UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, DC 20460

OFFICE OF CH E MI C AL SAFETY AND POLLUTION PREVENTION

10/13/11

M E MORANDUM

SUBJECT: Bis(trichlorometh y l)sulf o n e: Human Health Effects Scoping

Document for the Registration Re vi ew Decision

PC Code : 035601 DP Barcodes : D394302

Decision No .: 455122 Registration N o(s) .: Multiple

Petition No(s).: NA Regulatory Action: Registration Review

Ris k Assess Tvpe : Sinale Chemic a l Case No.: 2055

TXR No.: NA CAS No: 3064-70-8

MRID No(s).: NA 40 CFR: N A

TO:

FROM:

THRU: Seiichi Murasaki

, Ch e mical Review Manager Regulatory Management Branch II

Antimicrobials Divi s i on (7510P)

Jenny J. Tao

, To x i c o l o gist

# ~ Talia Lindheimer, Oc c upationallReside tial

### Assessor**c;;:{e,~** Jonathan Chen

, Ph .D

., Incident Data**~** William J. Hazel, Ph

. D

. , Risk Assesso**~** _ /

Risk Assessment and Science Support Br h " 

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Antimicrobials Divi s i on (7510P)

Nader Elkassaban y, P h

. D

., Chief

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Risk Assessment and Science Support Branch

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Antimicrobials Divisi on (7510P)

INTRODUCTION

T h e Antimicrobials Division (AD) h as generated this Human Health Effects Scoping Document for the Regis tr ation Review Decision on the broad-spectrum

antimicrobial pesticide bis(tric h lo r omethyl)sulfone. The hazard and exposure databases w ere examined as w e r e any available risk assessments conducted in
support of the registration or rere g istration of all pesticide products containing bis(trichlorometh y l )sulfone. The Ag ency will also determine w hether current2

science polic ies, use patter ns, or available data materially affect the overall risk picture. The purpose of this scoping document is to determine whether sufficient data are available to support registration review, whether new human health risk assessments are needed to support reg istration review, and to report why the Agency feels it may be appropriate to require additional data and/or conduct new risk assessments under the registration review process. A Reregistration Eligibility Decision (RED) document was issued for bis(trichlo romethyl)sulfone in September 1995 ; this was the primary source of information for this human health effects scoping document

.

EXECUTIVE SUMMARY

B is(trichloromethyl)sulfone is an organosulfur antimicrobial active ingredient in

nine registered products

. There are three manufacturing

- use products (MP) all registered to Verichem, Inc. Five end

- use products (EP) containing one or more other active ingredients are registered to Hercules, Inc. and Nalco Co. ; one single active ingredient product is registered t o Verichem. All EP p roducts are

used as slimicides to control bacteria l and fung al slimes in pulp and paper mill

process water systems and as a preservative of paper

- making chemicals

. These products are added to systems and industrial products using open

- p ouring and pumping methods. Verichem’s EP also bears use s in industrial air washing systems

, commercial and industrial process and water systems

, oil and gas field
water systems , and as a material preservative in a wide range of household and

construction materials including paints, coatings, and fuels; closed loading / application methods must be used in the water systems

.

Bis(trichloromethyl)sulfone is corrosive to the eyes and strongly irritating to the

skin and the lungs ( all are Toxicity Category I)

. Ac ute oral (Toxicity Category III) and dermal (Toxicity Category IV) toxicities are low to moderate

. I t is not a

d ermal sensitizer.

In a 21

- day rat dermal toxicity study

, t he systemic NOAEL was 2.0 mg/kg/day ; systemic adverse effects at the LOAEL of 5.0 mg/ kg/day were changes in hematology and clinical chemistry. The NOAEL for dermal irritation was 2.0 mg/kg/day.

Two developmental toxicity studies are available for bis(trichloromethyl)sulfone,

one in rats and the other in rabbits. In rats, the maternal toxi city NOAEL was 2 mg/kg/day based on decrease d body weight gain and food consum ption at the

LOAEL of 10 mg/kg/day. T he d evelopmental NOAEL was 10 mg/kg/day.

D ecreased fetal body weight and increase s in skeletal and external anomalies

occurred at the develop mental LOAEL of 50 mg/kg/day

. I n rabbits, t he maternal toxicity NOAEL was 20 mg/kg/day based on decrease d body weight gain and

food consum ption and increased incidence of clinical signs at the maternal

LOAEL of 45 mg/kg/day

. N o developmental toxicity was o bserved in rabbits at3

any dose; therefore, the high dose of 45 mg/kg/day is considered to be the developmental NOAEL

.

Preliminary studies have shown adverse affects of b is(trichloromethyl)sulfone on fertility in male rats which , in turn, resulted in lower reproductive rate s in female rats. In addition, b is(trichloromethyl)sulfone has been shown to immobilize rat spermatozoa in vitro at a lower concentration and within a very short period of

time. Therefore, a two

- generation reproductive toxicity study is a nticipated to be

needed.

Based on the registered uses, chronic dietary exposure to bis(trichloromethyl)

- sulfone via both food and drinking water sources as well as residential exposure are expected to be aggregated. Although residential exposures are like ly to be

short

- term and intermediate

- term in duration, the dietary sources would be chronic. Therefore, an oral chronic toxicity study is needed.

A carcinogenicity study is expected to be needed due to chronic human exposure

to bis(trichloromethyl)sulfone via food and drinking water sources, due to a number of positive mutagenicity studies, and the potential for degradation of bis(trichloromethyl)sulfone to chloroform, a probable human carcinogen.

There are several mutagenicity studies available for bis(t richloromethyl)sulfone.

I n three repeated Ames assays , the compound was mutagenic to the same

bacterial strain under both non activated and S9

- activated conditions as well as to

a second strain under nonactivated condition in one study. I n a mouse lymphoma cell line, b is(trichloromethyl)sulfone was also found to be positive under both

nonactivated and S9

- activated conditions in a sister chromatid exchange assay. Although negative results were shown in the other mutagenicity assays, they do

not negate the pos itive gene mutation results.

A rat metabolism study is anticipated to be needed because: (i) there is an

u nknown mode of antimicrobial action of bis(trichloromethyl)sulfone ; (ii) there is an unknown mechanism of mammalian irritation as well as systemic m ammalian toxicity; and (iii) there are no solid clues regarding metabolism from

environmental fate data because the database is very limited and of poor quality

.

No additional acute toxicity data are anticipated to be needed. Based on the

vapor pressure o f bis(trichloromethyl)sulfone and the currently registered uses, the Agency anticipates that a subchronic inhalation toxicity study is needed to

assess inhalation risks. N o additional subchronic oral , subchronic dermal , or developmental toxicity studies ar e needed. A two

- generation rat reproduction toxicity study is anticipated to be necessary due to concern for adverse effects on sperm motility observed in a published study. Resulting from the potential for chronic dietary exposure (food and drinking water ), a chronic toxicity study is anticipated to be needed. A carcinogenicity study is expected to be needed due

to chronic human exposure to bis(trichloromethyl)sulfone via food and drinking4

water sources , a number of positive mutagenicity studies, and the p otential for degradation of bis(trichloromethyl)sulfone to chloroform, a probable human carcinogen. In addition, a metabolism study is needed to better understand the behavior of bis(trichloromethyl)sulfone under biological conditions.

