UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

SUBJECT: 

### Copper Pyrithione : Hazard Assessment for Antifoulant Use

PC Code: 088001

DB Bar Code: D375749 and D 369393

FROM: Jonathan Chen, Ph.D.

Senior Toxicologist, Risk Assessment and Science Support Branch (RASSB) Antimicrobial Division (7510 P )

THROUGH: Tim Mcmahon, Ph.D. Senior Toxicologist, Antimicrobial Division (7510P)

And

Nader Elkassabany, Ph.D.

Chief

RASSB / AD

TO:

Attached is RASSB’s hazard a ssessment of c opper p yrithione

, proposed for use as a active ingredient in antifoulant paint use

.

### TABLE OF CONTENTS

0.0 BACKGROUND

................................ ................................ ................................ ... 1

1.0 HAZARD CHARACTERIZAT ION

................................ ................................ ....... 4

2.0 AVAILABLE DATABASE

................................ ................................ ..................... 4

3.0 HAZARD ASSESSMENT

................................ ................................ ..................... 5

3.1 Acute Toxicity

................................ ................................ ................................ ................................ ..................... 5

3.2 Short

- term Oral Toxicity

................................ ................................ ................................ ................................ ... 6

3.3 Subchronic Oral Toxicity Studies

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

3.4 Subchronic Inhalation Toxicity

................................ ................................ ................................ ........................ 9

3.5 Chronic Toxicity and Carcinogenicity Studies.

................................ ................................ ........................ 12

3.6 Developmental Toxicity

................................ ................................ ................................ ............................... 12

3.7 Reproductive toxicity

................................ ................................ ................................ ................................ ....... 13

3.8 Neurotoxicity Toxicity

................................ ................................ ................................ ................................ ..... 14

3.7 Mutagenicity and Carcinogenicity

................................ ................................ ................................ .................. 14

4.0 HAZARD ENDPOINT SELE CTION

................................ ................................ .. 15

4. 1 ACUTE DIETARY (Acute Reference Dose, aRfD)

................................ ................................ ....................... 15

4.2 CHRONIC DIETARY (Chronic Reference Dose, cRfD)

................................ ................................ .............. 15

4.3 OCCUPATIONAL / RESIDE NTIAL EXPOSURE

................................ ................................ ......................... 16

4.3.1 Dermal Absorption

................................ ................................ ................................ ................................ ... 16

4.3.2 Incidental Oral

- (Short

- and Intermediate

- term)

................................ ................................ ........................ 16

4.3.3 Incidental Dermal

- (Short

- and Intermediate

- term)

................................ ................................ .................... 17

4.3.4 Incidental Inhalation

- (Short

- and Intermediate

- term)

................................ ................................ ............... 18

5.0 RECOMMENDED MARGINS OF EXPOSURE

................................ .................. 20

6.0 AGGREGATE EXPOSURE R ISK ASSESSMENTS

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

7 .0 CARCINOGENIC/ MUTAGE NICITY POTENTIAL

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

8.0 FQPA CONSIDERATIONS

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

9.0 DATA GAPS

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

10.0 SUMMARY OF TOXICOLOG Y ENDPOINT SELECTION

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

11.0 REFERENCES

................................ ................................ ................................ ... 23.Page 1 of 24 0.0 BACKGROUND

The registrant, Arch Chemical's biocides (Arch) has submitted an application for registration of a manufacturing use product containing copper pyrithione (c oppe r omadine , CuPT), as the sole new active ingredient, for use only in formulating antifoulant paints. This application for registration was originally submitted in 2002. Arch requests that sodium pyrithione ( sodium omadine, NaPT) and zinc pyrithione ( zinc o madine, ZnPT) data be used as surrogate or bridging data for the copper pyrithione registration.

The chemical structures of these pyrithiones are listed below:

On the beginning , the information submitted including acute s tudies conducted by 3 relevant routes of exposure, s kin and eye irritation studies, a skin sensitization study, 28

- day repeated oral dosing studies conducted in the rat and monkey, in vitro bacterial gene mutation, and in vitro cytogenetic studies.

On Ma y 26, 2004, the submitted information was discussed in the Antimicrobials Division Toxicology Endpoint Selection Committee (ATDC). In comparison the available information, Agency noticed CuPT has low er water solubility compared with sodium pyrithione and z inc pyrithione

. The 2004 ADTC concluded that insufficient data are available for bridging between copper and zinc pyrithione . The primary reasons are:Page 2 of 24 Different physical chemical properties of copper, sodium, and zinc pyrithione will affect the absorptio n/bioavailability of the chemical;

1. A similar metabolic profile between pyrithione s does not necessarily relate to the mode of action for causing effects of concern;

2. Because emesis was observed in both sodium and zinc pyrithione in the subchronic monkey st udy, it is difficult to estimate the real exposed concentration; and

3. Signs of neurotoxic effects (skeletal muscle wasting, hind leg paralysis) were noticed in

the 90

- day rat oral studies for both sodium pyrithione and zinc pyrithione . There was no

90

- day copper pyrithione study can compare with.

To a ddress the Agency’s concern, Arch conducted a 90

- day repeated exposure oral neurotoxicity study (MRID 47023701) , and comparison metabolism studies between copper pyrithione and

zinc pyrithione (MRID 47844501) . After reviewing the inf ormation, RASSB concluded that

c ooper pyrithione and zinc pyrithione data cannot be bridged (Chen, 2008) . Reasons are listed

below:

1. Different physical chemical properties of copper, sodium, and zinc pyrithione will

affect the ab sorption/bioavailability of the chemical

In comparing the metabolism study results for copper pyrithione (MRID 4784451 ) and zinc pyrithione (MRID 47751201 ) , the tim e to maximum concentration for pyrithione (PT) derived from CuPT is approximately three tim es longer than when derived from Z n PT, and Cmax values from CuPT are

less than half those from Z n PT. The 0 −24 h Area under the plasma concentration time curve (AUC) for PT derived from CuPT is nearly twice that for PT derived from ZPT suggesting that absorption of PT derived from CuPT is much more prolonged than from Z n PT. This prolonged absorption likely pr oduces the longer apparent half

- life of PT derived from CuPT than from Z n PT as the half

- life of PT should be identical regardless of its source. Therefore, although CuPT and ZnPT may have similar biological metabolite in the body, the toxicological kineti cs in the system may be completely different.

2. Different mode of action may trigger copper pyrithione related toxicity through inhalation exposure route.

Copper pyrithione is much less water soluble when compared with both zinc pyrithione and/or

sodium pyrithione . At pH 7.0, at 20oC, zinc pyrithione solubility in water (6ppm) is 100 times more than copper pyrithione (0,06ppm). RASSB concluded similar kind of concern may occur at lower exposure concentration through inhalation route. The mode of action t rigger the toxic effects through inhalation route for CuPT maybe completely different from the mode of action causing systemic effects and/or ZnPT caused inhalation toxic effects

3. Sex differences in sensitivity to the toxic effects from copper pyrithione e xposure .

The female rats are more sensitive to the copper pyrithione exposure through oral route when compare male rats. Some of the toxic effects may not be able recover after stop the exposure. There is no developmental toxicity study associated with copper pyrithione exposure. Therefore, Agency cannot compare the potential developmental effects associated with copper pyrithionePage 3 of 24 exposure.

Therefore, RASSB decided that one 90

- day inhalation in rat and one p renatal developmental in

rat are need

. For d ermal exposure route, a conservative route to route exposure with conservative 100% dermal absorption will be used for dermal exposure risk assessment

.

