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. OCCU PATIONAL 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. ENVIRONMENTA L FATE CONSIDERATIONS

................................ ............................ 32
X. ECOTOXICITY

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

................................ ................................ ........................... 34 REFERENCES

................................ ................................ ................................ ................................ 38 APPENDIX

................................ ................................ ................................ ................................ ...... 393

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), pot assium (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 ap plied to growing crops and raw agricultural commodities and appli ed 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 ca re 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 rinse

off products that contain 2 % to 6% of isethionate salts

.

The acute oral toxici ty of ammonium isethionate is low . The acute oral LD 50 s in rats were > 1 000 mg/kg

- bw. The acute dermal toxicity in rats was > 1 000 mg/kg

- bw

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

. Ammonium iset hionate is not dermally irritating based on a primary skin irritation study in rabbits. Ammonium isethionate has an acute inhalation LC 50 > 6.295 m g/L and is not a dermal sensitizer

.

In a 90

- day oral toxicity study on rats via gavage with sodium isethio nate , d ecreased 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 show ed 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 isethio nate was administered to rats by gavage

. T he 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 NO AEL is 250 mg/kg/day

. T he 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 tes ts 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 OncoLogic TM 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 genotoxi city as well as the struct ure

- 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 f

unctional o b servational b attery (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 immunot oxicity 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; h owever, the chronic r eference d ose ( 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 r eference d ose (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 decrease d body weight, changes in hematology parameters, increase d spleen weights and macroscopic changes in the liver . This study provided the lowest NOAEL in the database (most s ensitive endpoint) and also provide s 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 t o derive the cRfD. This endpoint of concern was also used for all dermal and inhalation exposure scenarios. Both d ermal and inhalation absorption were assumed to be 100%.

EPA has determined that reliable data show the safety of infants and children wo uld be adequately protec ted if the FQPA SF were reduced to 1X.

An a cute 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 w as completed and performed using the Dietary Exposure Evaluation Model DEEM

FCID TM , Version 3.16. The chronic population

- adjusted dose (cPAD) is t he cRfD divided by the FQPA SF therefore t he chronic popu lation

- 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 fo r 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 leve l 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 th rough 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 ag gregate 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 backgr ound 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 wear ing protective respirators when using open pour loading in support of aerial and groundboom application. The estimated MOEs a re greater than 100 base d on 100% dermal and inhalation absorption

, e xcept 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

conservat ism 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 assu mes 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 conce rn is for MOEs that are lower than 100, these MOEs are not of concern.

Isethion ic acid and its salts are expected to have a minimal impact on the environment. The physical and chemical properties of isethion ic acid and its salts indicate it is generally r eadily biodegradable and will degrade rapidly in the environment. Isethion ic acid is expected to partition into the soil, but it may also remain in or enter the water where it may readily biodegrade. Isethion ic acid is not expected to bioconcentrate in aqu atic organisms. Isethion ic acid is not volatile, and so it will not be released into the air.6 Based on the read il y biodegradability of isethion ic acid and it s salts identified in the EPI Suite model, and the low toxicity to freshwater aquatic invertebrat e, 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 isethion ic acid and its salts as an inert ingredient are not anticip ated.

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 Population s and Low

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

Taking into consideration all available inf ormation on isethionic acid and its salts , EPA concludes that there is a reasonable certainty that no harm to any populatio n subgroup will result from aggreg ate exposure to isethionic acid and its salts when considering residential, occupation al

, dietary exposure and all other non

- occupational sources of pesticide exposure for which there is reliable information. Therefore, t he 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. 156 2

- 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 afte r 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 esta blish 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 ( che lators, 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 180.9 10 and 180.930

, respectively

.

II. INERT INGREDIENT PROFILE

A. Summary of Uses

I sethionic acid and its salts have been used for many years in personal care products. It is a common ingredient in bath soaps and detergent bar s (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 memb ranes, 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 i ts structure and nomenclature, are found in Table 1 a 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 prope rties and environmental fate of compounds when measured values are not available.

