Page 2 of 18 EXECUTIVE SUMMARY

Sodium omadine is registered for use as an industrial preservative and as a dry film mildewcide. The industrial preservation uses include metal working fluids, adhesives, caul ks, sealants, plastics, textile spin finishe s, leather and paints and coatings . Additional preservation

uses include carpet cleaners, surface cleaners, floor cleaners and sponges . The Registration Eligibility Decision ( RED ) for sodium omadine was complet ed in 1996 and the uses that existed

at the time were found to be eligible for registration.

There are twelve products that contain sodium omadine as the active ingredient (ai). Most of the labels have the statement “Do not use for applications involvi ng direct or indirect food/drinking water contact”. Three labels ( #1 258

- 990 , #1258

- 1205 and #39967

- 26 ) do not have

this statement and label #39967

- 26 is approved for use s such as paper, cleaning solutions and detergents that might involve food contact

. S odium omadine is also approved by FDA as a preservative of adhesives in food contact packaging (21 CFR 175.105).

Because it was thought that the low vapor pressure of sodium omadine and dilution during use would result in minimal exposure only two occu pational exposure scenarios were assessed during the RED and no residential exposures scenarios were assessed

. Because there is the potential for exposure to aerosols from certain occupational and residential uses and because the toxicological endpoints r elating to residential exposures are fairly low, however, t here are additional exposures that will need to be reassessed during registration review. The following exposure data will be needed to assess these exposures:

**•** Indoor exposure studies (dermal and inhalation) during open pouring of liquids for material preservation and during the use of treated materials such as paints, metal working fluids, and household cleaners

.

**•** Leaching studies on leather and textiles preserved with sodium omadine.

**•** Surface resi due dissipation studies on dishes, household floors and carpets cleaned with sodium omadine preserved dish detergents, floor cleaners and carpet cleaners

, respectively.

**•** Product use information

The toxicological database for sodium omadine is fairly robu st and includes a 90 day oral toxicity study on rats , a 90 day dermal toxicity study on rats , a 90 day inhalation toxicity study

on rats , a developmental study on rabbits, a two generation reproducti on study on rat s and a carcinogenicity study on rats. No additional toxicology studies will be needed for registration

review

.Page 3 of 18 1.0 B ACKGROUND

1 .1 Chemical Identity

The chemical identity of sodium omadine is listed in Table 1

. Sodium omadine exists as mixture of two tautomers ( A and B ) that result from the resona nce of the sodium ion between the sulfur and oxygen atoms

.

Table 1

- Chemical Identity of Sodium Omadine

Chemical Name A . 1

- hydroxy

- 2 (1H)

- pyridinethione, sodium salt

B . 2

- pyridinethion

- 1

- oxide, sodium salt

Common Name Sodium Omadine

PC Cod e 0 88004 CAS Registry Number 15922

- 78

- 8 ( A ), 3811

- 73

- 2 ( B )

Case No. 0209 Empirical Formula C 5 H 4 NO SNa

Structure

1.2 Chemical and Physical Properties

The physical and chemical properties of sodium omadine that are relevant for human health risk

assessment are listed in Table 2

.

Table 2

- Physical and Chemical Properties of Sodium O madine

Property Value Reference

Molecular Weight 149.2 Based on formula

Physical State Off White Powder US EPA, 199 6

Melting Point > 250 C US EPA, 199 6

Water S ol u bility 121 grams per 100 ml @ 2 5 C US EPA, 199 6 Vapor Pressure 7 x 10 - 8 mm Hg @ 22 C US EPA, 1996Page 4 of 18 2.0 USE INFORMATION

2.1 Formulation Types and Percent Active Ingredient

T h ere are twelve product s that contain sodium omadine as the active ingr edient (ai). Th ese product s are formulated as ready to use solutions or soluble concentrates

.

2.2 Summary of Registered Uses

Sodium omadine is registered for use in the preservation of a wide variety of materials as

listed in Table 3. Both in

- can and dry film uses are included on the labels. The application rate s range from 33 to 5000 ppm with the lower rates being for products that contain other active ingredients such as HHT

.