Dietary (food) expo sure to bis(trichloromethyl)sulfone is likely because it is used as a slimicide in food contact paper and paperboard production and to preserve

paper

- making chemicals. Migration of bis(trichloromethyl)sulfone from paper packaging to the food contents may o ccur to some extent. The FDA regulates bis(trichloromethyl)sulfone as an indirect food additive in paper, adhesives, and coatings. A migration study is anticipated to be needed as will a dietary (food source) risk assessment.

The registered uses of bis(tr ichloromethyl) sulfone may result in human exposure

via drinking water result ing from industrial discharges of treated water

. However, the need for a dietary ( drinking water ) exposure assessment will be determined upon review of environmental fate data the Agency anticipates requiring.

B is(trichloromethyl)sulfone may be used to preserve a number of construction and household materials that may be used in the home and other sites such that nonoccupational exposures may occur

. P reserved paints are of particu lar

concern in the residential setting . Both dermal and inhalation exposures of homeowner handlers and bystanders (including children) are expected. Postapplication exposure including mouthing of treated plastic toys of children may also occur ; a restricti on against use of treated materials for toys may negate

the need for this assessment . Data are anticipated to be needed to estimate exposures associated with residential paint use. A residential risk assessment is

also needed.

P otential contributors to ag gregate risk are exposures via food, nonoccupational

, and possibly via drinking water sources . Aggregate risk assessments combining the applicable bis(trichloromethyl)sulfone sources of exposure associated with registered use s will be conducted during the risk assessment stage of Registration Review.

Occupational exposure to b is(trichloromethyl)sulfone is expected based on its

use as an antimicrobial in industrial water systems and as a preservative of a wide range of water

- based liquid solutions, dispersi ons, and emulsions. Most water systems must be treated using closed loading/application or a meter

- pump system whereas open

- pour loading may be used for material preservation. Both

d ermal and inhalation exposure of workers to bis(trichloromethyl)sulfone is expected

. Due to the relatively high vapor pressure of bis(trichloromethyl)sulfone ( 1.1 x 10 - 3 mmHg ), worker inhalation exposure is likely to be due to vapor phase as well as aerosolized parent compound

. D ermal and inhalation exposure studies, product use , and human activity data are expected to be needed and any available relevant Industrial Hygiene air sampling data in commercial5

facilities should be submitted

. Occupational applicator and postapplication/ bystander risk assessments are anticipated to be necessary. Section 1. Chemical Identity and Generic Physical/Chemical Properties

Table 1.1 Chemical Identity of bis(trichloromethyl)sulfone

Common Name Bis(trichloromethyl)sulfone

Chemical Name s Trichloro(trichloromethylsulfonyl)methane; Methane,

sulfo nylbis(trichloro

- ) ; Hexachlorodimethyl sulfone ; Sulfone, bis(trichloromethyl)

Trade Name s N

- 1386®; Spectrum®; Nalcon®7642

Molecular Formula C 2 Cl 6 O 2 S Molecular Weight 300.8

PC Code 035601 CAS Registry Number 3064

- 70

- 8 Registration Review

Case No. 2055

Chemical Structure

Bis(trichloromethyl)sulfone is solid at room t emperature although it melts at 37°C. It has a pungent, aromatic odor. Bis(trichloromethyl)sulfone has a low water

solub ility ( 70 ppm at 20

- 22 °C ). The l og K o/w is estimated to be 3.3 . The v apor

p ressure is estimated to be 1.1 x 10 - 3 mmHg at 25 o C and the H enry's Law

Constant to be 1. 2 x 10 - 8 atm • m 3 /mole at 25 o C.

Section 2

. Toxicology

The toxicolog y database for the bis(trichloromethyl)sulfone registration review

case is primari ly comprised of studies submitted to the Agency before the RED

for bis(trichlo romethyl)sulfone was issued in 199 5

. T he toxic ity database con sist s of acute toxicity studies

, a subchronic dermal toxicity study

, developmental toxicity studies, and mutagenicity studies.

a. Acute Toxicity

Bis(trichloromethyl)sulfone is corrosive to the e yes and strongly irritating to the skin (both are Toxicity Category I) but it is not a dermal sensitizer. In addition, the compound is strongly irritating to the lungs via the inhalation route (Toxicity Category I). Acute oral (Toxicity Category III) and d ermal (Toxicity Category IV)

toxicities a re of less concern. The acute toxicity data are adequate to support regist ration . The Agency does not anticipate that any additional acute toxicity

information on the technical is needed.6

b. Subchronic Dermal and In halation Toxicity

In a 21

- day dermal toxicity study (MRID 40050701), bis(trichloromethyl)sulfone was administered to young adult rabbits of the Hra:(NZW)SPF strain in doses of 0, 0.8, 2.0, or 5.0 mg/kg/day. Systemic toxicity, such as reduced red blood cell and white blood cell counts and reduced hemoglobin, hematocrit, neutrophils (leukocytes), and blood glucose, was noted in the males of the high dose group. No similar findings were observed in the females. The systemic LO A EL was 5.0 mg/kg/day for males an d not established for females (>5.0 mg/kg/day). The systemic NO A EL was 2.0 mg/kg/day for males and ≥5.0 mg/kg/day for females based on changes in hematology and clinical chemistry. Dermal irritation was noted in the high dose groups as compared to control animals

. The LO A EL for

dermal irritation was 5.0 mg/kg/day for both sexes and the NO A EL for dermal

irritation was 2.0 mg/kg/day base d on dermal irritation scores compared to

control animals

.

Based on the vapor pressure and current ly registered use patterns

, the Agency anticipates that inhalation exposure to bis(trichloromethyl)sulfone will occur in

bot h occupational and residential settings . The Agency therefore anticipates the

need for a subchronic inhalation toxicity data to assess inhalation exposure risks

. A 90

- day rat inhalation toxicity study was called in 1/1/89 but has not been

received.

c. Develo pmental Toxicity

There are two developmental toxicity stud ies available for bis(trichloromethyl)

- sulfone, one in rats (MRID 40149101) and another in rabbits (MRID 43156602).

In rats

, bis(trichloromethyl)sulfone technical was administered by ga v age to
Ch arles River Crl:CD BR albino rats at doses of 0

, 2, 10 or 5 0 mg/ kg/day on gestation days 6 through 15 . The maternal toxicity NOAEL was 2 mg/kg/day based on decreased body weight gains and reduced food consumption occurring

at the LO A EL of 10 mg/kg/day. The d evelopmental NOAEL was 10 mg/kg/day based on decreased fetal body weight and an increase in skeletal and external

anomalies observed at the LOAEL of 5 0 mg/kg/day

.

