2

Table of Contents

EXECUTIVE SUMMARY

................................ ................................ ................................ ... 3

I. BACKGROUND

................................ ................................ ................................ ................... 7

II. INERT INGRED IENT PROFILE

................................ ................................ ......................... 7

A. Summary of Uses

................................ ................................ ................................ ....... 7

B. Physical Chemical Properties

................................ ................................ .................... 7

III. HUMAN HEALTH ASSESSMENT

................................ ................................ ..................... 8

A. Summary of Toxicity Data

................................ ................................ ......................... 8

B. Toxicity Endpoint Selection

................................ ................................ .................... 19

C. Special Considerations for Infants and Children

................................ ..................... 21

IV. EXPOSURE ASSESSMENT

................................ ................................ .............................. 21

A. Dietary Exposure:

................................ ................................ ................................ .... 22
i. Acute exposure

................................ ................................ ................................ ..... 22
ii. Chronic exposure

................................ ................................ ................................ . 22

iii. Can cer exposure

................................ ................................ ................................ . 23

B. Dietary Exposure from Drinking Water:

................................ ................................ . 24

C. Residential (Non

- Occupational, Non

- Dietary) Exposure:

................................ ....... 24

V. AGGREGATE RISK ASSESSMENT

................................ ................................ ................ 24

i. Acute Dietary Risk.

................................ ................................ ............................... 24
ii. Chronic Dietary Risk.

................................ ................................ .......................... 24
iii. Aggregate Cancer Risk for U.S. Population.

................................ ...................... 25

VI. OCCUPATIONAL EXPOSURE/RISK PATHWAY

................................ .......................... 25

A. Occupational Handler Risk

................................ ................................ ...................... 25

B. Occupational Post

- Application Risk

................................ ................................ ........ 29

VII. CUMULATIVE EXPOSURE

................................ ................................ ............................. 29

VIII. ENVIRONMENTAL JUSTICE STATEMENT

................................ ................................ .. 29

IX. ENVIRONMENTAL FATE CONSIDERATIONS

................................ ............................ 30

X. ECOTOXICITY

................................ ................................ ................................ ................... 31

XI. RISK CHARACTERIZATION

................................ ................................ ........................... 32

REFERENCES

................................ ................................ ................................ ...................... 35

APPENDIX

................................ ................................ ................................ ................................ ...... 373

EXECUTIVE SUMMARY

In August 2013 Exponent on behalf of Clariant Corporation submitted a petition to the EPA to amend 40 CFR 180.920 by establishing an exemption from the requirement of a tolerance for the use of secondary alkane (C13

- C17) sulfonates (SAS) (CAS Reg. Nos. 85711

- 69

- 9 and

97489

- 15

- 1) as pesticide inert ingredient s ( surfactants ) for use in food c rops in accordance with 40 CFR 180.920 (pre

- harvest pesticide applications ) with a limitation of 40% in formulation

.

Secondary alkane (C13

- C17) sulfonates ( which will be hereby referred to as SAS ) are widely used surfactant s in detergents and in industria l chemicals

. S AS are currently not approved for use as inert ingredients in non

- food or food

- use pesticide formulations in the US. There are currently no FDA approved cosmetic or food uses. There is a Human and Environmental Risk Assessment on ingredients of household cleaning product s by HERA ( 2005). SAS are synthetic anionic surfactants that can be described as sodium salts of secondary C13

- C17 alkane (paraffin)

sulfonic acids.

The acute oral LD 50 for SAS in rats is between 5 00 and 2000 mg/kg bw. The acute dermal exposure to mice did not indicate any potential for acute or systemic toxicity

. S A S is a mild eye irritant based on a primary eye irritation study in rabbits (Tox Category I II ). S A S is not dermally irritating based on primary sk in irritation study in rabbits (Tox Category I V ). SAS is not a dermal

sensitizer in guinea pigs and no acute inhalation studies were available in the database however

, due to the low vapor pressure , inhalation is not expected to be a major exposure route of concern

.

A chronic toxicity study (52 weeks) was conducted on SAS ( 60 %) in rats and demonstrated

a No Observed Adverse Effect Level (NOAEL) of 4,000 ppm (about 168 mg/kg bw/day in males and 227 mg/kg bw/day in females), and a Lowest Observed Adverse E ffect Level (LOAEL) of 20,000 ppm (about 920 mg/kg bw/day in males and 1281 mg/kg bw/day in females) based on reduced body weight, body weight gain and the clinical signs of reduced grooming in males and

females.

Developmental and reproductive toxicity was examined in a two

- generation reproduction study in rats dosed with SAS (60%) . There was no indication that offspring were more susceptible to test substance toxicity than the parental adults. The parental systemic LOAEL was 3000 ppm ( 177 m g/kg bw in males and 181 mg/kg bw in females) , based on decreased body weight gain during premating and on reduced organ weight. The parental NOAEL was 1000 ppm (58.2 mg/kg

bw for males and 66 mg/kg bw for females)

. The offspring LOAEL was 3000 ppm ( 177 mg/kg bw) ba sed on decreased pre

- and post

- implantation loss and decreased weight gain in offspring. The offspring NOAEL was 1000 ppm ( 58.2 mg/kg bw)

.

SAS ( 93 %) was not mutagenic when tested in the in vitro mammalian cell gene mutation assay, and SAS ( 30 %) was not mutagenic in the Salmonella typhimurium reverse mutation assay.

SAS ( 60 %) was admin istered in the diet to rats in a combined chronic toxicity/carcinogenicity study at concentrations (adjusted for the active ingredient content of 60%) of 0.0, 0.08, 0.40, or 2.0% (about 0.0, 27.9, 145.3, and 805 mg/kg bw/day for males and 0.0, 36.5, 182.9, and 1032 mg/kg bw/day for females, respectively) for 104 weeks. There were no treatment

-4

related neoplastic or non

- neoplastic microscopic effects observed up to 2.0% (M/F : 805/1032 mg/kg/day) . A LOAEL was not identified. However, body weights of high

- dose males and females were lower by about 20% relative to controls throughout most of the study. The decreased body weights were attributed to decreased food intake. Alth ough decreased body weight is typically viewed as an adverse effect, in this study survival of males and females from the high dose group was substantially higher than that of the control group. The improved survival was attributed to the leaner body conf ormation, so the decreased body weight was not viewed as an

adverse effect.

SAS ( 60 % ) was tested in a dermal carcinogenicity study in mice No indication of increased incidence relative to controls of malignant neoplasms was observed. No LOAEL was

demon strated . The NOAEL was 1.0% (about 0.6 mg/treatment ), the highest concentration applied

to the skin.

SAS was rapidly absorbed and excreted. Primary routes of excretion were feces and urine.

There was no bioaccumulation. Metabolites were not identified. Dermal application on male rats demonstrated low penetration potential of 14C

- radiolabled SAS. The e limination half

- life averaged about 41 hours (15% elimination in air

, 18% in urine and about 31% in feces ) . About 2.2% of the radioactivity was found in th e treated skin and 35% in the bandage used to cover the treated area.

SAS has a low potential for dermal absorption

.

No immunotoxicity or neurotoxicity studies on S A S were available in the database. However, evidence of immunotoxicity or neurotoxicity wa s not observed in the submitted studies.

EPA has also determined that reliable data show the safety of infants and children would 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 was completed and performed using the Dietary Exposure Evaluation Model DEEM

FCID TM , Version 3.16. The chronic R eference Dose ( cRfD) of 58.2 mg/kg/day was determined on

the basis of the reproductive toxicity study in rats. The LOAEL of 177 mg/kg/day S A S was based

on decreased body weight gain during premating and on reduced organ weight . This study provided the lowest NOAE L in th e database (most sensitive endpoint) and will also provide the most protective limits for human effects. An UF of 100X (10

- fold for interspecies extrapolation

and 10

- fold for intra species variability) was applied to the NOAEL of 58.2 mg/kg/day to derive the cRfD. The FQPA safety factor of 1X is applicable for chronic dietary risk assessment. Therefore, the chronic population

- adjusted dos e (cPAD) is 0.582 mg/kg/day. This endpoint of

concern was also used for all dermal and inhalation exposure scenarios. De rmal absorption was

determined to be 50 % based on the dermal absorption study and inhalation absorption was

assumed to be 100%

.

Based on analyses of estimated dietary risks for the general U.S. population and various population subgroups, the chronic d ietary exposure estimates for S A S are below the Agency’s

level of concern. The chronic dietary exposure estimate for the highest exposed population5

subgroup, children 1

- 2 years old is 97.1 % of the chronic population adjusted dose (cPAD) and

26.0 % of the c PAD for the general population

.

The Agency’s level of concern (LOC) for S A S occupational and residential dermal and inhalation exposures is 100. 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 intraspecies sensitivity.

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). SAS is an inert ingredient in pesticide products that is not expected to result in short

- term residential

exposure since the proposed uses are for commercial agricultural seed treatment and possible foliar applications

. Therefore t he Agency has determined that aggre gating chronic exposure through food

and water with short

- term residential exposures is not required

.

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).

SAS is an inert ingredient in pesticide products that is not expected to result in intermediate

- term residential exposure since the proposed uses are for commercial agricultural seed treatment and possible foliar applications

. Therefore t he Agency has determined that aggregating chronic exposure through food and water with inte rmediate

- term residential exposures is not required

.

Occupational handler risks are not expected to be of concern for all scenarios evaluated . It

is noted that this occupational handler assessment assumes that mixer/loader/applicators are not

wear ing p rotective respirators when using open pour in support of aerial and groundboom application. The estimated MOEs a re greater than 100 based on 100% inhalation absorption and 50% dermal absorption except for mixer/loader aerial/chemi g ation which had a combine d

herbicide i nhalation and dermal MOE of 64.3

. However based on the amount of conservatism built

into the model (i.e. liquid aerial /chemigation with no respirator, maximum application rate on corn and treating 1200 A/day) the estimated combined occupationa l herbicide MOEs are not expected

to be of concern. Additional, SAS is expected to be used in seed treatments and the occupational

handler dermal/ inhalation exposure and MOEs are calculated for this application method. The

lowest estimated combined seed treatment MOE was 620 for “multiple activities” exposure scenario, therefore the estimated combined occupational seed treatment MOEs are also not

ex pected to be of concern. This assessment is considered to be a screening level estimate, demonstrating that there are minimal potential risks to workers re

- entering fields treated with pesticides containing SAS as inert ingredients. Therefore an occupation al post application risk assessment was not performed.

Once SAS is released into the environment, it is expected to partition between soil and

water . B ased on fugacity modeling , SAS should partition primarily to the soil compartment.