Table 3

– Application Rates for Sodium Omadine

Use Application Rate No tes Adhesives, Latexes, Urethane Foams, Caulks, Patching Compounds, Sealants, Pastes, and Grouts (Dry Film Preservation) 2000

– 5000 ppm 1

Air Freshener Gels (Carrageenan Based) 400 ppm Aqueous Analytical and Diagnostic Reagents U sed in C hemical and C l inical A nalysis 33

– 500 ppm Architectural Paints, Industrial Paints and Coatings, including Wood Coatings, (Dry Film Preservation) 2000

– 5000 ppm 1

Building Materials (gypsum, pearlite, plaster

- like, mineral based or cellulose) used in

the manufactu re of ceilings, ceiling tile, walls and partitions 3840 ppm

Concrete Add

- Mixtures (Water Based Chemical or Mineral) 500 ppm Gypsum Wallboard 3840 ppm Inks, Aqueous Based 328

- 512 ppm Latex Emulsions Used in Adhesives, Caulks, Patching Compounds, Sealants, Pastes

and Grouts 98

- 410 ppm

Laundry Rinse Additives, Laundry Detergents, Carpet Cleaners, Surface Cleaners,

Floor Cleaners 640 ppm

Leather Preservation 4000 ppm Metal Working Fluids 74

- 512 ppm Spin Finishes

- Aqueous Synthetic Fibe r Lubricating 66

- 512 ppm
Paper Not Specified 2 Sponges, Zinc

- chitosan modified 6000 ppm 1. The highest rate of 5000 ppm is from label 1258

- 843. 2. This use is only listed on one label (39967

- 26). The rates for this label are listed on a technical information sheet.

Th e technical data sheet does not list a rate for paper.

The RED for sodium omadine was completed in 199 6 and all of existing use s w ere found to

b e eligible for registration

. S ome additional uses s uch as leather preservation , paper and sponges were added after the completion of the RED. The sponge use was evaluated in a risk assessment (EPA, 1999) and it was determined that the risks were not of concern for either workers involved in the sponge tre atment or residential users of the treated sponges. It should be noted that the

worker risks were assessed for sodium omadine while the residential risks were assessed for zinc omadine because sodium omadine reacts with zinc that is impregnated within the sponge and

forms zinc omadine. The leather and paper uses have not been evaluated.Page 5 of 18 3

. 0 T OXICOLOGY

At the time of the RED, the toxicology database for sodium omadine was considered to be complete and no additional studies were required. No additiona l toxicity studies, other than a few acute toxicity studies, have been submitted since the RED.

3.1 Acute Toxicity

A summary of the acute toxicity findings is included in Table 4

. Sodium omadine is of low

acute toxicity (toxicity category III) for oral , dermal and inhalation toxicity and it is a mild

dermal irritant (toxicity category IV) . It is not a dermal sensitizer. With respect to eye irritation

, the testing indicated sodium omadine belongs in Toxicity Category II, but this finding is

confounded by the fact that 3 of the 6 animals died by day 2.

Table 4

- Acute T oxicity V alues for Sodium O madine Test (species) MRID Result Toxicity Category

81

- 1 Oral Toxicity (rat) 402478

- 01 LD50 (males) = 2000 mg/kg

LD50 (females) = 1100 mg/kg LD50 (combined) = 1500 mg/kg III

81

- 2 Dermal Toxicity (rabbit) 402478

- 02 LD50 (males) = 1900 mg/kg

LD50 (females) = 1800 mg/kg LD50 (combined) = 1800 mg/kg III

81

- 3 Inhalation Toxicity (rat) 403390

- 01 L C 50 (males) = 1.26 mg/ l

L C 50 (females) = 0.81 mg/ l LC50 (combin ed) = 1.08 mg/l III

81

- 4 Eye Irritation (rabbit) 44322901 No corneal opacity noted. Iritis cleared by day 2. Conjuctival irritation cleared by day 14. II*

81

- 5 Dermal Irritation (rabbit) 402478

- 03 Slight transient erythema and edema IV

81

- 6 Dermal s ensitization (guinea pig) 402478

- 04 Not a sensitizer NA

81

- 6 Dermal sensitization ( human ) 403874

- 01 Not a sensitizer N/A *Three of the six test animals died by day 2 . N ecropsy indicated abnormalities of the lung, peritoneal cavity and

gastrointestinal t ract.

3.2 Subchronic and Chronic Toxicity

The following is a summary of the currently available toxicology studies for sodium

omadine

. All of these studies were done using an aqueous solution of 40 to 41 percent sodium

omadine.

3.2 a Subchronic Toxici ty

Oral Exposure Route

MRID 40756901

- In a subchronic toxicity/neurotoxicity study, sodium omadine was administered by oral gavage to groups of 20 male and 20 female rats for 13 weeks at doses of 0, 0.5, 2.0, or 8.0 mg/kg/day. In

- cage clinical observati ons for signs of neurotoxicity were madePage 6 of 18 prior to dosing, at 1 and 6 hours after dosing, and daily before dose administration throughout the study. Prior to initiation and during weeks 5 and 13, all animals were given functional tests for potential neuroto xicity (hindlimb grip strength, hindlimb tactile placing response, and landing hindfoot spread test).

