:

 i. Acute exposure. No adverse effects attributable to a single exposure of isethionic acid 

and/or its salts were seen in the toxicity databases. Therefore, acute dietary risk assessment 

for isethionic acid and/or salts is not required.

 ii. Chronic exposure. The chronic dietary exposure assessment for this inert ingredient 

utilizes the Dietary Exposure Evaluation Model Food Commodity Intake Database 

(DEEM-FCID), Version 3.16, EPA, which includes food consumption information from 

the U.S. Department of Agriculture’s national health and Nutrition Examination Survey, 

“What We Eat In America”, (NHANES/WWEIA). This dietary survey was conducted from 

2003 to 2008. In the absence of actual residue data, the inert ingredient evaluation is based 

on a highly conservative model which assumes that the residue level of the inert ingredient 

would be no higher than the highest established tolerance for an active ingredient on a 

given commodity. As to residue levels in food, no residue data were submitted for 

isethionic acid and its salts. In the absence of specific residue data, EPA has developed an 

approach which uses surrogate information to derive upper bound exposure estimates for

the subject inert ingredient. Upper bound exposure estimates are based on the highest 

tolerance for a given commodity from a list of high-use insecticides, herbicides, and 

fungicides. A complete description of the general approach taken to assess inert ingredient 

risks in the absence of residue data is contained in the memorandum entitled “Alkyl 

Amines Polyalkoxylates (Cluster 4): Acute and Chronic Aggregate (Food and Drinking 

Water) Dietary Exposure and Risk Assessments for the Inerts.” (D361707, S. Piper, 

2/25/09) and can be found at http://www.regulations.gov in docket ID number EPA-HQOPP-2008-0738.
22

In the dietary exposure assessment, the Agency assumed that the residue level of the inert 

ingredient would be no higher than the highest tolerance for a given commodity. Implicit in 

this assumption is that there would be similar rates of degradation (if any) between the 

active and inert ingredient and that the concentration of inert ingredient in the scenarios 

leading to these highest of tolerances would be no higher than the concentration of the 

active ingredient.

The Agency believes the assumptions used to estimate dietary exposures lead to an 

extremely conservative assessment of dietary risk due to a series of compounded 

conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the 

level of residue for the active ingredient will overstate exposure. The concentration of 

active ingredients in agricultural products is generally at least 50 percent of the product and 

often can be much higher. Further, pesticide products rarely have a single inert ingredient; 

rather there is generally a combination of different inert ingredients used which 

additionally reduces the concentration of any single inert ingredient in the pesticide product 

in relation to that of the active ingredient.

Second, the conservatism of this methodology is compounded by EPA’s decision to assume 

that, for each commodity, the active ingredient which will serve as a guide to the potential 

level of inert ingredient residues is the active ingredient with the highest tolerance level. 

This assumption overstates residue values because it would be highly unlikely, given the 

high number of inert ingredients, that a single inert ingredient or class of ingredients would 

be present at the level of the active ingredient in the highest tolerance for every commodity. 

Finally, a third compounding conservatism is EPA’s assumption that all foods contain the 

inert ingredient at the highest tolerance level. In other words, EPA assumed 100 percent of 

all foods are treated with the inert ingredient at the rate and manner necessary to produce 

the highest residue legally possible for an active ingredient. In summary, EPA chose a very 

conservative method for estimating what level of inert residue could be on food, and then 

use this methodology to choose the highest possible residue that could be found on food 

and assumed that all food contained this residue. No consideration was given to potential 

degradation between harvest and consumption even though monitoring data shows that 

tolerance level residues are typically one to two orders of magnitude higher than actual 

residues in food when distributed in commerce. 

Accordingly, although sufficient information to quantify actual residue levels in food is not 

available, the compounding of these conservative assumptions will lead to a significant 

exaggeration of actual exposures. EPA does not believe that this approach underestimates 

exposure in the absence of residue data.

Table 5. Summary of Chronic Dietary Exposure and Risk of Isethionic Acid and Salts

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

General U.S. Population

2.0

0.189343 9.5%

All Infants (<1 year old) 0.394428 19.7%

Children 1-2 years old 0.706242 35.3%

Children 3-5 years old 0.485634 24.3%

Children 6-12 years old 0.250554 12.5%

Youth 13-19 years old 0.134797 6.7%
23

Adults 20-49 years old 0.144740 7.2%

Adults 50+ years old 0.151788 7.6%

Females 13-49 years old 0.146333 7.3%

Based on analyses of estimated dietary risks for the general U.S. population and various 

population subgroups, the chronic dietary exposure estimates for isethionic acid and its 

salts are significantly below the Agency’s level of concern for all supported commodities. 

The chronic dietary exposure estimate for the highest exposed population subgroup, 

children 1-2 years old is 35.3% of the chronic population adjusted dose (cPAD). The 

chronic dietary exposure estimate for the general U.S. population is 9.5% of the cPAD.

iii. Cancer exposure. Isethionic acid and its salts are not expected to be carcinogenic based 

on Oncologic modeling. Also the mutagenicity study on ammonium isethionate was

negative. Therefore, a cancer dietary exposure assessment is not necessary to assess cancer 

risk.

B. Residential (Non-Occupational) Exposure:

The screening-level assessment was conducted using an Antimicrobials Division (AD) 

assessment tool developed to assess Amine Oxide (“900439, (C10-16); C10-C18-

Alkyldimethylamine oxides; Human Health Risk Assessment and Ecological Effects 

Assessment to Support Proposed Exemption from the Requirement of a Tolerance When 

Used as Inert Ingredients in Pesticide Formulations.” 22 SEPT 2009; Memorandum L. 

Austin to P. Shah; Reg. Div./OPP/EPA). The assessment tool uses standard assessment 

methodology developed by the Antimicrobials Division and the Science Advisory Council 

for Exposure (EXPOSAC), Health Effects Division/Office of Pesticide Programs. The 

methodology can also be found in part at: 

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html

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

In its simplest form, exposure is assessed as follows:

Unit Exposure * Amount applied/Unit * Units treated/day * absorption factor ÷ Body Wt.