Therefore SAS used in either seed or foliar applications can be expected to have limited mobility

in the environment. SAS is not expected to bioconcentrate or bioaccumulate based on a low logKow of 0.2

.6 Based on studies conducted with various aquatic species , SAS is considere d highly toxic to aquatic organisms. Based on a 9 day chronic fish toxicity study, the NOEC was 0.9 mg/ml and a 21 day chronic daphnia toxicity study, the NOECrepro was 0.4 mg/ml. SAS is not expected to be

toxic to birds based on the lack of bioconcentrati on and bioaccumulation.

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal

Actions to Address Environmental Justice in Minority Populations and Low

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

Taking into consideration all available inf ormation on SAS , EPA concludes that there is a reasonable certainty that no harm to any population subgroup will result from aggreg ate exposure

to SAS when considering residential, occupation al , dietary exposure and all other nonoccupational sources of pesticide exposure for which there is reliable information. Therefore, the establishment of an exempt ion from tolerance under 40 CFR 180.92 0 for residues of Secondary Alkane (C13

- C17) Sulfonates ( CAS Reg. No. 85711

- 69

- 9 and 97489

- 15

- 1 ) when used as a pesticide inert ingredient applied to pre

- harvest crops with a limitation of 40% in formulation, can be co nsidered assessed as safe under section 408(q) of the FFDCA.7

I. BACKGROUND

Exponent on behalf of Clariant Corporation ( EPA Company Number 8340, 4000 Monroe Road Charlotte, NC 28205 ) is requesting that EPA establish a tolerance exemption for secondary

alkane (C13

- C17) sulfonates ( CAS Reg. No. 85711

- 69

- 9 and 97489

- 15

- 1 ) as pesticide inert ingredients under 40 CFR 180.920 (pre

- harvest for seed treatment and foliar applications in food

crops )

. Secondary alkane (C13

- C17) sulfonates also referred to as (C13

- C17 SAS ) is currently not approved for use as inert ingredients in non

- food or food

- use pesticide formulations in the US. There are currently no FDA approved cosmetic or food uses

. T oxicology, environmental and use/exposure data reported by the Human and Envi ronmental Risk Assessment on ingredients of household cleaning products ( HERA 2005) for CAS Reg. No. 85711

- 69

- 9 are referenced in this

document as well as data provided by REACH Chemical Safety Report (2010) for CAS Reg. No.

97489

- 15

- 1.

SAS are syntheti c anionic surfactants that can be described as sodium salts of secondary

C13

- C17 alkane (paraffin) sulfonic acids , which will be used as surfactants in pesticide formulations applied to growing crops only under 40 CFR 180.920. It is proposed that because CAS Reg. No. 97489

- 15

- 1, s ulfonic a cids, C14

- C17 secondary alkane, has an alkyl carbon chain length that falls within the carbon chain length range of sulfonic acids, C13

- C17 secondary alkane (CAS Reg. No. 85711

- 69

- 9) it is appropriate to bridge data for t he SAS surfactant CAS Reg. No.

85711

- 69

- 9 to CAS Reg. No. 97489

- 15

- 1.

II. INERT INGREDIENT PROFILE

A. Summary of Uses
SAS surfactants are currently used in detergents and for industrial chemical use in the EU.

B. Physical Chemical Properties
Some of the physical and chemical characteristics of SAS , along with its structure and nomenclature, are found in Table 1.

Table 1. P hysical and Chemical Properties of Secondary Alkane (C13

- C17) Sulfonates (SAS )

Parameter Value Source

Structure Various

CAS # 85711

- 69

- 9

97489

- 15

- 1

Molecular Formula Various Molecular Weight (g/mol) ~328.0

Common Names Sulfonic acids, C14

- C17 sec

- alkane, sodium salts; secondary alkane sulfonate sodium salts; Sec

- alkane sulfonate

sodium salts Submitted petition

Color yellowish HERA 2005 Physical State waxy HERA 2005

Odor

Flash Point pH 7 (at 20°C 10g/L) HERA 20058

Table 1. P hysical and Chemical Properties of Secondary Alkane (C13

- C17) Sulfonates (SAS )

Parameter Value Source Viscosity (dynamic) Melting Point <200°C (softening) HERA 2005 Boiling Point (°C) @ 19 hPa Not determined HERA 2005 Specific Gravity

Bulk Density 600 kg/m 3 HERA 2005 Dissociation Constant (pK
a ) pK
a <0 estimated for C16 SAS (at 25°C) HERA 2005

Octanol/water Partition Coefficient (K
ow ) Log Kow = 0.2 (at 20°C) Log Kow = 2.76 (at 20°C) calculated for

C16 SAS EPISuite 4.1 by Clariant (2010)

HERA 2005

Soil organic carbon/water Partition coefficient (Koc) Log Koc = 2.181 (Kow method) EPISuite 4.1 by Clariant (2010)

Solubility (at 25°C) 115.6 mg/L water (at 25°C) EPISuite 4.1 by Clariant (2010)

Vapor Pressure 1.97 x 10

- 11 mg/HG (at 25 ° C)

5.3 x 10

- 11 Pa (at 25°C) calculated for

C16 SAS EPISuite 4.1 by Clariant (2010)

HERA 2005

Henry's Law Constant 3.6 x 10

- 5 calculated for C16 SAS HERA 2005

III. HUMAN HEALTH ASSESSMENT

A. Summary of Toxicity Data
Clariant Corporation has submitted studies on SAS at varying con centrations

.

Acute Oral Toxicity

T he following summary is cited from 2010 REACH Chemical Safety Report on SAS.

The acute oral toxicity of sec

- alkane sulfonate

- sodium salts SAS (93%) was investigated in rats using water as vehicle. 5 male and 5 female rats per dose group were administered the test compound by single

- dose gavage at dose levels of 500 or 2000 mg/kg body weight. The observation period was 14 days. After administration of 2000 mg/kg body weight al l animals died within 24 hours p.a. Fatal intoxicated animals showed the following symptoms: bristled coat, squatting posture, stilted gait, irregular respiration and decreased spontaneous activity. At necropsy the following findings were revealed: stomach full of reddish

- black mass (haemoccult positiv), intestinal tract filled with reddish mucous (haemoccult positv), lungs partly filled with blood. After administration of 500 mg/kg body weight no mortalities occurred. Unspecific clinical symptoms (bristled coat, squatting posture, stilted gait) were present up to 24 hours p.a. No clinical symptoms were observed from day 1 until the end of the observation period. Based on the findings of this limit

- test the median lethal dosage (LD50) of sec

- alkane sulfonate

- sodium salts SAS (93%) in rats is between 500 and 2000 mg/kg body weight. (Hoechst AG 1988)

Dermal Toxicity

T he following summary is referenced from 2010 REACH Chemical Safety Report on SAS

.9 In an acute dermal toxicity study, female CD

- 1 mice were dosed with SAS (60%). Acute dermal exposures to mice (non

- GLP) did not indicate any potential or acute and/or systemic toxicity. The LD50 is > 2000 mg/kg bw (Life Science Research 1975).

Inhalation Toxicity

No inhalation studies were available in the database.

Primary Eye Irritation

T he following summary is cited from 2010 REACH Chemical Safety Report on SAS

.

Sec

- alkane sulfonate

- sodium salts SAS (30%) was tested for primary eye irritation

accord ing to OECD 405 and GLP. Based on the observed skin irritating potential in rabbits, testing for eye irritation was conducted in only one rabbit. 0.1 mL of undilauted Hostapur SAS 30 was applied into the left conjunctival sac of this rabbit. The right eye served as a control. Assessments were made 1, 24, 48 and 72 hours p.a. as well as 7 days after treatment. From one hour up to seven days moderate irritations including corneal and iridial effects were observed. After seven days a

clear vascularisation of t he cornea was observed. Based on the results of this study,

sec

- alkane sulfonate

- sodium salts SAS (30%) when tested according to OECD guideline 405 was considered to be severely irritating to eyes and thus no further

animals were included in the test.

In a primary eye irritation study (MRID 49146412), 10 μL of undiluted SAS [ 30% purity; Batch No. 04665 (September 93) ; liquid; pH ~7 ] was instilled as received directly on the cornea between its center and the superior limbus of the left eye of one male and two female young adult New Zealand White rabbits (CRL:KBL (NZW) BR; age: 15 weeks; body weight: male: 2.7 kg and female: 2.9

- 3.0 kg; source: Charles River, Stolzenseeweg

32

- 36, D

- 88353 Kisslegg). The untreated eye served as a control. The animals were

ob served at 1, 24, 48, and 72 hours and 7 days post

- instillation.

No iritis was noted on any animal during the study

. Co rneal opacity was noted on one animal 48 and 72 hours after test material instillation with clearance by day 7. P ositive conjunctival ir ritation was noted on three animal s one hour after test material instillation with clearance on two rabbits by 24 hours and on one rabbit by day 7. The highest maximum mean total score was 13.3, recorded one hour after test material instillation.

Based on highest maximum mean total score and no irritation by day 7

, SAS ( 30 %) was mildly irritating. This study as indicated that only 0.01 mL instead of 0.1 mL of test material was instilled into the rabbit eye. If 0.1 mL of test material was used, the test material likely would have caused cause further irritation/damage.

All available OECD 405 stud ies conducted with C13

- C17 SAS aqueous solutions were consistent and demonstrated concentration dependent irritant effects. Results demonstrate

that C13

- C17 is slightly irritating to the eye at 15% and that irritation increases with increasing concentratio ns, i.e., irritating to eye at concentrations of 30% and above. However, when the low

- volume technique (LVET) is utilized even a 30% aqueous solution10 does not cause significant eye irritation. Based on the results of the available studies, C13

- C17 SAS up t o 30% is moderately irritating to the eye (EPA Category III).

Primary Skin Irritation

In a primary dermal irritation study (MRID 49146409), three male young adult New Zealand White rabbits (age: not reported; body weight: at least 1.5 kg; source: Paulis tee, Mairipora, SP) were dermally exposed to 0.5 g of undiluted SAS ( 93 %) ( concentration not reported; Batch No. 2703061 ; pH 7.5 ) for 4 hours on a 6 cm 2 area of the clipped flank skin

that was covered with a semi

- occlusive gauze patch and held in place wit h non

- irritating tape. The patch was removed and the residual test material was removed with water at the

end of a 4

- hour exposure. The animals were observed and irritation was scored at 1, and 24, 48, and 72 hours and 7 days after patch removal.

All a nimals survived the study . Very slight erythema was noted on three animals one hour after removal of the patch with clearance on one animal by 72 hours and on two animals by day 7. One animal had very slight edema one hour after patch removal with cleara nce by 48 hours. Another animal had very slight edema one hour after patch removal that became slight edema then reduced to very slight edema with clearance by day 7.

In this study, the test material was slightly irritating and the P rimary Irritation Ind ex (PII)

was 1.5.

Dermal Sensitization

T he following summary is cited from 2010 REACH Chemical Safety Report for SAS

.