In rabbits , bis(trichloromethyl)sulfone technical was administered by ga v age to groups of 20 pregnant New Zealand white rabbits at doses of 0, 10 , 20, or 4 5 mg/kg/day on gestation days 6 through 1 8 . The maternal toxicity NOAEL was 20 mg/kg/day based on a statistically significant decrease in maternal body weight gain, reduced food consumption, and increased incidence of clinical signs of toxicity observed at the LOAEL of 45 mg/kg/day. There was no developmental toxicity observed at any dose level tested. T he N OAEL for developmental toxicity7

was considered to be 4 5 mg/kg/day (highest dose tested)

. A L OAEL was not established for developmental toxicity

.

d. Reproductive Toxicity

There is no reproductive toxicity study available for bis(trichloromethyl)sulfone in the Agency’s hazard database. A study described in the open literature

addressed the in fe rtility effect s of bis(trichloromethyl)sulfone in rats. Male Sprague

- Dawley (SD) rats (10/dose) were administered bis(trichloromethyl)

- sulfone by gavage at doses of 0, 10 mg/kg/d ay , or 30 mg/kg/d ay. Animals were

dosed once daily, 6 times a week, for 8 week s (10 mg/kg/d ay ) or 4 weeks (30 mg/kg/d ay ). Female animals were not treated with bis(trichloromethyl)sulfone. A

dose

- related, statistically significant (p<0.001) reduction in both number and motility of the spermatozoa in the cauda epididym ides was demonst rated compared to the controls. A corresponding lower pregnancy rate (p<0.001) was shown in female animals. There were no effects of bis(trichloromethyl)sulfone on body weight, sexual behavior, blood testosterone level, or histopathology of the

treated mal e animals. An in vitro study was also performed and it was found that bis(trichloromethyl)sulfone, at a concentration of 0.31mg/ml, immobilized rat spermatozoa within 20 seconds (MRID 48638801 ).

Due to the adverse effects on fertility observed in this pu blished study, a two

generation rat reproduction toxicity study is anticipated to be necessary.

e. Chronic Toxicity

Resulting from the potential for chronic dietary exposure (food and drinking water), a chronic toxicity study is anticipated to be needed to characterize chronic hazard and to calculate chronic dietary risks

.

f. Carcinogenicity

C arcinogenicity studies are also needed for bis(trichloromethyl)sulfone to

evaluate its potential to induce cancer for the following reasons :

Positive results evidenced in mutagenicity assays (three repeated Ames assays and a sister chromatid exchange assay)

Potential dietary exposure to bis(trichloromethyl)sulfone

, including food

and drinking water sources In an anaerobic aquatic metabolism study ( MRID 40317101 ), one of the metabolites of bis(trichloromethyl)sulfone (half life <0.5 day) was hexachloroethane. The Agency has concerns that chloroform may be an active intermediate in the process. Chloroform is classified as “a Group B2; probable human carcinogen” by the Agenc y (U.S. EPA, 2006).8

g. Mutagenicity

A number of mutagenicity studies are available for bis(trichloromethyl)sulfone with both positive and negative mutagenic responses. The studies and results of

the tests are summarized below:

In two Ames bioassays , bi s(trichloromethyl)sulfone was tested in strains

of Salmonella typhimurium (TA1535, TA1537, TA1538, TA98, and TA100) . The test material was posi tive as indicated by increased

numbers of revertants in strain TA1535 under both nonactivated and S9

- activated c onditions (MRIDs 00152330 and 00152331)

. In another gene mutation assay, bis(trichloromethyl)sulfone was tested in

strains of Salmonella typhimurium (TA1535, TA1537, TA1538, TA98, and TA100) and found to be positive to TA1535 under both nonactivated and

S9

- activated conditions and also positive to TA100 under nonactivated

condition s (MRID 00152332)

. In a forward mutation assay using Fischer mouse lymphoma L5178Y cells ( MRID 00 152333 )

, bis(trichloromethyl)sulfone did not elicit a mutagenic

response ( negative ) under either nonactivated and S9

- activated

conditions. In a sister chromatid exchange assay in mouse lymphoma L5178Y cells (MRID 00 152335 ), bis(trichloromethyl)sulfone was found to be positive

under both nonactivated and S9

- activated conditions.

In a mul tiple endpoint (gene mutation, chromosomal aberration, sister chromatid exchange) assay using mouse lymphoma L5178Y cells ( MRID

00 152334 ), an equivocal positive result in gene mutation was observed in the absence of S9, but was n egative in the presence of S9. Negative

results were found in the chromosomal aberration and sister chromatid exchange assays; however, the tested doses were not considered adequate to reveal full mutagenic potential. Therefore, these two assays (chromosomal aberration and sister ch romatid exchange) were classified

as unacceptable

. In a mouse bone marrow micronucleus assay (MRID 42372701), bis(trichloromethyl)sulfone technical was tested at doses of 100, 200, o r 400 mg/kg/day in males and 150, 300, or 600 mg/kg/day in females for 2

c onsecutive days. T here was no significant increase in the frequency of micronucleated polychromatic erythrocytes (MPEs) in bone marrow9 (harvested 24 or 48 hours after final dosing) , i.e., the test material was negative for genotoxicity

. In a morphologic tr ansformation assay in BALB/3T3 cells (MRID

00 152335 ), bis(trichloromethyl)sulfone was found to be negative

. In an in vitro malignant transformation assay in BALB/3T3 cells (MRID not assigned), there was no indication of a positive response induced by bis(t richloromethyl)sulfone

.

h. R at Metabolism

A rat metabolism study is anticipated to be needed because: (i) there is an

u nknown mode of antimicrobial acti on of bis(trichloromethyl)sulfone ; (ii) there is

an unknown mechanism of mammalian irritation as well a s systemic mammalian toxicity; and (ii i ) there is no metabolism information in the environme ntal fate database that could be applicable to a mammalian system and the database is very limited and of poor quality

.

Section 3. Use Directions

B is(trichlorome thyl)sulfone is the active ingredient in nine registered products

. EPs are formulated as S oluble C oncentrate /Liquids (SC/L)

. There are three manufacturing

- use products (MP) containing 35

- 98% ai; all are registered to Verichem, Inc. Six end

- use products (EP ) are registered containing 3.33

- 20% ai. Five of the six EPs also contain one or more other active ingredients; these are registered to Hercules, Inc. and Nalco Co. All EP p roducts are used as slimicides

to control bacteria l and fung al slimes in pulp and p aper mill process water systems and as a preservative of paper

- making chemicals (pulp, broke, polymers, defoamers, alum, emulsions, adhesives, paper mill coatings, pigment slurries, and paper products). These products are added to water systems and

industr ial products using open

- pouring and pumping methods.

Only the EP containing 20% bis(trichloromethyl)sulfone as the sole active ingredient (Verichem, Inc.; EPA Reg. No. 67869

- 32; 4/21/11) bears the use to control bacteria, fungi, and algae in industrial a ir washing systems as well as commercial and industrial process and water systems. This product is also approved to control slime

- forming and sulfate

- reducing bacteria in oil and gas field water systems including oil field injection waters, enhanced recove ry injection fluids, and drilling fluids . It is also used as a material preservative to control fungi and bacteria in : adhesives and tackifier s ; construction products and household products (caulking materials, mastics, ceramic glazes, concrete,

concrete admixtures, plasters); dispersed pigment s (kaolin clay, montmorillonite clay, titanium dioxide, calcium carbonate, calcium sulfate, barium sulfate, magnesium silicate, and kieselguhr used in paint and paper production); paints, coatings, and stains; water

- based coatings such as paper coatings; photo processing system s ; synthetic and natural polymeric lat ices ; and liquid10

hydrocarbon fuels and oils ( crude oils, aviation fuels, kerosene, heating oils,

diesel fuels

, residual fuel oils, coal slurries, liqu e fied petroleum gases, and petrochemical feedstock). Verichem’s 20% EP (EPA Reg. No. 67869

- 32) requires that a meter

- pump system or a closed loading/application system be used to load and apply the product to oil recovery drilling muds/packer fluids,

commercial/ industrial water cooling systems, evaporative condenser water systems, and heat exchanger systems.