At 2.0 mg/kg/day, slight atrophy of the hindlimb skeletal muscle was observed in 5/20 males and 5/20 females, and minimal atrophy was seen in one female . Atrophy of the panniculus muscle was observed in 3/20 females receiving 2.0 mg/kg/day; the atrophy was considered a neurotoxic effect (neurogenicatrophy). Both males and females dosed at 0, 0.5, and 2.0 mg/kg/day had similar body weights throughout the study. The 8.0 mg/kg/day groups consistently gained less weight than the other groups, and weighed as much as 21% and 22% less than controls for males and females, respectively. Significant decreases in weight gains were seen for males (30%) and females (4 7%).

The body weight and clinical observation data suggest a steep dose response. In the high

dose groups, minimum to marked hindlimb atrophy was observed in 95

- 100% of the males and females (more severe in females), minimal paravertebral muscle atrophy was seen in 2/20 males and 17/20 females, and atrophy of the subcutaneous panniculus muscle was seen in 20/20 males

and 17/20 females. Treatment

- related neurotoxic signs observed in the high

- dose animals consisted of slight hypoactivity, piloerection, atax ia (hindlimb), slight head searching, emaciation, hindlimb paralysis, and hunched posture. As a consequence of severe hindlimb motor dysfunction, 10 high

- dose females were sacrificed in extremis . Effects on neuromuscular function included significant decre ases in landing foot spread, hindlimb grip strength, and hindlimb tactile placing response.

The study Lowest Observed Effects Level ( LOEL ) was 2.0 mg/kg/day based on evidence of neurotoxicity in males and females (neurogenic skeletal muscle atrophy) and t he No Observed Effects Level ( NOEL ) was 0.5 mg/kg/day.

The neurotoxicity portion of the study was classified as supplemental because cage observations were limited, many of the usual functional observation battery (FOB) parameters were not performed, grip strength measurements and motor activity were not quantified, guideline procedures for preparation of neural tissues (including perfusion) were not followed, and the histological examination of neural tissues was inadequate.

Dermal Exposure Route

MRID 40936201

- In a subchronic dermal toxicity study, rats were administered sodium omadine daily for 90 days at 0, 5, 15, or 50 mg/kg/day. There was no evidence of dose related

dermal irritation. Dose

- related clinical signs seen in high

- dose females included emaciation, hunched posture, stiff hindlimbs, incoordination, and tremors. Among the males, one high

- dose rat was emaciated; there were no neurologic signs. The high dose ( 50 mg/kg/day ) males and females consistently gained less weight than the other group s, and a t termination, high

- dose body weights were 9% and 17% less than controls for males and females, respectively. Food consumption was not affected. There were no dose

- related effects on eye health or clinicalPage 7 of 18 pathology. Statistically significant incre ases in relative brain, pituitary, heart, lung, liver, kidney, and spleen weights in the high

- dose males and females were attributed to retarded growth. There

were no dose

- related effects on absolute organ weights. The only dose

- related gross lesion was

wa sting of the hindlimb skeletal muscle in 3/20 mid

- dose females, and in 2/20 males and 19/20 females in the high

- dose. The gross findings were confirmed histopathologically as a reduction

of muscle fiber diameter, fatty replacement, and an increase in the n umber of sarcolemmal nuclei. The subcutaneous panniculus muscle displayed atrophy in the mid

- dose females and the high

- dose males and females. In addition, degeneration of sciatic nerve fibers and minimal atrophy in the paravertebral muscles was seen in 10 /20 high

- dose females. Degenerated fibers

showed a loss of myelin.

The LOEL was 50 mg/kg/day in males and 15 mg/kg/day in females, based on atrophy of the hindlimb muscles and subcutaneous panniculus muscles. The NOEL was 15 mg/kg/day in males, and 5 mg/ kg/day in females

. At 50 mg/kg/day, both sexes had decreased weight gain compared to controls, and females showed minimal atrophy of the paravertebral muscle, neurotoxic symptoms, and degeneration of some sciatic nerve fiber bundles.