In 2009, i nstead of conducting the data agency requested, Arch continues to pursue the possibility of b ridging the data between copper and zinc pyrithiones. Arch submitted one set of new acute studies ( acute studies through oral, dermal and inhalation routes and one dermal sensitization study), and five additional studies:

1. A 4

- Week CuPT inhalation toxicity MRID 48006403;

2. A 4

- Week Zn PT inhalation toxicity MRID 48006404;

3. An i nhalation of 14 C

- Copper Pyrithione metabolism study ( MRID 48006401 ) ;

4. An i nhalation of 14 C

- Zinc Pyrithione metabolism study ( MRID 48006402 ) ; and

5. One rat Copper Pyrithione developmenta l study.

Based on the available information, ADTC met on 11/04/2010 to discuss the significanc e of the new findings. The meeting made following conclusions:

(1) With the newly available 28

- day inhalation study conducted with CuPT and the inhalation

meta bolism study, the ADTC concluded that the available information was adequate to address the issues associated with inhalation hazard concern. Therefore, the 90

- day CuPT inhalation study requirement can be waived;

(2) Based on the newly submitted inhalati on metabolism studies, the ADTC agreed that the high death rate in the CuPT acute inhalation toxicity study may be caused by crystal (dust) formation due to its low water solubility as the registrant suggested;

(3) The mode of action for the hindlimb weak ness caused by pyrithiones (NaPT, ZnPT and CuPT) is still not clearly defined;

(4) The available study results between ZnPT and CuPT show similar hazard end

- points. The ADTC agreed that CuPT and ZnPT data can be bridged up to intermediate

- duration

exposu re scenarios (0

- 6 month exposure), including developmental effects.

(5) The different physical/chemical properties between CuPT and ZnPT result in varying absorption and bioavailability between the two chemicals. This is demonstrated by the

oral metabolis m study for CuPT, where a longer biological half life is observed with CuPT when compared with ZnPT. With long

- term exposure scenarios, the ADTC is concerned that the slower absorption and excretion may result in differences in body burden, especially in c hronic exposure conditions.Page 4 of 24 (6) There are no reproductive toxicity data or other long

- term studies (chronic and/or cancer studies) to compare CuPT and ZnPT. Therefore, the ADTC does not consider it appropriate to bridge the databases between CuPT and ZnPT for reproductive effects and

chronic use conditions.

(7) Since the antifoulant paint use is the only currently intended use for CuPT and no chronic exposure is expected, the databases for CuPT, ZnPT and NaPT can be bridged for this

risk assessment.

The hazard Assessment associated with C uPT for antifoulant u se is prepared based on the ADTC

conclusions.

1.0 HAZARD CHARACTERIZATION

In comparison the toxicology studies, metabolism/disposithion studies (both oral and inhalation routes), Agency agreed that copper pyrithione (copper omadine, CuPT) and zinc pyrithione (zinc omadine, ZnPT) data can be bridged up to intermediate

- duration exposure scenarios (0

- 6 month exposure), including developmental effects. There are no reproductive toxicity data or othe r long

term studies (chronic and/or cancer studies) to compare CuPT and ZnPT. Therefore, it appropriate to bridge the databases between CuPT and ZnPT for reproductive effects and chronic

use conditions.

CuPT is corrosive to eyes and mild or slight irrita ting to skin. Copper pyrithione is not a dermal

sensitizer. It is of moderate acute toxicity by oral, dermal, or inhalation routes of exposure. As indicated by the 9

- day rat toxicology study, 28

- day rat oral study, 90

- day rat oral neurotoxicological s tudy and rat developmental study

, hind limb weakness were consider as the primary effects of concern. It appears female is sensitive the effect.

In the inhalation study, t est substance

- related mortality was observed in the 0.005 mg/L group

females. At 0.0015 mg/L group d ecreased food consumption in the females, effects on BALF parameters (increased LDH, total protein, total cell counts, lymphocytes, alveolar macrophages, and neutrophils) and histopathology in the lungs (subacute inflammation and alve ola r macrophages) in both sexes were noticed.

There is one developmental study associated with oral exposure to CuPT. At high dosed group(10 mg/kg/day) , decreased body weight, body weight gain, and food consumption in both sexes and on mortality, clinica l signs of toxicity, and muscle fiber atrophy in the females. No developmental effects were noticed in any dose tested.

There is no reproductive study to study the reproductive effects associated with CuPT exposure. No chronic toxicity or carcinogenici ty studies are available to assess the chronic toxicity or carcinogenicity of CuPT. There is a battery of negative mutagenicity studies.

2.0 AVAILABLE DATABASEPage 5 of 24 The toxicology studies that have been submitted for copper pyrithione are shown in Table 1

.

Table 1. Toxicology Database for Copper Pyrithione

Guideline

Number Test Technical

Required Satisfied MRID

Number

OPPTS

870.3050 28

- day Oral Study

- Rat N Y 45774311

OPPTS

870.3050 28

- day Oral Study

- Monkey N Y 45774312

OPPTS

870.3465 28

- day

– inhalation Study Y Y 48006403

OPPTS

870.3700 Developmental Toxicity

- Rat Y Y 48158006

OPPTS

870.5375 A Chromosomal Aberration

- in

Cultured Chinese Hamster Cells Y Y 45774313

OPPTS

870.6200 90

- day Oral Neurotoxicity Study

- Rat Y Y 47023701

OPPTS

870.7485 Oral metabolism

- Rat N N 45774326

OPPTS

870.7485 Oral Metabolism

– Rat Y Y 47844501

OPPTS

870.7485 Inhalation metabolism N Y 48006401

Non

- Guideline 9

- Day Toxicity and Metabolism Study in Rats N Y 45774326

Y

- Yes; N

- no

In this toxi cology assessment chapter, the toxicology database of copper pyrithione is evaluated, and the toxicological endpoints used for risk assessment are selected. In addition, the data gaps in the

database are also identified.

3.0 HAZARD ASSESSMENT

3.1 Acute T oxicity

The acute toxicity data on CuPT is summarized below in Table 2. CuPT is corrosive to ey e s and mild or slight irritating to skin. CuPT is not a dermal sensitizer. CuPT is of moderate acute toxicity by oral, dermal, or inhalation routes of exp osure.Page 6 of 24 Table 2. Acute toxicity decisions for Copper Pyrithione

Guideline

No. Study Type MRID number (s) Results Toxicity Category

OPPTS

870.1100 [§ 81

- 1] Acute Oral 45774305

and 4815002 LD50 = 1075 mg/kg (M);

500

- 1000 mg/kg (F)

LD50 > 200 mg/k g II

OPPTS

870.1200 [§81

- 2] Acute Dermal 48158003 LD50 > 400 mg/kg 2 rats dead at 2000 mg/kg II

OPPTS

870.1300 [§ 81

- 3] Acute Inhalation 48158004 LC 50 (M) 0.14 (0.11

- 0.18) mg/L (F) 0.17 (0.13

- 0.23) mg/L (C) 0.15 (0.13

- 0.18) mg/L II

81

- 4 Primary Ey e Irritation 45774307 Corrosive

81

- 5 Primary Skin

Irritation 45774308 Mild or slight

OPPTS

870.2600 [§ 81

- 6] Dermal

Sensitization 4158001 1 Non

- sensitizer

3.2 Short

- term Oral Toxicity

There is one short

- term ( 9

- Day ) toxicity and m et abolism study in r ats ( MRID 45774326 ). In the study, female Sprague

- Dawley rats were treated with copper in aqueous 0.5% Darvan (sodium polynaphthalenesulfonate) by daily oral gavage in a dose volume of 5 mL/kg. An initial range

finding study was performed to investigat e the toxicity. In this study, animals (3/dose group) were dosed for 9 consecutive days with vehicle or 4, 6, 9, or 12 mg/kg/day CuPT. Mortality, clinical signs, body weight, muscle mass, and muscle tone were reported. The results from this study

were u sed to select the doses for a metabolism study; the doses selected represented toxicologically equivalent doses. In the metabolism study, animals (5/dose group) were treated with 4 mg/kg/day CuPT; radiolabeled test compounds were administered on Days 7 an d 8. Mortality, clinical signs, body weight, food consumption, excretion profile, blood partitioning, muscle mass, muscle tone, and metabolite characterization were reported.

In the range

- finding study, CuPT treatment of rats resulted in neurological s igns such as irregular gait, lethargy, and paralysis. CuPT treatment resulted in a dose

- dependent decrease in body weight. In the CuPT

- treated animals, muscle mass and tone were greatly reduced.