(mg/lb handled) (lb applied/unit) (acres etc) kg

Inhalation, dermal and oral absorption are assumed to be 100%. Also isethionic acid 

and/or its salts was assumed to be at max 50% of formulation instead of the typical 100% 

default conservative assumption. Though no specific limitations are proposed, the 

maximum concentration of isethionic acid or its salts in pesticide formulations are expected 

to be 25%.

The result is an estimated average daily dose (ADD or “exposure”) expressed as mg 

material/kg bw/day. That value is used then to calculate the Margin of Exposure (MOE) 

(estimated measure of risk). An MOE is calculated by dividing the value of the average 

daily dose into the toxicological endpoint of concern (also expressed in mg material/kg 
24

bw/day). Typically, resulting MOEs ≥ 100 do not exceed the Agency’s level of concern.

MOEs less than 100 typically exceed the Agency’s level of concern.

For the dietary, dermal and inhalation exposure assessments the Agency uses the 

toxicological endpoint of 200 mg/kg/day identified from the 90 day oral toxicity study in 

rats based on decrease body weight, changes in hematology parameters, increase spleen 

weights , macroscopic changes in the liver and microscopic changes in the liver, bile duct 

and spleen.

Results of the screening-level assessments are presented in the document. Margins of 

exposure are presented as summaries for residential “handlers” (non-occupationally 

associated applicators) and for occupational pesticide handlers. Since lawn and turf uses 

may be involved, assessments of post-application exposures to “residents” were also 

conducted. Estimated exposure doses as well as margins of exposure are presented for 

inhalation, dermal and incidental oral exposure. Post-application oral exposures (hand-tomouth activity) are presented for toddlers (children ages 1-2 years), the highest exposed 

population. 

i. From non-dietary exposure. The term “residential exposure” is used in this document to 

refer to non-occupational, non-dietary exposure (e.g., for lawn and garden pest control, 

indoor pest control, termiticides, and flea and tick control on pets). Isethionic acid and its 

salts may be used as inert ingredients in pesticide products that are registered for specific 

uses that may result in indoor or outdoor residential exposures. Possible routes of exposure 

are expected to be inhalation and dermal exposure as a result of contact with areas treated 

with isethionic acid and its salts. A screening level residential exposure and risk assessment 

was completed. The Agency conducted exposure assessments based on typical end-use 

product application methods and labeled application rates. However no example product 

labels were provided by the registrant and conservative assumptions for application rates 

were used. The Agency conducted an assessment to represent worse-case residential 

exposure by assessing residential applicator and post-application exposures and risk from 

isethionic acid and its salts in pesticide formulations.

Table 6. Residential Handler Short- and Intermediate-term Exposures and Risks for Isethionic Acid and its 

Salts Inerts

Pesticid

e Type

Exposure 

Scenario

Applicati

on Rate1

Exposed 

Populatio

n & 

Exposure 

Duration2

Dermal 

Dose 

(mg/kg/da

y)3

Inhalation 

Dose 

(mg/kg/da

y)3

Derm

al

MOE4

Inhalati

on 

MOE4

Total

Combin

ed

MOE5

Herbicid

e/

Fungicid

e/

Insectici

de

Liquids/Low 

Pressure 

Handwand

0.125

lb/day

Short & 

Intermedia

te Term

0.296875 0.000023 670 8500000 670

Liquids/Hose 

End Sprayer

Short & 

Intermedia

te Term

0.085938 0.000133 2300 1500000 2300

Liquids/Trig

ger SprayerHG, IS, C&C

Short & 

Intermedia

te Term

0.421875 0.000015 470 1300000

0

470
25

1 Application rates for isethionic acid and its salts are based on default values provided in the AD assessment tool. Assumed inert 

ingredient was 50% of formulation.

2 ST and IT indicate short- or intermediate-term exposure durations

3 Average Daily Dose = Application rate * Quantity Treated (5 gallons) * Unit Exposure (Varies by exposure scenario) * 

Absorption Factor (100%) / Body Weight (80 kg)

4 MOE = PoD (NOAEL of 200 mg/kg/day)/ Daily dose (mg/kg/day)

5 Total MOE = 1/((1/ Dermal MOE)+(1/inhalation MOE))

Table 7. Residential Post-Application Short- and Intermediate-term Exposures and Risks for Isethionic Acid 

and Salts Inerts

Pesticide 

Type

Exposure Scenario Application 

Rate1

Exposed Population & 

Exposure Duration2

Daily Dose 

(mg/kg/day)3

MOE4

Outdoor Products

Herbicide

Insecticide

Fungicide

Post-App Dermal 

Treated Lawn

2.25 lb/day

Adult ST 0.457313 437

Adult IT 0.230233 870

Child ST 0.874676 230

Child IT 0.437338 460

Hand-to-Mouth from 

Treated Lawn Child ST 0.033641 5900

Object-to-Mouth 

from Treated Lawn Child ST 0.008410 24000

1 Application rates for isethionic acid and its salts are based on default values provided in the AD assessment tool. Assumed inert 

ingredient was 50% of formulation.

2 ST and IT indicate short- or intermediate-term exposure durations

3 Daily Dose is calculated differently for each exposure scenario. Refer to AD assessment tool for more details.

4 MOE = PoD (NOAEL of 200 mg/kg/day)/ Daily dose (mg/kg/day)

EPA has calculated the residential applicator and post-application exposures. Three 

exposure scenarios, low pressure handwand, hose end sprayer and trigger sprayer were 

assessed for each pesticide type, herbicide, insecticide and fungicide in both short- and 

intermediate-term scenarios. The combined dermal and inhalation MOEs ranged from 470 

to 2300. As the level of concern is for MOEs that are lower than 100, these MOEs are not 

of concern. 

The short- and intermediate-term MOEs for post-application dermal exposure to treated 

lawns was calculated to be 437 and 870 for adults respectively and 230 and 460 for 

children respectively. The post-application child (hand-to-mouth) short-term MOE was 

calculated to be 5900 from treated lawns. As the level of concern is for MOEs that are 

lower than 100, these MOEs are not of concern.

