Document ID: EPA-HQ-OPP-2004-0147-0028
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-05-14T04:00Z

DATE:	June 26, 2008	

MEMORANDUM

SUBJECT:	ZINC PYRITHIONE (ZINC OMADINE®) - REVISED Toxicology Endpoint
Selection Report –Revised to address Registrant Error comments 

FROM:	Timothy F. McMahon, Ph.D.

Senior Toxicologist	 

Antimicrobials  Division (7510C)				

THROUGH:	 John Redden, Roger Gardner, Ph.D., Stephen Dapson, Ph.D.,
Karen Hamernik,                Ph.D., Melba Morrow, D.V.M., Sanyvette
Williams-Foy, D.V.M, Jonathan Chen,                Ph.D.; Michelle
Centra; Najm Shamim, Ph.D.; Timothy Leighton. 

 

PC Code: 088002

On February 4, 1999, the Health Effects Division's Hazard Identification
Assessment Review Committee (HIARC) evaluated the toxicology data base
of zinc pyrithione (zinc omadine®), established acute and chronic
Reference Doses (RfD) and selected the toxicological endpoints for acute
dietary as well as occupational exposure risk assessments.  The HIARC
also addressed the potential increased susceptibility of infants and
children from exposure to zinc pyrithione as required by the Food
Quality Protection Act (FQPA) of 1996.   

On September 3rd and September 30th, 2003, the Antimicrobials
Division’s Toxicology Endpoint Selection Committee (ADTC) met to
discuss scientific issues with respect to the endpoints previously
selected for  zinc pyrithione.   Specifically, discussions were held to
determine the suitability of bridging the toxicology data for sodium
pyrithione to be applicable to zinc pyrithione risk assessments, the
determination of the need for a developmental neurotoxicity study for
zinc pyrithione, the use of a maternal endpoint for selection of the
chronic Reference Dose value for zinc pyrithione, and  the magnitude of
the special hazard-based FQPA factor and database uncertainty factor for
zinc pyrithione .  The results of the ADTC’s discussions are included
in this memorandum and this memorandum reflects the latest conclusions
regarding endpoint selection for zinc pyrithione, thus superceding the
previous HIARC memo (HED document number 013318).

1999 HIARC Committee Members in Attendance

Members present were: David Anderson, Bill Burnam, Virginia Dobozy, Pam
Hurley, Mike Ioannou, Tina Levine, Sue Makris, Nicole Paquette, Kathleen
Raffaele, Jess Rowland, PV Shah, and Brenda Tarplee (executive
secretary).  Data was presented by  Tim McMahon of the Risk Assessment
and Science Support Branch, Antimicrobials Division.  

2003 ADTC Committee Members in Attendance

John Redden, Roger Gardner, Ph.D., Stephen Dapson, Ph.D.,  Sanyvette
Williams-Foy, D.V.M,  Jonathan Chen, Ph.D., Timothy F. McMahon, Ph.D;
Najm Shamim, Ph.D.; Timothy Leighton. 

Member(s) in absentia: Karen Hamernik, Melba Morrow (provided comments
via email) Michelle Centra (provided comments via email) 

Other Attendees: Debbie Smegal, Bill Burnam

Data evaluation prepared by: Timothy F. McMahon, Ph.D.

 

 



COMMITTEE MEMBERS	(Signature indicates concurrence unless otherwise
stated)

Stephen Dapson					                                                  

Jonathan Chen					                                                 

Roger Gardner					                                                 

Karen Hamernik					                                                 

Tim McMahon (chair)				                                                

Melba Morrow					                                               

John Redden					                                               

Sanyvette Williams-Foy				                                              

Tim Leighton					_______________________

Michelle Centra					_______________________

Najm Shamim					______________________

OTHER ATTENDEES:

William Burnam					_________________

Deborah Smegal					_____________________



I.  INTRODUCTION

On February 4, 1999, the Health Effects Division's Hazard Identification
Assessment Review Committee evaluated the toxicology data base of zinc
pyrithione, established a Reference Dose (RfD) and selected the
toxicological endpoints for acute dietary as well as occupational

exposure risk assessments.  The HIARC also addressed the potential
increased susceptibility of infants and children from exposure to zinc
pyrithione as required by the Food Quality Protection Act (FQPA) of
1996. A report was issued by the HIARC on March 19, 1999 for zinc
pyrithione.  