Sec

- alkane sulfonate

- sodium salts SAS (60%) was examined for its capacity to cause contact allergy by the maximization test according to Magnusson and Kligman with guinea pigs. Based on a screening study using groups of 6 male guinea pigs the highest non

- irritating concentration of sec

- alkane sulfonate

- sodium salts SAS (60%) was established to be 5% in water. In the main study 15 male

g uinea pigs were used. Induction exposure included 10 intracutaneous injections of 0.05 mL of a solution of 500 mg sec

- alkane sulfonate

- sodium salts SAS (60%) in 10 mL of Freund`s complete adjuvant. Challenge was made 14 days after the last injection using 0.1 mL of sec

- alkane sulfonate

- sodium salts SAS (60%) at 5% test concentration. Readings performed 24 and 48 hours after the challenge treatment revealed no signs of skin reactions (sensitization incidence = 0%). Additionally, also a second challenge treat ment using the same test conditions like in the first challenge revealed no signs of skin reactions (sensitization incidence = 0%). Thus it

was concluded that sec

- alkane sulfonate

- sodium salts SAS is not a skin sensitizer. (Hoechst AG 1974)

Sec

- alkane sul fonate

- sodium salts (60%) (Marlon PS 60) was tested for skin sensitization according to OECD guideline 406 but without GLP using the maximaization test protocol of Magnusson and Kligman. Based on prescreening,11 the primary irritating as well as non

- irritati ng concentration was 5% and 1% respectively. 20 guinea pigs in the test group and 10 guinea pigs as control were used. Intradermal induction was performed using 0.1 mL of a 0.05% solution of Marlon PS 60 in Freund`s complete adjuvant. Dermal induction was performed one week later by dermal exposure with a 5% solution of Marlon PS 60 in water. 14 days after the dermal induction phase challenge treatment was conducted using a 1% solution of the test material in water. Readings performed after 24 and 48 hours after challenge treatment revealed no signs of skin reactions (sensitization incidence = 0%). Based on the test results, the authors concluded that sec

- alkane sulfonate

sodium salts (Marlon PS 60) is not a skin sensitizer. ( Huls AG 1986).

The results of the available acute toxicity s tudies are summarized in Table 2

. Acute Toxicity

Table 2 . Acute Toxicity Profile of Secondary Alkane (C13

- C17) Sulfonates ( SAS ) Study Type Results MRIDs # /Reference

Acute Oral

- rat LD 50 =500

- 2000 mg/kg bw Hoechst AG 1971, 1977, 1979, 1988 and Life

Science Research 1975

Acute Dermal

– rats/rabbits No potential for acute/systemic toxicity Life Science Research 1975

Acute Inhalation

- N/A N/A N/A Primary Eye Irritation

- rabbit Moderately irritating Hoechst AG 1989; RCC 1990, 1995; Huls AG

1986 Mildly irritating MRID 49146412 Primary Skin Irritation

- rabbit Slightly irritating MRID 49146409

Dermal Sensitization Not a dermal sensitizer Hoechst AG 1974 and Huls AG 1986

C hronic Toxicity

- A chronic toxicity study was conducted on SAS ( 60 % ) in Sprague

- Dawley rats (MRID

49146406 ) . The test material was administered to 20 rats/sex/dose in the diet for 52 weeks at dose levels of 0, 800, 4,000, or 20,000 ppm ( calculated as equi valent to 0, 34, 168, and 920 mg/kg bw/day in males, respectively; and 0, 45, 227, and 1281 mg/kg bw/day in females, respectively and corrected for purity )

. Groups of 10 rats/sex/dose served as satellite animals and were fed diet containing the same dose levels followed by interim sacrifice after 26 weeks of treatment. Hematology (10 rats/sex/group) and clinical chemistry (5 rats/sex/group) analyses were conducted on blood drawn at 26 and 52 weeks. Urinalysis was conducted on urine from 5 rats/sex/group after 26 and 52 weeks. Ophthalmoscopic examinations were conducted on all rats prior to the study and all rats

scheduled for sacrifice at 26 or 52 weeks. All animals that died and those sacrificed at 26 or 52 weeks were subjected to gross pathological examination, selected organs were weighed, and selected tissues examined histologically.

A lack of grooming activity was observed throughou t the study in rats given 20,000 ppm (not verifiable since the incidence data for clinical signs were not provided)

. The study authors reported only mean absolute body weight, but the study reviewer subsequently calculated body weight gains and conducted comparative statistics. In males at 20,000 ppm

, mean absolute body weight from Weeks 1

- 4 was 91

- 94% of controls , and f rom w eek 5 to12 study termination was 77

- 89% of controls. The final mean body weight in males at the high

dose was 82% of controls (p≤0.01). Body weight gain at the high dose was reduced to 85%

of controls over w eeks 0

- 13 and to 58 % of controls over weeks 13

- 25, but was comparable

to control over weeks 25

- 52. However, overall body weight gain ( w eeks 0

- 52) in high dose

males was 80% of contro ls (p≤0.01) . A similar pattern was seen in females at the high

dose . Mean absolute body weight was decreased to 91

- 93% of controls for w eeks 3

- 5.

From w eek 6 to study termination, mean absolute body weight was reduced to 81

- 91% of controls. Body weight gain was reduced to 84% of controls over w eeks 0

- 13 and to 51% of

controls over weeks 13

- 25. Although not attaining statistical significance, body weight gain over w eeks 25

- 52 was reduced to 73% of controls. Overall body weight gain for

w eeks 0

- 52 was 7 7% of controls (p≤0.01)

. No statistically significant or biologically significant decreases in mean body weight or body weight gain were observed in males or

females at 800 ppm (34 mg/kg bw/day for males and 45 mg/kg bw/day for females) or 4000 ppm (168 m g/kg bw/day for males and 227 mg/kg bw/day for females)

.

The reductions in body weight at the high dose were not accompanied by concomitant

reductions in food consumption in females. F ood consumption was statistically reduced in

males , but only over the first few weeks of the study (food consumption at w eeks 2, 3, 4, 5,

and 11 w as 85, 80, 81, 77, and 86% of controls, respectively); by 12 weeks

, food consumption was generally comparable to controls. No other adverse effects on food
consumpt ion were observed in high

- dose males or females, indicating that food efficiency was compromised.

A total of eight animals died during the course of the study, but the deaths were not related to treatment. No definitive, treatment

- related effects were ob served in hematology, clinical chemistry, ophthalmoscopic findings (data not included so this could not be verified), organ weights, or macroscopic or microscopic pathology. No tumors were related to

treatment.

Based on these findings, t he LOAEL was 20,0 00 ppm (calculated as equivalent to 920 mg/kg bw/day in males and 1281 mg/kg bw/day in females) based on reduced body weight and body weight gain and the clinical signs of reduced grooming in males and females

. T he NOAEL is 4,000 ppm (calculated by review er as equivalent to 168 mg/kg bw/day in males and 227 mg/kg bw/day in females). This chronic oral study was conducted prior to the current Guideline (OCSPP 870.4100, OECD 452) without the indication that it was conducted to GLP requirements (40 CFR 160). N o data on the concentration, homogeneity, and stability of the test diet preparations were provided. However considering these

deficiencies , they do not have a significant impact on the overall toxicity of the chemical.

Genotoxicity

SAS ( 93 %) was evaluat ed for mutagenicity in the in vitro mammalian cell gene mutation assay ( MRID 49146410 ). Chinese hamster V79 cell cultures were exposed in a preliminary toxicity assay for 4 hours at concentrations of 0, 0.158, 0.5, 1.58, 5, 15.8, 50, 158, and 500 μg/mL and for 20 hours at concentrations of 0, 5, 10, 15, 20, 25, 35, and 50 μg/mL without activation, and they were also exposed f or 4 hours with activation at13 concentrations of 0, 0.316, 1, 3.16, 10, 31.6, 100, 316, and 1000 μg/mL. Activation was carried out using S

- 9 from male Wistar rat liver induced with phenobarbital and β

napthoflavone. The cultures treated for 4 hours withou t S

- 9 activation showed no cell survival at concentrations of 15.8 μg/mL or higher, while the 20

- hour exposures showed no toxicity up to 50 μg/mL, the highest concentration tested. This discrepancy in the pre

- test results was not considered important beca use significant toxicity was seen at the highest

concentrations used in subsequent mutage nicity tests without activation

. Based on the results of that pre

- test, the first mutation assay used a 4

- hour exposure and concentrations of 0, 0.2, 0.5, 1.0, 3.0, 4 .5, 5.5, 6.5, 7.5 and 8.25 μg/mL without activation and concentrations of 0, 30, 35, 40, 47, 50.2, 52.6, 53.8 and 55.0 μg/mL with activation. In the confirmatory assay, concentrations of 0, 10.0, 80.0, 90.0, 92.5, 95.0, 100.4, 102.2 and 104.0 μg/mL were us ed without activation for a 20

- hour exposure, and concentrations of 0, 20.0, 42.5, 45.0, 49.6, 50.8, 52.0, 53.2 and 54.4 μg/mL were used with ac tivation for a 4

- hour

exposure. Without activation, the relative growth was 6.4% for the highest concentration (8.25 μg/mL) in Exp. I and 19.3% for the highest concentration (104.0 μg/mL) in Exp. II. With activation, the relative growth was 20.2% for the highest concentration (55.0 μg/mL) in Exp. I and 18.8% for the highest concentration (54.4 μg/mL) in Exp. II. T hese results

demonstrate that SAS ( 93 %) was tested up to toxic levels without and with activation.

Either without or with activation, SAS ( 93 %) did not induce a mutagenic response in Chinese hamster V79 cells at any concentration level

. All of the positiv e controls gave appropriate responses, without and with activation, and the concurrent negative controls were in agreement with historical laboratory background values. There fore, SAS ( 93 %)

was not mutagenic in the in vitro mammalian cell gene mutation assay under the conditions of this testing using Chinese hamster V79 cell cultures ( OCSPP 870.5300, OECD 476 )

.

SAS ( 30 %) A 297 T3/131 was tested in a reverse gene mutation assay (MRID 49146413) using Salmonella typhimurium st rains TA98, TA100, TA1535, and TA1537 without and with S9 activation at concentrations of 0, 0.001, 0.01, 0.1, 1, and 5 μL/plate. Cytotoxicity

was indicated in all strains at 5 μL/plate based on zero revertants at that concentration

under all test conditi ons. The number of revertants per plate was not increased over the concurrent solvent control value at any test substance concentration, without or with S9

- mix, in any tester strain. Because no historical data were presented, it is unknown whether

solvent controls gave appropriate responses. There were no positive controls. There was no evidence of induced mutant colonies over background up to the maximum concentration tested. However, no confirmatory mutagenicity assay was conducted and there were no

pos itive controls. Major deficiencies of the study were that there were no positive controls, only four or fewer concentrations were tested at which revertants were found, and three of the four concentrations with revertants were far below cytotoxic levels ( OCSPP 870.5100 )

.