V. AGGREGATE RISK ASSESSMENT

EPA determines whether acute and chronic pesticide exposures are safe by comparing 

aggregate exposure estimates to the acute population adjusted dose (aPAD) and chronic 

population adjusted dose (cPAD). The aPAD and cPAD represent the highest safe 

exposures, taking into account all appropriate safety factors (SFs). EPA calculates the 

aPAD and cPAD by dividing the POD (i.e. toxicological endpoint) by all applicable UFs. 
26

For linear cancer risks, EPA calculates the probability of additional cancer cases given the

estimated aggregate exposure. Short-, intermediate-, and chronic-term risks are evaluated 

by comparing the estimated aggregate food, water, and residential exposure to the POD to 

ensure that the MOE called for by the product of all applicable UFs is not exceeded. 

i. Acute Dietary Risk. 

An acute aggregate risk assessment takes into account exposure estimates from acute 

dietary consumption of food and drinking water using the exposure assumptions discussed 

in Section IV for acute exposure. However there was no hazard attributable to a single 

exposure seen in the toxicity database for isethionic acid and salts; therefore there is no 

concern for an acute dietary risk and an acute aggregate risk assessment was not conducted.

ii. Chronic Dietary Risk. 

A chronic aggregate risk assessment takes into account exposure estimates from chronic 

dietary consumption of food and drinking water using the exposure assumptions discussed 

in Section IV from chronic exposure. The chronic analysis was based on a 90-day oral

toxicity study with a NOAEL of 200 mg/kg/day based on decrease body weight, changes in 

hematology parameters, increase spleen weights, macroscopic changes in liver and 

microscopic changes in the liver, bile duct and spleen. The chronic dietary exposure from 

food and water to isethionic acid and its salts is 9.5% of the cPAD for the U.S. population 

and 35.3% for children 1-2 yrs old, the most highly exposed population subgroup.

iii. Aggregate Cancer Risk for U.S. Population. 

The Agency has not identified any concerns for carcinogenicity relating to isethionic acid 

and its salts; therefore, a cancer dietary exposure assessment was not performed and an 

aggregate risk assessment is not a concern.

iv. Short-term Aggregate Risk. 

Short-term aggregate exposure takes into account short-term residential exposure plus 

chronic exposure to food and water (considered to be a background exposure level). 

Isethionic acid and its salts may be used as an inert ingredient in pesticide products that 

could result in short-term residential exposure. The Agency has determined that it is 

appropriate to aggregate chronic exposure through food and water with short-term 

residential exposures. Using the exposure assumptions described in Section IV, EPA has 

calculated the combined short-term aggregated food, water, and residential exposures. The 

adult short-term aggregate MOE was calculated to be 187 for both males and females. 

Adult aggregate MOE combines average food and water exposure from the chronic dietary 

exposure with high end residential applicator exposure (liquid trigger sprayer). As the level 

of concern is for MOEs that are lower than 100, this MOE is not of concern. EPA has 

concluded the combined short-term aggregated food, water, and residential exposures 

results in an aggregate MOE of 123 for children. Children’s aggregate MOE combines 

average food and water exposure from the chronic dietary exposure with residential 

exposure associated with contact with treated lawns (post-app dermal exposure + hand-tomouth + object-to-mouth). As the level of concern is for MOEs that are lower than 100, 

these MOEs are not of concern.
27

Table 8. Short-Term Aggregate Risk Calculations for Isethionic Acid and Salts

Population

PoD

mg/kg/day LOC1

Max 

Allowable

Exposure2

mg/kg/day

Average

Food & 

Water

Exposure3

mg/kg/day

Residential 

Exposure4

mg/kg/day

Aggregate 

MOE

(food and

residential)5

Adult 200 100 2.00 0.189343 0.879188 187

Child 200 100 2.00 0.706242 0.91684 123

1 The LOC (Level of Concern) is based on the standard inter-, intra-species uncertainty factors totaling 100.

2 Maximum Allowable Exposure (mg/kg/day) = PoD (Point of Departure)/LOC.

3 Average Food & Water Exposure = Chronic Dietary Exposure Table 5.

4 Residential Exposure = Adult worse case scenarios for [Handler Exposure + Post App. Exposure]; Child [Post App Dermal + 

HTM +OTM]

5 Aggregate MOE = [PoD/ (Avg Food & Water Exposure + Residential Exposure)].

v. Intermediate-Term Aggregate Risk. 

Intermediate -term aggregate exposure takes into account intermediate-term residential 

exposure plus chronic exposure to food and water (considered to be a background exposure 

level). Isethionic acid and its salts may be used as an inert ingredient in pesticide products 

that could result in intermediate-term residential exposure. The endpoint of concern 

selected for short- and intermediate-term exposure assessment is the same NOAEL, 

therefore intermediate term exposure is not expected to exceed short term aggregate 

exposure and therefore there are no concerns for intermediate-term aggregate exposure. 

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY

The representative occupational scenarios selected by the Agency for assessment are 

evaluated based on likely maximum application rates for products which may contain the inert 

ingredient for the short-term exposure assessment, and average application rates for products likely 

to contain the inert ingredient for the intermediate- and long-term exposure durations. Active 

ingredient application rates are corrected for the maximum amount of inert ingredient likely to be 

in the final formulations to determine exposure and risk from exposure to the inert ingredient by 

fungicide/insecticide or herbicide. 

The Agency traditionally considers a level of concern (LOC) for these risk assessments to 

be an MOE of 100 based on the standard 10X inter and 10X intra species extrapolation safety 

factors. 

A. Occupational Handler Risk

Exposure Scenarios

Dermal and inhalation exposure are estimated using the Pesticide Handlers Exposure 

Database (PHED) and Outdoor Residential Exposure Task Force (ORETF) data. The 

analytical techniques are those developed by the Science Policy Council on Exposure 
28

(ExpoSAC), Heath Effects Division, Office of Pesticide Programs, US Environmental 

Protection Agency. The quantitative exposure/risk assessment developed for occupational 

handlers to support the requested exemption for the inert ingredient based on scenarios to 

represent the highest potential exposure. 