Inhalation Exposure R oute

MRID 41178201

- In the rat inhalation toxicity study, sodium omadine was administered by

whole

- body inhalation to male and female rats for 6 hours per day, 5 days per week, for 13 weeks at analytical concentrations of 0 .0 , 0.00046, 0.0011, and 0.0038 mg/l. The high

concentration of 0.0038 mg/l was increased to 0.0081 mg/l at week 6 because of the lack of signs of toxicity. The systemic NOEL(s) were 0.0081 mg/l in males and 0.0011 mg/l in females. The systemic LOEL was 0.0081 mg/l in females, based on clinical signs of hindlimb dysfunction, histopathologic skeletal muscle regeneration, and decreases in female body weight and body weight gain.

3.2b

. Chronic Toxicity

MRID 41178101

- Sodium omadine was administered by gavage to groups of 5 male and 5

fe male Cynomolgus monkeys for 1 year at 0, 5, 25, or 150 mg/kg/day. The dose of 150 mg/kg/day was lowered to 75 mg/kg/day at week 6 because of adverse effects on survival. No evidence of toxicity was seen at 5 mg/kg/day other than emesis in some m onkeys. Eme sis was observed in all monkeys at higher doses. Male body weights were un

- affected by dosing, but female body weights were decreased as much as 8%, 17%, and 23% at the 5, 25, and both 75 and

150 mg/kg/day, respectively. At 150 mg/kg/day, one female was sa crificed inextremis at week 6. At 75 mg/kg/day, one male and one female died at weeks 13 and 35, respectively; the cause of death was not apparent for either animal. Clinical signs noted prior to death in the dead and

sacrificed females included prostratio n, decreased activity, emesis, thinness, weakness, and cold

extremities. Emesis and ptyalism were seen in the male that died. Hematologic changes (i.e., decreases in erythrocyte count, hemoglobin, and hematocrit levels) were slight and considered of

minor toxicological importance.

The No Observed Adverse Effects Level ( NOAEL ) was 5 mg/kg/day. The Lowest Effects Level ( LEL ) was 25 mg/kg/day based on emesis and decreased female body weight.Page 8 of 18 3.2c

. Carcinogenicity

MRID 42100801

- In an 80

- week dermal carc inogenicity study, sodium omadine 40% aqueous solution was administered topically to groups of 50 male and 50 female mice at 0, 5, 15, or 40 mg/kg/day. At 40 mg/kg/day, an increase in the incidence of epidermal hyperplasia at the application site was seen in males (20% compared to 0% in controls, p <0.01) and in females (20% compared to 6% for controls; nonsignificant by pairwise comparison but a significant trend, p <0.05). No systemic toxicity was observed. D ermal application of sodium omadine did

not in duce any benign or malignant neoplasms. The NOEL for systemic effects was 40 mg/kg/day
, which was the highest dose tested, and was supported by the range

- finding study.
The NOEL for irritation was 15 mg/kg/day. The dermal LEL (lowest effect level) was 40

m g/kg/day based on an increase in epidermal hyperplasia at the skin application site. The high

dose was considered inadequate to assess carcinogenicity.

MRID 42100901

- Sodium omadine was administered daily by oral gavage to groups of 70

rats per sex at 0 , 0.5, 1.5, or 5.0 mg/kg/day for 2 years. The highest dose was reduced to 3.5 mg/kg/day after 12 weeks because of excessive weight loss in females. At the highest dose tested (5.0/3.5 mg/kg/day) there was a significant decrease in mean body weight (as much as 10%) and body weight gain in females throughout the study; a marked increase in nerve fiber degeneration

in the sciatic nerve and spinal cord in both sexes; and an increased incidence of retinal atrophy in

both sexes. A n increase in neoplasia was not o bserved at any site. Dosing was considered adequate to assess carcinogenicity. The NOEL was 0.5 mg/kg/day. The LOEL was 1.5 mg/kg/day, based on significant increases in the incidence of degeneration of the skeletal muscle

of the hindlimbs in both sexes.

The OPP RfD/Peer Review Committee met on 3/30/95 to discuss the adequacy of the carcinogenicity studies described above. The rat carcinogenicity study was found to be acceptable. The dermal carcinogenicity study in mice was found to be inadequate because t he chemical was not tested at a sufficiently high dose level. However, the Agency concluded that a new study will not be required as long as the use patterns do not dramatically change and the potential for human exposure remains low. Sodium omadine was cl assified as a Group D carcinogen (insufficient weight of evidence).

