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 D369393

FROM: Jonathan Chen, Ph.D.

Senior Toxicologist, 

Risk Assessment and Science Support Branch (RASSB)

Antimicrobial Division (7510P)

THROUGH: Tim Mcmahon, Ph.D.

Senior Toxicologist, 

Antimicrobial Division (7510P)

And

Nader Elkassabany, Ph.D.

Chief

RASSB / AD

TO:

Attached is RASSB’s hazard assessment of copper pyrithione, proposed for use as a active 

ingredient in antifoulant paint use. 
TABLE OF CONTENTS

0.0 BACKGROUND ................................................................................................... 1

1.0 HAZARD CHARACTERIZATION....................................................................... 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 SELECTION .................................................................. 15

4.1 ACUTE DIETARY (Acute Reference Dose, aRfD).......................................................................................15

4.2 CHRONIC DIETARY (Chronic Reference Dose, cRfD)..............................................................................15

4.3 OCCUPATIONAL / RESIDENTIAL 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 RISK ASSESSMENTS............................................ 21

7.0 CARCINOGENIC/ MUTAGENICITY POTENTIAL......................................... 21

8.0 FQPA CONSIDERATIONS ................................................................................ 21

9.0 DATA GAPS....................................................................................................... 21

10.0 SUMMARY OF TOXICOLOGY 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 (copper 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 omadine, 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 studies conducted by 3 relevant 

routes of exposure, skin 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 May 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 lower water solubility compared with sodium pyrithione and zinc 

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 

absorption/bioavailability of the chemical;

1. A similar metabolic profile between pyrithiones 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 study, 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 address 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 information, RASSB concluded that 

cooper 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 absorption/bioavailability of the chemical

In comparing the metabolism study results for copper pyrithione (MRID 4784451) and zinc 

pyrithione (MRID 47751201), the time to maximum concentration for pyrithione (PT) derived from 

CuPT is approximately three times longer than when derived from ZnPT, and Cmax values from CuPT are 

less than half those from ZnPT. 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 ZnPT. This prolonged absorption likely produces the longer 

apparent half-life of PT derived from CuPT than from ZnPT 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 kinetics 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 trigger 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 exposure .

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 pyrithione
Page 3 of 24

exposure.

Therefore, RASSB decided that one 90-day inhalation in rat and one prenatal developmental in 

rat are need. For dermal exposure route, a conservative route to route exposure with conservative 

100% dermal absorption will be used for dermal exposure risk assessment.

In 2009, instead of conducting the data agency requested, Arch continues to pursue the 

possibility of bridging 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 ZnPT inhalation toxicity MRID 48006404;

3. An inhalation of 14C-Copper Pyrithione metabolism study (MRID 48006401); 

4. An inhalation of 14C-Zinc Pyrithione metabolism study (MRID 48006402); and

5. One rat Copper Pyrithione developmental 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 

metabolism 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 inhalation 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 weakness 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 

exposure 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 metabolism 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 chronic 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 CuPT for antifoulant use 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 other longterm 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 irritating 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 study 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, test substance-related mortality was observed in the 0.005 mg/L group 

females. At 0.0015 mg/L group 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 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, clinical 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 carcinogenicity studies are available to assess the chronic toxicity or 

carcinogenicity of CuPT. There is a battery of negative mutagenicity studies. 

2.0 AVAILABLE DATABASE
Page 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 toxicology 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 Toxicity

The acute toxicity data on CuPT is summarized below in Table 2. CuPT is corrosive to eyes 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 exposure. 
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/kg

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 LC50 

(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 Eye 

Irritation

45774307 Corrosive 

81-5 Primary Skin 

Irritation

45774308 Mild or slight

OPPTS 

870.2600

[§ 81-6]

Dermal 

Sensitization

41580011 Non-sensitizer

3.2 Short-term Oral Toxicity

There is one short-term (9-Day) toxicity and metabolism study in rats (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 rangefinding study was performed to investigate 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 used 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 and 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 signs 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 study, 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-responsive, prostrate, salivating 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 acceptable/non-guideline. 