Table 1 a
. P hysical and Chemical Properties of Ethanesulfonic acid, 2

- hydroxy

- (Isethionic Acid)

Parameter Value Source
Structure
CAS # 107

- 36

- 8 EPI Suite
Molecular Fo rmula C 2 H 6 SO 4 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 K ow ) - 3.36 EPI Suite

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

- 1.345 d EPI Suite

Solubility 1.0E+6 a EPI Suite8

Table 1 a
. P hysical and Chemical Properties of Ethanesulfonic acid, 2

- hydroxy

- (Isethionic Acid)

Parameter Value Source
1.0E+6 b Vapor Pressure (mmHg at 25 °C) 8.8E

- 5 EPI Suite Henry's Law Constant ( atm*m 3 /mole at 25°C) 6.11E

- 13 EPI SuiteTable 1 b . Physical and Chemical Prope rties 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
M olecular Formula C 2 H 6 SO 4 C 2 H 5 SO 4 NH 4 C 2 H 5 SO 4 K C 4 H 10 S 2 O 8 Zn 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 K ow )

- 3.3 6

- 2.65

- 5.5

- 2.37

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

- 1.345 d 0 c

- 0.791 d 0 c

- 2.529 d 0 c

- 0.886 d

Solubility 1.0E+6 a 1.0E+6 b 1.0E+6 a

8.55E+5 b 1.0E+6 a 9.814E+5 b 1.0E+6 a 1.0E+6 b 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*m 3 /mole at 25°C) 6.11E

- 13 1.386E

- 16 2.96 E

- 19 5.648 E

- 21

Probability of Rapid Biodegradation (BIOWIN) 0.9546 e 0.9999 f 3.273 days

- weeks g 0.5969 h
0.6787 i 0.8381 e 0.8903 f 3.04 days

- weeks g 0.5370 h
0.6250 i 0.9546 e 0.9999 f 3.273 days

- weeks g 0.5969 h
0.6787 i 0.97147 e

0.6819 f
2.8216 weeks g 0.2931 h
0.0542 i 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+9 j
1.174 E+10 k 2.38 E+17 j

2.39 2.6 E+18 k 2.535 E+15 j
2.765 E+16 k 1.842 E+17 j

2.009 E+18 k

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 S oil: 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 results10 d Kow method results

e Biowin1 (linear model)

f Biowin2 (non

- linear mode l)

g Biowin3 (Ultimate survey model)

h Biowin5 (MITI linear model)

i Biowin6 (MITI non

- linear model)
j Model River

k Model LakeIII. HUMAN HEALTH ASSESSMENT

A. Summary of Toxicity Data

Acute Oral Toxicity In an acute oral toxicity study (MRID 49285804), four fasted, young adult female Sprague

Dawley 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 a nimal was dosed at 2000 m g/kg . Two additional ani mals 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 necr opsy.

Oral LD 50 f

emales > 2000 (1000 corrected for purity) mg/kg

.

Based on the observed LD 50 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

appr oximately 10% of the total body surface area on the clipp ed 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

tru nk 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 an imals appeared normal, gained weight, and survived the study. No visible lesions were noted from any animal at necropsy

.

LD 50 Males > 2000 (1000 corrected for purity) mg/kg.
LD 50 Females > 2000 (1000 corrected for purity) mg/kg.
LD 50 Combined > 2000 (10 00 corrected for purity) mg/kg.12 Based on the observed LD 50 , 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) we re exposed by nose

- only inhalation to 55%

a mmonium isethio nate ( 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

- exp osure, 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 g eometric standard deviation ( GSD ) 2.07 and 2.08, re spectively.

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 du ring the first week, all animals gained weight during the study. No macroscopic findings were noted at necropsy.

LC 50 Males > 6.295 mg/L LC 50 Females > 6.295 mg/L LC 50 Combined > 6.295 mg/L

Based on the observed LC 50, 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 a mmoniu m 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 s erved 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. P ositive conjunctival irritation (chemosis) w as noted on all treated rabbit s 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 t oxicity c ategory 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 amm onium 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 wer e 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 ir ritation 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 i rritation i ndex (PII) was 0.0, based on the non

- irritation at 72 hours. Ammonium isethionate is classified as EPA

t oxicity c ategory I V 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 a mmonium isethionate , 20 male and 20 female young adult Hartley guinea pigs; were tested using the Buehler Method. Dose levels were based o n 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 Hill top c hambers that were occluded with a rubber dental dam and secured with restra iner 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 in duction 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 isethion ate wa s 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 870.260 0; OECD 406) in the guinea pigs.