3.2d

. Developmental Toxicity

MRID 40487201

- In a developmental toxicity study, rabbits were given sodium omadine by daily dermal application for 6 hours at doses of 0, 1, 2.5, or 5 mg/k g/day on gestation days 6

- 19,

inclusive. There was no evidence of maternal or fetal toxicity at any dose. The NOEL was 5 mg/kg/day which was the highest dose tested. This NOEL was supported by the range

- finding dose of 7.5 mg/kg/day that resulted in subst antial toxicity

.

3.2e

. Reproductive Toxicity

MRID 41097201

- In a two

- generation reproduction study, rats received sodium omadine by gavage at dose levels of 0, 0.5, 1.5, or 3.5 mg/kg/day. The highest dose level was changed from

4.5 mg/kg/day to 3.5 mg/k g/day after 3 weeks of dosing because of marked toxicity at 4.5Page 9 of 18 mg/kg/day. The parental NOEL was 0.5 mg/kg/day. The parental LOEL was 1.5 mg/kg/day in females, and 3.5 mg/kg/day in males, based on increased incidence of histologic atrophy in the upper hind limb skeletal muscles (reduction in fiber diameter) in F 1 females (3/25), F 0 males (7/23), and F 1 males (9/25). Additional parental effects seen at 3.5 mg/kg/day included increased histologic atrophy in the upper hindlimb skeletal muscles in F 0 females (19 /24), and F 1 females (20/23); and significantly decreased body weight in F 0 and F 1 females.

The reproductive NOEL was 1.5 mg/kg/day . The reproductive LEL was 3.5 mg/kg/day, based on slightly decreased number of pups per litter born in both generations (p ossibly a consequence of reduced mating success due to hindlimb atrophy), delayed development in pups from both generations (including open ears and eyes and startle response), and decreased pup body weight and weight gain in both sexes.

3.2f Mutagenicit y

MRID 40411501

- Sodium omadine did not induce forward gene mutations at the HGPRT locus in cultured Chinese hamster ovary (CHO) cells at conce ntrations of up to 0.08 μg/ml

without S9 activation or 27 μg/ml with S9 activation. These concentrations were found to be severely cytotoxic (i.e., <10% cell survival).

MRID 40343701

- In the in vivo Micronucleus Assay, sodium omadine did not cause

micro nucleus induction in the bone marrow cells of male or female CD

- 1 mice at 30, 48, or 72 hours after the intraperitoneal administration of 575 mg/kg (238 mg/kg/active ingredient). Clinical signs of toxicity (decreased body tone, body drop, abnormal gait, pt osis, lacrimation,

and tremors) and target cell cytotoxicity were observed at this level.

MRID 40387501

- Sodium omadine did not induce unscheduled DNA synthesis (UDS) in primary rat hepatocytes treated with doses up to 220 ng/ml (300 ng/ml, based on ana lytical determinations). Concentrations 71 ng/ml (80 ng/ml) were cytotoxic.

3.2g Absorption, Distribution, Metabolism and Excretion (ADME)

MRID No. 41269001

- The ADME of sodium omadine w as studied in groups of rats

administered either: 1. A single oral dose of 0.5 mg/kg 14 C

- sodium omadine, 2. A single oral

dose of 25 mg/kg 14 C

- sodium omadine, 3. Oral dosing of 0.5 mg/kg/day of unlabeled sodium

omadine for 14 days followed by a single oral dose of 14 C

- sodium omadine (0.5 mg/kg), or 4. A single (IV) dos e of 0.5 mg/kg 14 C

- sodium omadine. Sodium omadine was rapidly absorbed, metabolized, and excreted at all dosing levels. Total recovery of administered radioactivity was

85%

- 95% at 4 days postexposure. The urine is the major route of excretion of sodium om adine (73

- 85% of the dose); the feces are only a minor route of excretion (5

- 12% of the dose). Sodium

omadine and its metabolites were not excreted in expired air. In the single oral low

- dose group

and the IV

- dose group, most of the administered radioactiv ity was excreted within the first 12 hours postdosing. In the repeated oral low

- dose group and in the single oral high

- dose group, the majority of the administered radioactivity was excreted within 24 and 48 hours postdosing, respectively. There was no evi dence of bioaccumulation of sodium omadine or its metabolites in

the tissues. The metabolic profiles in the urine were similar in all dose groups; 12 urinaryPage 10 of 18 metabolites (A

- L) were characterized. The major metabolite in the urine , which was 41.4%

- 67.2% of the recovered radioactivity, was 2

- pyridinethiol

- 1

- oxide

- S

- glucuronide (Metabolite K), while unchanged parent compound was not detected in the urine.