The algorithm used to estimate exposure is:

U.E. * AR * Units Treated/day * absorption factor ÷ body weight.

UE Unit Exposure in mg of material per lb of material handled. Unit Exposures 

are derived in the Pesticide Handlers Exposure Database (PHED) and are 

recently summarized in the “Occupation Pesticide Handler Unit Exposure 

Surrogate Reference Table” US EPA Office of Pesticide Programs, March 

2012 (unpublished)

AR Application Rate in lbs of material per unit (acres). In this case taken from 

Herbicide Occupational Handler Inert Exposure Calculator. An assumption 

of 50% limitation in formulation was applied to these application rate values

based on the assumption that the petitioner stated no more than 25% of a 

formulation would be expected to contain isethionic acid and/or its salts

even though no specific limitation is being proposed.

Units Treated/day - - In this case acres treated per day taken from the Antimicrobials 

Division (AD) assessment tool developed to assess Amine Oxide (“900439, 

(C10-16); C10-C18-Alkyldimethylamine oxides; Human Health Risk 

Assessment and Ecological Effects Assessment to Support Proposed 

Exemption from the Requirement of a Tolerance When Used as Inert 

Ingredients in Pesticide Formulations.” 22 SEPT 2009

AF Absorption factor - - 100% default for dermal and inhalation routes of 

exposure

BW Body Weight - - 80 kg for combined adults in the U.S. Taken from “Use of 

New Human Body Weight Data as Presented in the EPA’s Exposure Factors 

Handbook: 2011 Edition” HED “HotSheet” No. 31. Although due to 

software limitations of the assessment tool, the calculations provided below

used the older default 70 kg. 

In this case occupational exposures are presented for aerial applicators, ground applicators 

and for mixer/loaders preparing and applying liquid formulations diluted for use in 

applications. These are the occupational activities believed to be associated with the highest 

exposures use patterns. The occupation exposure assessment utilized the baseline values for 

highest exposure herbicide, insecticide and fungicide. Only the herbicide data is provided 

below because it provided the lowest and most conservative MOEs. 

Table 10. Summary of Exposure & Risk to Occupational Handlers From Isethionic Acid and its Salts

Scenario Unit 

Exposure1

Application 

Rate1

Units 

Treated1

Avg. Daily 

Exposure2

MOE3
29

1. Default values are taken from Antimicrobials Division (AD) assessment tool developed to assess Amine Oxide (“900439, (C10-

16); C10-C18-Alkyldimethylamine oxides

2. Average Daily Exposure = Unit Exposure * Application Rate (corrected for 50% limitation) * Units Treated * Absorption Rate÷ 70

kg Body Weight

3. MOE = Margin of Exposure = NOAEL  ADE. 

The dermal and inhalation absorption was default at 100%. The dermal and inhalation 

toxicity was also assumed to be equivalent to oral toxicity (NOAEL 200 mg/kg/day). Risks 

mg inert/lb 

handled

lb inert/unit mg inert/kg bw/day

Herbicide Mixer/Loaders

Liquids: Aerial Dermal:

Single-layer 

gloves

0.023

Inhalation: 

No respirator 

0.0012

5.2 lb ai/A

Corn (Max/ST) 1200 A/day

Dermal:

Single-layer gloves

2.05029

Inhalation: 

No respirator 

0.10697

Dermal:

98

Inhalation:

1900

Combined:

93

Liquids: Airblast Dermal:

Single-layer 

gloves

0.023

Inhalation: 

No respirator 

0.0012

3.6 lb ai/A

Nut Trees 

(Max/ST)

40 A/day

Dermal:

Single-layer gloves

0.04731

Inhalation: 

No respirator 

0.002469

Dermal:

4200

Inhalation:

81000

Combined:

4000

Liquids: 

Groundboom

Dermal:

Single-layer 

gloves

0.023

Inhalation: 

No respirator 

0.0012

5.2 lb ai/A

Corn (Max/ST) 200 A/day

Dermal:

Single-layer gloves

0.34171

Inhalation: 

No respirator

0.01783 

Dermal:

590

Inhalation:

11000

Combined:

560

Herbicide Applicator

Liquid: Airblast Dermal:

Single-layer 

gloves

0.24

Inhalation:

Open Cab

0.0045

0.8 lb ai/A

Nut Trees 

(Max/ST)

40 A/day

Dermal:

Single-layer gloves

0.10971

Inhalation:

Open Cab

0.002057

Dermal:

1800

Inhalation:

97000

Combined:

1800

Liquid: Groundboom Dermal:

Single-layer 

gloves

0.014

Inhalation:

Open Cab

0.00074

5.2 lb ai/A

Corn (Max/ST) 200 A/day

Dermal:

Single-layer gloves

0.20800

Inhalation:

Open Cab

0.01099

Dermal:

960

Inhalation:

18000

Combined:

910

Herbicide Mixer/Loader/Applicator

Liquid: Low Pressure 

handwand

Dermal:

Single-layer 

gloves

0.43

Inhalation:

No respirator

0.030

3.6 lb ai/A

Ornamentals 

(Max/ST)

5 A/day

Dermal:

Single-layer gloves

0.11057

Inhalation:

No respirator

0.007714

Dermal:

1800

Inhalation:

26000

Combined:

1700
30

were calculated using the MOE approach, which is a ratio of the exposure to the 

toxicological PoD. Occupational handler risks are not of concern. The Agency’s level of 

concern for inhalation and dermal exposure is for MOEs <100. The lowest estimated 

combined MOE was 93, based on liquid aerial mixer/loader with gloves and no respirator, 

maximum application rate on corn and treating 1200 Acres/day. Even though this estimated 

occupational MOEs is slightly under 100, based on the amount of conservatism and 

uncertainty factors used in the estimation, this MOE and other occupational MOEs are not 

of concern.

B. Occupational Post-Application Risk

Exposure Scenarios

RD uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to 

as re-entry exposure). Such exposures may occur when workers enter previously treated 

areas to perform job functions, including activities related to crop production, such as 

scouting for pests or harvesting. Post-application exposure levels vary over time and 

depend on such things as the type of activity, the nature of the crop or target that was 

treated, the type of pesticide application, and the chemical’s degradation properties. In 

addition, the timing of pesticide applications, relative to harvest activities, can greatly 

reduce the potential for post-application exposure. Inhalation exposures are also not 

typically calculated for occupational post-application scenarios because inhalation 

exposures generally account for a negligible percentage of the overall body burden for most 

pesticide chemicals.