Acute Toxicity

Table 2 . Acute Toxicity Profile of Iset hionic Acid and S alts

Study Type Results MRIDs # /Reference
Acute Oral

– rat OCSPP 870.1100 OECD 425 LD 50 (female) > 1 000 mg/kg MRID 49285 804 Vasquez, R. 2011

Acute Dermal

– rat OCSPP 870.1200 OECD 402 LD 50 >1 000 mg/kg MRID 49285806 Vasquez, R. 2011

Acute Inhalation

– rat OCSPP 870.1300 OECD 403 LC 50 >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 MRI D 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 g roup 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 rat s 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 paramete rs 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 c onsidered 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 chang es in the liver in rats at 1000 mg/kg/day. Histopathology findings included15 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 c orpuscular 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 w as identifi ed 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 i n 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 s acrifices 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 i nterval 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 dela yed 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 d ecreases in erythrocyte count (5.22 vs. 8.21 10 6 /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 histo pathological 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 con trols; 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) a nd 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 for16 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 NO AEL in male rats is 250 mg/kg /day.

There were no clear treatment

- related effects on the reproductive indices, the mean numbers of corp ora 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 pup s, 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 reproductiv e/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 a cceptable / g uideline 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 adre nals as potential target organs . It must be noted that the st udy 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 ba cteria (MRID 49285811), S almonella typhimurium strains TA98, TA100, TA1535, and TA1537 and E scherichia coli strain WP2 uvr A were exposed to test article ammonium isethionate dissolved in water, without and with S9 activation, in two independent plate incor poration tests. In the first test the concentration s 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 uvr A with activation, the tester strain was retested based on the precipitate and toxicity profiles observed. In the re

- test of tester strain WP2 uvr A in the presence of S9 activation, the concentrations of the test article were 50, 150, 500, 1 500 and 5000 μg/plate. In the repeat experiment the concentration s 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 ob tained 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 to17 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 colon ies over background.

This study is classified as acceptable/guideline and does satisfy the guideline requirement for Test Guideline OCSPP 870.5100 1 ; 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 ho ur 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 i sethionate to induce micronuclei was evaluated in human lymphocytes with and without metabolic activation (CIR, 2013). Two expe riments 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 micronucleu s test with or without metabolic activation.

Carcinog enicity 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 caus e cancer. Structure

activity 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 gen otoxicity 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 S ee Developmental Toxicity section

.
Immunotoxicity No i mmunotoxicity studies were available in the database for isethion ic 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 with18 the reproduction/developmental toxicity screening test (MRID 492858 10 ) 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 t he 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 Toxici ty 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 purit y ) 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 st udy

– rats (gavage) Sodium ise thionate 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 change s 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 t he 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

an d 10x for intraspecies variability. A default value of 100 % absorption will be used for dermal and inhalation exposure scenarios.19

T able 4 . Summary of Toxic ological 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 therefo re an acute dietary assessment is not

necessary.

Chronic dietary (All populations) NOAEL= 200 mg/kg/day
UF A = 10 x UF H = 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 de crease 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 short

term (1 to 30 days) NOAEL= 200 mg/kg/day
UF A = 10 x UF H = 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 duc t and spleen.
Incidental oral intermediate

- term (1 to 6 months) NOAEL= 200 mg/kg/day
UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE

= 100 [ 90

- day oral toxicity

- rat ] LOAEL = 100 0

mg/kg/day based on decrease body weight, changes in hematology parameters, i ncrease 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%)
UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE

= 100 [ 90

- day oral toxicity

- rat ] LOAEL = 100 0

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.
In halation short

- and intermediate term O ral study NOAEL= 200 mg/kg/day (inhalation absorption rate = 100%)
UF A = 10 x UF H = 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 inflammati on 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 aci d as potential carcinogens.

UF A = extrapolation from a nimal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (i ntraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term st udy for long

- term risk assessment. UF DB = to account for the absence of data or other data deficiency. FQPA SF = Food20

Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference do se. MOE = margin of expos ure. 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 safet y 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 t he combined developmental/reproduction toxicity screening test in rats. Neither offspring nor reproduction toxicity was obse rved in this study. Parenta l 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 chemical s

. Although no neurotoxicity studies were availabl e 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 chemical s

. 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

, th e cRfD is based on this study and is protective of these effects. Therefore, there is no need for a n immunotoxicity study or additional UFs to account for immunotoxicity.

v. The dietary food exposure assessment utilizes proposed tolerance leve l or highe r residues and 100% crop treated information for all commodities. By using these screening

level assessments, chronic exposures/risks will not be underestimated.