Dose of 4 mg/kg/day CuPT was chosen for the metabolism s tudy, as these doses provided the most similar toxicological effects, based on clinical signs. All animals were slightly lethargic on Day 5 at 4 hours post

- dosing. At 0.5 hours post

- dosing, the following findings were observed:Page 7 of 24 slightly lethargic

, non

- r esponsive

, prostrate

, saliva ting and lachrymating . These signs were first observed at Days 5 or 6

. The animals maintained their initial body weight through Day 6. After administration of the radiolabeled compound (Days 7 and 8), losses of 31 g the CuPT treated groups, respectively. In the CuPT

- treated animals, muscle mass was slightly reduced in 1 animal and greatly reduced in 3 animals; likewise, no muscle tone was noted in 3 rats and 1 rat only had

moderate tone

.

This study is classified as accepta ble/non

- guid eline.

3. 3 Subchronic Oral Toxicity Studies

There are three subchronic oral studies (one 28

- day Cynomolgus monkey oral study, one 28

- day

rat feeding study , and one 90

- day rat feeding study ) available in the toxicology database

.

Rat 28

- day oral Study ( In a repeat dose toxicity study (MRID 45774311), copper pyrithione (100 % purity) by gavage at doses of 0, 0.6, 2.5 or 10 mg/kg/day to 5 or 10 male and femal e s Crj:CD (SD) rats/group for 28 days. Further groups of control and hig h dose animals (5/sex) were retained for an additional 14 days to assess recovery from any adverse effects. Due to the deaths occurring in high dose females, this recovery group consisted of only 2 animals. The vehicle employed was 0.5 % carboxymethylcellu lose (sodium salt). MRID 45774311)

At 10 mg/kg/day, two females were sacrificed in extremis on Day 17 of the dosing period. Additionally, one 10 mg/kg/day female was found dead on Day 2 of the recovery period. These three animals exhibited the following clinical sign s prior to death or euthanasia: emaciation; decreased spontaneous activity, piloerection, ataxic gait, paralysis of the hind leg, urine

- stained abdomen, reddish eye gum; prone position; and lateral position. Additionally , hypothermia and bradypnea were n oted in the females sacrificed in moribund condition, and a trace of red dish rhinorrhea was observed in the animal found dead. Among the surviving 10 mg/kg/day females, similar clinical signs of emaciation, piloerection

, decreased spontaneous activity, at axic gait and/or paralysis of the hind leg; reddish eye gum; urine

- stained abdomen; and prone position w ere found . However, almost all of these findings decreased in severity or occurrence during the final week of dosing . During the initial recovery peri od, decrease d spontaneous activity , ataxic gait, and piloerection were still observed in 1 or 2 females , but th ese abnormalities disappeared by Day 5 of the recovery period. Emaciation was also observed in 2 females during the recovery period,

but these a nimals appeared to be recovering.

N o treatment

- related clinical signs were noted in the 10 mg/kg/day males , o ther than slight emaciation in three males on Days 21 to 28 or on Days 0

- 2 of the recovery period,

B ody weights were decreased ( p<0.05 ) by 10

- 13 % in the 10 mg/kg/day males during Weeks 3 and 4 and by 19

- 36 % in the females during Weeks 2

- 4

. During the recovery period, body weights remained decreased by 13% in these males during Week 1 and by 25

- 33% in the females during

Weeks 1 and 2. Body weight gains were decreased (p<0.05) by 18

- 39% in the males duringPage 8 of 24 Weeks 2

- 4. The females at this dose actually lost significant (p<0.01) weight during Week 2 (

- 0.6 g) and Week 3 (

- 18.8 g) compared to gains of 24.6 and 28.6 g, respectively, in the controls.

Ov erall (Weeks 0

- 4) body weight gain was decreased by 22% in the males and 76% in the females. During the recovery period, body weight gains were increased compared to controls by 28% in the males during Week 2 and by 82

- 123% in females during Weeks 1 and 2 . F ood consumption was decreased (p<0.01) by 11

- 12% in the males during Weeks 3 and 4 and by 34

- 37% in the females during Weeks 2 and 3. Food consumption was similar to controls in both sexes during the recovery period.

At the high

- dose, treatment

- relat ed g ross lesions were limited to slight to moderate atrophy of the biceps femoris in 2/5 females and slight to marked emaciation in all females at the end of the dosing period. Microscopic observations of muscle fiber atrophy were observed in the
gastrocn emius, soleus, flexor digitorum longus, and anterior tibial muscles in all (5/5) females at this dose compared to 0/5 controls. Additionally, muscle fiber atrophy of the biceps femoris was found in 2/5 females at 10 mg/kg/day compared to 0/5 controls. In the high

- dose males, muscle fiber atrophy in the anterior tibial muscle was observed in 2/5 rats compared to 0/5 controls. The severity of the muscle fiber atrophy was generally very slight to slight.

No treatment

- related effects were observed at 0.6 or 2.5 mg/kg/day in either sex.

T he LOAEL was 10 mg/kg/ day based on decreased body weight, body weight gain, and food consumption in both sexes and on mortality, clinical signs of toxicity, and muscle fiber atrophy in the females. The NOAEL is 2.5 mg/kg/da y.

In a repeat dose toxicity study

, groups of cynomolgus monkeys (MRID 45774312), copper pyrithione (100 % purity) were administered to groups of Cynomolgus monkey (6/sex) via gelatine capsules at doses of 0, 21 11, 22 or 44 mg/kg/day , for 28 days. Two animals from the control and high dose groups were retained for an additional 14 days to assess recovery from any

adverse effect. The following examinations were conducted at the end of the recovery and treatment phases; ophthalmoscopy, urinalysis, haematology, and gross necropsy and histopathology, including of the sciatic nerve and quadriceps muscle. No deaths occurred. Clinical signs of toxicity were confined to diarrhoea and green stools at the high dose and sporadic instances of loss of appetite at 11 mg/kg/day

, becoming widespread at 22 mg/kg/day . No body weight, ophthalmoscopy, or urinalysis changes were observed. Haematological changes were confined to high dose males at the end of the test phase only: statistica lly significant decreases in erythrocyte numbers (by 22 %), haematocrit (by 18 %) and haemoglobin concentration (by 19 %)

and increased platelets (by 45 %) were observed. All these changes were comparable to the controls at the end of the recovery period. Following clinical chemistry analysis, a statically significant increase (330 and 400 % in males and females, respectively) in serum triglycerides was

observed at 44 mg/kg/day . These increases were apparent from week 1 of the study, but were comparable to controls at the end of the recovery period. The only treatment

- related changes observed at necropsy were statistically significant increases (by approximately 40 and 50 % in both sexes) in absolute and relative liver weight respectively at 44 mg/kg/day , at the end of the Cynomolgus Monkey 28

- day oral StudyPage 9 of 24 test period. However, no treatment

- related changes were observed at the end of the recovery period. No histopathological abnormalities were observed in either period. Overall, a NOAEL was not identified; as loss of appetite was observed at all dose levels. A LOAEL can be identified of 11 mg/kg/day, on the basis of findings from this study.

In a subchronic neurotoxicity study (MRID 47023701 ), copper pyrithione ( 96.8% a.i., Lot No.

0103239911 ) in aqueous 0. 5% carboxymethylcellulose was administered orally via gavage (10 mL/kg) once daily to 16 Sprague

- Dawley rats/sex/dose at doses of 0 and 2.25 mg/kg/day and to 10 rats/sex/dose at 0.5 and 1.25 mg/kg/day for 91 consecutive days . At the end of the dosing peri od, a subset of 10 rats/sex/dose from the control and 2.25 mg/kg/day groups were allowed to recover for an additional 6 weeks. Neurobehavioral assessment (functional observational battery [FOB] and motor activity testing) was performed on all animals at p re

- dosing and Weeks 2, 4, 8, and 13. At study termination, 5 rats /sex/group were anesthetized and perfused in situ for neuropathological examination. 90

- Day Rat Oral Neurotoxicity Study

The tissues from the perfused animals in the control and 2.25 mg/kg/day groups were subjected to

histo pathological evaluation of brain and peripheral nervous system tissues. Acceptable positive control data were provided. No compound

- related effects were observed in clinical signs of toxicity, body weight, body weight gain, food consumption, ophthalmoscop ic effects, FOB, motor activity, brain weights, or gross pathology.