Post-application worker exposure is estimated using HED procedure that assumes 20% of 

the application rate is available as dislodgeable foliar residue on the day of treatment. HED 

does not expect postapplciation exposure to exceed short term exposure. Therefore, only 

short term exposure are assessed.

HED expects post-application agricultural exposures to workers would typically be shortterm (1-30 days). The following convention is used to estimate post-application agricultural 

worker exposure. 

DFRt = AR * F * (1-D)t* CF2 * CF3 where:

DFR = Dislodgeable Foliar Residue

AR = Application rate (lb inert/A)

F = fraction of inert retained on foliage (unitless) (default 20%)

D = fraction of residue that dissipates daily (unitless) (default 10%)

T = post application day on which exposure is being assessed

CF2 = weight unit conversion factor to convert the lbs inert in the application rate to μg for 

the DFR value (4.54E8 μg/lb)

CF3 = Area unit conversion factor to convert the surface area units (ft2) in the application 

rate to cm2for the DFR value (1.08E-3 ft2/cm2or 2.47E-8 acre/cm2)
31

Average Daily Dose (ADD) (mg inert/kg/day) = DFR μg/cm2 * TC cm2/hr * hr/day * 

0.001 mg/μg * 1/70 kg

In this case occupational post-application exposures are presented for tall field row, turf

and for vinetrellis. These are the post-occupational activities believed to be associated with 

the highest exposures use patterns. The occupation post-application exposure assessment 

utilized the baseline values for highest exposure herbicide, insecticide and fungicide. The 

default value is provided below because it provided the lowest and most conservative 

MOEs. 

1. Default values are taken from Occupational Postapplciation Risk Assessment Calculator Version 2 (12/2008)

2. Dislodgeable foliar residue = Fraction of inert retained on foliage * Application Rate (corrected for 50% limitation) * (1-daily 

dissipation)t * conversion factors 

3. Short-term dose = DFR * Tc * hours of daily exposure (8 hrs) * conversion factors (μg to mg) / 70 kg

4. MOE = Margin of Exposure = NOAEL  Short-term dose.

The dermal absorption was default at 100%. The dermal toxicity was also assumed to be 

equivalent to oral toxicity (NOAEL 200 mg/kg/day). Risks were calculated using the MOE 

approach, which is a ratio of the exposure to the toxicological PoD. Occupational postapplication risks are not of concern. The Agency’s level of concern for dermal exposure is 

for MOEs <100. The lowest estimated MOE was 110, based on hand harvesting, leaf 

pulling, thinning, pruning, training/tying grapes. As the level of concern is for MOEs that 

are lower than 100, these MOEs are not of concern.

VII. CUMULATIVE EXPOSURE

Table 11. Summary of Exposure & Risk to Occupational Post-Application From Isethionic Acid and its Salts

Exposure Potential Transfer 

Coefficients1

cm2/hr

Application 

Rate1

lb inert/Acre

DFR 

Levels2

μg/cm2

Short-term 

Dose3

mg inert/kg 

bw/day

MOE3

Short-term Tall Field Row

Low: scouting, weeding immature/low 

foliage plants 100

3.12 lb ienrt/A 7.001

0.0800 2500

Medium: scouting, weeding more 

mature/foliaged plants 400 0.3200 620

High: scouting, irrigation, weeding 

mature/full foliage plants 1000 0.8001 250

Short-term Turf

Low: Mowing 500 3.12 lb inert/A 1.750 0.100 2000

High: Transplanting, handweeding 6800 1.360 150

Short-term Vinetrellis

Low: Hedging, irrigation, scouting, 

hand weeding, training/tying 

blueberries

500

1.44 lb inert/A 3.231

0.1846 1100

Medium: Scouting, training, tying 1000 0.3693 540

High: hand harvest, leaf pulling, 

thinning, pruning, training/tying grapes 5000 1.8463 110
32

Cumulative effects from substances with a common mechanism of toxicity. 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 has not found isethionic acid and/or its salts to share a common mechanism of toxicity 

with any other substances, and that isethionic acid and/or its salts do not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA 

has assumed that isethionic acid and/or its salts do not have 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 

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

VIII. ENVIRONMENTAL JUSTICE STATEMENT 

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

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

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

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

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

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

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

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

residential setting. Extensive data on food consumption patterns are compiled by the USDA under 

CSFII and are used in pesticide risk assessments for all registered food uses of a pesticide. These 

data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and 

region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized 

subgroups and exposure assessments are performed when conditions or circumstances warrant. 

Whenever appropriate, non-dietary exposures based on home use of pesticide products and 

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

treated areas post-application are evaluated. Further considerations are currently in development 

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

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

dietary patterns among specific subgroups.

IX. ENVIRONMENTAL FATE CONSIDERATIONS

The physical-chemical properties and environmental fate characteristics of isethioic acid, 

ammonium isethionate, potassium isethionate, and zinc isethionate were estimated using EPI Suite. 

EPI Suite is a screening-level tool used to estimate the physical chemical properties and 

environmental fate of compounds if measured values are not available. 
33

Water solubility for all the isethionates modeled are estimated to be high using the EPA 

EPI Suite 4.0 model, WSKOW (8.55 E5 – 1.0 E6 mg/l). Additionally isethionates have high 

melting points (76.88 to 233.13°C). The predicted vapor pressure (8.8E-5 to 1.36E-14 mmHg) are 

low (i.e., <10-6 mmHg), indicating the isethionates exist primarily as a solid. Henry’s Law 

constants are also low (6.11 E-13 atm*m3/mol to 5.648 E-21 atm*m3/mol), indicating the 

isethionates are not likely to volatilize from surface water. 