Carcinogenicity

SAS ( 60 % ) was tested in a combined chronic toxicity/carcin ogenicity study (MRID 49146408). The test material was admin istered to groups of 50 Sprague Dawley

rats/sex/dose in the diet at concentrations (adjusted for the active ingredient content of 60%) of 0.0, 0.08, 0.40, or 2.0% in the diet ( calculated as equivalent to 0.0, 27.9, 145.3,14 and 805 mg/kg bw/day for males and 0.0, 36.5, 182.9, and 1032 mg/kg bw/day for females

, respectively and corrected f or purity ) for 104 weeks.

Treatment did not induce long

- term toxicity. Although rats of both sexes displayed a lack of grooming activity exacer bated by adherence of diet particles from the start of treatment through the end of the first year; the effe ct disappeared during the second year of treatment. Reduced body weights (12

– 16%) and body weight gains were seen in rats of both sexes receiving diets containing 2.0% test material during the first 13 weeks of treatment. There

after, the body weight s of high

- dose males and females were lower by 18

- 22% relative to

control s through the remainder of the study. The decreased body weights were attributed to

decreased food intake. Although decreased body weight is typically viewed as an adverse effect, in this study survival of high

- dose male s at study termination was 58% compared to

18% in controls and in female rats

, survival was 66% vs. 42% in controls

. The improved survival was attributed to the leaner body conformation at the high dose

. Therefore, th e decreased body weight observed at the high

- dose was not viewed as an adverse effect. The growth of both sexes receiving diets containing 0.40 and 0.08% in the diet were similar to

controls. No treatment

- related effects were found on hematology or urinal ysis results (clinical chemistry, neurotoxicity studies, ophthalmoscopic examinations, and organ weights were not measured) and no treatment

- related effects were noted at necropsy.

There were no treatment

- related neoplastic or non

- neoplastic microscopic e ffects observed.

Based on the study results, a LOAEL was not identified. The NOAEL for male and female Sprague Dawley rats was > 2.0% SAS ( 60 % ) in the diet ( calculated by the reviewer as equivalent to 805 mg/kg bw/day in males and 1032 mg/kg bw/day in females)

. This chronic/carcinogenicity study in the rat was conducted prior to the current Guideline for a combined Chronic Toxicity/Carcinogenicity Oral Study (OCSPP 870.4300 ) without the indication that it was conducted to GLP requirements (40 CFR 160). D eficiencies of the study included lack of data on the concentration, homogeneity, and stability of the test diet preparations were not provided; s tatistical analyses as provided were not appropriate; and survival was below 25% in the male control group a t study termination. However despite of

all these deficiencies , this study demonstrates that there is no tumorigenic effect of this chemical at very high doses.

SAS ( 60 % ) was tested in a dermal carcinogenicity study in mice (MRID 49146407 ). The

test substance was administered by dermal application (0.1 mL) to groups of 100 CD

- 1

mice /sex at dilutions with distilled water of 0 (no treatment), 0 (vehicle control), 0.1%, 0.5%, or 1.0% three times/week for 80 weeks and observed for an additional 24 weeks. The amounts estimated by the reviewer that were applied to the skin for the respective concentrations were about 0.06, 0.3, and 0.6 mg/treatment.

No test substance

- related clinical finding w ere observed. The test substance did not alter

survival relati ve to controls and there was no treatment

- related effect on the distribution of factors contributing to death. No differences between treated and control groups were apparent in the body weight data, though statistical analyses were not performed. Females from the high dose group had slightly increased incidence of enlarged spleen (40/100) relative to controls (31/100 and 27/100 vehicle only) and increased incidence of lymph15 node enlargement (18/100 vs. 11/100 and 9/100 vehicle only). Similar findings were not
observed in males. No marked differences were observed between treated and control groups in microscopic lesions of the skin. No indication of increased incidence relative to controls of malignant neoplasms was observed in males or females from the tre ated groups. The findings were similar with the incidences of benign neoplasms with no differences indicated between control and treated groups. No LOAEL was demonstrated in mice

administered SAS on the skin

. The NOAEL was 1.0% (about 0.6 mg/treatment ), t he highest concentration applied to the skin. The study did not meet any OCSPP guideline requirement and did not meet GLP requirements (40 CFR 160). The major deficiencies

relative to the current Guideline (OCSPP 870.4200b) we re: the lack of toxicity at any dose, including at the site of application; n o dose selection rationale was provided ; t he test material was applied only three times per week ; n o statistical analyses of the data were

conducted ; and t he incidence of microscopic lesions was vague, s ince no indication was provided on the number of animals found dead for which microscopic observation of tissues was either limited or not possible to perform due to autolysis.

No treatment

- related tumors were observed in a chronic dietary toxicity study (52 weeks) conducted on Hostapur (SAS 60) in Sprague

- Dawley rats (MRID 49146406; details presented in “ Chronic Toxicity” in Section III of this document ).

Reproductive Toxicity

D evelopmental and reproductive toxicity was examined in a two

- generation repro duction study conducted in Charles River CD rats (MRID 49146411). For 60 days prior to mating,

SAS ( 60 % ) was administered continuously in the diet to groups of 25 rats/sex/dose at dietary levels of 1000, 3000, or 10,000 ppm (equivalent to 58.2, 177, or 57 0 mg/kg bw/day in males, and 66, 181, or 566 mg/kg bw/day in females corrected for purity )

. Three additional groups of 25 female rats were not treated prior to mating, but were given diets containing 1000, 3000, or 10,000 ppm SAS during gestat ion day (GD) 6 to 15 ; male rats in these groups were not treated. Groups of males and females not treated were considered control animals for both the continuously treated rats and those treated only during gestation.

Several parameters were evaluated which are not routinely done in reproduction studies. Prior to mating, after continuous treatment for 8 weeks with 1000, 3000, or 10,000 ppm

and non

- treatment for 60 days 5 males and 5 females per group were selected for hematological evaluation, organ weight, and macro scopic and microscopic evaluation. After the third mating (F 1C and F 2C litters), each litter was divided into two subgroups, one subgroup was euthanized at GD 13 and one subgroup was euthanized at GD 21. For each female in each subgroup, developmental toxi city parameters were measured.

Continuous treatment with SAS during premating provided some indication of toxicity. Mean body weight of F 0 males treated during pre

- mating showed a dose

- related decrease at 3000 and 10,000 ppm, and a dose

- related and signi ficant decrease in F 1 males at 3000 and 10,000 ppm. The data for F 1 males showed a dose

- related decrease in body weight for each week for all treated groups (1

, 000

- 10,000 ppm) and significant decreases for each week at 3000 and 10,000 ppm. Mean body weight of females in F 0 and F 1 generations showed a16 significant decrease at 10,000 ppm. The F 0 data showed a consistent decrease in body weight during the 8 weeks of treatment which culminated in significance at 8 weeks in the high

- dose group, and the F 1 data sh owed a consistent and dose

- related decrease in body weight for each week for each treated group, although the decreases did not reach statistical significance. Of the organ weights measured, relative liver weights were significantly reduced at 10,000 ppm in F 0 males and absolute liver weight of F 1 females at 3000 and 10,000 ppm. Relative liver weight in females was significantly reduced at 10,000 ppm in F 1 premating females. Weight of sex organs was not affected by the compound. The parental systemic LOAEL wa s 3000 ppm, based on decreased body weight gain during premating and on reduced organ weigh t. The parental systemic NOAEL wa s 1000 ppm (58.2 mg/kg bw/day)

.

In F 1C and F 2C litters, there were scattered increases and decreases in pre

- and post

implantation losses at both G estation D ay (GD) 13 and GD 21. S ome of the increases are not significant because of the small number of litters utilized. Looking at F 1C , on GD 21, at

gro ups of control vs 10,000 ppm, pre

- implantation loss increased from 8.3 to 17.8%, and

the loss was dose

- related in all groups. In F 2C , at GD 13, there was an increase in pre

implantation loss from 3.0 to 10.2%. Looking at dose levels of control vs 10,000 pp m dosed during gestation in F 1C , on GD 21, there was a significant and dose

- related increase from 8 to 31.5% in pre

- implantation loss. In F 2C , at GD 13, there was an increase from 3.0 to 12.7% in pre

- implantation loss and in post

- implantation loss from 4.0 to 8.7%. At GD 21, in F 2C , there was an increase in post

- implantation loss from 4.8 to 11.8%. Continuous treatment with 10,000 ppm SAS produced a significant decrease in pup weights at GD 21

in F 1A , a decrease in F 1B not statistically significant, and a statistically significant decrease

in F 2B

. The offspring LOAEL was 3000 ppm based on decreased pre

- and post

implantation loss and decreased weight gain in offspring. The offspring NOAEL was 1000

ppm (58.2 mg/kg bw/day)

.

This two

- generation reproduction study was conducted prior to the current Guideline (OCSPP 870.3800, OECD 416) and prior to GLP requirements (40 CFR 160). Major deficiencies of the study were: 1) pathology results showed that there was widespread pneumonia (100% in males) and changes in lung pathology in males and females (eg., congestion, hyperplasia) after 60 days of treatment (prior to any mating); 2) there was a lack of individual animal data which reduced the robustness of the data; 3) too few litters

were utilized which decreased the rob ustness of litter observations; and 4) insufficient information was provided on diet preparation (incorporation of the test substance, frequency of mixing, diet storage, and diet analyses for homogeneity, stability, and

concentration. However, this study c learly demonstrates that there is a lack of reproductive toxicity and the lack of susceptibility of infants and children.

Immunotoxicity

No i mmunotoxicity studies were available in the database for SAS

. However, evidence of immunotoxicity was not observe d in the submitted studies.

Neurotoxicity17 No neurotoxicity studies were available in the database for SAS

. However, evidence of neurotoxicity was not observed in the submitted studies except decrease in grooming at high dose, however there were no inciden ces provided therefore it is difficult to conclude

whether the effect is treatment related or not

.

Metabolism and Pharmacokinetics Sections of the following summary are cited directly from Clariant Corporation’s petition.

HERA (2005) and additional references cited therein, have reported that primary n

alkanesulfonates are metabolized to bisulfite and the corresponding aldehyde by Pseudomonas sp. By analogy HERA postulated that the proposed metabolic pathway may also be app licable to C13

- C17 SAS.

Accordingly, the SAS surfactants are initially oxidized to generate a keto

- bisulfite, which is degraded to bisulfite and an alkyl ketone metabolite. The ketone metabolite may be further metabolized through oxidative degradation (pr esumably to alkyl acetate ester metabolites). Ester cleavage would yield acetate and an alcohol, which should be further metabolized by β

- oxidation fatty acid processes to ultimately generate carbon dioxide and water.