Section 4

. Dietary Exposure

a. Food Exposure

Dietary (food) exposure to bis(trichloromethyl)sulfone could potentially occur

because it is used to inhibit sl ime

- forming bacteria and fungi in paper process water systems culminating in production of paper and paperboard that may be used for food contact. Also, bis(trichloromethyl)sulfone is used to preserve a number of paper

- making chemicals as well as paper and paperboard coatings, adhesives, dispersed pigments , etc. B is(trichloromethyl)sulfone is regulated by

t he FDA as an indirect food additive at 21 CFR 176.300 for use as a paper

slimicide , at 21 CFR 17 5 .1 05 to preserve food

- packaging adhesives, and at 21

CFR 176.1 8 0 to preserve coatings to be used on paper and paperboard in contact with dry foods

. Migration of bis(trichloromethyl)sulfone from paper packaging to the food contents is likely to occur to some extent. Therefore, a migration study is expected to be needed as is a dietary (food source) risk

assessment.

b. Drinking Water Exposure

The registered uses of bis(trichloromethyl) sulfone may result in contamination of

surface water and possibly ground water as a result of discharges of treated

water from indus tries using this antimicrobial in their water systems or as a material preserv ative. Therefore, drinking water exposure is a reasonable possibility

. However, the need for a dietary drinking water exposure assessment

for bis(trichloromethyl)sulfone will be determined upon review of environmental

fate data the Agency anticipates requiring. The se environmental fate data will be

useful to determine if bis(trichloromethyl)sulfone can pass through wastewater treatment facilities into drinking water or migrate int o residential groundwater wells as a result of its current use patterns. Therefore, the need for a drinking water assessment will be revisited upon submission and review of the environmental fate data anticipated to be needed

.

Section 4. Residential Expo sure

B is(trichloromethyl)sulfone may be used to preserve a number of construction and household materials that may be used in the home and/or in commercial,11

institutional, and industrial settings resulting in residential and other nonoccupational exposure s. Of the preserved materials, paints are expected to

result in the highest residential exposure. Both dermal and inhalation exposures

of homeowner handlers and bystanders (including children) are expected. Postapplication exposure of children may also occ ur as may incidental oral exposure from playing with toys made of treated plastic

. Data are anticipated to

be needed to estimate exposures associated with residential paint use . A

residential risk assessment is also needed.

Section 5. Aggregate Risk

Bas ed on the registered use of bis(trichloromethyl)sulfone as a paper chemical preservative and use as a slimicide during the manufacture of paper and paperboard that may contact food, dietary exposure may occur. Residues of

b is(trichloromethyl)sulfone may re ach drinking water although this will be determined upon review of the environmental fate data anticipated as being needed. Also, exposure of adults and children to bis(trichloromethyl)sulfone in residential and other nonoccupational settings is likely to occur from the use of preserved materials to be represented by preserved paint. Thus, the potential contributors to aggregate risk are exposures via food

, in the home , and possibly via drinking water . Aggregate risk assessments combining the applicable

exp osure sources associated with registered bis(trichloromethyl)sulfone use will

be conducted during the risk assessment stage of Registration Review.

Section 6. Occupational Exposure

B is(trichloromethyl)sulfone products are added to pulp and paper water s ystems and other industrial water systems as well as to many different materials during

the manuf acturing process

. The labels instruct the handler to wear protective eyewear (goggles, face shield, or safety glasses), rubber gloves, and protective clothing

. The EP labels are silent on the type of loading and mixing equipment to be used in all cases except Verichem’s 20% EP (EPA Reg. No. 67869

- 32) which requires that a meter

- pump system or a closed loading/application system be used to load and apply the prod uct to oil recovery drilling muds/packer fluids, commercial/industrial water cooling systems, evaporative condenser water systems, and heat exchanger systems . Therefore, open

- pour loading is permissible in most cases

.

During open

- pour activities

, dermal a nd inhalation exposure of workers to bis(trichloromethyl)sulfone is expected. D ue to the relatively high vapor pressure

of bis(trichloromethyl)sulfone ( 1.1 x 10 - 3 mmHg ), worker inhalation exposure is likely to be due to gaseous as well as aerosolized paren t compound

. D etailed product use and human activity information are needed to permit more realistic estimates of worker exposure. T o estimate occupational exposure

, dermal and12

inhalation exposure studies are recommended . In lieu of inhalation exposure

stud ies, the registrant may opt to conduct small chamber emission studies

. These small chamber studies permit inhalation exposure estimat ion and are recommended for representative scenarios to estimate potential occupational (handler

, factory bystander , painte r ) exposure. If chosen to be conducted, small chamber study protocols should be approved by the Agency. The generated air emissions data will also be useful to estimate residential exposures. I t is also recommended that relevant Industrial Hygiene air samp ling data in commercial facilities manufacturing, storing, or using large quantities of bulk or end

- products made from preserved materials be submitted

. Occupational risk assessments for handlers and postapplication/ bystanders are expected to be performed

.

Section 7. Cumulative Risk

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to bis(trichloromethyl)sulfone and any other

s ubstances

. For the purposes of this Registration Review, therefore, EPA has not

assumed that bis(trichloromethyl)sulfone has a common mechanism of toxicity

with other substances. For information regarding EPA’s efforts to determine

which chemicals have a c ommon mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to

have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Section 8. Endocrine Disrupt ion

As required under FFDCA section 408(p), EPA has developed the Endocr ine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or

other such endoc rine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical substance to interact wi th the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will deter mine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T

effect.13

Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the pote ntial for human exposure through pathways such as food and water, residential activity, and certain postapplication agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors.

B is(trichloromethyl)sulfone is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call

- ins fo r all pesticide active ingredients

.

For further information on the status of the EDSP, the policies and procedures,

the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

Sec tion 7

. Incidents

Based on a search of OPP’s databases, there have been no reported human poisoning incidents associated with bis(trichloromethyl)sulfone.

Section 8

. Anticipated Data Needs

a. Data Needs

The Agency anticipates need ing the following toxi city studies (utility and rationale provided in Appendix A) to characterize the hazards and assess human health risks associated with exposure to bis(trichloromethyl)sulfone :

90

- day Rat Inhalation Toxicity Study (GLN 870.3465) Reproductive toxicity study (GLN 870.3800) Chronic Oral Toxicity Study in Rats (GLN 870.4100) Carcinogenicity Studies in Two Rodent Species (GLN 870.4200) Rat Metabolism Study (GLN 870.7485)

The Agency anticipates need ing the following exposure studies (utility and rationale provide d in Appendix A) to assess dietary, occupational

, and residential risks associated with registered uses of bis(trichloromethyl)sulfone:

Migration Studies (No GLN) Outdoor Dermal Exposure ( GLN 875.1100) or
In door Dermal Exposure ( GLN 875.1200)14 Outdoor Inha lation Exposure ( GLN 875.1300) or
Indoor Inhalation Exposure ( GLN 875.1400) Applicator Exposure Monitoring Data Reporting for Dermal and Inhalation

Data ( GLN 875.1600)

Product Use Information

– Outdoor (GLN 875.1700) Indoor Surface Residue Dissipation (GLN 875.2300) Inhalation Exposure (Post a pplication) (GLN 875.2500)