At 2.25 mg/kg/day, the incidence of excessive salivation was increased during the dosage period

in both sexes. O ne female (#16197) was sacrificed in extremis on Day 89, and prior to sacr ifice, this animal displayed adverse clinical signs that correlated with those previously observed with

this test material in the ran ge finding study. An increased (p ≤0.01) incidence of slightly reduced hindlimb muscle mass was noted at Weeks 6 through 13 in the males and during Weeks 4 through 13 in the females. During the recovery period, males showed signs of recovery; however, the majority of the females still displayed decreased (p ≤0.01) muscle mass up to Week 19. The females also had a corresponding decrease (p ≤0.01) in the average maximum amplitude in the electrophysiological measurements of Compound Motor Action Potential (CMA P) (decr 28%) that remained reduced, but to a lesser extent (decr 13%), following the 6

- week recovery period.

Treatment

- related neuropathological were limited to the skeletal muscle sections in the 2.25 mg/kg/day animals, with definitive muscle fiber atro phy in 1/5 (minimal) males and 3/4 (mild to moderate) females. Additional findings in the muscle of these animals included minimal to mild myositis, mild muscle fiber degeneration, and minimal muscle fiber necrosis. At 1.25 mg/kg/day, treatment

- related e ffects were limited to an increased incidence of excessive salivation during the dosage period in 4/10 males and 3/10 females.

The LOAEL is 2.25 mg/kg/day based on mortality, reduced hindlimb muscle mass, decreased electrophysiological measurements (fem ales), and microscopic lesions in the

skeletal muscle. The NOAEL is 1.25 mg/kg/day.

3.4 Subchronic Inhalation ToxicityPage 10 of 24 There is one 28

- day inhalation study associated with copper omadine exposure (MRID 48006403). In the study Copper Omadine ® (97% a.i ., Lot no. 0103239911) was administered as a dust aerosol to 15 Crl:CD(SD) rats/sex/concentration by nose

- only exposure at concentrations of 0 (air), 0.5, 1.5, or 5.0 mg/m 3 (equivalent to analytical concentrations of 0, 0.0005, 0.0015, and 0.0049 mg/L) for 6 hours per day, 5 days/week for up to 4 weeks (up to 20 exposure days). Five rats/sex/concentration were euthanized following 1, 2, and 4 weeks of exposure and subjected to a gross necropsy. Selected organs were weighed and examined microscopically. A special emphasis was placed on the evaluation of pulmonary effects, including assessment of bronchoalveolar lavage fluid (BALF) parameters and microscopic examination of the lungs.

Test substance

- related mortality was observed in the 0.005 mg/L group fem ales. Two females (nos. 6047 and 6062) were found dead on Day 12, and one female (no. 6029) was found dead on Day 19. Test substance

- related clinical observations noted for the animals found dead included hypoactivity, thin body condition, and body cool to touch. Additionally, female no. 6029 was noted with decreased defecation on Day 17, as well as dermal atonia and impaired muscle coordination on Day 18. The majority of these clinical observations were noted within 24 hours of death. However, the cau se of death for these three females was undetermined. Microscopic findings in the lungs (broncho

- interstitial pneumonitis characterized by subacute inflammation and an increase in alveolar macrophages) and skeletal muscle (atrophy and degeneration) were

s imilar in nature and severity to that which occurred in females at the scheduled necropsy on Day 26. The three surviving females in this group were held without further exposures between Day 19 and the scheduled necropsy on Day 26. Test substance

- related clinical observations were noted

for the 0.005 mg/L group females surviving to scheduled termination. These findings included the following: thin body condition noted by D ay 11 and continuing throughout the duration of the study , dermal atonia noted from D ays 12 to 19, and pale extremities noted in a single animal on

D ay 20. Impaired use of right and left hindlimbs was noted for two animals ranging from D ay 20

to 24. Other treatment

- related clinical findings in this group were limited to yellow and/or re d material on various parts of the body (including ocular, nasal, urogenital, and anal).

Treatment

- related effects on body weights were observed in both sexes at 0.005 mg/L. In the 0.005 mg/L males, b ody weights were significantly (p ≤0.01) decreased on Day 4 and continued to be decreased (not significant) throughout the remainder of the study. A significant (p ≤0.01) body weight loss was noted for Days 0

- 4 in the 0.005 mg/L males (

- 10 g) compared to a gain of 11 g in the controls, and cumulative body weight gains were 42

- 56% lower than controls for all other intervals throughout the study; these decreases were statistically significant for all intervals, except for Days 0

- 25. In the 0.005 mg/L females, b ody weights were significantly (p ≤0.01) decreased throughout the study. Cumulative body weight gains in the 0.005 mg/L females were 90% lower (p ≤0.01) than controls for Days 0

- 4, and cumulative body weight losses of 22

- 48 g

were noted for each of the rema ining intervals throughout the study in this group compared to body weight gains of 23

- 48 g in the control group. Food consumption was decreased (p ≤0.05) in the 0.0015 mg/L females for Days 0

- 4. Additionally at 0.005 mg/L, food consumption was decreased (p ≤0.01) for Days 0

- 4 in the males and for Days 0

- 4, 4

- 11, and 11

- 18 in the females

.Page 11 of 24 Treatment

- related effects on BALF samples were found at 0.0015 and 0.005 mg/L in both sexes. Lactate dehydrogenase was increased over controls at 0.0015 mg/L in the males on Days 12 and 26 and in the females on Day 5 and at 0.005 mg/L in the males throughout the study and in the females on Days 5 and 12. Total protein levels were increased at 0.0015 and 0.005 mg/L in the males throughout the study and in the females on Da ys 5 and 12. Total cell counts and the number of lymphocytes were increased at 0.0015 and 0.005 mg/L in the males throughout the study and in the females on Day 5. Alveolar macrophages were increased in the 0.0015 and 0.005 mg/L males throughout the stud y and in the 0.005 mg/L females on Day 5. With the exception of the 0.005 mg/L females on Day 26, the number of neutrophils was increased throughout the study in the 0.0015 and 0.005 mg/L males and females.

Examination of the BALF leukocyte differential data showed that the proportion of neutrophils increased with concentration and time in both sexes at 0.0015 and 0.005 mg/L, with the exception of the 0.005 mg/L females on Day 26. The remaining three females exposed to 0.005 mg/L had apparently recovered (following the final exposure on Day 18), and neutrophils were not present in the BALF on Day 26. The proportion of lymphocytes was higher than controls in the 0.005 mg/L males and females on Days 5 and 12. Due to these increases in neutrophils and lymp hocytes, the proportion of alveolar macrophages was lower in the 0.005 mg/L males on Days 5, 12, and 26 and females on Days 5 and 12. The proportion of alveolar macrophages was slightly lower than controls at 0.0015 mg/L in both sexes at all three interva ls. At 0.0015 mg/L, relative (to body weight) lung weights were increased (p ≤0.01) over controls in the males on Day 12. The following increases (p ≤0.05) in lung weights were observed in the 0.005 mg/L animals: (i) relative to body weight and relative to brain weight in the males and females at Day 5; (ii) absolute and relative to body weight in the males at Days 12 and 26; and (iii) relative to body weight in the females at Days 12 and 26. Terminal body weights were decreased (p ≤0.05) at this concentrat ion in the males on Day 5 and in the females on Days 12 and

26. Subacute inflammation was observed in the lungs in males at 0.0015 mg/L (4/15) and 0.005 mg/L (13/15) compared to controls (0/15) and in the females at 0.005 mg/L (9/12) compared to

controls (1/15). The severity of subacute inflammation of the lungs ranged from minimal to moderate in the males and from minimal to mild in the females. Minimal alveolar macrophages were observed in the 0.0015 mg/L males (5/15) and females (3/15), and mild alveo lar macrophages were found at 0.005 mg/L in the males (12/15) and females (9/12) compared to controls (0/15 males; 1/15 females). Perivasculitis was found in the 0.005 mg/L males (1/15) and females (2/12) compared to controls (0/15 males; 1/15 females). These findings were considered to be due to direct effects of the test material on the respiratory tract. With the exception of the perivasculitis in the females, the findings increased in severity with increasing concentration.