3.2h Neurotoxicity

Results of a 13 week oral subchronic toxicity/neurotoxicity study were previously de scribed

in section 3.2a. Although the neurotoxicity portion of this study was found to be supplemental due to reporting deficiencies, enough information was provided to derive a LOEL of 2.0 mg/kg/day based on evidence of neurotoxicity in male and female rats (neurogenic skeletal

muscle atrophy). The NOEL was found to be 0.5 mg/kg/day. In the subchronic dermal toxicity study, dose

- related clinical signs seen in high

- dose female rats included emaciation, hunched posture, stiff hindlimbs, incoordination, and tremors. Among the males, one high

- dose rat was emaciated; there were no neurologic signs. The LOEL was 50 mg/kg/day in males and 15 mg/kg/day in females, based on atrophy of the hindlimb muscles and subcutaneous panniculus

muscles. The NOEL was 15 mg/kg/ day in males, and 5 mg/kg/day in females.

3.3 T oxicology Endpoints

The following endpoints were used for assessing risks for the RED.

**•** Dermal Exposure, S hort

- term

- NOEL of 5 mg/kg/day based on the dermal developmental toxicity study in rabbits. The target Margin of Exposure (MOE) is 100.

**•** Dermal Exposure, I ntermediate term

- NOEL of 5 mg/kg/day based on the 90

- day dermal toxicity study in rats. The target MOE is 100.

**•** Inhalation Exposure, Intermediate term

- systemic NOEL of 0.0011 mg/l, based on th e 90

- day inhalation study in rats. The target MOE is 100.

**•** RfD

- 0.005 mg/kg/day based on a NOEL of 0.5 mg/kg/day from the chronic rat study and an uncertainty factor of 100. The rat reproduction study with a parental NOEL of 0.5 mg/kg/day supports the RfD as a co

- critical study.

No additional toxicology data were required in the RED and no additional data will be needed for registration review. Additional PBPK data are currently being reviewed for a related chemical, zinc omadine, and if appropriate, this data will be used for sodium omadine.

4

. 0 DIETARY ASSESSMENT

4.1 Dietary Exposure

M ost of the labels have the statement “Do not use for applications involving direct or indirect food/drinking water contact. ” Three labels (#1258

- 990, #1258

- 1205 a nd #39967

- 26) do not have this statement; however, and label #39967

- 26 is approved for uses such as paper, cleaningPage 11 of 18 solutions and detergents that might involve food contact. Sodium omadine is also approved by FDA as a preservative of adhesives in food con tact packaging (21 CFR 175.105). Given th ese approvals, it will be necessary to assess indirect food contact exposures from these uses and

residue data will be needed as listed in Table 5

.

4.2 Drinking Water Exposure

The registered uses of sodium oma dine might result in contamination of surface and ground water as a result of discharges of treated water from industries using this antimicrobial as a material preservative. Therefore, drinking water exposure might occur. However, the need for a drinking water exposure assessment will be determined upon review of the environmental fate data that the Agency anticipates requiring. These data will be used to determine if sodium omadine can pass through wastewater treatment plants into drinking water. There fore, the need for a drinking water assessment will be revisited upon submission and review of the

environmental fate data

5

. 0 OCCUPATIONAL AND RESIDENTIAL EXPOSURE S

5.1 Occupational Exposures

O ccupational handler exposures were assessed in the RED fo r the mixing and loading for the general preservation and metal working fluid uses

. The exposures were calculated based on the

combined dermal and inhalation unit exposures from the Chemical Manufacturer’s Association study along with a daily treatment vol ume of 10,000 gallons for both scenarios and application rates of 46 ppm for general preservation and 500 ppm for MWF

. The MOEs were calculated from these exposures using the dermal NOEL of 5 mg/kg/day. The MOEs of 4700 for general preservation and 450 f or MWFs were greater than t he target MOE of 100 and were not

considered to be of concern.

Occupational post application exposures that occur during the use of treated materials were

not assessed for the RED because it was believed at the time that thes e exposures would be minimal because of low application rates and because sodium omadine has low vapor pressure. Although it is true that vapor exposures to sodium omadine will be minimal as stated in the RED

, there is the potential for dermal and inhala tion exposures to aerosols during the use of materials such as paints, metal working fluids, surface cleaners and floor cleaners treated with sodium

omadine

. The exposures that will need to be assessed and the data that will be needed are listed

in Table 5

. In addition

, it will be necessary to reassess the general preservative uses because some materials have application rates of up to 5000 ppm which is much greater than the rate of 46 ppm that was assessed in the RED.