Product Use Information

– Indoor (GLN 875. 2 700) Descriptions of Human Activity (GLN 875.2800) Data Reporting and Calculations (GLN 875.2900)

b. Risk Assessments Needed

A dietary risk ( food ) ass essment will be needed to determine risks resulting from dietary exposure to bis(trichloromethyl)sulfone used in pulp and paper mill water systems, coatings, adhesives, and other paper

making chemicals used to manufacture food contact paper/paperboard. If a restriction against use in paper

- making chemicals other than coatings and adhesives is not added to the label (see Label Issues below), these will all be assessed for their contributing dietary exposure. A dietary risk (drinking water) assessment will be needed to reflect discharges of bis(trichloromethyl)sulfone residues from industries using this antimicrobial as a slimicide and as a preservative. If, upon receipt, the environmental fate ( biodegradation ) studies provi de evidence that drinking

water expo sure to bis(trichloromethyl)sulfone residues of toxicological

concern is not likely, a dietary risk (drinking water) assessment will not be

needed. Residential applicator/user dermal and inhalation risks to adults from
exposure to bis(trichloromethyl)sulfo ne residues following use of

consumer products consisting of or containing preserved materials (paints and construction products ). Residential postapplication dermal and inhalation risks to adults and

children , including bystanders, from exposure to bis(tr ichloromethyl)

- sulfone residues following use of products consisting of or containing preserved materials (paints, and construction products ). Incidental oral

risks also need to be determined for children handling and mouthing toys made of preserved polyme rs unless a restriction against such use is added to Verichem’s 20% product label (EPA Reg. No. 67869

- 32)

. At this point, it appears as though aggregate risk will consist of dietary (both food and drinking water) and residential exposures. However, the

det ails of any needed aggregate assessments will be determined during the risk assessment stage of this Registration Review. Occupational handler dermal and inhalation risks to bis(trichloromethyl)

- sulfone resulting from open

- pour application of the antimicro bial in pulp and paper mill water systems and in manufacturing facilities to preserve

materials should be assessed except for those use sites on Verichem’s15 20% product label (EPA Reg. No. 67869

- 32) for which open pouring is prohibited

. Occupational handler dermal and inhalation risk resulting from use or application of materials preserv ed with bis(trichloromethyl)sulfone should

be assessed including a painting assessment

. Occupational bystander inhalation risk due to bis(trichloromethyl)sulfone

gas exposure resulting from volatilization during and after preserv ation of

materials , treatment of industrial water systems, and treatment of oil and gas fields should be assessed.

Label Issues

The Verichem 20% label (EPA Reg. No. 67869

- 32) needs to be

revised to add the following: (i) weight of product per gallon just under the ingredient statement; (ii) a restriction against using the product to preserve food contact materials except coatings and adhesives unless the FDA regulations are broadened (otherwise, the contribution of each to dietary exposure will be assessed); (iii) a restriction against use to preserve polymers that may be used for children’s toys (otherwise, incidental oral risks to children handling and mouthing toys will be assessed); and (iv)

rest riction against using the product to preserve polymers that may be used for human food such as xanthan gum, gum arabic, guar gum, starches, etc.

All five other labels should add a restriction against using the product to preserve food contact materials exc ept coatings and adhesives unless the FDA regulations are broadened (otherwise, the contribution of each to dietary exposure will be assessed).

Section 9. Reference s

Bis(trichloromethyl)sulfone Reregistration Eligibility Decision Document (RED), S e pt emb er 199 5

. http://epa.gov/oppsrrd1/REDs/2055red.pdf Summary of Residential and Occupational Exposure Data for the Bis(trichloromethyl)sulfone Registration Review Decision Document . Talia

Lindheimer. 10 / 11 /11. D394306

. Bis(trichloromethyl)sulfone: Summary of Human Health Effects Data for the Registration Review Decision Document . Jenny J. Tao. 10 / 7 /11.

D394304

.16

Appendix A

.

1. Need for

, and Uses of

, the Data

G uideline Number: 870.3465 Study Title: 90

- Day Inhalation Toxicity (Rat) Rationale for Requiring the Data

This study is required because several use scenarios involve generation of aerosols (such as painting). Also, the relatively high vapor pressure of bis(trichloromethyl)sulfone ( 1.1 x 10 - 3

mm Hg) is likely to result in the compound in the gaseous phase. There is a likelihood of significant repeated inhalation exposure to homeowners and occupational handle rs using direct

pour methods and breath ing aerosols and gas during or after use/appl ication of materials preserved with bis(trichloromethyl)sulfone

, especially while painting with preserved paint or coatings. Many preserved homeowner, commercial, and institutional liquid spray products are preserved with bis(trichloromethyl)sulfone and will resu lt in significant inhalation exposure professional ly and in the home. A 90

- day inhalation toxicity study has not been conducted and is required. The inhalation route is a major route of human exposure to bis(trichloromethyl)sulfone per se for a number of scenarios because of aerosols forming and it is a volatile gas. The air

concentrations of bis(trichloromethyl)sulfone in the chamber should be monitored over time. Practical Utility of the Data 1. How did the Agency make its earlier regulatory decision s without th ese data?

Residential risk ha s never been assessed for bis(trichloromethyl)sulfone even though both

dermal and inhalation routes of exposure are expected

. Also, inhalation exposure and risk have

never been assessed for occupational handlers and bystanders

. As a major exposure route is inhalation and a subchronic inhalation toxicity study is not available, there is no route

- specific study to appropriately use in a quantitative risk assessment, particularly via the inhalation route.

2. How will the data be used?

The data will be used to properly characterize and quantify the inhalation hazard and risks to occupational workers as well as residential adults during painting and children exposed to

materials that ha ve been preserved with bis(tric hloromethyl)sulfone , including paint, often a scenario resulting in the highest exposures

.

3. How could the data impact the Agency’s future decision

- making?

In the absence of inhalation toxicity data, the Agency would have to estimate inhalation risks

u sing an oral developmental toxicity stud y and rely on the assumption that absorption and toxicity of bis(trichloromethyl)sulfone are the same via the oral and inhalation routes of exposure. Note that absorption of pesticides into the bloodstream via the lu ngs is often higher than that via the dietary route and often many times higher than via the dermal route. Paired with the requested chemical

- specific bis(trichloromethyl)sulfone inhalation exposure data, the route

specific 90

- day rat inhalation toxicity s tudy on bis(trichloromethyl)sulfone will permit EPA to conduct residential and occupational risk assessments that are refined and in which there is a high degree of confidence.17

Guideline Number: 870.3800 Study Title: Reproduction and fertility effects Rationale for Requiring the Data

The 2

- generation reproduction study tor bis(trichloromethyl)sulfone is triggered by evidence from a published study that this compound adversely affects male fertility by reducing sperm number

and motility.

This guideli ne (870.3 8 00) for two

- generation reproduction testing is designed to provide information concerning the effects of a test substance on the integrity and performance of the male and female reproductive systems, including gonadal function, the estrous cycle, mating behavior, conception, gestation, parturition, lactation, and weaning, and on the growth and development of the offspring. The study may also provide information about the effects of the test substance on neonatal morbidity, mortality, target organs in the offspring, and preliminary data on prenatal and postnatal developmental toxicity and may also serve as a guide for subsequent tests. Additionally, since the study design includes in utero as well as postnatal exposure, this study provides the oppor tunity to examine the susceptibility of the

immature/neonatal animal.