The C13

- C17 SAS surfactants toxicokin etic data in rats (Clariant, 2010) substantiated the likelihood of a β

- oxidation pathway since excretion of radiolabeled CO 2 was observed. The mammalian toxicokinetics data also confirmed rapid excretion with the absence of

bioaccumulation.

14 C

- radiolabe led C13

- C17 SAS administered by gavage to male rats at concentrations of 0.5, 5.3 or 51 mg/kg was excreted according to a biphasic elimination with a biological

half

- life of 11 hours to 65 hours. Up to 17% of the administered radioactivity was exhaled

as C O 2 , approximately 30% was excreted via urine and about 45% with feces. In total more than 90% of the applied radioactivity was excreted within the first 24 hours after application. There was no indication of bioaccumulation as demonstrated by very low

resi dual radioactivity (< 1ppm) in organs after 7 days. Potential metabolites were no t
identified.

Dermal application o n male rats demonstrated low penetration potential of 14C

- radiolabled

C13

- C17 SAS. Elimination half

- life averaged about 41 hours (15% elimination in air 18% in urine and about 31% in feces. About 2.2% of the radioactivity was found in the treated

skin and 3 5% in the bandage used to cover the treated area. All of which indicate a low potential for dermal absorption (calculated 50 %).18

Table 3 . Toxicology Profile of Secondary Alkane (C13

- C17) Sulfonates

Guideline No./ Study Type Doses Levels Results MRID No. (year)/References Chronic Toxicity Rat (diet)

OCSPP 870.4100a

OECD 452 0, 34, 168 and 920

mg/kg bw /day (males)

0, 45, 227 and 1281 mg/kg bw/day (females)

Doses were

reviewer

calculated NOAEL 168 mg/kg bw /day ( males )

LOAEL 920 mg/kg bw /day (males) based on reduced body weight and body weight gain and the clinical signs of reduced grooming. MRID 49146406

Ben

- Dyke, R, and Newman, A.J. (1977)

In vitro bacterial gene mutation test

– Chinese hamster V79

cells

OCSPP 870.5300

OECD 476 0, 0.158, 0.5, 1.58,

5, 15.8, 50, 158,

and 500 μg/ml

with metabolic

activation

0, 5, 10, 15, 20, 25, 35 and 50 μg/ml without

metabolic

activation Negative MRID 49146410

Wallner, Barbara (2010)

In vitro bacterial gene mutation ( Salmonella typhimurium and

Escherichia coli

OCSPP 870.5100

OECD 471 & 472 0, 0.001, 0.01, 0.1,

1 and 5 μg/plate

with and without

metabolic

activation Negative MRID 49146413

Gericke, D. (1977)

Carcinogenicity

– rat (diet)

OCSPP 870.4300

OECD 453 0.0, 0.08, 0.40, or

2.0% in diet Equivalent to: 0.0, 27.9, 145.3, and 805 mg/kg bw/day (males) 0.0, 36.5, 182.9 and 1032 mg/kg bw/day (females) NOAEL > 2.0% (805 mg/kg bw/day in males

and 1032 mg/kg bw/day in females calculated by reviewer)

LOAEL was not identified. MRID 49146408

Ben

- Dyke, r, Finn, J.P., and Newman, A.J. (1978)

Carcinogenicity

–

mouse (dermal)

Non

- guideline 0 (no treatement),

0 (vehicle control), 0.1%, 0.5% or

1.0% three

times/week for 80

weeks. Equivalent to: 2.4, 12, and 24 mL (males) 2.7, 14, and 27 mL (females) NOAEL 1% (24 mL i n males and 27 mL in

females)

LOAEL was not identified. MRID 49146407

McSheehy, TW, Finn, JP, Kiss, I. (1978)19

Table 3 . Toxicology Profile of Secondary Alkane (C13

- C17) Sulfonates

Guideline No./ Study Type Doses Levels Results MRID No. (year)/References Reproduction and Fertility Effects Study

– rat
OCSPP 870.3800

OECD 416 1000, 3000, or

10,000 ppm Equivalent to: 58.2, 177, or 57 0 mg/kg bw/day (males) 66, 181, or 566 mg/kg bw/day (females) Parental systemic NOAEL is 1000 ppm.

Parental systemic LOAEL is 3000 ppm based

on reduced body weight gain during premating and on reduced organ weight.

Offspring NOAEL is 1000 ppm.

Offspring L OAEL is 3000 ppm based on decreased pre

- and post

- implantation loss and decreased weight gain in offspring. MRID 49146411

Tesh, J.M., Davidson, E.J., Newman, A.J. (1978)

Toxicokinetics

– rat (gavage)

Equivalent to OCSPP

870.7485 or OECD

417 0.51, 5.3 o r 51

mg/kg Blood level reached maximum about 2 to 6

hours after administration. Elimination from blood was biphasic with half

- lives of 11 and 65 hours. 17% was exhaled as Co2, 30% excreted

via urine and 45% with feces. 90% excreted in

first 24 hours. No bi oaccumulation potential

based on results. Hoechst AG (1977a)

Toxicokinetics

– rat (dermal absorption)

Equivalent to OECD

427 0.25 mg per

animal Blood level reached maximum about 2 to 6

hours after application. Elimination half

- life was average of 41 hours (air approximately 15%, urine 18%, feces 31%). Most radioactivity as found in bandage (35%) whereas only 2.2% was detected in treated skin 7 day s post application. Low skin penetration potential based on results. 50 % absorption rate. Hoechst AG (1977b)

B. Toxicity Endpoint Selection

The two generation reproductive toxicity study in rats was selected for oral, dietary and inhalation exposure scenarios (all durations) for this risk assessment. The parental systemic

NOAEL in this study was 1000 ppm and calculated to be 58.2 mg/kg/day for males . The parental systemic LOAEL was 3 000 ppm and calculated to be 177 mg/k g/day for males

based on based on reduced body weight gain during premating and on reduced organ weight. The rationale for selecting this study for the dietary, oral and inhalation exposure scenario is based on the fact that this study provided the lowest and most conservative toxicity endpoint.

A default 100 % inhalation absorption will be used for inhalation exposure scenarios. A 50% dermal absorption rate will be used for dermal exposure scenarios based on the toxicokinetic dermal absorption study. The 50% dermal absorption rate was calculated by summing and rounding the percent of radiolabeled material found in both the urine and feces in the study.20

T able 4

. Summary of Toxic ological Doses and Endpoints of Secondary Alkane (C13

- C17) Sulfonates (SAS )

for Use in Human Health Risk Assessment Exposure/Scenario Point of Departure and Uncertainty/Safety Factors RfD, PAD,

LOC for Risk

Assessment Study and Toxicological Effects

Acute dietary (General population including infants and children) An acute effect was not found in the database therefore an acute dietary assessment is
not necessary.

Chronic dietary (All populations) NOAEL= 58.2 mg/kg/day

UF A = 10 x UF H = 10 x FQPA SF = 1 x Chronic RfD =

58.2 mg/kg/day

cPAD = 0.582 mg/kg/day [ Repro

- toxicity

- rat ] LOAEL =

177 mg/kg/day based on

decreased weight gain during premating and reduced organ weight

. Incidental oral short

- term (1 to 30 days) NOAEL= 58.2 mg/kg/day

UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE =

100 [ Repro

- toxicity

- rat ] LOAEL =

177 mg/kg/day based on decreased weight gain during premating and reduced organ weight

. Incidental oral

intermediate

- term (1 to 6 months) NOAEL= 58.2 mg/kg/day

UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE =

100 [ Repro

- toxicity

- rat ] LOAEL =

177 mg/kg/day based on decreased weight gain during premating and reduced organ weight

. Dermal short

- term (1 to 30 days) Repro. study NOAEL= 58.2 mg/kg/day ( dermal absorption

rate = 5 0%)

UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE =

100 [ Repro

- toxicity

- rat ] LOAEL =

177 mg/kg/day based on decreased weight gain during premating and reduced organ weight

.

Dermal intermediate

term (1 to 6 months) Repro. study NOAEL= 58.2 mg/kg/day ( dermal absorption

rate = 5 0%)

UF A = 10 x UF H = 10 x FQPA SF = 1 x L OC for MOE =

100 [ Repro

- toxicity

- rat ] LOAEL =

177 mg/kg/day based on decreased weight gain during premating and reduced organ weight

.

Inhalation short

- term (1 to 30 days) Repro. study NOAEL= 58.2 mg/kg/day (inhalation absorption rate = 100%)

UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE =

100 [ Repro

- toxicity

- rat ] LOAEL =

177 mg/kg/day based on decreased weight gain during premating and reduced organ weight

.

Inhalation (1 to 6 months) Repro. study NOAEL = 58.2 mg/kg/day (inhalation absorption rate = 100%)

UF A = 10 x UF H = 10 x FQPA SF = 1 x LOC for MOE =

100 [ Repro

- toxicity

- rat ] LOAEL =

177 mg/kg/day based on decreased weight gain during premating and reduced organ weight

.

Cancer (Oral, dermal, inhalation) Based on the lack of increased incidenc e of tumor formation compared to controls in multiple carcinogenicity studies and the lack of mutagenicity, SAS is considered not likely to be carcinogenic.

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 study for long

- term risk assessment. UF DB = to account for the absence of data or other data deficiency. FQPA SF = Food21

Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference do se. MOE = margin of exposure. LOC = level of concern.

C. Special Considerations for Infants and Children

FFDCA, as am ended 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

mo dify the 10X FQPA SF only if reliable data demonstrate that the resulting level of exposure would be safe for infants and children. EPA concludes that the FQPA safety

factor could be reduced to 1X for SAS for the following reasons:

i. The toxicity databa se for S A S includes a subchronic, developm ental /reproductive

, and chronic/carcinogenicity studies

, several mutagenicity studies , and two toxicokinetic

studies

.

ii. Maternal and developmental toxicity was observed at 3000 ppm (177 mg/kg/day ) in

rats based on decreased body weight gain during premating and on reduced organ weight. The parenta l systemic NOAEL is 1000 ppm (58.2 mg/kg/day). The o ffspring LOAEL is 3000 ppm based on decreased pre

- and post

- implantation loss and decreased weight gain in offsp ring. The offspring NOAEL is 1000 ppm.

iii. There is no indication that S A S is a neurotoxic chemical. Although no neurotoxicity studies were available in the database, no clinical signs of neurotoxicity were

observed in the available subchronic and chron ic studies. Therefore, there is no need for a developmental neurotoxicity study or additional UFs to account for neurotoxicity.

iv. There is no indication that S A S is an immunotoxic chemical. Although no immunotoxicity studies were available in the d atabase, no signs of immunotoxicity were observed in the available studies. Therefore, there is no need for a immunotoxicity study or additional UFs to account for immunotoxicity.

v. The dietary food exposure assessment utilizes proposed tolerance leve l or higher 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 10 X FQPA safety factor can be reduced to 1X.