Taking into consideration the available information, EPA concludes the additional 10X FQPA s afety factor can be reduced to 1X.21

IV. EXPOSURE ASSESSMENT

The petitioner request ed 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, livesto ck, residential uses indoor and outdoor. The petitioner did not provide any exposure or risk assessments regarding human occupational or residential exposure.
Resources con straints prohibit the Agency fro m conducting monographic, “all

- inclusive”

assessment s 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 method s of application and site s 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 is ethionic 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 utili zes 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 woul d be no higher than the highest established tolerance for an active ingredient on a given commodity. As to residue levels in food, n o 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 insecticide s, 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

- HQ

OPP

- 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 t olerance 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 dietar y exposures lead to an extremely conservative assessment of dietary risk due to a seri es of compounded conservatisms. First, assuming that the level of residue for an inert ingredient is equal to the level of residue for the active ingre dient will overstat e 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 combin ation 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 wit h the highest tolerance level. This assumption overstates residue values becau se 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 compou nding conservatism is EPA’s assumption that all foods contain the inert ingredient a t 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 hi ghest residue legally poss ible 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 al l 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 highe r 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 exaggeratio n of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of residue data.

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

Population Subgroup cPAD (mg/kg/day) Chronic Expo sure (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 di etary 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 subgrou p, 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 modeli ng

. Also the mutagenicity stud y 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 Tol erance 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 Advisor y Council for Exposure (EXPOSAC), Health Effects Division/O ffice 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 f actor ÷ 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 cons ervative assumption. Though no specific limitation s are proposed, the maximum concentration of isethion ic 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 m g material/kg bw/day. That value is used then to calculate the Margin of Exposure (MOE) (estimated meas ure of risk). An MOE is calculated by dividing the value of the average daily dose into the toxicological endpoint of concern (also expre ssed in mg mate rial/kg24 bw/day). Typically, result ing 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 t he 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

e xposure are presented as summaries for residential “handlers” (non

- occupationally associated applicators) and for oc cupational pesticide handlers. Since lawn and turf uses may be involved, assessments of post

- application exposures to “ residents” were also conducted. Estim ated exposure doses as well as margins of exposure are presented for inhalation , dermal and incidental oral exposure. Post

- application oral exposures (hand

- to

mouth activity) are prese nted 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 route s 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 expo sure 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. T he Agency conducted an ass essment 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 Expo sures and Risks for Isethionic Acid and its Salts Inerts Pesticid e Type Exposure

Scenario Applicati

on Rate 1 Exposed

Populatio n & Exposure Duration 2 Dermal

Dose ( mg/kg/da y) 3 Inhalation

Dose (mg/kg/da y) 3 Derm

al MOE 4 Inhalati

on MOE 4 Total

Combin ed MOE 5

Herb icid 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 Sprayer

HG, IS , C&C Short & Intermedia
te Term 0.421875 0.000015 470 1300000 0 47025 1 Application rates for isethionic acid and its salts are based on d efault 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 )/ Dail y dose (mg/kg/day)

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

Table 7. Residential Post

- A pplication Short

- and Intermediate

- term Exposures and Risks for Isethionic Acid and Salts Inerts Pesticide Type Exposure Scenario Application Rate 1 Expo sed Population &

Exposure Duration 2 Daily Dose (mg/kg/day) 3 MOE 4

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 ing redient 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 fungi cide in both short

- and intermediate

- term scenarios. The combined dermal and inhalation MOEs ranged from 470 to 23 00 . 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 p ost

- application dermal exposure to treate d 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 adj usted dose ( aPAD ) and chronic population adjusted dose ( cPAD ). The aPAD and cPAD represent the highest safe exposures, taking into account all app ropriate safety factors (SFs). EPA calculates the aPAD and cPAD by dividing the POD (i.e. toxicological endpoi nt) 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, wat er, and residential exposure to the POD to ensure that the MOE called for by the product of all a pplicable UFs is not exceeded.