The log Kow is an indicator of whether a chemical is hydrophilic or lipophilic in an aquatic 

environment. Lipophilic chemical can bioaccumlate in fatty tissues of fish and in animals that 

consume the fish. A log Kow of 0 indicates the chemical has an equal affinity for lipids and water. 

The isethionates, with log Kows of -2.37 to -5.5 have a higher affinity for water than lipids and so, 

are not likely to bioconcentrate. The organic carbon adsorption coefficient or Koc provides an 

indication of whether a compound is likely to partition to soil or sediment from water. A low log 

Koc value, less than 1.5, suggests the chemical is not likely to bind to soils, sediments, or sludge 

and will remain in water. A high Koc value, greater than 4.5, suggests the chemical will bind to 

soils and sediments, or sludge, and is not likely to be found in surface water or ground water. The 

estimated log Koc values of the isethionates are in the low range, from -0.791 to -2.529, suggesting 

that sorption to soils and sediments from water is not likely to occur.

The probability of rapid biodegradation of isethonates were evaluated using EPI Suite in 

the BIOWIN module. Three of the isethionates were estimated to undergo rapid biodegradation 

and were categorized as readily degradable. The zinc salt has a slightly different structure than the 

other compounds that appears to be more stable. A study was conducted to determine the aerobic 

degradability of ammonium isethionate in water containing mineral salts and microbial inoculum 

from the secondary effluent of a wastewater treatment plant (MRID 49285802). Ammonium 

isethionate was classified as readily biodegradable and not toxic to the inoculum. 

The estimated bioconcentration factor (BCF) for isethionates indicated a low 

bioconcentration potential. The BCF is reported as the ratio (in L/kg) of a chemical’s concentration 

in the tissue of an aquatic organism to its concentration in the ambient water, when BCFs 

considered high are ≥5,000, moderate BCFs are in the range of 1,000 to 5,000, and low BCFs are < 

1,000. The BCF for each of the modeled isethionates is 3.162, indicating that the isethionates are 

not expected to bioconcentrate in aquatic organisms.

The fugacity models indicate that once released to the environment, 62.2 to 69.4% of the 

isethionates would reside in the soil, 30.6 to 37.7% would reside in the water, 0.06 to 0.07% would 

reside in the sediment and a very small percent, 2.1 E-5 to 2.6E-12%, would be in the air. 

Isethionic acid and its salts are expected to have a minimal impact on the environment. The 

physical and chemical properties of isethionic acid and its salts indicate it is generally readily 

biodegradable and will degrade rapidly in the environment. Isethionic acid is expected to partition 

into the soil, but it may also remain in or enter the water where it may readily biodegrade. 

Isethionic acid is not expected to bioconcentrate in aquatic organisms. Isethionic acid is not 

volatile, and so it will not be released into the air. 
34

X. ECOTOXICITY

Based on the ready biodegradability of isethionic acid and its salts identified in the EPI 

Suite model, and the low toxicity to freshwater aquatic invertebrate, Daphnia magna, and 

the lack of inhibition on growth of the unicellular algae, Pseudokirchneriella subcapitata, 

effects of concern to nontarget aquatic species resulting from the use of isethionic acid and 

its salts as an inert ingredient are not anticipated. 

Fish Acute Toxicity

No acute fish toxicity studies are available in the database.

Aquatic Invertebrate Toxicity

In an acute toxicity study on Daphnia magna (OCSPP Guideline 850.1010), containing 

ammonium isethionate (50% purity) and under static conditions for 48 hours, Daphnia 

magna were placed into concentrations of approximately, 0, 3.15, 6.5, 12.5, 25, and 50 

mg/L (corrected for purity). Water temperature, pH and dissolved oxygen were measured 

periodically. There were no sublethal effects noted in any of the exposure groups. After 48 

hours of exposure, immobility was reported to be: 5, 0, 0, 0, 5, and 0% in the control, 3.15,

6.5, 12.5, 25, and 50 mg/L groups, respectively. The 48-hour NOEC was identified as 50 

mg/L ammonium isethionate, based on the nominal concentrations. (MRID 49285803)

Aquatic Plant Toxicity

In a growth inhibition test with unicellular green algae (OECD Guideline 201), containing 

ammonium isethionate (50% purity) and under static conditions for 72 hours, 

Pseudokirchneriella subcapitata were placed into concentrations of approximately, 0, 3.15, 

6.5, 12.5, 25, and 50 mg/L (correct for purity). Within 30 minutes of test article 

preparation, three replicates of each dose level were inoculated with 1 mL of algal 

concentrate resulting in a final density of approximately 5.0 x 103cells/ml. Cell density 

was measured in each replicate at 24, 48 and 72 hours by direct microscopic counting with 

a hemacytometer. After 72 hours of exposure, the mean cell density in the control was 79.4 

x 104 cells/ml, which is 158 times the initial cell density. Algal growth in the treated flasks 

was greater than in the control flasks, with the cell number in the high concentration (50 

mg/l), 83 x 104cells/ml. Ammonium isethionate did not inhibit the growth of the 

unicellular green algae, Pseudokirchneriella subcapitata following 72 hours of exposure 

under static conditions. The EC50 was > 50 mg/ml for ammonium isethionate based on the 

lack of a statistically significant reduction in growth rate.

XI. RISK CHARACTERIZATION 

Technology Sciences Group Inc. (TSG) on behalf of Huntsman Corporation. (8600 Gosling 

Rd., The Woodlands, Texas 77381, USA) is requesting that EPA establish an exemption from the 

requirement of a tolerance for ethanesulfonic acid, 2-hydroxy- (CAS Reg. No. 107-36-8) and the 
35

corresponding ammonium (CAS Reg. No. 57267-78-4), sodium (CAS Reg. No. 1562-00-1), 

potassium (CAS Reg. No. 1561-99-5), calcium (CAS Reg. No. 10550-47-7), magnesium (CAS 

Reg. No. 17345-56-1), and zinc (CAS Reg. No. 129756-32-7) salts, when used as inert ingredient 

(chelators, sequestrants and conditioning agents) in pesticide formulations applied to growing 

crops and raw agricultural commodities and applied to animals, in accordance with 40 CFR 

180.910 and 180.930, respectively.