Enlarged bronchial lymph nodes were noted in one 0.005 mg/L female on Day 5, one 0.0015 mg/L male on Day 12, two 0.005 mg/L males on Day 12, one 0.005 mg/L female on Day 12, and one 0.005 mg/L male on Day 26. Enlarged mediastinal lymph nodes were noted in one 0.0015 mg/L male on Day 12, one 0.005 mg/L male on Day 12, two 0.005 mg/L females on Day 12, and one 0.005 mg/L male on Day 26. These findings, noted at gross necropsy, corresponded to lymphoid hyperplasia confirmed upon microscopic examination.Page 12 of 24 Examination of the skeletal muscle in the 0.005 mg/L females revealed minimal to moderate degeneration (4/15 treated vs 0/15 controls) and mild to moderate atrophy (5/15 treated vs 0/15 controls).

The LOAEL is 0.0015 mg/L based on decreased food consumption in the females, effects on BALF parameters (increased LDH, total protein, total cell counts, lymphocytes, alveolar macrophages, and neutrophils) and histopathology in the lungs (subacute inflammation and alveolar macrophages) in both sexes . The NOAEL is 0.0005 mg/L.

This 28

- da y study is classified as acceptable/non

- guideline.

3.5 Chronic Toxicity and Carcinogenicity Studies.

No chronic toxicity or carcinogenicity studies are available to assess the chronic toxicity or carcinogenicity of CuPT.

3.6 Developmental Toxicity

Through Oral Route

There is one rat developmental toxicity study. In the rat developmental toxicity study (MRID 48158006), copper pyrithione (99.6%; batch/lot #990128) in 1% carboxymethyl cellulose was administered via daily oral gavage in a dose volume of 10 mL/kg to 25 time

- mated Sprague

Dawley rats/dose group at doses of 0, 0.5, 1.5, or 3 mg/kg/day from gestation days (GD) 6

- 15. On GD 20, all dams were euthanized; each dam’s uterus was removed via cesarean section and its

contents examined. Fetuses were examined for external, visceral, and skeletal malformations and

variations.

In the 3 mg/kg/day group, body weight gains (relative to GD 6, start of dosing) were decreased by

6

- 31% throughout the dosing period and food consumption was decreased (p<0.0 1) by 10% during GD 6

- 9. The maternal LOAEL is 3 mg/kg/day, based on decreases in body weight gain and food consumption during the dosing period. The maternal NOAEL is 1.5 mg/kg/day.

There were no abortions, premature deliveries, complete litter resorpti ons, or dead fetuses and no effects of treatment on the numbers of litters, live fetuses, or total resorptions. Similarly, fetal weights, sex ratio, and pre

- and post

- implantation losses were unaffected by treatment. There were

no treatment

- related extern al, visceral, or skeletal variations or malformations. The developmental LOAEL was not observed. The developmental NOAEL is 3 mg/kg/day.

Through Dermal Route:Page 13 of 24 Based one available study results between ZnPT and CuPT show similar hazard end

- points. The ADTC agreed that CuPT and ZnPT data can be bridged up to intermediate

- duration exposure scenarios (0

- 6 month exposure), including developmental effects. Therefore one ZnPT dermal

d evelopmental toxicity stud y (MRID 46534001) was also considered. In the s tudy, zinc pyri thione (98.3% a.i., batch/lot # 0108244691) was dermally administered to 23

- 25 Crl:CD ®
(SD)IGS BR VAF/Plus ® rats/dose at dose levels of 0, 10, 15, 30, or 60 mg/kg bw/day from day 0 through 20 of gestation.

Dermal administration of zinc pyr ithione resulted in maternal toxicity at 30 and 60 mg/kg/day.

Treatment

- related effects at 60 mg/kg/day included clinical signs of toxicity (grade 1 erythema; grade 1 flaking; limited or no use of hindlimb s; shuffling gait; dehydration; low carriage;

chro modacyorrhea; emaciation; chromorhinorrhea; hunched posture; d ecreased body weight and body weight gain, decreased uterine weight, decreased corrected body weight and corrected body weight gain, decreased absolute and relative feed consumption, and decreas ed muscle tone and

mass.

At 30 mg/kg/day, there was an increase in the number of dams with limited use of hindlimb s, shuffling gait, decreased body weight and body weight gain, decreased corrected body weight and corrected body weight gain, and decrease d absolute feed consumption. There were no treatment

related maternal effects at 10 or 15 mg/kg/day. The maternal LOAEL is 30 mg/kg bw/day,

based on an increase in the number of dams with limited use of hindlimb s, shuffling gait, decreased body weight a nd body weight gain, decreased corrected body weight and corrected body weight gain, and decreased absolute feed consumption. The maternal NOAEL is 15 mg/kg bw/da y.

Developmental toxicity occurred at 60 mg/kg/day. Treatment

- related findings at 60 mg/kg /day included decreased fetal weight (total, male, and female), an increase in the percentage of litters and fetuses with incomplete ossification of the sternal centra, an increase in the percentage of fetuses with wavy ribs, and a decrease in the ossifica tion site averages for the caudal vertebrae, forelimb phalanges and metacarpals, and hindlimb phalanges and metatarsals per fetus per litter.

There were no treatment

- related developmental effects at 10, 15, or 30 mg/kg/day.

The developmental LOAEL is 60 mg/kg bw/day, based on decreased fetal weight (total, male, and female), an increase in the percentage of litters and fetuses with incomplete ossification of the sternal centra, an increase in the percentage of fetuses with wavy ribs, and

a decrease in th e ossification site averages for the caudal vertebrae, forelimb phalanges and metacarpals, and hindlimb phalanges and metatarsals per fetus per litter. The developmental NOAEL is 30 mg/kg bw/day.

3.7 Reproductive toxicity

No reproductive studies are av ailable to assess the reproductive concern of CuPT.Page 14 of 24 3.8 Neurotoxicity Toxicity

It is understood through the available rat studies, hind limb weakness were consider as the primary effects of concern for all the pyrithione studies. It appears there is sex in sensitivity to the toxic effects from copper omadine exposure (female is more sensitive to the effects). In the 90

- day neurotoxicity study (MRID 47023701), neuropathological were conducted and the findings

were limited to the skeletal muscle sect ions, with definitive muscle fiber atrophy in 1/5 (minimal) males and 3/4 (mild to moderate) females. Additional findings in the muscle of these animals included minimal to mild myositis, mild muscle fiber degeneration, and minimal muscle fiber

necrosis. Similar findings are noticed in the 9

- day toxicity study MRID 45774326), 28

- day rat oral study ( MRID 45774311) , rat developmental study (MRID 48158006), and other pyrithiones (CuPT and ZnPT) studies.

3.7 Mutagenicity and Carcinogenicity

There is a battery of negative mutagenicity studies

.

Salmonella typhimurium Assay/ CHO

- HGPRT Assay

Mutagenicity studies (MRID # 45785505 and 45804101 ) were submitted for CuPT but have not been currently reviewed. Summaries below are taken from the study reports.

In MRID 45785505, copper pyrithione was examined for mutagenicity in Salmonella strains TA98, TA100, TA1535, and TA1537 and in one strain of E. coli (WP2uvr A) in the presence and

absence of metabolic activation. No increase in the number of revertant c olonies was observed in this study for any of the strains tested.

In MRID 45804101, copper pyrithione was tested using the CHO/HGPRT assay in the presence and absence of metabolic activation. In the assay, no cultures with mutant frequencies were

observe d over solvent

- treated controls.

The results of these studies appear to show that, similar to ZnPT and NaPT , there is no evidence of a mutagenic effect associated with CuPT in either the absence or presence of metabolic

activation.

Chromosome Aberra tion Test in Monkey Lymphocytes

This study (MRID 45774314) was an in vitro chromosomal aberration test using peripheral lymphocytes obtained from cynomolgus monkeys. This test used both the direct method test and

the metabolic activation test. As noted in the report, “In the direct method test, no significant difference was noted in the average frequencies of structural aberrations or polyploidy between the test article treated groups and the control group.Page 15 of 24 In the metabolic activation method test, no sig nificant difference was noted in the average frequencies of structural aberrations or polyploidy between the results of the metaboli c activation

method test with S 9 Mix and the results of the metabolic a ctivation method test without S 9 Mix. Further, in the metabolic activation method test, no significant difference was noted in the avenge frequencies of structural aberrations or polyploidy between the test article treated groups and the control group.