In the 1999  report, the following  recommendations were made as listed
below:

1) The committee recommended retaining the special hazard-based FQPA
safety factor (10x), based on qualitative evidence of increased
susceptibility in the rat and rabbit prenatal developmental toxicity
studies.   

Since that time, updated guidance on interpretation of the FQPA safety
factor 

( http://www.epa.gov/oppfead1/trac/science/determ.pdf ) has been
published which necessitated re-consideration of this safety factor for
zinc pyrithione.  

2) The 1999 HIARC report recommended the conduct of a developmental
neurotoxicity study for zinc pyrithione, based on evidence of
significant nervous system deficits following either acute or subchronic
oral administration of zinc pyrithione. For example,  intravenous
administration of 5 mg/kg zinc pyrithione to female Yorkshire pigs
produced  cholinergic effects lasting for 30-60 minutes post- dose (HED
document 003933). Increased salivation was reported immediately after
dosing in the rat developmental toxicity  study at a dose of 3 mg/kg/day
(MRID # 42827904).  Subchronic administration of zinc pyrithione at 3.75
mg/kg/day has been shown to produce hindlimb weakness (HED document no.
003933). Peripheral neuropathy in the form of axonal degeneration has
been observed. 	

The issue of the requirement for a developmental neurotoxicity study was
re-considered by the ADTC. 

In addition to the above, two other issues were raised from the Risk
Assessment Oversight Review committee’s (RAOC) review of the draft
risk assessment for zinc pyrithione as listed below:

1) Selection of the chronic dietary endpoint for zinc pyrithione.  It
was stated in the RAOC memo that a maternal effect should not be used
for chronic risk 

2) Whether the toxicology database for sodium pyrithione can be used in
risk assessments for zinc pyrithione.  The toxicology database for zinc
pyrithione is missing a two-generation reproduction toxicity study,
which is required for the food contact uses of zinc pyrithione. 
However, a reproduction study exists for sodium pyrithione. 

The ADTC’s discussion of these issues and the conclusions reached are
summarized below as part of the updated toxicology endpoint selection
document.

II.  HAZARD IDENTIFICATION

A. ACUTE DIETARY (Acute Reference Dose)  

A.1.  Acute RfD		Subpopulation: Females 13+		

          

Study Selected:  Developmental Toxicity - Rabbit					§83-3a

MRID No.: 42827905

Executive Summary: In a developmental toxicity study in rabbits (MRID
#42827905), inseminated New Zealand White rabbits, randomly assigned to
one control and three treatment groups of 20 animals each, were
administered zinc pyrithione 48% Aqueous Dispersion by oral gavage at
doses of 0, 0.5, 1.5, or 3.0 mg/kg/day on gestation days (GD) 6 - 18.
Cesarean section examinations were performed on all surviving does on GD
29, followed by an examination of all fetuses. One mid-dose doe died on
GD 16, probably due to a gavage error.  A decrease in body weight gain
(p  0.01) during the dosing period for the mid and high-dose groups (41%
and 99%, respectively) cannot be considered biologically significant
since the absolute body weight changes were only -4% and -6%,
respectively.  There was no dose-related effect on food consumption. 
The does' body weights rebounded after the dosing interval.  There were
no compound-related gross lesions.  One high-dose doe aborted on GD 27,
and five others had total resorptions. One mid-dose doe had total litter
resorption.  Dose-related early resorptions were seen in the mid and
high-dose does.  These findings corresponded with a dose-related
increase in post-implantation loss(early resorption) and a decrease in
viable fetuses.  It is not clear whether the resorptions were due to
maternal or developmental toxicity.  No statistically significant
differences were seen in the incidence of external, visceral, or
skeletal anomalies in the treated groups as compared to controls.  Three
fetuses from two high-dose litters contained multiple cephalic and limb
malformations.  The Maternal/Developmental NOAEL is 0.5 mg/kg/day.  The
LOAEL is 1.5 mg/kg/day, based on increased post-implantation loss and
decreased number of viable fetuses (it is not clear whether the
resorptions were due to maternal or developmental toxicity).		

Dose Selected for Risk Assessment:  NOAEL=0.5 mg/kg/day based on
increased post-implantation loss and decreased viable fetuses at 1.5
mg/kg/day (LOAEL).