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 females Crj:CD (SD) rats/group for 28 

days. Further groups of control and high 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 % 

carboxymethylcellulose (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 signs 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 noted in the females sacrificed in moribund condition, and a trace of reddish 

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, ataxic gait 

and/or paralysis of the hind leg; reddish eye gum; urine-stained abdomen; and prone position were 

found. However, almost all of these findings decreased in severity or occurrence during the final 

week of dosing. During the initial recovery period, decreased spontaneous activity, ataxic gait, 

and piloerection were still observed in 1 or 2 females, but these abnormalities disappeared by Day 

5 of the recovery period. Emaciation was also observed in 2 females during the recovery period, 

but these animals appeared to be recovering.

No treatment-related clinical signs were noted in the 10 mg/kg/day males, other than slight 

emaciation in three males on Days 21 to 28 or on Days 0-2 of the recovery period,

Body 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 during 
Page 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. 

Overall (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. Food 

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-related gross 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 

gastrocnemius, 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.

The 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/day.

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: statistically 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 Study 
Page 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 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 

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 

histopathological 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, ophthalmoscopic 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. 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 the range 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 (CMAP) (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 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. 

At 1.25 mg/kg/day, treatment-related effects 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 (females), and microscopic lesions in the 

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

3.4 Subchronic Inhalation Toxicity
Page 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/m3 (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 females. 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 cause 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 

similar 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 Day 11 and continuing throughout the duration of the 

study, dermal atonia noted from Days 12 to 19, and pale extremities noted in a single animal on 

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

to 24. Other treatment-related clinical findings in this group were limited to yellow and/or red 

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, body 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, body 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 remaining 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 Days 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 study 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 

lymphocytes, 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 intervals.

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 concentration 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 alveolar 

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-day 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 SpragueDawley 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<0.01) 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 resorptions, 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 external, 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 

developmental toxicity study (MRID 46534001) was also considered. In the study, zinc 

pyrithione (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 pyrithione 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 hindlimbs; shuffling gait; dehydration; low carriage; 

chromodacyorrhea; emaciation; chromorhinorrhea; hunched posture; decreased 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 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 body weight gain, and decreased absolute feed consumption. There were no treatmentrelated 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 hindlimbs, shuffling gait, 

decreased body weight and 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/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 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 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 the 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 available 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 sections, 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 colonies 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 

observed 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 Aberration 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 significant difference was noted in the average 

frequencies of structural aberrations or polyploidy between the results of the metabolic activation 

method test with S9 Mix and the results of the metabolic activation method test without S9 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 results 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 metabolic activation method test, no significant difference was noted in the average 

frequencies of structural aberrations or polyploidy between the results of the metabolic activation 

method test with S9 Mix and the results of the metabolic activation method test without S9 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 assessments.

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 factor 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

Executive 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 

neuropathological 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 compound-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 was 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 the range 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 (CMAP) (decreased 28%) that remained 

reduced, but to a lesser extent (decreased 13%), following the 6-week recovery period. Treatmentrelated neuropathological effects were limited to the skeletal muscle sections in the 2.25 mg/kg/day 

animals, with definitive muscle fiber atrophy in 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 effects 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 mortality, 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/Endpoint:

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 hindlimb 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 intermediateterm end-points.

4.3.3 Incidental Dermal - (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 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 pyrithione 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 hindlimbs; shuffling gait; dehydration; low carriage; 

chromodacyorrhea; emaciation; chromorhinorrhea; hunched posture; decreased 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 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 body weight gain, and decreased absolute feed consumption. There were no treatmentrelated maternal 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 body 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 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 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 the 

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.

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 pregnant 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 Incidental 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), the 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. Based 
Page 19 of 24

upon toxicological equivalence, the inhalation endpoint 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 0.01 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/day, 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 similar 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 human 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/LOAEL
Page 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 studies. 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 HEC = 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 standard 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 EXPOSURE

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, 10x 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 cannot 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 carcinogenicity 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 this 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 risk 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 TOXICOLOGY 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 Antifoulant 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) (CuPT)

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 -term 

 

Dermal 

NOAEL = 15 

mg/kg/day

MOE = 100 

(residential)

MOE = 100 

(occupational)

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 = 0.0005 

mg/L/day

HEC = 0.58 

mg/m3 

MOE = 30

(residential)

MOE = 30

(occupational)

Subchronic Inhalation Toxicity-Rats

(MRID 42827903) (ZnPT)

LOAEL = 0.0025 mg/L

Based on clinical signs of toxicity, 

decreased activity, 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, 1999. 

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 

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