Therefore, under these two test conditions, the test r esults indicate that CuPT did not induce clastogenicity in the cynomolgus monkey peripheral lymphocyte. “

Chromosomal Aberration Test in Chinese Hamster Ovary Cells

In this study, clastogenic potential of CuPT was evaluated in Chinese Hamster Ovary cells (CHL/IU cell line). As noted in the report,” In the direct method test, no significant difference

was noted in the average frequencies of structural aberrations or polyploidy between the test

article treated groups and the control group.

In the metabol ic activation method test, no significant difference was noted in the ave ra ge frequencies of structural aberrations or polyploidy between the results of the metabolic activation

method test with S 9 Mix and the results of the metabolic activation method tes t without S 9 Mix. Further, in the metabolic activation method test, no significant difference was noted in the average frequencies of structural aberrations or polyploidy between the test article treated groups and the

control group .”

4.0 HAZARD ENDPOINT SELECTION

The doses and endpoints for short

- term and intermediate

- term occupational or residential exposure

have been selected for CuPT for antifoulant paint use. Table 3 summarizes the toxicological dose and endpoints for CuPT for use in human risk as sessments.

4.1 ACUTE DIETARY (Acute Reference Dose, aRfD )

An acute dietary endpoint (acute Reference Dose) was not selected for CuPT because the chemical has no food uses and dietary exposure is not expected.

4.2 CHRONIC DIETARY (Chronic Reference Dose , cRfD )

A chronic dietary endpoint (chronic Reference Dose) was not selected for CuPT because the chemical has no food uses and dietary exposure is not expected.Page 16 of 24 4.3 OCCUPATIONAL / RESIDENTIAL EXPOSURE

4.3.1 Dermal Absorption

A dermal absorption f actor for CuPT is not required since a dermal NOAEL is available from a study

conducted with ZnPT.

4.3.2 Incidental Oral

- (Short

- and Intermediate

- term)

Study Selected: 90 Day Oral Neurotoxicity Study Rat

MRID No.: 47023701

Execu tive Summary: In a subchronic neurotoxicity study (MRID 47023701), copper omadine (96.8% a.i., Lot No. 0103239911) in aqueous 0.5% carboxymethylcellulose was administered orally via gavage (10 mL/kg) once daily to 16 Sprague

- Dawley rats/sex/dose at doses of 0 and 2.25 mg/kg/day and to 10 rats/sex/dose at 0.5 and 1.25 mg/kg/day for 91 consecutive days. At the end of the dosing period, a subset of 10 rats/sex/dose from the control and 2.25 mg/kg/day groups were

allowed to recover for an additional 6 weeks. Neurobehavioral assessment (functional observational battery [FOB] and motor activity testing) was performed on all animals at pre

- dosing and Weeks 2, 4, 8, and 13. At study termination, 5 rats/sex/group were anesthetized and perfused in situ for

neuropa thological examination. The tissues from the perfused animals in the control and 2.25 mg/kg/day groups were subjected to histopathological evaluation of brain and peripheral nervous system tissues. Acceptable positive control data were provided.

No comp ound

- related effects were observed in clinical signs of toxicity, body weight, body weight gain, food consumption, ophthalmoscopic effects, FOB, motor activity, brain weights, or gross pathology.

At 2.25 mg/kg/day, the incidence of excessive salivation wa s increased during the dosage period in both sexes. One female (#16197) was sacrificed in extremis on Day 89, and prior to sacrifice, this animal displayed adverse clinical signs that correlated with those previously observed with this test

material in th e range finding study. An i ncreased (p ≤0.01) incidence of slightly reduced hindlimb muscle mass was noted at Weeks 6 through 13 in the males and during Weeks 4 through 13 in the females. During the recovery period, males showed signs of recovery; however, the majority of the

female s still displayed decreased (p ≤0.01) muscle mass up to Week 19. The females also had a corresponding decrease (p ≤0.01) in the average maximum amplitude in the electrophysiological measurements of Compound Motor Action Potential (CMAP) (decreased 28%) that remained reduced, but to a lesser extent (decreased 13%), following the 6

- week recovery period. Treatment

related neuropathological effects were limited to the skeletal muscle sections in the 2.25 mg/kg/day animals, with definitive muscle fiber atrophy i n 1/5 (minimal) males and 3/4 (mild to moderate)Page 17 of 24 females. Additional findings in the muscle of these animals included minimal to mild myositis, mild muscle fiber degeneration, and minimal muscle fiber necrosis.

At 1.25 mg/kg/day, treatment

- related effec ts were limited to an increased incidence of excessive salivation during the dosage period in 4/10 males and 3/10 females. These non

- toxicological effects may have been caused by irritation of the oral mucosa.

The LOAEL is 2.25 mg/kg/day based on mortali ty, reduced hindlimb muscle mass, decreased electrophysiological measurements (females), and microscopic lesions in the skeletal muscle. The NOAEL is 1.25 mg/kg/day.

Dose Selected for Risk Assessment: NOAEL of 1.25 mg/kg/day.

Comments about Study/Endp oint:

Based on the observation in the 9

- day female rat oral metabolism study (MRID 45774326), all the 4 mg/kg/day CuPT animals had irregular gait by Day 7 and paralysis by Day 9 at 0.5 and 4 hours
post

- dose. Therefore, committee agreed that reduced hindli mb muscle mass, decreased electrophysiological measurements (females), and microscopic lesions in the skeletal muscle can happened in short

- term exposure condition and are appropriate for both short

- and intermediate

term end

- points.

4.3.3 Incidental D ermal

- (Short

- and Intermediate

- term)

Study Selected: Dermal Developmental toxicity Rats

MRID No.: 46534001

Executive Summary: In a developmental toxicity study (MRID 46534001), zinc pyrithione (98.3% a.i., batch/lot # 0108244691) was derma lly administered to 23

- 25 Crl:CD® (SD)IGS BR VAF/Plus® rats/dose at dose levels of 0, 10, 15, 30, or 60 mg/kg bw/day from day 0 through 20 of gestation.

Dermal administration of zinc pyrithione resulted in maternal toxicity at 30 and 60 mg/kg/day.

Treat ment

- related effects at 60 mg/kg/day included clinical signs of toxicity (grade 1 erythema; grade 1 flaking; limited or no use of hindlimbs; shuffling gait; dehydration; low carriage; chromodacyorrhea; emaciation; chromorhinorrhea; hunched posture; decreas ed body weight and body weight gain, decreased uterine weight, decreased corrected body weight and corrected body weight gain, decreased absolute and relative feed consumption, and decreased muscle tone and mass.

At 30 mg/kg/day, there was an increase i n the number of dams with limited use of hindlimbs, shuffling gait, decreased body weight and body weight gain, decreased corrected body weight and corrected body weight gain, and decreased absolute feed consumption. There were no treatment

related matern al effects at 10 or 15 mg/kg/day.Page 18 of 24 The maternal LOAEL is 30 mg/kg bw/day, based on an increase in the number of dams with limited use of hindlimbs, shuffling gait, decreased body weight and body weight gain, decreased corrected body weight and corrected b ody weight gain, and decreased absolute feed consumption. The maternal NOAEL is 15 mg/kg bw/day.

Developmental toxicity occurred at 60 mg/kg/day. Treatment

- related findings at 60 mg/kg/day included decreased fetal weight (total, male, and female), an in crease in the percentage of litters and fetuses with incomplete ossification of the sternal centra, an increase in the percentage of fetuses with wavy ribs, and a decrease in the ossification site averages for the caudal vertebrae, forelimb phalanges

and m etacarpals, and hindlimb phalanges and metatarsals per fetus per litter. There were no

treatment

- related developmental effects at 10, 15, or 30 mg/kg/day.

The developmental LOAEL is 60 mg/kg bw/day, based on decreased fetal weight (total, male,

and fema le), an increase in the percentage of litters and fetuses with incomplete ossification of the sternal centra, an increase in the percentage of fetuses with wavy ribs, and a decrease in the ossification site averages for the caudal vertebrae, forelimb phala nges and metacarpals, and hindlimb phalanges and metatarsals per fetus per litter. The developmental NOAEL is 30 mg/kg bw/day.