i. Acute Dietary Risk. An acute aggregate risk assessment takes into account exposure estimates from acute dietary consumptio n of food and drinking water using the exposure assu mptions discussed in S ection IV for acute exposure. However there was no hazard attributable to a single exposure seen in the toxicity database fo r isethionic acid and salts ; therefore there is no

concer n 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 exp osure assumptions discussed in S ection IV from chronic exposure. The chronic analysis was based on a 90

- day oral

to xicity study with a NOAEL of 200 mg/kg /day based on decrease body weight, changes in hematology paramet ers, increase spleen weights, macr oscopic changes in liver and microscopic changes in the liver, bile duct and spleen

. The chronic dietary exposure f ro m 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).
Ise thionic 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 exp osure assumptions described in S ection 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 fema les. 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 conc ern. 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 resid ential exposure associated with contact with treated lawns ( post

- app dermal exposure + hand

- to

mouth + 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 Calcul ations for Isethionic Acid and Salts

Population PoD

mg/kg/day LOC 1 Max Allowable Exposure 2 mg/kg/day Average

Food & Water Exposure 3 mg/kg/day Residential

Exposure 4 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 12 3

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. Interme diate

- 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 exp ected to exceed short term aggregate exposure and therefore there are no concerns for intermediate

- term aggregate exposure.

VI. O CCUPATIONAL EXPOSURE/RISK PATHWAY

The representative occupational scenarios selected by the Agency for assessment are evaluate d 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 ex posure 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 fungi cide/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 Exposure28 (ExpoSAC), Heath Effec ts 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 t he hig hest 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 materi al per lb of material handled. Unit Exposures

are derived in the Pesticide Handlers Exp osure 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 5 0% limitation in formulation was applied to these application rate values based on the a ssumption 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 SE PT 2009

AF Absorption factor

- - 100% default for dermal and inhalation routes of

exposure

BW Body Weight

- - 80 kg f or combined adults in the U.S. Taken from “Use of New Human Body Weight Data as Presented in the EPA’s Exposure F actors Handbook: 2011 Ed ition” 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 valu es 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

Exposure 1 Application

Rate 1 Units

Treated 1 Avg. Daily

Exposure 2 MOE 329 1. Default values are taken from Antimicrob ials 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 5 0% limitation ) * Units Treated * Absorption Rate÷ 70 kg Bo dy 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 0.0 23 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:

42 00 Inhalation: 8 1000 Combined: 4000

Liquids: Groundboom Dermal: Single

- layer gloves 0.0 23 Inhala tion: 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: 11 000 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:

18 00 Inhalation: 97 000 Combined: 18 00

Liquid: Groundboom Dermal: Single

- layer gloves 0. 0 14 Inhalation: Open Cab 0. 000 74 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: 1 8 000 Combined: 910

Herbicide Mixer/Loader/Applicator Liquid: Low Pressure handwand Dermal: Sing le

- layer gloves 0. 43 Inhalation:
No r espirator 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:

18 00 Inhalation: 2 6000 Combined: 17 0030 were calculated using the M OE 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 der mal exposure is for MOEs <100. The lowest estimated combined MOE was 93 , based on li quid aerial mixer/loader with gloves and no respirator, maximum application rate on corn and treating 1200 A cres /day. Even though this estimated occupational MOEs is slightly under 100, based on the amount of conservatism and uncertainty factors used in th e 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 ref erred 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

sc outing for pests or harve sting. 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 che mical’s degradation properties. In addition, the timi ng 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 ge nerally 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 short

term (1

- 30 days). The following convention is used to estimate post

- application agricultural worker exposure.

DFR t = 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 (unitle ss) (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 μ g for the DFR val ue (4.54E8 μ g/lb) CF3 = Area unit conversion factor to convert the surface area units (ft 2 ) in the application

rate to cm 2 for the DFR value (1.08E

- 3 ft 2 /cm 2 or 2.47E

- 8 acre/cm 2 )31 Average Daily Dose (ADD) (mg inert/kg/day) = DFR μ g/cm2 * TC cm2/hr * hr/day * 0.001 mg/ μ g * 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 occ upation 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. Dislodgeab le foliar residue = Fraction of inert retained on foliage * Application Rate (corrected for 50% limitation) * (1

- daily dissipation) t * conversion factors

3. S hort

- term dose = DFR * Tc * hours of daily exposure (8 hrs) * conversion factors ( μ g 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 r atio of the exposure to the toxicological PoD. O ccupational post

application 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. C UMULATIVE EXP OSURE Table 11 . Summary of Exp osure & Risk to Occupational Post