Practical Utility of the Data How did the Agency make its earlier regulatory decisions without this data?

The Agency made earlier regulatory decisions in the absence of knowledge of the potential reproductive and fertility effects this compound may exert. At this time, EPA would make a decision regarding the necessity of adding a database uncertainty factor of 10X in the absence of a reproductive toxicity study to conduct the human h ealth risk assessment

.

How will the data be used and how could the data impact the Agency’s future decision

making?

After review and evaluation of the reproductive toxicity study, EPA will use the data to determine whether the 10X database uncertainty fa ctor should remain, be reduced

, or removed (reduced to zero)

. A dose and adverse systemic effect from the reproductive toxicity study may be selected for use in quantitative risk assessments in which the Agency has high confidence

.

Guideline Number: 870 .4 1 00 Study Title : Chronic Oral Toxicity Study in Rats Rationale for Requiring the Data A chronic toxicity stud y is expected to be needed due to the chronic (>6 months) human dietary exposure to bis(trichloromethyl)sulfone via indirect food and drinking water sources

. The study would provide insight into toxici ty via chronic dietary and long

- term exposures. It may also provide a toxicity endpoint applicable to risk assessment. Food may be contaminated by the migration of residues from paper or paperboard food packaging consisting of treated paper pulp and preserved chemicals such as adhesives, coatings , and pigments. Drinking water may be contaminated by discharges of waste water from the large number of industrial, high

- volume types of water systems

. Pr actical Utility of the Data How did the Agency make its earlier regulatory decision s without th ese data?

No e arlier regulatory decisions were made that would necessitate a chronic toxicity study. The18

Agency has never assessed dietary exposure and risk as sociated with the registered uses of bis(trichloromethyl)sulfone. In the 1995 RED (pre

- FQPA) , such dietary exposures were referred to as being “regulated by FDA” and were not considered further.

How will the data be used?

The data will be used to charac terize the long

- term effects of bis(trichloromethyl)sulfone via the

oral route . A dietary risk assessment has never been conducted as noted above

. A toxicity endpoint may be selected from this study for use in a quantitative chronic risk assessment. With

t he passage of FQPA in 1996 and ARTCA in 1998, EPA’s safety finding for registration under FIFRA must also meet the standard of safety for FFDCA sec. 408. This means EPA must make a safety finding that aggregate risks are not of Agency concern; aggregate ri sks include chronic dietary ris ks from food and drinking water as well as residential risks regardless of duration

.

How could the data impact the Agency's future decision

- making?

Th is chronic oral toxicity stud y would greatly increase the Agency’s confid ence in the hazard profile of bis(trichloromethyl)sulfone which increases the confidence in future risk assessment s and, hence, regulatory decisions. This study could be used as the source for selection of a chronic or long

- term toxicity endpoint for use i n quantitation of human risks. If t he human health

risks are of EPA concern

, mitigation would be necessary

.

Guideline Number: 870.4200 Study Title : Carcinogenicity Stud ies in Rat and M ouse Rationale for Requiring the Data

C arcinogenicity stud ies are expected to be needed due to chronic human exposure to bis(trichloromethyl)sulfone via food and drinking water sources, due to a number of positive mutagenicity studies, and due to the potential for degradation of bis(trichloromethyl)sulfone to chloroform, a probable human carcinogen.

Practical Utility of the Data

How will the data be used?

The data will be used to characterize the carcinogenic potential of bis(trichloromethyl)sulfone. A

cancer assessment has never been conducted due to the lack of can cer stud ies

. If one or both of the cancer studies in two different rodent species are positive for carcinogenicity, a toxicity endpoint will be selected/calculated for use in a quantitative cancer risk assessment.

How could the data impact the Agency's fu ture decision

- making?

These cancer studies would greatly increase the Agency’s confidence in the hazard profile of bis(trichloromethyl)sulfone which increases the confidence in future risk assessment s and, hence, regulatory decisions. P ositive result s fro m one or both of th ese stud ies would necessitate

evaluation by OPP’s Cance r Assessment Review Committee. This could result in calculation of a cancer slope factor or other measure of carcinogenic potency for use in quantitation of human

cancer risks. A can cer hazard endpoint is often the most sensitive measure of a given pesticide’s hazard which may result in human health risks of EPA concern that would necessitate mitigation.19

G uideline Number: 870. 7485 Study Title: Rat Metabolism Study

Rationale for Requiring the Data

A rat metabolism study is anticipated to be needed because very little is known about the reactions of bis(trichloromethyl)sulfone regardless of the type , e.g. , whether abiotic or biological

, microbial or mammalian , etc. It is unknown w hether the compound: is a strong oxidizing agent, interferes with an enzyme active site, disrupts cell membranes, etc. EPA doesn’t know the chemical species that humans would be exposed to initially via different routes and as the compound is distributed to the various compartments and organs . The magnitude and identities

of residues in the various tissues are not known . The magnitude and identities of the residues

excreted and at what rate are also not known. If the following were known, these are type s o f

information that could provide clues re garding metabolism: mode of antimicrobial action

, mechanism of mammalian irritation , mechanism of systemic mammalian toxicity

, mechanism by which it causes bacterial mutations, metabolism information in another sys tem that could be applicable to a mammalian system ( the environmental fate database is very limited and of poor quality )

. Practical Utility of the Data 1. How did the Agency make its earlier regulatory decision s without th ese data?

In the case of antim icrobials, the Agency virtually never has a rat metabolism study. Historically, the parent compound or its well

- known degradates have been assumed to be the only residues to which humans are exposed. In many cases, chemicals used as antimicrobials are eith er simple compounds, are naturally

- occurring, and/or are well

- understood . Many are oxidizing agents , surface

- active agents, metal ions, etc. Most frequently, they have a fairly generalized, nonspecific mode of action. They often disrupt cell membranes of a ll organisms. They are often rapidly acting and rapidly degraded to simple, nontoxic compounds in the process. They often are irritating to the eyes and lungs but do not cause systemic adverse effects in mammals. In the

case of bis(trichloromethyl)sulfone

, however, systemic toxicity in mammals and bacterial

mutations are induced

.

2. How will the data be used?

The data will be used to help understand the absorption, distribution, metabolism, and excretion

of bis(trichloromethyl)sulfone by mammals, incl uding humans. This study contributes to EPA’s understanding of the effects caused by this compound and its metabolites/degradates. The metabolism study permits a better characterization of both hazard and exposure.

3. How could the data impact the Agency ’s future decision

- making?

The metabolism study could serve as the basis for future data requirements or Agency decisions on waiver requests. It will allow the Agency to render regulatory decisions based on sound

science.

Guideline Number: None Study Title: Migration Study Rationale for Requiring the Data

B is(trichloromethyl)sulfone is used to control bacteria and fungi in pulp and paper water systems and to preserve paper

- making chemicals. Residues of this antimicrobial are likely to remain in20

the final food contact paper and paperboard from which they may migrate into food. These migration data will allow the Agency to conduct chemical

- specific

, quanti tative assessments of dietary exposure and risk based on measured rates of bis(trichloromethyl)sul fone migrati o n from the paper/paperboard packaging

. If the registrant does not elect to add a label restriction against use of registered products to preserve plastics to be used for children’s toys, a study of migration from impregnated plastics would be necessary for Verichem’s 20% product label (EPA Reg. No.