Dose Selected for Risk Assessment: NOAEL=15 mg/kg/day based on the maternal LOAEL of 30 mg/kg/day, where an increased number of dams with limited use of hindlimbs was observed, as well as observations of shuffling gait, decreased body weight and body weight gain, and decreased food consumption.

Comments about Study/Endpoint: A 90

- day dermal toxicity study was available for ZnPT (MRID 42827902) and was previously used for the dermal endpoint. However, the dermal developmental study demonstrated a lower NOAEL and is protective of effects occurring in developing mammalian organisms, as the endpoint is based upon effects in pr egnant animals. Effects of ZnPT appear to differ in pregnant animals based on the available data comparing toxicity in pregnant vs. non

- pregnant animals. Therefore, this study (MRID 46534001) is appropriate for dermal risk assessments.

4.3.4 Inciden tal Inhalation

- (Short

- and Intermediate

- term)

Initially, inhalation toxicity was identified as a data gap for CuPT. However, with the submitted 28

- day inhalation toxicity study for CuPT (MRID 48006403) and inhalation metabolism study (MRID 48006401), t he ADTC concluded that the available information is adequate to address the issues associated with inhalation hazard concern for CuPT. In addition, other 28

- day inhalation toxicity studies conducted with both ZnPT (MRID 48006404) and CuPT (MRID 48006403) addressed the issue of toxicological equivalence between ZnPT and CuPT for short and intermediate

- term exposures. Therefore, the requirement of a 90

- day inhalation study for CuPT can be waived. BasedPage 19 of 24 upon toxicological equivalence, the inhalation endpoin t for CuPT is established from the existing 90

- day study conducted with ZnPT as shown below.

Study Selected: Subchronic Inhalation Rats

MRID No.: 42827903

Executive Summary: Groups of 15 male and 15 female Sprague Dawley rats were dynamically exposed in whole body exposure chambers to zinc pyrithione aerosols at concentrations of 0.0005, 0.0025, or 0.01 mg/L/day for 6 hours/day, 5 days/week for 13 weeks. One male and 1 female exposed to 0.0025 mg/L/day and 3 males and 4 females exposed to 0.0 1 mg/L/day died over the course of the study. Treatment related clinical signs of toxicity included rales, labored breathing, and gasping in animals that died on study. At 0.01 mg/L/day, body weights of females were depressed as much as 23%, compared to controls, total food consumption was decreased 10%, and food efficiency was decreased 53%. Hematologic, clinical chemistry, or urinalysis effects were not considered biologically significant for any of the exposure groups, and ophthalmologic examinations and gross necropsy findings were negative. Biologically significant increases in absolute and (relative) lung weights of +20% (+34%) and +22% (+38%) in males, and +13% (+18%) and +25% (+68%) in females were seen at concentrations of 0.0025 and 0.01 mg/L/d ay, respectively. The increased lung weights corresponded to histopathologic findings of trace to mild subacute inflammation of the interstitial tissue of the lung and medial hypertrophy of pulmonary arteries which were biologically significant at 0.01 mg /L/day. NOAEL = 0.0005 mg/L/day. LOAEL = 0.0025 mg/L/day (labored breathing, rales, increased salivation, decreased activity, dry red brown material around the nose, increased absolute and relative lung weights, and death of undetermined cause).

Comments about Study/Endpoint: The selected endpoint from the 90

- day study will be used for

short

- and intermediate

- risk assessments. A 21

- day inhalation toxicity study is also available for ZnPT (MRID 46528101). This study demonstrated a LOAEL of 0.002 mg/L/ day, similar to the

LOAEL in the 90

- day study, but did not test at lower concentrations as the 90

- day study did. The

effects observed in the 21

- day study (gasping, respiratory gurgling, increased lung weight, histopathological changes in the lung) were si milar to that of the 90

- day study. Therefore, the 21

- day study is considered supportive of the endpoint selected from the 90

- day study.

Human Equivalent Concentration (HEC) Calculation :

For inhalation risk assessment, a human equivalent concentration (HEC) is calculated using the Agency’s RfC guidance (USEPA, 1994: Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. Office of Research and Development, publication # EPA/600/8

- 90/066F). Derivation of h uman equivalent concentrations reduces the magnitude of uncertainty and also provides a more direct comparison with estimated human exposures for calculation of inhalation risk Details of this derivation are provided below.

1) Step one: Adjustment of NOAEL/LOAELPage 20 of 24 The NOAEL value selected for the exposure scenario of interest is first adjusted to reflect the duration of the exposure scenario and to account for differences between the human exposure duration and that reported in experimental animal studi es. For ZnPT inhalation risk assessments, short

- , intermediate

- , and long

- term term occupational exposures are expected, as are short

- term residential exposures. As the animal studies were conducted using a 6 hour exposure time, adjustment for an 8 hour work day for occupational assessments will be needed, and will also be sufficient for residential exposures, which are expected to be less than 8 hours.

Based on the above, the NOAEL is adjusted as follows for occupational and residential exposures:

NOAEL [ADJ] = 0.5 mg/m3 x (6hr/8hr) = 0.375 mg/m3

2) Step two: Calculation of Human Equivalent Concentration

Adjusted NOAEL or LOAEL values are used to calculate a human equivalent concentration (HEC) based on the general equation

NOAEL or LOAEL H EC = NOAEL or LOAEL [ADJ] x DAF

DAF is a dosimetric adjustment factor for the respiratory tract region, either the regional deposited dose ratio (RDDR) for particles or the regional gas dose ratio (RGDR) for gases. In the case of ZnPT (an aerosol), the RDDR method is used to calculate the DAF. Based on the calculated RDDR, the HEC is calculated as:

0.375 mg/m3 x 1.57 [RDDR] = 0.58 mg/m3

3) Step three: Application of Uncertainty Factors for calculation of inhalation Reference

Concentrations

For calculation of ‘RfC’ values for occupational and residential exposures, a total uncertainty factor of 30 is employed (3x for inter

- species extrapolation, 10x for human variability). A 3x for inter

- species extrapolation is used in place of the standar d 10x factor as calculation of the RDDR incorporates dosimetric adjustments and therefore accounts for pharmacokinetic differences between animals and humans, leaving the 3x pharmacodynamic uncertainty component (USEPA, 1994).

5.0 RECOMMENDED MARGINS OF E XPOSURE

For incidental oral exposures, a margin of exposure (MOE) of 100 (10x for inter

- species extrapolation, 10x for intra

- species variation) is adequate for occupational exposure risk assessments.Page 21 of 24 A MOE of 100 (10x for inter

- species extrapolation, 10 x for intra

- species variation) is also considered adequate for oral and dermal residential exposures to CuPT. For inhalation exposures, a MOE of 30 (3x for inter

- species extrapolation, 10x for human variability) is adequate for inhalation

risk assessments . The typical 10x inter

- species scaling factor is reduced to 3x based on the

calculation of an HEC.

6.0 AGGREGATE EXPOSURE RISK ASSESSMENTS

For short

- and intermediate

- term aggregate exposure risk assessment, the oral, dermal and inhalation

MOEs cann ot be combined due to different toxicological endpoints for oral (neuromuscular), dermal (decreased body weight gain and food consumption) and inhalation (clinical signs) routes.

7.0 CARCINOGENIC / MUTAGENICITY POTENTIAL

No chronic toxicity or carc inogenicity studies are available to assess the chronic toxicity or carcinogenicity of CuPT. There is a battery of negative mutagenicity studies.

8.0 FQPA CONSIDERATIONS

There are no food uses for CuPT. FQPA considerations do not currently apply to t his chemical. It is noted; however, that the previous FQPA assessment for ZnPT in the October 21, 2010 ADTC memo identified no concerns for susceptibility, and there were sufficient data to characterize neurotoxicity of

the chemical.

9.0 DATA GAPS

For r isk assessment associated with antifoulant use, no data gap was identified. However, if any risk assessment associated with long term exposure scinarios, chronic toxicity and carcinogenicity and reproductive toxicity data are not available for CuPT. The lack of these data and the inability to bridge based on pharmacokinetic differences of CuPT compared to ZnPT and NaPT identify these areas as data gaps that would need to be satisfied if uses involving chronic exposures are sought.