- Application From Isethionic Acid and its Salts Exposure Potential Transfer Coefficients 1

cm 2 /hr Application

Rate 1
lb inert/Acre DFR

Levels 2 μg/cm 2 Short

- term

Dose 3 mg inert/kg bw/day MOE 3

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 : Scouti ng, training, tying 1000 0.3693 540 High : hand harvest, leaf pulling, thinning, pruning, training/tying grapes 5000 1.8463 11032 Cumulative effects from substances with a common mechanism of toxicity . Section 408(b)(2)(D)(v) of FFDCA req uires 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 toxic ity.”

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 purpos es 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. E NVIRONMENTAL 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, R D estimates risks to popula tion 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 co mpiled 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. Additio nally, 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 associ ated 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. E NVIRONMENTAL 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 compo unds 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*m 3 /mol to 5.648 E

- 21 atm*m 3 /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 coefficien t 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, an d is not likely to be found in s urface water or ground water. The estimated log Koc values of the isethionates are in the low range, from

- 0.791 to

- 2.529, sugge sting that sorption to soils and sediments from water is not likely to occur.

The probability of rapid biodegr a dation of isethonates were evaluated using EPI Suite in

t h e BIOWIN module. Three of the isethionates were estimated to undergo rapid biodegradat ion and were categorized as readily degradable. The zinc salt has a slightly different structure than t he other compounds that appears to be more stable. A study was conducted to determine the aerobic degradability of ammonium isethionate in water containi ng 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) f or isethionates indicated a low bioconcentration potential. Th e 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.

Isethion ic acid and its salts are expected to have a minimal impact on the environment. The physical and chemical properties of isethion ic acid and its salts indicate it is generally readily biodegradable and will degrade rapidly in the environment. Isethion ic acid is expected to partition into the soil, but it may also remain in or enter the water where it may readily biodegrade. Isethion ic acid is not expected to bioconcentrate in aquatic organisms. Isethion ic acid is not volatile, and so it will not be released into the air.34

X. E COTOXICITY

Based on the ready biodegradability of isethion ic 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 t o nontarget aquatic species resulting from the use of isethion ic 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 t oxicity 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 G uideline 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 minu tes 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 10 3 cells/ml. Cell density was measured in each replicate at 24, 48 and 72 hours by dire ct microscopic counting with a hemacytometer. After 72 hours of exposure, the mean cell density in the control was 79.4 x 10 4 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 10 4 cells/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 wa s > 50 mg/ml for ammonium isethionate based on the lack of a statistically significant reduction in growth rate.

XI. R ISK 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 the35

corresponding ammonium (CAS Reg. No. 57267

- 78

- 4), sodium (CAS Reg. No. 1562

- 00

- 1), potassium (CAS R eg. 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 grow ing 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 rinse

off products that contain 2 % to 6% of isethionate salts.

The chronic r eference d ose (cRfD) o f 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 decrease d body weight, changes in hematology parameters, increase d spleen weights and macrosco pic changes in the liver . This study provided the lowest NOAEL in the database (most sensitive endpoint) and also provide s 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 d ermal and inhalation absorption were assumed to be 10 0%.

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 exp osure was identified in the available studies. A chronic dietary exposure assessment was completed and performed using the Dietary Exposure Evaluation Model DEEM

FCID TM , Version 3.16. The chronic polulation

- adjusted dose (cPAD) is the cRfD divided by the FQPA SF therefore t he chronic popu lation

- 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 f or 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 no t 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 expo sure. 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

c ombines 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 supp ort 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 ha rvesting, 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

conser vatism 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 it s 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 Addres s 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 reas onable 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 whic h 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 gr owing 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. St udy 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. S tudy 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 w ith 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 wit h 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 toxic ity 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. (20 11 ) 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/iseth0920 13final.pdf

NLM, HPDB, National Library of Medicine, Household Products Database, Sodium Isethionate entry, accessed 11/12/2013. http://householdproducts.nlm.nih.gov/cgi

bin/household/brands?tbl=chem&id=453&query=isethionate&searchas=TblChemical&prodcat=all39

APPENDIX

US EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Ch ronic 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 0.2 50554 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%

-------------------------------------------------------------------------------