67869

- 32) only

. Practical Utility of the Data 1. How did the Agency make its earlier regulatory decisions without these data?

The Agency has never assess ed dietary exposure and risk associated wi th this use pattern. In the 1995 RED, such dietary exposures were referred to as being “regulated by FDA” and were

not considered further. Wi th the passage of FQPA in 1996 and ARTCA in 1998, EPA’s safety finding for registration under FIFRA must also meet the standard of safety for FFDCA sec. 408.

2. How will the data be used?

The data will be used to determine the rate of migration of bis(trichloromethyl)sulfone fro m various types of paper and paperboard food packaging to various foods as a result of its use to treat pulp slurries and paper chemicals

. This migration rate will be used to estimate realistic dietary exposures and risks resulting from these uses. These dietary risk estimates will be aggregated with other sources of exposure including drin king water and residential.

3. How could the data impact the Agency’s future decision

- making?

The data will permit the first EPA assessment of dietary exposure that has ever been conducted

for bis(trichloromethyl)sulfone

. Along with drinking water and r esidential exposure sources, the dietary exposure will be aggregate d to conduct the first aggregate risk assessment for this antimicrobial as required by FQPA. T his information will permit a determination of wh ether these

uses in the food

- contact paper/pap erboard industry are likely to result in exposures less than or greater than the Agency’s level of concern, whether they must be supported by additional data,

and , if they are likely to result in risks of concern , to permit mitigation

.21

G uideline Number: 875.1100 Guideline Number: 875.1200 Study Title: Indoor Dermal Exposure Study Title: Outdoor Dermal Exposure
Rationale for Requiring the Data The dermal exposure route is very important for s cenarios such as those associated with oil and

gas field activities, pulp and paper mill activities, material preservation, and indoor and outdoor painting with brushes, rollers

, and airless sprayers whe re direct contact and splashing may occur

and aerosol s will be generated. However, very limited worker exposure monitoring data are available for antimicrobial pesticides, including material preservatives used in pain t and other consumer products. EPA used these limited data to perform screening level risk a ssessments for the bis(trichloromethyl)sulfone RED.

The existing data in the Chemical Manufacturers Association (CMA) database and Pesticide Handlers Exposure Database (PHED) for worker exposure scenarios are limited in scope and quality. The CMA data a lso has QA/QC problems, including the lack of field fortification, laboratory recoveries, and/or storage stability information. In addition the CMA data have an insufficient number of replicates.

EPA presented the need for additional handler exposure da ta to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that additional data are warranted.

To protect workers from dermal exposures to pesticides, EPA requires de rmal expo sure monitoring data. The RED identified the lack of chemical

- specific dermal exposure data, which this study will provide, as a data need. The data are needed to support handler exposures for the

industrial and residential uses. Practical Utility of the Data

1. How did the Agency make its earlier regulatory decisions without these data?

The Agency conducted a risk assessment in 1995 using limit ed, preliminary exposure data. There is dermal exposure associated with registered bis(trichloromethyl) sulfone uses. This triggers the need for chemical

- and use pattern

- specific occupational and residential exposure data upon which to base a more solid quantitative risk assessment.

2. How will the data be used?

The dermal exposure data will be used to assess t he occupational and residential exposure of workers using materials preserved in

- can, particularly latex paints.

3. How could the data impact the Agency’s future decision

- making?

The dermal exposure data will provide more accurate estimations of the der mal risks to occupational workers using the formulated products and materials preserved with bis(trichloromethyl)sulfone. These data will be used to generate a sound risk assessment to more accurately reflect the actual exposure. If future risk assessments are performed in the absence of these data, the Agency will have a significant degree of uncertainty in its regulatory

decision

- making process and current mitigation measures (i.e., personal protective equipment) may not provide adequate protection for wo rkers that may contact bis(trichloromethyl)sulfone in industrial settings. The lack of these data will limit the flexibility of the Agency and registrants with respect to decisions made from high

- end screening level assessments that may overestimate exposu res.22

Guideline Number: 875.1300 Study Title: Outdoor Inhalation Exposure Guideline Number: 875.1400 Study Title: Indoor Inhalation Exposure

Guideline Number: 875.2500 Study Title: Inhalation Exposure (Post Application)

Rationale for Requiring the Data Note: Inhalation exposure data are needed for both resi dential and occupational uses. The

selection of an outdoor ver sus an indoor site is based on the high end exposure scenario (for

inhalation the se lection is typically indoors). In almost all cases, repeating an exposure study for the same scenario outdoors and indoors is not necessary

The inhalation exposure route i s very important for indoor painting, outdoor painting, and indoor

open

- pouring of liquids and liquid pumps during preservation. exposures and from painting with a brush, paint rollers and airless sprayers wher e aerosols would be generated. Also, the relati vely high vapor pressure of bis(trichloromethyl)sulfone ( 1.1 x 10 - 3 mmHg) is likely to result in vapor formation which affects handlers as well as bystanders

. In addition, inhalation exposures from liquid pouring are evident in exposure studies in the Pest icide Handlers Exposure Database (PH ED). The existing Chemical Manufacturer Association (CMA) data base and PHED for these scenarios are limited in scope for QA/QC and number of monitoring units. EPA presented the need for additional handler exposure data to the January 2007 Science Advisory Panel (SAP) as well as to the April 2007 Human Studies Review Board (HSRB) and both groups agreed that

additional data are warranted.

This data requirement may be satisfied either by conducting an inhalation exposure monitoring study or by cooperating with the Agency to develop and conduct small chamber studies to determine air emission rates, which then may be used to estimate inhalation exposure in occupational and residential settings. Practical Utility of the Data 1. How did the Agency make its earlier regulatory decisions without these data?

The Agency did not conduct an inhalation risk assessment in 1995, as it was stated that inhalation exposur es were assumed to be minimal. There is

, in fact

, significant inha lation exposure associated with registered bis(trichloromethyl)sulfone uses due to aerosol and gas

formation. This triggers the need for chemical

- and use pattern

- specific occupational and residential exposure data upon which to base a solid quantitative r isk assessment.

2. How will the data be used?

The inhalation exp osure data will be used to assess the residential short

- term duration of painting with a paint brush/ roller and an airless sprayer. For occupational uses, the inhalation exposure data would be used to assess the short

- and intermediate

- term painting as well as pouring bis(trichloromethyl)sulfone concentrates (e.g., poured into paint as a preservative in manufacturing settings for industrial and household water

- based liquids ). These data will also be used to assess by stander exposures to the vapors that may result from the relatively high vapor pressure of bis(trichloromethyl)sulfone.

3. How could the data impact the Agency’s future decision

- making?

The inhalation exposure data w ill be used to estimate inhalation risks to both residential and occupational workers using the formulated products and in

- can

- preserved materials in residential and industrial settings ; inhalation risks have never been estimated. If future risk assessments are23

perfo rmed without these data, the Agency will have to assume a significant degree of uncertainty in its regulatory decision

- making process. The lack of these data could result in underestimation

or overestimation of handler risks. The former would result in the Agency not protecting human health whereas the latter could greatly limit the flexibility of the Agency and registrants with respect to decisions made from high

- end screening level assessments. If risks warrant mitigation, the inhalation exposure data wou ld help EPA decide on the types of mitigation necessary such as respiratory protection from respirators or closed systems for commercial uses to potential removal of uses from the label.