Ethanesulfonic acid, 2-hydroxy-, (also referred to as isethionic acid) has been used for 

many years in personal care products. It is a common ingredient in bath soaps and detergent bars. 

A number of personal care products contain sodium isethionate and the majority of these are rinseoff products that contain 2% to 6% of isethionate salts. 

The chronic reference dose (cRfD) of 2.0 mg/kg/day was determined on the basis of the 

NOAEL from the 90-day oral toxicity study in rats. The LOAEL of 1000 mg/kg/day sodium 

isethionate is based on decreased body weight, changes in hematology parameters, increased

spleen weights and macroscopic changes in the liver. This study provided the lowest NOAEL in 

the database (most sensitive endpoint) and also provides the most protective limits for potential 

human effects. An uncertainity factor (UF) of 100X (10-fold for interspecies extrapolation and 10-

fold for intra species variability) was applied to the NOAEL of 200 mg/kg/day to derive the cRfD. 

This endpoint of concern was also used for all dermal and inhalation exposure scenarios. Both 

dermal and inhalation absorption were assumed to be 100%.

EPA has determined that reliable data show the safety of infants and children would be 

adequately protected if the FQPA SF were reduced to 1X. 

An acute dietary risk assessment was not conducted because no endpoint of concern 

following a single exposure was identified in the available studies. A chronic dietary exposure 

assessment was completed and performed using the Dietary Exposure Evaluation Model DEEMFCIDTM, Version 3.16. The chronic polulation-adjusted dose (cPAD) is the cRfD divided by the 

FQPA SF therefore the chronic population-adjusted dose (cPAD) is equal to the RfD of 2.0 

mg/kg/day.

Based on analyses of estimated dietary risks for the general U.S. population and various 

population subgroups, the chronic dietary exposure estimates for isethionic acid and its salts are 

significantly below the Agency’s level of concern for the general U.S. population and all 

population subgroups. The chronic dietary exposure estimate is 9.5% of the cPAD for the general 

population and 35.3% of the cPAD for the highest exposed population subgroup, children 1-2 

years old.

The Agency’s level of concern (LOC) for occupational and residential inhalation exposures 

to isethionic acid and its salts is 100 [i.e., a margin of exposure (MOE) greater than 100 is not of 

concern to EPA]. The LOC is based on a 10X uncertainty factor (UF) to account for interspecies 

extrapolation to humans from the animal test species and 10X UF to account for intra-species 

sensitivity.
36

Short-term aggregate exposure takes into account short-term residential exposure plus 

chronic exposure to food and water (considered to be a background exposure level). Isethionic acid 

and its salts may be used as an inert ingredient in pesticide products that could result in short-term 

residential exposure. The Agency has determined that it is appropriate to aggregate chronic 

exposure through food and water with short-term residential exposures. The adult short-term 

aggregate MOE was calculated to be 187 for both males and females. Adult aggregate MOE 

combines average food and water exposure from the chronic dietary exposure with high end 

residential applicator exposure (liquid trigger sprayer). As the level of concern is for MOEs that 

are lower than 100, this MOE is not of concern. EPA has concluded the combined short-term 

aggregated food, water, and residential exposures results in an aggregate MOE of 123 for children. 

Children’s aggregate MOE combines average food and water exposure from the chronic dietary 

exposure with residential exposure associated with contact with threated lawns (dermal post-app, 

hand-to-mouth and object-to mouth). As the level of concern is for MOEs that are lower than 100, 

these MOEs are not of concern.

Intermediate -term aggregate exposure takes into account intermediate-term residential 

exposure plus chronic exposure to food and water (considered to be a background exposure level). 

Isethionic acid and its salts may be used as an inert ingredient in pesticide products that could 

result in intermediate-term residential exposure. The endpoint of concern selected for short- and 

intermediate-term exposure assessment is the same NOAEL, therefore intermediate term exposure 

is not expected to exceed short term aggregate exposure and therefore there are no concerns for 

intermediate-term aggregate exposure. 

Occupational handler risks are not of concern for all scenarios. It is noted that this 

occupational handler assessment assumes that mixer/loader/applicators are not wearing protective 

respirators when using open pour loading in support of aerial and groundboom application. The 

estimated MOEs are greater than 100 based on 100% dermal and inhalation absorption, except for 

the estimated combined MOE of 93 for liquid aerial application with gloves and no respirator on 

corn. Even though this estimated occupational MOE is slightly under 100, based on the nature of 

conservatism and uncertainty factors used in the estimation, this MOE and the other occupational 

MOEs are not of concern.

Occupational post-application risks are not of concern for all scenarios. It is noted that this 

occupational post-application assessment assumes default 20% dislodgeable foliar residue. The 

estimated MOEs are greater than 100 based on 100% dermal absorption. The lowest estimated 

MOE was 110, based on hand harvesting, leaf pulling, thinning, pruning, training/tying grapes. As 

the level of concern is for MOEs that are lower than 100, these MOEs are not of concern.

Even though this estimated occupational MOE is slightly under 100, based on the nature of 

conservatism and uncertainty factors used in the estimation, this MOE and the other occupational 

MOEs are not of concern.

Isethionic acid and its salts are expected to have a minimal impact on the environment. The 

physical and chemical properties of isethionic acid and its salts indicate it is generally readily 

biodegradable and will degrade rapidly in the environment. Isethionic acid is expected to partition 

into the soil, but it may also remain in or enter the water where it may readily biodegrade. 
37

Isethionic acid is not expected to bioconcentrate in aquatic organisms. Isethionic acid is not 

volatile, and so it will not be released into the air. 

Based on the readily biodegradability of isethionic acid and its salts identified in the EPI 

Suite model, and the low toxicity to freshwater aquatic invertebrate, Daphnia magna, and the lack 

of inhibition on growth of the unicellular algae, Pseudokirchneriella subcapitata, effects of 

concern to nontarget aquatic species resulting from the use of isethionic acid and its salts as an 

inert ingredient are not anticipated. 

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.