Uncertainty Factors: 100 (10 x for inter-species variation and 10x for
intra-species extrapolation) 

Comments about Study/Endpoint Uncertainty Factor: The endpoint of
concern (increased post-implantation loss and decreased viable fetuses)
is an in utero effect, and therefore is applicable only to this
subpopulation (Females 13+).  Also, these developmental effects are
presumed to occur after a single exposure (dose), thus are applicable
for this exposure period of concern.  

Acute RfD (aPAD) (Females 13+) =           0.5 mg/kg/day (NOAEL) = 0.005
mg/kg							              100 (UF) 

This risk assessment is required.

A.2.  Acute RfD 	 Subpopulation:   General Population including Infants
and children 

Study Selected :  Developmental Toxicity - Rat         		Guideline #:
§83-3

MRID No.:  42827905

Executive Summary:  In a developmental study (MRID 42827904), thirty
pregnant Sprague-Dawley rats per group were administered Zinc Pyrithione
by oral gavage on days 6-15 of gestation at doses of 0, 0.75, 3, or 15
mg/kg/day.  One dam in the 15 mg/kg/day dose group died on gestation day
16 of unspecified causes.  No maternal or developmental toxicity was
observed at 0.75 mg/kg/day.  The most sensitive indicator of maternal
toxicity was increased salivation immediately after dosing which was
observed in the 3 and 15 mg/kg/day groups (27% and 97% of dams,
respectively).  Other dose-related signs seen at 15 mg/kg/day included
biologically significant decreases in body weight gains (67%; p   0.01;
absolutes of 4-12%) and food consumption (24% during dosing, 16%
throughout gestation; p   0.01), and dilated pupils (57%).  The maternal
toxicity NOEL is 0.75 mg/kg/day, and the maternal toxicity LOAEL is 3.0
mg/kg/day, based upon excessive salivation during the dosing period. 

Developmental toxicity was characterized by a dose related increase in
post-implantation loss at the mid and high doses with the 15 mg/kg/day
group being significantly different than controls (p < 0.01).  This
correlated with an increase in early resorptions (3.6%/dam) with whole
litter resorption occurring in 3 high dose dams.  There was also a
significant reduction (p < 0.05) in the number of live fetuses per
litter (12.5/litter compared to 14.5/litter in the controls), mean fetal
weights (16%), and gravid uterine weights (16%; p   0.01) in the 15
mg/kg/day group as compared to controls.  A significantly greater number
of litters in the 15 mg/kg/day group contained fetuses with external,
visceral, or skeletal malformations/variations.  The most common were
digit anomalies (5 of 24 treated litters vs. 0 of 27 control litters; p 
 0.05), dilated renal pelvis (7 of 24 treated litters vs. 1 of 27
control litters; p   0.05)which is considered indicative of
hydronephrosis, and a vertebral/rib anomaly (24 of 24 treated litters
vs. 0 of 27 control litters; p <0.01).  Others included sternal, rib,
and limb (radius or ulna absent)malformations.  Dose-related fused ribs
were observed in the mid and high- dose groups (3 fetuses/2 litters, and
5 fetuses/4 litters, respectively).  Although pairwise comparisons, on
the basis of litters, were not statistically significant (p=0.226 and
p=0.060 for the mid and high- dose groups, respectively), a
statistically significant linear trend was evident (Cochran-Armitage
test; p=0.009), and historical control values were exceeded.  The
developmental toxicity NOEL is 0.75mg/kg/day, and the developmental
toxicity LOAEL is 3.0 mg/kg/day, based upon increased incidences of
fused ribs.  

Dose Selected for Risk Assessment:  NOAEL= 0.75 mg/kg/day based on
salivation in dams at 3.0 mg/kg/day (LOAEL).

Uncertainty Factor: 100 (10 x for inter-species variation and 10x for
intra-species extrapolation )

Acute RfD (aPAD gen. pop.) =          0.75 mg/kg/day (NOAEL)  =  0.0075
mg/kg	

              100 (UF)

Comments about Study/Endpoint Uncertainty Factor: The endpoint
(salivation) was seen in maternal animals during the dosing period, and
is thus relevant for this subpopulation and exposure period of concern.
In addition, the ADTC expressed concern that, although the chemical may
have been irritating, that it may also be reflective of a neurotoxic
effect. 

B. CHRONIC DIETARY (Chronic Reference Dose)

Type of Study:  Developmental  Toxicity - Rabbits 			Guideline #: 
§83-3

MRID No.:   42827905

Executive Summary:  See Acute Dietary Females 13+.  