IV. EXPOSURE ASSESSMENT

The petitioner has requested use of S A S with out limitation in pesticide formulation s . The petitioner request ed the ability to use S A S in any type of pesticide i.e., insecticide, fungicide or herbicide on seed treatment and foliar applications

.22 Therefore, the Agency has conducted a “screening

- level” assessment of a wide variety of sites and use patterns in an effort to obtain a qualita tive idea of the possible results of human exposures that might result from such combinations of method s of application and

site s of application.

A. Dietary Exposure:

i. Acute exposure . No adverse effects attributable to a single exposure of S A S were s een in the toxicity databases. Therefore, acute dietary risk assessment for S A S is not required.

ii. Chronic exposure

. In conducting the chronic dietary exposure assessment using the Dietary Exposure Evaluation Model DEEM

- FCID TM , Version 3.16 , EPA used 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 . As to residue levels in food, n o residue data

were submitted for S A S

. 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 bas ed 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 mem orandum 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.

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 i n 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 concen tration of the active ingredient.

The Agency believes the assumptions used to estimate dietary exposures lead to an extremely conservative assessment of dietary risk due to a 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 overstate exposure. The concentration of active ingredients in agricultural products is generally at least 50 percent of the product and often can be much higher. Further, pesticide products rarely have a single inert ingredient; rather there is generally a combination of different inert ingredients used which additionally reduces the concentration of any single inert ingredient in the pesticide product

in relation to that of the active ingredient.23 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

le vel of inert ingredient residues is the active ingredient wit h the highest tolerance level. This assumption overstates residue values because it would be highly unlikely, given the high number of inert ingredients, that a single inert ingredient or class o f ingredients would be present at the level of the active ingredient in the highest tolerance for every commodity. Finally, a third compounding conservatism is EPA’s assumption that all foods contain the inert ingredient 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 highest 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 higher than actual

residues in food when distributed in commerce.

Accordingly, although sufficient information to quantify actual residue levels in food is not available, the compounding of these conservative assumptions will lead to a significant exaggeration of actual exposures. EPA does not believe that this approach underestimates exposure in the absence of resid ue data.

The additional adjustment factor 2 of 0.8 was utilized in this analysis to account for the

40% limitation in formulation.

Table 5 . Summary of Chron ic Dietary Exposure and Risk of Secondary Alkane (C13

- C17) Sulfonates ( SAS )

Population Subgroup c PAD (mg/kg/day) Chronic Exposure (mg/kg/day) %cPAD General U.S. Population

0.582 0. 151474 26.0 % All Infants (<1 year old) 0

. 315542 54.2 %

Children 1

- 2 years old 0. 564993 97.1 %

Children 3

- 5 years old 0. 388507 66.8 %

Children 6

- 12 years old 0. 200443 34.4 %

Youth 13

- 19 years old 0. 107838 18.5 %

Adults 20

- 49 years old 0. 115792 19.9 % Adults 50+ years old 0. 121430 20.9 %

Females 13

- 49 years old 0. 117067 20.1 %

Based on analyses of estimated dietary risks for the general U.S. population and various population subgroups, the chronic dietary exposure estimates for SAS are 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 97.1 % of the chronic population adjusted dose (cPAD). The chronic dietary exposure estimate for the general U.S. population is 26.0 % of the cPAD.

iii. Cancer exposure

. S A S is not expected to be carcinogenic based on multiple carcinogenicity studies which showed no increase in incidence of tumors when compared24 to the controls

. Also all mutagenicity studies on S A S were negative. Therefore, a cancer dietary exposure assessment is not necessary to assess cancer risk.

B. Dietary Exposure from Drinking Wate r :

For the purpose of the screening level dietary risk assessment to support this request for an exemption from the requirement of a tolerance for SAS , a conservative drinking water concentration value of 100 parts per billion (ppb) based on screening lev el modeling was used to assess the contribution to drinking water for chronic dietary risk assessments for

SAS . These values were directly entered into the dietary exposure model.

C. Residential ( Non

- Occupational, Non

- Dietary ) Exposure:

The term ‘‘residenti al 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). However, residential exposure is not expected for SAS as the use is for agricultural applications only.

V. AGGREGATE RISK ASSESSMENT

EPA determines whether acute and chronic pesticide exposures are safe by comparing aggregate exposure estimates to the acute population adjusted dose ( aPAD ) and chronic populati on 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 endpoint) by all applicable UFs.

For linear cancer risks, EPA calculates the probability of additional cancer cases given the estimated aggregate exposure. Short

- , intermediate

- , and chronic

- term risks are evaluated by comparing the estimated aggregate food, water, and residential exposure to the PO D 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 consumption 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 S A S ; therefore there is no concern for an acute dietary risk and an acute aggregate risk asses sment 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 2

- gene r ation reproductive toxici ty study with a NOAEL of 58.2 mg/kg/day based on decreased weight gain during premating and reduced organ weight . The chronic dietary exposure f ro m food25 and water to S A S is 26.0 % of the cPAD for the U.S. population and 97.1 % 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 S A S ; therefor e,

a cancer dietary exposure assessment was not performed and an aggregate cancer risk is not

a concern

.

VI. O CCUPATIONAL EXPOSURE/RISK PATHWAY

The representative occupational scenarios selected by the Agency for assessment are evaluated based on likely ma ximum application rates for products which may contain the inert ingredient for the short

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

to contain the inert ingredient for the intermediate

- and long

- term exposure durations. Ac tive 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 expos ure are estimated using the Pesticide Handlers Exposure Database (PHED) and Outdoor Residential Exposure Task Force (ORETF) data. The analytical techniques are those developed by the Science Policy Council on Exposure (ExpoSAC), Heath Effects Division, Off ice 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 highest potential e xposure.

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 Exposure Database (PHED) and are recently summarized in the “Occupation Pesticide Handler Unit Exposure Surrogate Reference Table” US EPA Office of Pesticide Programs, March 2012 (unpublished)

AR Application Rate in lbs of material per unit (acres)

.26 Units Treated/day

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

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

, (C10

- 16); C10

- C18

- Alkyldimethylamine oxides; Human Health Risk Assessment and Ecological Effects Assessment to Support Proposed Exemption from the Requirement of a Tolerance When Used as Inert Ingredients in Pesticide Formulations.” 22 SEPT 2009

AF Absorption factor

- - 100% default for inhalation routes of exposure and

50% for dermal routes of exposure based on dermal absorption study.

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 Edition” HED “HotSheet” No. 31. Although due to

limitations of the assessmen t 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 applica tions. These are the occupational activities believed to be associated with the highest

exposures use patterns

. The occupation exposure assessment utilized the baseline values for highest exposure herbicide, insecticide and fungicide. Only the herbicide da ta is provided below because it provided the lowest and most conservative MOEs.

Table 10. Summary of Exposure & Risk to Occupational Handlers From Secondary Alkane (C13

- C17) Sulfonates (SAS)

Scenario Unit Exposure 1

mg inert/lb

handled Application Rate 1

lb inert/unit Units

Treated 1 Avg. Daily

Exposure 2 mg inert/kg bw/day MOE 3

Herbicide Mixer/Loaders Liquids: Aerial / Chemigation Dermal:

Single layer

with glove

0.023

Inhalation: No respirator

0.0012 4.16 lb ai/A (Corn) 1200 A/day Dermal: Single layer with glove s 0.82011

Inhalation: No respirator

0. 08558 Dermal :

70.97

Inhalation:

680.1

Combined:

64.3

Liquids: Airblast Dermal:

Single layer

with glove

0.023

Inhalation: No respirator

0.0012 2.88 lb ai/A

(Nut Trees) 40 A/day Dermal: Single layer with glove s 0.0 1893

Inhalation: No respirator

0.001975 Dermal :

3100

Inhalation:

29000

Combined:

2800

Liquids:

Groundboom Dermal:

Single layer

with glove

0.023

Inhalation: No respirator

0.0012 5.2 lb ai/A (Corn) 200 A/day Dermal: Single layer with gloves

0.13669

Inhalation: No respirator

0. 01426 Dermal :

430

Inhalation:

4100

Combined:

39027 1. Default values are taken from Antimicrobials Division (AD) assessment tool d eveloped to assess Amine Oxide (“ 900439 , (C10

- 16); C10

- C18

- Alkyldimethylamine oxides

2. Average Daily Ex posure = Unit Exposure * Application Rate * Units Treate d * Absorption Rate (Dermal 50 % ; Inhalation 100% ) ÷

7 0 kg Body Weight

3. MO E = Margin of Exposur e = NOAEL  ADE. NOAEL = 97 mg/kg bw/day . Combined MOE = 1/(1/Dermal MOE+1/Inhalation MOE)

The inhalation absorption was default at 100%. The inhalation toxicity was also assumed to be equivalent to oral toxicity (NOAEL 58.2 mg/kg/day)

. The dermal absorption was set to 50% based on the dermal absorption study. Risks were calculated using the MOE approach, which is a ratio of the exposure to the toxicological PoD. Occupational handler risks are

not of concern. The Agency’s level of concern for inhalation and der mal exposure is for

MOEs <100. Although t he lowest estimated combined herbicide MOE was 64.3 , based on amount of conservatism build into the model (i.e. liquid aerial/chemigation with no respirator, maximum application rate on corn a nd treating 1200 A/day ) the estimated combined occupational MOEs are not expected to be of concern.