Taking into consideration all available information on isethionic acid and its salts, EPA 

concludes that there is a reasonable certainty that no harm to any population subgroup will result 

from aggregate exposure to isethionic acid and its salts when considering residential, occupational, 

dietary exposure and all other non-occupational sources of pesticide exposure for which there is 

reliable information. Therefore, the establishment of an exemption from the requirement of a 

tolerance under 40 CFR 180.910 and 180.930 for residues of ethanesulfonic acid, 2-hydroxy-

(CAS Reg. No. 107-36-8), and the corresponding ammonium (CAS Reg. No 57267-78-4), sodium 

(CAS Reg. No. 1562-00-1), potassium (CAS Reg. No. 1561-99-5), calcium (CAS Reg. No. 10550-

47-7), magnesium (CAS Reg. No. 17345-56-1), zinc (CAS Reg. No 129756-32-7), salts when used 

as a pesticide inert ingredient applied to growing crops, raw agricultural commodities after harvest 

and animals can be considered assessed as safe under section 408(q) of the FFDCA.
38

REFERENCES

Vasquez, R. (2011) Acute Oral Toxicity Study in the Rat – Up-and-Down Procedure with 

TERMIX AIS 4000. Study Identification 0406RH11.046. Calvert Laboratories, Inc., Scott 

Technology Park, 130 Discovery Drive, Scott Township, PA 18477. October 3, 2011. MRID 

49285804.

Vasquez, R. (2011) Acute Dermal Toxicity Study in Rats with with TERMIX AIS 4000. Study 

Identification 0422RH11.041. Calvert Laboratories, Inc., Scott Technology Park, 130 Discovery 

Drive, Scott Township, PA 18477. October 3, 2011. MRID 49285806.

Ferreira, T. (2012) Acute Inhalation Toxicity Test with TERMIX AIS 4000 using Wistar Rats. 

Study Identification RF – 3984.309.029.11. BIOAGRI Laboratorios, Fazenda Lagoa Bonita, 

Chacara 13, Caixa Postal: 08287, Planaltina, DF, 73310-970, Brazil. November 14, 2012. MRID 

49285805.

Vasquez, R. (2011) Primary Eye Irritation Study in the Rabbits with TERMIX AIS 4000. Study 

Identification 0421LH11.048. Calvert Laboratories, Inc., Scott Technology Park, 130 Discovery 

Drive, Scott Township, PA 18477. October 3, 2011. MRID 49285807.

Vasquez, R. (2011) Primary Dermal Irritation Study in Rabbits with TERMIX AIS 4000. Study 

Identification 0420LH11.061. Calvert Laboratories, Inc., Scott Technology Park, 130 Discovery 

Drive, Scott Township, PA 18477. October 3, 2011. MRID 49285808.

Vasquez, R. (2011) Delayed Contact Hypersensitivity in Guinea Pigs (Buehler Method) with 

TERMIX AIS 4000. Study Identification 0424GH11.041. Calvert Laboratories, Inc., Scott 

Technology Park, 130 Discovery Drive, Scott Township, PA 18477. October 3, 2011. MRID 

49285809.

Martell, A. (2013) Combined repeated dose toxicity study with the reproduction/developmental 

toxicity screening test in rats for TERMIX AIS 4000. BIOAGRI Laboratorios, Planaltina/DF, 

Brazil. Laboratory report number 3984.329.002.11, January 31, 2013. MRID 49285810. 

Unpublished.

Wagner, V.O. (III) and Divi, K. (2011) Bacterial Reverse Mutation Assay. Test Substance 

TERMIX AIS 4000. BioReliance, 9630 Medical Center Drive, Rockville, MD 20850; BioReliance 

Study Number: AC11VJ.503.BTL, April 25, 2011. MRID 49285811. Unpublished.

CIR, 2013. Amended safety assessment of isethionate salts as used in cosmetics. Cosmetic 

Ingredient Review. Final Amended Report October 4, 2013

http://www.cir-safety.org/sites/default/files/iseth092013final.pdf

NLM, HPDB, National Library of Medicine, Household Products Database, Sodium Isethionate 

entry, accessed 11/12/2013.

http://householdproducts.nlm.nih.gov/cgibin/household/brands?tbl=chem&id=453&query=isethionate&searchas=TblChemical&prodcat=all
39

APPENDIX

US EPA Ver. 3.16, 03-08-d

DEEM-FCID Chronic analysis for ETHANESULFONIC ACID AND SALTS

 NHANES 2003-2008 2-day

Residue file name: E:\DEEM\Ethanesulfonic acid and salts\Ethanesulfonic acid and salts no 

limit NOAEL 200.R08

 Adjustment factor #2 used.

Analysis Date 05-01-2015/08:27:14 Residue file dated: 05-01-2015/08:26:03

Reference dose (RfD, Chronic) = 2 mg/kg bw/day

COMMENT 1: Inert 57 active ingredients + drinking water (100ppb)

===============================================================================

 Total exposure by population subgroup

-------------------------------------------------------------------------------

 Total Exposure

 -----------------------------------

 Population mg/kg Percent of 

 Subgroup body wt/day Rfd 

-------------------------------------- ------------- ----------------

Total US Population 0.189343 9.5%

Hispanic 0.206762 10.3%

Non-Hisp-White 0.185800 9.3%

Non-Hisp-Black 0.175951 8.8%

Non-Hisp-Other 0.223356 11.2%

Nursing Infants 0.248204 12.4%

Non-Nursing Infants 0.459734 23.0%

Female 13+ PREG 0.165239 8.3%

Children 1-6 0.546673 27.3%

Children 7-12 0.227410 11.4%

Male 13-19 0.133762 6.7%

Female 13-19/NP 0.135932 6.8%

Male 20+ 0.140996 7.0%

Female 20+/NP 0.153162 7.7%

Seniors 55+ 0.152687 7.6%

All Infants 0.394428 19.7%

Female 13-50 0.146403 7.3%

Children 1-2 0.706242 35.3%

Children 3-5 0.485634 24.3%

Children 6-12 0.250554 12.5%

Youth 13-19 0.134797 6.7%

Adults 20-49 0.144740 7.2%

Adults 50-99 0.151788 7.6%

Female 13-49 0.146333 7.3%

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