Uncertainty Factor: 300 ( 10 x for inter-species variation, 10x for
intra-species extrapolation ). 

Chronic  RfD  =	      0.5 mg/kg/day (NOAEL) = 0.005 mg/kg/day	

100 (UF)

Comments about Study/Endpoint Uncertainty Factor:   The ADTC concluded
that a chronic toxicity study is not required for the indirect food use
of zinc pyrithione, based upon the Tier I data requirements for indirect
food uses for antimicrobial pesticides that do not require such studies.
 Therefore, use of the rabbit developmental toxicity  study is
conservative by nature since, of the data available for zinc pyrithione,
this study showed the lowest NOAEL value.   As support, the committee
also noted the available chronic toxicity study for  for sodium
pyrithione (MRID 42100901) with  a NOAEL of 0.5 mg/kg/day. 

C.  OCCUPATIONAL / RESIDENTIAL EXPOSURE

1.  DERMAL ABSORPTION 

Study Selected:  Dermal Absorption - Domestic Swine   	Guideline #:
§85-2

MRID No.:  HED document no. 003933

Executive Summary:  Twenty-six mature Yorkshire pigs were used in this
study. Radiolabeled zinc pyrithione was applied for 8 hours either as a
single dose (50,100, and 400 mg/kg) or as a 5 day repeated dose (100
mg/kg). Serial samples of blood, urine, and feces were taken after
dosing. Radioassay of necropsy material, urine, blood, and feces showed
recovery of 86.8-98.2% of applied radioactivity. Greater than 90% of
recovery was obtained from washings of the application site. Urinary
excretion was 3% in animals with intact skin. Levels of radioactivity in
blood, urine, and feces returned to background by 48 hours
post-application. 

Dermal Absorption Factor: 3% 		

Comments about Dermal Absorption Factor:  A dermal absorption factor is
not required since a dermal NOAEL was selected for dermal risk
assessments.  However, it is noted that the 3% dermal absorption factor
demonstrated in the swine study is supported by a literature study in
mice (1975; HED Doc. No. 003933) which also showed a dermal absorption
of 3%.  Additionally, low dermal absorption is indicated by the lack of
systemic toxicity in male rats following repeated dermal applications at
the Limit Dose (1000 mg/kg/day) for 90-days in a dermal toxicity study. 

		2. Incidental Oral (short- and intermediate-term)

		Study Selected: Developmental Toxicity Study in Rabbits    MRID
42827905

		Executive Summary: In a developmental toxicity study in rabbits (MRID
# 

42827905), inseminated New Zealand White rabbits, randomly assigned to
one control and three treatment groups of 20 animals each, were
administered Zinc Pyrithione 48% Aqueous  Dispersion by oral gavage at
doses of 0, 0.5, 1.5, or 3.0 mg/kg/day on gestation days (GD) 6 – 18. 
Cesarean section examinations were performed on all surviving does on GD
29, followed by an examination of all fetuses.

One mid-dose doe died on GD 16, probably due to a gavage error.  A
decrease in body weight gain (p (0.01) during the dosing period for the
mid and high-dose groups (41% and 99%, respectively) cannot be
considered biologically significant since the absolute body weight
changes were only -4% and -6%, respectively.  There was no dose-related
effect on food consumption.  The does' body weights rebounded after the
dosing interval.  There were no compound-related gross lesions.  One
high-dose doe aborted on GD 27, and five others had total resorptions. 
One mid-dose doe had total litter resorption.  Dose-related early
resorptions were seen in the mid and high-dose does.  These findings
corresponded with a dose-related increase in postimplantation loss
(early resorption) and a decrease in viable fetuses.  It is not clear
whether the resorptions were due to maternal or developmental toxicity. 
No statistically significant differences were seen in the incidence of
external, visceral, or skeletal anomalies in the treated groups as
compared to controls.  Three fetuses from two high-dose litters
contained multiple cephalic and limb malformations.  The
Maternal/Developmental NOAEL is 0.5 mg/kg/day.  The LOAEL is 1.5
mg/kg/day, based on increased postimplantation loss and decreased number
of viable fetuses (it is not clear whether the resorptions were due to
maternal or developmental toxicity).

2. SHORT-TERM DERMAL (1 - 7 days)

Study Selected:  Dermal Developmental toxicity - Rats     MRID 46534001

EXECUTIVE SUMMARY:  In a developmental toxicity study (MRID 46534001),
zinc pyridinethione (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 pyridinethione 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
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 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.