Additional, SAS is expected to be used in seed treatments and the occupational handler dermal and inhalation exposure and MOEs are calculated for this appl ication method. The Occupational Exposure and Risk from Commercial Seed Treatment Margin of Exposure (MOE) Calculator was created in 2004 by Gustafson with guidance from EPA. Th e seed

treatment c alculated used an example pyraclostrobin label as a conservat ive seed treatment scenario with a high application rate (1.67 lbs per gallon of product)

. The crop selected was Soybean with a default value of 720,000 lbs of seed treated per day and 12,000 lb of seed planted per day. T he toxicological end point of 58.2 mg/kg/day was selected and the dermal absorption rate of 50% and inhalation absorption rate of 100%. Herbicide Applicator Liquid: Airblast Dermal:

Open Cab

0. 24

Inhalation: Open Cab

0.0045 0.64 lb ai/A

(Nut Trees) 40 A/day Dermal: Open Cab

0.04389

Inhalation: Open Cab

0.001646 Dermal :

1300

Inhalation:

35000

Combined:

1300 Liquid:

Groundboom Dermal:

Open Cab

0.014

Inhalation: Open Cab

0.00074 4.16 lb ai/A (Corn) 200 A/day Dermal: Open Cab

0.08320

Inhalation: Open Cab

0.008795 Dermal :

700

Inhalation:

6600

Combined:

630 Herbicide Mixer/Loader/Applicator Liquid: Low

Pressure handwand Dermal:

Single layer

with glove

0.43

Inhalation:

No r espirator

0.030 2.88 lb ai/A

(Ornamentals) 5 A/day Dermal: Single layer with gloves

0.04423

Inhalation: No respirator

0.006171 Dermal :

1300

Inhalation:

9400

Combined:

1200

Table 11

. Summary of Exposure & Risk to Occupational Handlers From Secondary Alkane (C13

- C17) Sulfonates (SAS) when using Seed Treatment28 1. UE from standard Operating Procedure (SOP) for Seed Treatment, Guidance no. 14, May 1, 2003

2. Label Rate (fl. Oz. per cwt) x Concentration (lbs. ai per gallon) / 128 / 100

3. Daily Exposure (loader, sewers, bagger & multi. activities) = [Rate(lb inert/lb seed) x Amt Seed Treated per Day x %Absorpt ion x UE (mg/lb inert)] / [Body Weight (BW) kg]

4. Daily Exposure (Seed Planters) = [Rate(lb inert/lb seed) x Amt Seed Planted per Day x %Absorption x UE (mg/lb inert)] / [Body Weight (BW) kg]

5. MOE (unitless) = Toxicological Endpoint (mg/kg/day) / Daily Exposure (mg/kg/day)

6. COMBINED MOE (unitless) = 1 / (1/Dermal MOE) + (1/Inhalation MOE)

The inhalation absorption was default at 100%. The inhalation toxicity was also assumed to be equivalent to oral toxicity (NOA EL 58.2 mg/kg/day). The dermal absorpti on was set to 50% based on the dermal absorption study. Risks were calculated using the MOE approach, which is a ratio of the exposure to the toxicological PoD. Occupational handler risks are

not of concern. The Agency’s level of concern for inhalation and der mal exposure is for

MOEs <100. The lowest estimated combined seed treatment MOE was 620 for “multiple activities” exposure scenario, therefore the estimated combined occupational seed

treatment MOEs are not expected to be of concern. Scenario Unit

Exposure 1 mg inert/lb

handled Application

Rate

lb inert/unit Units Treated Avg. Daily Exposure 3, 4 mg inert/kg bw/day MOE 5, 6

Loader/Applicator: Dermal:

0.0230

Inhalation:

0.00034 3.1 fl. oz./100

lbs. of seed

0.0004045 lbs/

lb. of seed 2 720,000 lbs seeds

treated per day (Soybean)

12,000 lbs seeds planted per day (Soybean) Dermal:

0. 047841

Inhalation:

0.001414 Dermal :

1200

Inhalation:

41000

Combined:

1200

Sewer: Dermal:

0.0062

Inhalation:

0.00023 Dermal:

0. 012896

Inhalation:

0. 000957 Dermal :

4500

Inhalation:

61000

Combined:

4200 Bagger: Dermal:

0.0091

Inhalation:

0.00016 Dermal:

0. 018928

Inhalation:

0. 000666 Dermal :

3100

Inhalation:

87000

Combined:

3000 Multiple Activities: Dermal:

0.0420

Inhalation:

0.00160 Dermal:

0. 087362

Inhalation:

0. 006656 Dermal :

670

Inhalation:

8700

Combined:

620

Seed Planters: Dermal:

0.2500

Inhalation:

0.00340 Dermal:

0. 008667

Inhalation:

0. 000236 Dermal :

6700

Inhalation:

250000

Combined:

650029

B. Occup ational Post

- A pplication 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 expo sures 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 harvesting. Post

- application exposure levels vary over time and depend on such things as th e 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 timing of pesticide applications, relative to harvest activities, can greatly reduce the p otential for post

- application exposure. Inhalation exposures are not typically calculated for occupational post

- application scenarios because inhalation exposures generally account for a negligible percentage of the overall body burden for most pesticide

c hemicals.

This assessment is considered to be a screening level estimate, demonstrating that there are minimal potential risks to workers re

- entering fields treated with pesticides containing SAS as inert ingredients. Therefore an occupational post appl ication risk assessment was not performed.

VII. C UMULATIVE EXP OSURE

Cumulative effects from substances with a common mechanism of toxicity . Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

EPA has not found S A S to share a common mechanism of toxicity wi th any ot her substances, and that S A S do es not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has assumed that S A S does

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 L ow

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

.30 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 population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under CSFII and are used in pesticide r isk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups

IX. E NVIRONMENTAL FATE CONSIDERATIONS

EPISuiteTM 4.1 was run using CAS Reg. No. 97489

- 15

- 1 using C15 alkyl carbon chain length since the average ca rbon chain length was 15.2. SAS is expected to be nonvolatile with a vapor pressure of 1.97 x 10

- 11 mg/Hg @ 25°C. Experimentally it was < 0.001 Pa @ 20 °C. It is soluble in water (115.6 mg/L @ 25°C). SAS is not expected to hydrolyze or undergo direct photo lysis. The Log Kow is 0.2 at 20°C and indicates a low potential to cross biological membranes. The Log Koc is 2.181 (Kow method) and 3.3 (MCI Methods) which indicate a moderate soil adsorption. The probability of rapid biodgradation (0.82 Biowin1 linear) and (0.99 Biowin non

- linear) are consistent with experimental environmental degradation data. Atmospheric o xidation indicates a relatively rapid oxidation rate with a half

- life of 6.6 hours when reacting with hydroxyl radicals. The

BCF factor is the concen tration of a particular chemical in a biological tissue per concentration of that chemical in the water surrounding that tissue. EPISuite estimates that BCF is 70.79 L/kg wet

- wt. BCF lower than 250 are considered low risk. The Primary Level III Fugacity Mo deling indicates the highest affinity for the soil (70.1%) environmental compartment, little affinity for sediment (0.34%) and moderate affinity for water (25.9%). The primary degradation persistence is estimated to be 99 hours (about 4 days). The

Ultimate (complete mineralization) Level IV Fugacity Modeling indicates a high affinity for the soil (77.6%) environmental compartment, little affinity for sediment (1.29%) and moderate affinity for water (20.5%). The Ultimate Degradation Persistence Time is

estim ated to be 574 hours (about 24 days).

O nce SAS is released into the environment, it is expected to partition between soil

and water

, B ased on fugacity modeling , SAS should partition mainly in the soil compartment. SAS used in either seed or foliar applic ations can be expected to have limited mobility in the environment. Additionally bioaccumulation in mammalian tissues is unlikely to occur.31 Based on six ready biodegradability (OECD 301) studies, rapid degradation takes place over a period of 18

- 28 days . The most recent OECD Guideline 301B Ready Bioavailability; CO2 evolution (Clariant 2001) demonstrated 78% after 28 days.

Four activated sludge (OECD 303A) studies showed rapid and substantial degradation over a period of 25 days (98.6%) to 74 days (96. 1%). The most recent Hoechst (1992) simulated aerobic sewage treatment demonstrated 98.6% after 25 days (DOC removal).

Table 11 . Summary of Environmental Fate for Secondary Alkane (C13

- C17) Sulfonates

Study Results Reference Aerobic Aquatic Biodegradation Ultimately biodegradable and Readily biodegradable HERA 2005

Anaerobic Aquatic Biodegradation Not biodegraded under strict anaerobic conditions HERA 2005

Hydrolysis Does not hydrolyze in water HERA 2005 Photolysis Does not photolysis in surface water or top soil based on

molecular structure HERA 2005

Volatilization Based on Henry coefficient of SAS, volatilization is not a

relevant elimination factor. HERA 2005

Bioconcentration Not expected to occur HERA 2005

Bioaccumulation Not expected to occur LogKow=0.2 BCFfish=1.4 L/kg wwt BCFworm=0.9 L/kg wwt REACH 2010

EUSES: MacKay Fugacity

Model <0.003% air

99.98% water
0.014% soil

0.0001% sediment Dow HPV

2004

X. E COTOXICITY

Acute and chronic toxicity data on SAS is available for f ish, daphnia and algae. SAS is most toxic to Daphnia base on the chronic 21 day Daphnia reproduction study which had a NOECrepro of 0.4 mg/L. NOEC of 0.4 mg/L is consider to be highly toxic.

A chronic 3 day nematode study was carried out resulting in a N OEC reproduction of 939 mg/kg dw (a.i.). Additional a 56 day Earthworm reproduction study was carried out and resulted in a NOEC reproduction of 470 mg/kg dw (a.i.).

Toxicity to birds is not expected due to the lack of expected bioconcentration and

bioacc umulation based on the low octanol water partitioning coefficient for SAS (Log kow = 0.2).

Table 12

. Summary of Aquatic Ecological Toxicity Studies for Secondary Alkane (C13

- C17) Sulfonates Test Type Species Effect Results Units Guideline

Acute fish Leuciscus idus LC50 (96h) 5.5 mg/l OECD 20332

Acute Daphnia Daphnia

magna EC50 (48h) 9.2 mg/l OECD 202

Algae Desmodesmus

subspicatus ErC50 (72h) >61 mg/l OECD 201

Cell growth

inhibition test Pseudomonas

putida NOEC (16h) 1000 mg/l DIN38412, Part 8

Chronic fish Oncorhynchus

mykiss NOEC (9d) 0.9 mg/L OECD 212

Chronic daphnia Daphnia

magna NOECrepro

(21d) 0.4 mg/L OECD 211

Chronic Algae Desmodesmus

subspicatus ErC10 (72h) 59 mg/L OECD 201

Sediment Organism Caenorhabditis

elegans NOEC (96h) 939 mg/kg

Soil Macro

organism Eisenia

fetida(annelids) NOEC (56d) 470 mg/kg OECD 222

Table data from Clariant 2010 REACH Chemical Safety Report on SAS.

XI. R ISK CHARACTERIZATION

In August 2013 Exponent on behalf of Clariant Corporation submitted a petition to the EPA to amend 40 CFR 180.920 by establishing an exemption from the requirement of a tolerance for the use of secondary alkane (C13

- C17) sulfonates (SAS) (CAS Reg. Nos. 857 11

- 69

- 9 and

97489

- 15

- 1) as pesticide inert ingredients (surfactants) for use in food crops in accordance with 40 CFR 180.920 (pre

- harvest pesticide applications) with a limitation of 40% in formulation.

An acute dietary risk assessment was not conducted b ecause no endpoint of concern following a single exposure was identified in the available studies. A chronic dietary exposure assessment was completed and performed using the Dietary Exposure Evaluation Model DEEM

FCID TM , Version 3.16. The chronic Referen ce Dose (cRfD) of 58.2 mg/kg/day was determined on

the basis of the reproductive toxicity study in rats. The LOAEL of 177 mg/kg/day S A S was based

on decreased body weight gain during premating and on reduced organ weight . This study provided the lowest NO AEL in the database (most sensitive endpoint) and will also provide the most protective limits for human effects. An UF of 100X (10

- fold for interspecies extrapolation

and 10

- fold for intra species variability) was applied to the NOAEL of 58.2 mg/kg/day t o derive the cRfD. The FQPA safety factor of 1X is applicable for chronic dietary risk assessment. Therefore, the chronic population

- adjusted dos e (cPAD) is 0.582 mg/kg/day. This endpoint of

concern was also used for all dermal and inhalation exposure sce narios. Dermal absorption was

determined to be 50 % based on the dermal absorption study and inhalation absorption was

assumed to be 100%.