5.2 Residential Exposures

Sodiu m o madine residential exposure may occur during the use of treated products such as paints and coatings

, surface cleaners, floor cleaners, carpet cleaners, textiles and leather.Page 12 of 18 Residential exposures were not assessed in the RED because it was believed at the time that the exposures would be very low due to dilution

. While it is true that the use rates are fairly low, the toxicological endpoints are also fairly low and therefore it will be necessary to assess these exposures during registration review. Th e se exposures and the data that will be needed to assess

them are listed in Table 5

.

6

. 0 AGGREGATE AND CUMULATIVE EXPOSURE

In examining aggregate exposure, EPA takes into account the available and reliable information concerning exposures to pesticide residues in food and drinking water, a s well as

non

- occupational (i.e. residential) pesticide exposures

. In the case of sodium omadine

, an aggregate risk assessment will likely be needed because of the use pattern which is likely to result in dietary, dri nking water and residential exposures.

With respect to cumulative exposure, sodium omadine is toxicologically very similar to zinc omadine and it may be necessary to conduct a cumulative risk assessment based on these two

chemicals. This determination will be made during registration review.

7

. 0 INCIDENTS

There are no human incidents reported in the OPP incident database that are associated with

sodium omadine exposure

. However, there are literature reports of allergic contact dermatitis (Le Coz, 2001) and contact dermatitis (Totsi et al., 1990) associated with occupational exposure to sodium omadine in metal working fluids.

8

. 0 TOLERANCES

There are no tolerances or exemptions from tolerances established by the EPA for sodium

omadine

. Sodium om adine is approved by FDA as a preservative of adhesives in food contact packaging (21 CFR 175.105).

9

. 0 ENDOCRINE DISRUPTION EFFECTS

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determin e 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 endocrine 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 with 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 determine which, if any, of the Tier 2 tests are nece ssary 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.Page 13 of 18 Between October 2009 and Februa ry 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 potential for human exposure through pathways

such as food and water, residential activity, and certain post

- application agricultural scenarios. This list should not be construed as a list of known or likely endocrine disruptors. Sodium

omadine is not among th e group of 58 pesticide active ingredients on the initial list to be

screened under the EDSP

. Under FFDCA S e ction 408 (p), the Agency must screen all pesticidal chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call

- ins f or all pesticide active ingredients. F urther infor mation on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, is

available on the website: http://www.epa.gov/endo/.

10

. 0 ANTICIPATED DATA NEE DS

10.1 Toxicology Studies

No new toxicology studies are needed for the registration review of sodium omadine.

10.2 Exposure Studies

There are three exposures studies that are needed to assess dietary and occupational/residential exposure scenario s. These studies are listed in Ta ble 5 and de tailed justifications are provided in Appendix A.

Table 5

– Exposure Studies Needed for Sodium Omadine Registration Review Study Needed Guideline Applicable Exposure Scenarios Indoor Exposure , Dermal Indoor Exposure, Inhalation Data Reporting /Calculations 875.1100

875.1300

875.1600 O pen pour liquid s during material preservation Brush/roller application of preserved paints A,B

Airless sprayer application of preserved paints B

Use of treated m etal w orking f luids B

Trigger sprayer and mop applic ation of preserved cleaners B

B
Surface Residue Dissipation 875.2300 Dishes washed with preserved dish detergents. Floors and carpets cleaned with preserved household cleaners. Textiles and leather preserved with sodium omadine.

Product Use Information 87 5.1700 All above scenarios

A. If the labels are amended to require closed mixing / loading, then the exposure stud y for this scenario can be waived. B. It may be possible to use proprietary surrogate exposure data if data compensation issues can be addres sed.Page 14 of 18 1 1

. 0 REFERENCE S

Le Coz, C.J. 2001. Allergic Contact Dermatitis from Sodium Pyrithione in Metalworking Fluid.

Contact dermatitis. Volume 45 , pages 58

- 59.