10.0 SUMMARY OF TOXIC OLOGY ENDPOINT SELECTION

The doses and toxicological endpoints selected for CuPT up to intermediate

- term exposures are
summarized in Table 3.

.Page 22 of 24 Table 3 Toxicological Dose and Endpoints for Copper Pyrithione for use in human risk

assessments for Antifou lant Paint Use.

Exposure

Scenario Dose Used in

Risk

Assessment/ UF LOC for Risk

Assessment Study and Toxicological Endpoints

Acute Dietary Endpoint is not required for CuPT as there are no food uses.

Chronic Dietary Endpoint is not required for CuPT as there are no food uses.

Incidental Oral

Short

- and

Intermediate

- Term Maternal

NOAEL= 1.25 mg/kg/day MOE = 100 (residential)

MOE = 100 (occupational) 90

- day Oral Toxicity Study

- Rats (MRID 47023701 ) (Cu PT )

LOAEL = 2.25 mg/kg/day, based on mortality, reduced hindlimb muscle mass, decreased electrophysiological measurements (females), and microscopic

lesions in the skeletal muscle.

Dermal

Short

- and

Intermediate

- t erm Dermal

NOAEL = 15 mg/kg/day MOE = 1 00 (residential)

MOE = 100 (oc cupational) Dermal Developmental Toxicity

- Rats (MRID 46534001) (ZnPT)

Maternal LOAEL = 30 mg/kg/day,

based on increased no. of dame with limited use of hindlimbs, shuffling gait, decreased body weight and body weight gain, and decreased food consumption

.

Inhalation

Short and

Intermediate

- Term Inhalation

NOAEL = 0.000 5 mg/L/day

HEC = 0.58 mg/m 3 MOE = 30 (residential)

MOE = 30 (occupational) Subchronic Inhalation Toxicity

- Rats (MRID 42827903) (ZnPT)

LOAEL = 0.0025 mg/L Based on clinical sig ns of toxicity,

decreased activi ty, and increased lung weights.Page 23 of 25 11.0 REFERENCES

Barnett, J. (2005) Percutaneous Developmental Toxicity Study of Zinc Pyridinethione (ZPT) in Rats: Final Report. Project Number: AEN00006, AEN00005, AEN00006AA. CR

- DDS Argus

Division and CR

- DDS

- Worcester. MRID 46534001 Unpublished.

Blagden, S.M. (1999) Copper pyrithione: acute inhalation toxicity (nose only) study in the rat. Safepharm Laboratories Limited, Derby, UK. Laboratory Project No.: 696/033, June 9, 19 99. MRID 48158004. Unpublished.

Blagden, S.M. (1999) Copper pyrithione: acute inhalation toxicity (nose only) study in the rat. Safepharm Laboratories Limited, Derby, UK. Laboratory Project No.: 696/033, June 9, 1999. MRID 48158004. Unpublished.

Chen, J. 2008. Copper Pyrithione and Zinc Pyrithione

- Toxicology Data Bridging Issues

. DB Bar Code: 339760,344368

.

Cerven, D. (1998) Primary Eye Irritation and/or Corrosion in Rabbits: Copper Omadine: MB Research Laboratories, Inc. Lab Project Number: MB 94

- 3647 D: 236

- 04. MRID 45774307 Unpublished.

Dreher, D.M. (1999) Copper pyrithione: acute oral toxicity study in the rat

– acute toxic class method. Safepharm Laboratories Limited, Derby, UK. Laboratory Project No.: 696/041, June 11, 1999. MRID 4 8158002. Unpublished.

Dreher, D.M. (1999) Copper pyrithione: Magnusson

- Klingman maximization study in the guinea pig. Safepharm Laboratories Limited, Derby, UK. Laboratory Project No.: 696/044, August 25, 1999. MRID 48158001. Unpublished.

Jeffcoat , A. (2007). Disposition of copper pyrithione (CuPT) in female rats: Repeated dose oral gavage pharmacokinetic studies. Research Triangle Institute. Report Number 0209593.000, July 25, 2007. MRID 47844501. Unpublished.

Jeffcoat, A. (2007). Disposi tion of zinc pyrithione (ZPT) in female rats: Repeated dose oral gavage and dermal pharmacokinetic studies. Research Triangle Institute. Report Number 0208173.000, July 25, 2007. MRID 47751201. Unpublished.

Kieffer, L. (1998) Primary Dermal Irritati on in Albino Rabbits: Copper Omadine: MB Research Laboratories, Inc. Lab Project Number: MB 94

- 3647 C: 166

- 04. MRID 45774308. Unpublished.

Kirkpatrick, D.T. (2009) A 4

- week inhalation toxicity study with emphasis on pulmonary effects of zinc omadine in Sp rague Dawley rats. WIL Research Laboratories, LLC, Ashland, OH.Page 24 of 25 Laboratory Study No.: WIL

- 544008, December 14, 2009. MRID 48006404. Unpublished

Kirkpatrick, Daniel T. ( 2009) A 4

- Week inhalation toxicity study with emphasis on pulmonary

effects of c opper omadine in Sprague

- Dawley rats. WIL Research Laboratories, LLC, Ashland, OH. Laboratory Study No.: WIL

- 544009, December 14, 2009. MRID 48006403. Unpublished.

Omnimaru, T. (1993) An Acute Toxicity Study of Copper Pyrithione in Rats: Final Repor t: Shin Nippon Biomedical Laboratories, Ltd. Lab Project Number: SBL 40

- 40. MRID 45774305 Unpublished

Omori, M. (1995) A repeated dose toxicity study of copper pyrithione administered orally to rats for 28 days followed by a 14

- day recovery period. Shin Nippon Biomedical Laboratories, Ltd, Kagoshima, Japan. Laboratory Project ID: SBL 40

- 46, July 18, 1995. MRID 45774311. Unpublished.

Oneda, S. (1994) A Repeated Dose Toxicity Study of Copper Pyrithione Administered Orally to Cynomolgus Monkeys for 28 Days Followed by a 14

- Day Recovery Period: Final Report: Lab Project Number: SBL 40

- 43. MRID 45774312

. Unpublished.

Prinsen, M.K. (2002) Acute dermal toxicity study with copper pyrithione in rats. TNO Nutrition and Food Research, Zeist, Netherlands. La boratory Study No.: 4416/02, July 2002. MRID 48158003. Unpublished.

Skoulis, N.P. (2008) Difference in Inhalation Toxicity of Copper pyrithione Vs. Zinc Pyrithione.

MRID 474303·01

. . Unpublished.

Thomas, J. A. (2010) Inhalation of 14C

- Copper Omadin e. WIL Research Laboratories, LLC, Ashland, OH. Report number: WIL

- 544012, February 19, 2010. MRID 48006401. Unpublished.

Thomas, J. A. (2010) Inhalation of 14 C

- Zinc Omadine

. WIL Research Laborator ies, LLC, Ashland, OH. Re port number : WIL

- 544011, Februar y 19, 2010 . MRID 48006402 . Unpublished

.

Ulrich, C. (1993) Thirteen Week Subchronic Inhalation Toxicity Study on Zinc Omadine in Rats: International Research and Development Corp. Lab Project Number: 397

- 052: IRDC. MRID

42827903 . U npublished

.

Valentine, J.L. (2002) Final report

– amended: in vivo dissociation of copper pyrithione (CuPT) in female rats. Bioorganic Chemistry, RTI International, Research Triangle Park, NC. Laboratory Project ID: 08363.000, August 5, 2002. MRID 45774326. Unpublished.

Wood, E. (1999) Copper pyrithione: preliminary oral gavage teratology study in the rat. Safepharm Laboratories Limited, Derby, UK. Laboratory Project No.: 696/034, November 16, 1999. MRID 48158005. Unpublished.Page 25 of 25 Wood, E. (2000) Copper pyrithione: oral gavage teratology study in the rat. Safepharm Laboratories Limited, Derby, UK. Laboratory Project No.: 696/035, February 17, 2000. MRID 48158006. Unpublished.