Based on analyses of estimated dietary risks for the general U.S. population and various population subgroups, the c hronic dietary exposure estimates for S A S are below the Agency’s

level of concern. The chronic dietary exposure estimate for the highest exposed population subgroup, children 1

- 2 years old is 97.1 % of the chronic population adjusted dose (cPAD) and

26.0 % of the cPAD for the general population.33 The Agency’s level of concern (LOC) for S A S occupational and residential dermal and inhalation exposures is 100. The LOC is based on a 10X uncertainty factor (UF) to account for interspecies extrapolation to huma ns from the animal test species and 10X UF to account for intraspecies sensitivity.

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). SA S is an inert ingredient in pesticide products that is not expected to result in short

- term residential

exposure since the proposed uses are for commercial agricultural seed treatment and possible foliar applications

. Therefore t he Agency has determined th at aggregating chronic exposure through food

and water with short

- term residential exposures is not required

.

Intermediate

- term aggregate exposure takes into account intermediate

- term residential exposure plus chronic exposure to food and water (consider ed to be a background exposure level).

SAS is an inert ingredient in pesticide products that is not expected to result in intermediate

- term residential exposure since the proposed uses are for commercial agricultural seed treatment and possible foliar appl ications

. Therefore t he Agency has determined that aggregating chronic exposure through food and water with intermediate

- term residential exposures is not required

.

Occupational handler risks are not expected to be of concern for all scenarios evaluate d . It is noted that this occupational handler assessment assumes that mixer/loader/applicators are not wearing protective respirators when using open pour in support of aerial and groundboom application. The estimated MOEs are greater than 100 based on 100 % inhalation absorption and 50% dermal absorption except for mixer/loader aerial/chemigation which had a combined

herbicide inhalation and dermal MOE of 64.3

. However based on the amount of conservatism built

into the model (i.e. liquid aerial /chemigation with no respirator, maximum application rate on corn and treating 1200 A/day) the estimated combined occupational herbicide MOEs are not expected

to be of concern. Additional, SAS is expected to be used in seed treatments and the occupational

handler derma l/inhalation exposure and MOEs are calculated for this application method. The lowest estimated combined seed treatment MOE was 620 for “multiple activities” exposure scenario, therefore the estimated combined occupational seed treatment MOEs are also not expected to be of concern. This assessment is considered to be a screening level estimate, demonstrating that there are minimal potential risks to workers re

- entering fields treated with pesticides containing SAS as inert ingredients. Therefore an occupational post application risk assessment was not performed.

Once SAS is released into the environment, it is expected to partition between soil and water. Based on fugacity modeling, SAS should partition primarily to the soil compartment. Therefore SAS used in either seed or foliar applications can be expected to have limited mobility in the environment. SAS is not expected to bioconcentrate or bioaccumulate based on a low logKow of 0.2.

Based on studies conducted with various aquatic species, SAS is considered highly toxic to aquatic organisms. Based on a 9 day chronic fish toxicity study, the NOEC was 0.9 mg/ml and a 21 day chronic daphnia toxicity study, the NOECrepro was 0.4 mg/ml. SAS is not expected to be

toxic to birds based on the lack of bioconcentration and bioaccumulation.34 Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Exe cutive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

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

Taking into consideration all available information on SAS , EPA concludes that there is a reasonable certainty that no harm to any population subgroup will result from aggregate exposure

to SAS when considering residential, occupational, dietary exposure and all other nonoccupational sources of pesticide exposure for which there is reliable information. Therefore, the establishment of an exemption from tolerance under 40 CFR 180.92 0 for residues of Secondary Alkane (C13

- C17) Sulfonates ( CAS Reg. No. 85711

- 69

- 9 and 97489

- 15

- 1 ) when used as a pesticide inert ingredient applied to pre

- harvest crops with a limitation of 40% in formulation, can be considered assessed as safe under section 408(q) of the FFDCA.35

REFERENCES

Hoechst AG (1988). Hostapur SAS 93: Akute orale Toxizitat. Testing laboratory: Hoechst AG. Report no.: 88.0798. Ow ner company: Clariant. Study number: 1988.0798. Report date: 1988

- 06

- 13.

Hoechst AG (1974). Hostapur SAS 60: Prufng auf sensibilisierende Eigenschaften an Meerschweinchen nach Magnusson und Kligman. Testing laboratory: Hoechst AG. Report no.:

0294/74. Own er company: Clariant. Study number: 1974.0294. Report date: 1974

- 11

- 05.

Huls AG (1986). Prufung auf hautsensibilisierende Wirkung am Meerschweinchen von Marlon PS60. Testing laboratory: Huls AG. Report no.: 0636. Owner company: Sasol. Study number:

0636. Report date: 1986

- 06

- 24.

Life Science Research (1975). Hostapur SAS 60: Toxicity in dermal application to mice (preliminary study). Test laboratory: Life Science Research. Report no.: 75/HAG22/255. Laboratory: Life Science Research. Report no.: 75/HAG22/255. Owner company: Clariant. Study number: 1975.0650. Report date: 1975

- 12

- 31.

MRID 49146406: Ben

- Dyke, R., and Newman, A.J. (1977) Hostapur (SAS 60): Toxicity in dietary administration to rats for one year. Life Science Research, Stock, Essex Cm4 9PE, England. Study Identification Number: Bericht Mr. 0554/78, May 10, 1977. Unpublished.

MRID 49146407: McSheehy, TW, Finn, JP, Kiss, I. (1978) Hostapur SAS 60: Potential oncogenicity in dermal application to mice for a period of 80 weeks (final rep ort: 0

- 104 weeks). Life Science Research, Stock, Essex England. Study ID: 76/HAG15/028 , March 20, 1978. Unpublished.

MRID 49146408: Ben

- Dyke, R., Finn, J.P., and Newman, A.J. (1978) Hostapur (SAS 60): Toxicology and carcinogenicity in dietary administrat ion to rats for two years. Life Science Research, Stock, Essex CM4 9PE, England. Laboratory report number 79/HAG16/045. February 14, 1978. Unpublished.

MRID 49146409 : Alves, C. (2007) Acute Dermal/Corrosion Study in Rabbits (Oryctolagus cuniculus) for HOSTAPUR SAS 93. Study Identification No. RL4737

- 06IC

- B. TECAM Technologia Ambiental Seo Roque Ltda., Estrada do Carmo, 371, Post Box n 312

– Cep: 18130

- 970, Sao Roque, SP

- Brasil. May 29, 2007. Unpublished.

MRID 49146410: Wallner, Barbara (2010) In V itro Mammalian Cell Gene Mutation Test (HPRT

Locus) in Chinese Hamster V79 Cells with Hostapur SAS 93. BSL Bioservice, Scientific Laboratories GmbH, Behringstrabe 6/8, 82152 Planegg, Germany. Study Identification Number (BSL Bioservice Study No.): 092292, January 18, 2010. Unpublished.

MRID 49146411: Tesh, J.M., Davidson, E.J., Newman, A.J. (1978) Hostapur (SAS 60): Effects upon Reproductive Function and Intra

- Uterine Development of the Rat. Life Science Research,36

Stock Essex, CM4 9PE, England. LSR No. 76/ HAG19/020, LSR Report No. 78/HAG19/020, January 24, 1978. Unpublished.

MRID 49146412: Braun, W. (1995) Primary Eye Irritation Study with HOSTAPUR SAS 30 in Rabbits (Low Volume Procedure). Study Identification No. RCC Project 388225. RCC Research

& Consu lting Company, Ltd., Zeigliweg 1, 4452 Itingen, Switzerland. March 10, 1995. Unpublished.

MRID 49146413 : Gericke, D. (1977) Hostapur SAS 30 A 297 T3/131. Test for Mutagenicity in Bacteria Strains in the Absence and Presence of a Liver Preparation. Krebsf orschungslabor, Frankfurt/M, West Germany. Study Identification Number: Bericht Nr. 644/77 A, June 16, 1977. Unpublished.

REACH Chemical Safety Report 2010 on Sulfonic acids, C14

- C17

- sec

- alkane, sodium salts. http://apps.echa.europa.eu/registered/data/dossiers/DISS

- a0 017598

- 8f1c

- 50d1

- e044

- 00144f67d031/DISS

- a0017598

- 8f1c

- 50d1

- e044

- 00144f67d031_DISS

- a0017598

- 8f1c

- 50d1

- e044

- 00144f67d031.html37

APPENDIX

US EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysis for SECON DARY ALKANE (C13

- C17) SULFONATES

NHANES 2003

- 2008 2

- day

Residue file name: E: \ DEEM \ Secondary Alkane (C13

- C17) Sulfonates \ Secondary Alkane (C13

- C17) Sulfonates with 40% Limit Purity Adjusted.R08 Adjustment factor #2 used. Analysis Date 01

- 28

- 2015/07:08:30 Residue file dated: 01

- 28

- 2015/07:07:24 Reference dose (RfD, Chronic) = .582 mg/kg bw/day COMMENT 1: Inert 57 active ingredients + drinking w ater (100ppb)

=============================================================================== Total exposure by population subgroup

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

Total Exposure

----------------------------------- Population mg/kg Percent of
Subgroup body wt/day Rfd

-------------------------------------- ------------- ---------------- Total US Population 0.151474 26.0% Hispanic 0.165410 28.4%

Non

- Hisp

- White 0.148640 25.5%

Non

- Hisp

- Black 0.140761 24.2%

Non

- Hisp

- Other 0.178685 30.7% Nursing Infants 0.198564 34.1%

Non

- Nursing Infants 0.367787 63.2%

Female 13+ PREG 0.132191 22.7%

Children 1

- 6 0.437338 75.1%

Children 7

- 12 0.181928 31.3%

Male 13

- 19 0.107010 18.4%

Female 13

- 19/NP 0.108746 18.7%

Male 20+ 0.112797 19.4% Female 20+/NP 0.122530 21.1%

Seniors 55+ 0.122150 21.0%

All Infants 0.3155 42 54.2%

Female 13

- 50 0.117122 20.1%

Children 1

- 2 0.564993 97.1%

Children 3

- 5 0.388507 66.8%

Children 6

- 12 0.200443 34.4%

Youth 13

- 19 0.107838 18.5%

Adults 20

- 49 0.115792 19.9%

Adults 50

- 99 0.121430 20.9%

Female 13

- 49 0.117067 20.1%

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