Guideline Number: 875.1600 and 875.2900 Study Title: Data Reporti ng and Calculations (Handler and Post a pplication) Rationale for Requiring the Data

This data requirement is linked to the dermal and inhalation exposure data also being required. The submission of these data serves as quality assurance and control (QA/QC ) information and

to validate t he dermal and inhalation data. These data are intended to ensure that the product manufacturer and registrant conducting the study adhere to a defined set of quality criteria and

meet the stu dy requirements of the Agency. The se data allow the Agency to determine if the quality of data provided will serve the risk assessment needs of the Agency and support the registrant’s goal for product registration review. Submission of data reporting and calculations increases the Agency’s confidence in the data submitted.

Rationale for Requiring the Data/Practical Utility

1. How did the Agency make its earlier regulatory decisions without these data?

There were no chemical

- specific data available to assess worker or residential der mal or inhalation exposures to b is(trichloromethyl)sulfone. Therefore, there were no reporting data.

2. How will the data be used?

These studies will be used to validate the data provided from the indoor and outdoor dermal and

inhalatio n applicator ex posure studies. These data are important because it allows EPA to assess the adequacy and q uality of the exposure study. Information that must be submitted includes a description of the purpose of the study and what requirement(s) it is intended to satisfy , a summary of the study, a comprehensive section on materials, methods, and calculations, a section interpreting the scientific results of the study, a discussion of quality assurance, identification of the location of the raw data, and any references, co mmunications, and protocols relevant to the conduct of the study.

3. How could the data impact the Agency’s future decision

- making?

The data will be needed to interpret the dermal and inhalation exposure (indoor and outdoor)

data expected to be submi tted in response to this registration review. If the exposure monitoring data reporting is not submitted in conjunction with the indoor and outdoor dermal and inhalation applicator exposure studies, the Agency may not be able to utilize the studies to the fullest extent to conduct its human health exposure and risk assessments.24

Guideline Number: 875.1700 and 875.2700 Study Title: Product Use Information (Outdoor and Indoor) Rationale for Requiring the Data

Product use information is a narrative description of which, when, and how materials are preserved when the product is actually app lied; it is not a field study. A description of how products containing b is(trichloromethyl)sulfone are used will provide a comprehensive, realistic

assessment of i ts potential applications and resulting ha ndler and postharvest exposure. Descriptions are needed of: (i) what specific types of materials are treated; (ii) what stage in the manufacturing process each material is treated; (iii) the conditions to which th e b is(trichloromethyl)sulfone will be exposed (temperatures, pH’s, etc); etc. These will provide a comprehensive, realistic assessment of potential residential and occupational exposures. Therefore, these data are required.

Product use information permits EPA to more accurately assess pesticide exposure to applicators by describing how the pesticide is actually used and applied. EPA requires this information because differences in use can translate to significant differences in exposure, and

thus in risk.

The guideline for postapplication product use information was presented to the FIFRA Science Advisory Panel (SAP) in March 1998. (The draft guideline is available at http://w ww.epa.gov/scipoly/sap/meetings/1998/march/contents.htm .). The guideline for applicator product use information should be substantially similar to the one for postapplication. Practical Utility of the Data 1. How did the Agency make its earlier regulat ory decisions without these data?

The Agency used its best professional judgment based on its years of experience and general use information from the registered product labels and product chemistry data.

2. How will the data be used?

The descripti on of the materials preserved, application techniques, degradation conditions , and physicochemical disposition will be used to determine the scenarios for which exposure studies will be required . These will be used in risk assessment and for the Agency to determine how representative the exposure data are of the “real

- world” use scenarios.

3. How could the data impact the Agency’s future decision

- making?

These data will enable the Agency to understand how the EPs are applied and ensure that the

risk asse ssment is inclusive of the types of exposures occurring during pesticide use and from any pote ntial postapplication contact. This information will permit a determination of which use patterns are expected to result in exposures less than the Agency’s level of concern, which ones must be supported by additional data, and which ones are likely to have risks of concern and, therefore, must be mitigated.25

Guideline Number: 875.2300 Study Title: Indoor Residue Dissip ation Rationale for Requiring the Data

Data will only be required if the bis(trichloromethyl)sulfone

- treated plastics are

manufactured into toys These leaching/migration data will allow the Agency to conduct chemical specific quantitative

assessments tha t utilize the measured quantities of bis(trichloromethyl)sulfone and/or major metabolites/degradates leaching/migrati ng from the preserved polymer. Exposures to these residues may occur as a result of dermal and non

- dietary contact. In the absence of chemi cal specific migration data, the Agency uses a default leaching rate from plastic of 0.5%. The leaching study will be used to confirm or replace this default leaching rate.

Practical Utility of the Data 1. How did the Agency make its earlier regulatory decisions without these data?

The Agency did not initially assess this use pattern. Based on professional judgment and general information on this use pattern, it is now necessary to consider.

2. How will the data be used?

The data would be used t o determine the leachability of the active ingredient expressed as a rate of migration or percentage s of the or iginal preservative incorporated over time

. However, the registrant may seek a data waiver by proposing a label restriction against preserving pl astics that may be manufactured into toys. If this is pursued and the labels are revised to include this restriction, this will override this data requirement.

3. How could the data impact the Agency’s future decision

- making?

The migration data on bis (trichloromethyl)sulfone in plastic toys will be used to estimate

children’s dermal and incidental oral exposure and associated risk. This exposure source and these routes will be aggregated with dietary, drinking water, and any other co

- occurring

nondieta ry sources ; it is possible that the children’s aggregate risk could represent a risk of Agency concern which would necessitate mitigation. This information will permit a determination of which use patterns are expected to result in exposures less than the Agency’s level of concern, which ones must be supported by additional data, and which ones are likely to have risks of concern and, therefore, must be mitigated.26

Guideline Number: 875.2800 Study Title: Descriptions of Human Activity Rationale for Requiring the Data

Very limited worker activity data are available for antimicrobial pesticides, including material preservatives used in pain t and other consumer products. Worker a pplicat ion parameters are generally defined by the physical nature of the formulation (e.g., formula and packaging), by the equipment required to deliver the chemical to the use site, and by the application rate required to

achieve an efficacious dose. The risk a ssessment noted that many of the use parameters used (e.g., amount handled and duration of use) were based on professional judgments. These data are needed to fill this data gap and provide information needed to refine the risk assessment.

Practical Util ity of the Data 1. How did the Agency make its earlier regulatory decisions without these data?

The Agency used its best professional judgment and general use information from the registered product labels, product chemistry data, as well as communicati on with the registrants of registered products.

2. How will the data be used?

The discussion of human activity would be used to define the exposure scenarios to be assessed in the risk assessment. Additionally, a complete description of activity patt erns would ensure that the risk assessment is inclusive of the types of exposures occurring during residential and occupational use.

3. How could the data impact the Agency’s future decision

- making?

T his information will allow the Agency to assess, with greater confidence, the risks that may result from contact with or use of antimicrobial products containin g bis(trichloromethyl)sulfone. This information will also permit selection of appropriate label warnings, PPE, and any necessary risk mitigation.

Sign

- off Date : 10/13/11

DP Barcode No. : D39430 2