Tosti, A.; Piraccini, B.; and Brasile, G.P. 1990. Occupational Contact D ermatitis d ue to Sodium Pyrithione. Contact Derma t itis. Volume 22

, pages 118

- 119

US EPA, 199 6

. Reregistration Eligibility Decision ( RED) for Sodium O madine

, J anuary 199 6

, http://www.epa.gov/pestici des/reregistration/status.htm

US EPA, 1999. Zinc 2

- pyridinethiol

- 1

- oxide (Zinc Omadine): Assessment of New Use. D249404, February 16, 1999.Page 15 of 18 

# Appendix A

– Justification for the
Studies Needed for the Human Health Registration Review of Sod ium OmadinePage 16 of 18 Study Title: Indoor Exposure Dermal , Indoor Exposure Inhalation, Data Reporting and Calculations
Guideline Numbers : 875.1 1 00

, 875.1 3 00, 875.1600 Rationale for Requiring the Data

Dermal and inhalation exposures to sodium omadine are expect ed during the open pour addition A of liquids during materials preservation

. Although dermal exposures were assessed in the RED, it will be necessary to reassess dermal exposures because some materials have application rates of up to 5000 ppm which is muc h greater than the rate of 46 ppm that was assessed in the RED. It will also be necessary to assess inhalation exposures because these exposures were not assessed in the RED.

Dermal and inhalation exposures are also expected during the use of preserved p roducts such as paints, metal working fluids and household surface cleaners. These exposures were not assessed in

the RED because it was believed at the time that the exposures would be very low due to dilution.

While it is true that the use rates are fa irly low, the toxicological endpoints are also fairly low and therefore it will be necessary to assess these exposures during registration review.

D ermal and inhalation exposures from these scenarios are evid ent in exposure studies in the Pesticide

Handl ers Exposure Database (PHED). The existing Chemical Manufacturer Association (CMA) data

base and PHED for these scenarios are limited in scope for QA/QC and the number of replicates (i.e., number of times a worker is monitored for a specific activity) . E PA 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.

Practical Utility of th e Data

1) How would the data be used? The data would be used to assess dermal and inhalation exposures that result from the open pour

addition A of liquids during materials preservation and during the use of treated materials including paints B

, metal work ing fluids and household surface cleaners B

.

2) How could the data impact the Agency’s future decision making?

T he exposure data would be used to assess the risks of exposure and to determine if mitigation

measures , such as closed system loading, decreased application rates or use of PPE are needed to

reduce these risks. If exposure data are not available, these assessment s will have to be made using models which might lead to the overestimation of risk and the requirement for excessive and onerous mitigat ion measures.

A. If the labels are amended to require closed mixing / loading, the stud y for the open pour scenario can be waived.

B. There are proprietary studies that can be used as surrogate data for th ese exposure scenario s if data compensation

issues are addressedPage 17 of 18 Study Title: Surface Residue Dissipation
Guideline Numbers: 875.2300 Rationale for Requiring the Data

Dermal and incidental oral exposures to sodium omadine are expected for toddlers who sit or play on

household floors and carpets afte r they are cleaned with floor or carpet cleaners that are preserved

with sodium omadine , during use of consumer goods such as clothing, towels and blankets made from textiles that are treated with spin finishes that are preserved with sodium omadine and du ring the use of consumer goods made from sodium omadine preserved leather. In addition, indirect dietary exposures to sodium omadine are expected during the use of dish detergents that are preserved with

sodium omadine. Surface residue dissipation data a re needed to accurately assess these exposures. These exposures were not assessed in the RED

.

Practical Utility of the Data

1) How would the data be used? The surface residue data would be used to assess sodium omadine exposures that result from th e use of floor and carpet cleaners preserved with sodium omadine

, the use of clothing, towels and blankets made from textiles that are treated with spin finishes that are preserved with sodium omadine , the use of consumer goods made from sodium omadine pre served leather and the use of dish detergents preserved with sodium omadine.

2) How could the data impact the Agency’s future decision making? The surface residue data will be used during registration review to decide if the exposures to sodium

omadine from it ’ s use in household cleaners, textiles, leathers and dish detergents generates a risk of concern that requires mitigation. This mitigation could include reduction of the application rate or

elimination of the use. If surface residue data are not available, then the standard assumption of 100 percent transferable surface residue will be used which might overestimate the risk and require excessive mitigation.Page 18 of 18 Study Title: Product Use Information
Guideline Numbers: 875.1700 Rationale for Requi ring the Data

Product use information serves as the basis for determining what exposure scenarios should be assessed and what assumptions and exposure data are needed to perform these assessments in a manner that does not over

- or underestimate the actua l risk.

Practical Utility of the Data

1 ) How would the data be used?

The product use information will be used to define and characterize the exposure scenarios that will be

assessed in the risk assessment

.

2 ) How could the data impact the Agency’s fut ure decision making ? A complete description of product use would ensure that the risk assessment is inclusive of the types of exposures occurring during and after use and that these exposures are accurately assessed

. Without product use information the Agency will have to use default assumptions that might over

estimate the actual risk.