Comments about Study/Endpoint:  A 90-day dermal toxicity study was
available for zinc omadine (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 zinc omadine appear to differ in pregnant
animals based on the available data comparing toxicity in pregnant vs.
non-pregnant animals. Therefore this study is appropriate for dermal
risk assessments.  

This risk assessment is required.

3.  INTERMEDIATE-TERM DERMAL (1-Week to Several Months)

Study Selected:  Dermal Developmental toxicity - Rats     MRID 46534001

Comments about Study/Endpoint:  This study is appropriate for the route
(dermal) and exposure period (7-90 days). 

This risk assessment is required.

4.  LONG-TERM DERMAL (Several Months to Lifetime)

Study Selected:  Dermal Developmental toxicity - Rats     MRID 46534001

Executive Summary:   See Short-Term   

5.  INHALATION (ANY-TIME PERIOD).

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, intermediate and long-term exposure risk
assessments. A 21-day inhalation toxicity study is also available for
zinc pyrithione (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. 

For inhalationrisk 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

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 zinc omadine 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:

 

  SEQ CHAPTER \h \r 1 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 zinc omadine (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
interspecies extrapolation, 10x for human variability).  A 3x for
interspecies 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).

D.  Recommended Margins of Exposure

A  MOE of 100 is adequate for occupational exposure risk assessments. A 
MOE of 100 is also considered adequate for residential exposures to zinc
pyrithione.   Previously, a Margin of Exposure of 300 had been
recommended for residential exposures based on the application of a 3x
database uncertainty factor for lack of neurotoxicity studies. Although
a subchronic neurotoxicity study was not submitted for zinc pyrithione,
an acute neurotoxicity study was submitted and found to be acceptable,
and the dermal developmental toxicity study reviewed recently also
showed some indication of neurotoxic effects. Thus, these studies were
felt to be adequate in characterizing the doses at which neurotoxic
effects of zinc pyrithione start to appear. Thus, the 3x database
uncertainty factor can be removed for residential assessments. 

E.  Aggregate Exposure Risk Assessments (Food+water+Residential
exposures)

For acute aggregate exposure risk assessment, combine the high end
exposure values from food + water and compare it to the acute RfD for
Females 13+ and the acute RfD for the General Population including
Infants and Children.

For Short, intermediate and long-term aggregate exposure risk
assessment, the oral, dermal and inhalation MOEs cannot be combined due
to different toxicological endpoints for oral (developmental), dermal
(decreased body weight gain and food consumption) and inhalation
(clinical signs) routes.

IV.  CLASSIFICATION OF CARCINOGENIC POTENTIAL

   						

No chronic toxicity or carcinogenicity studies are available to assess
the carcinogenic potential of zinc pyrithione.  Two studies are
available for sodium pyrithione.  The first study  (MRID 42100901) 
showed no evidence of carcinogenicity when administered to
Sprague-Dawley rats by oral gavage for 2 years at doses of 0, 0.5, 1.5,
and 5.0 mg/kg/day. The second study (MRID 42100801) showed no evidence
of carcinogenicity when sodium pyrithione was administered dermally to
CD-1 mice at doses of 0, 5, 15, and 40 mg/kg/day for 18 months.   As
noted in the sodium pyrithione RED, sodium pyrithione is classified as
Group “D” (insufficient evidence to classify). 

V. MUTAGENICITY 

I. Salmonella typhimurium Assay

In a mutagenicity study (MRID # 41906502), doses of  zinc omadine
(48%aqueous dispersion) ranging from 0.03-5.0  g/plate under
non-activated conditions and 10-333  g/plate under S-9 activated
conditions were evaluated for the potential to induce reverse gene
mutations in five tester strains of  Salmonella typhimurium (TA98,
TA100, TA1535, TA1537, TA1538). Cytotoxicity was observed in this assay
at 3.3  g/plate and above under non-activated conditions, and at 333 
g./plate and above under activated conditions. There was no reproducible
evidence of a mutagenic effect in either the absence or presence of
metabolic activation in this study. 

ii. Gene Mutation in Cultured Chinese Hamster Ovary Cells

In a mutagenicity study using Chinese Hamster Ovary (CHO) cells (MRID #
41906503) assays were conducted in the absence of metabolic activation
(doses of 0.25-2.0 g/ml) and the presence of metabolic activation
(2.5-30  g/ml).  In this study, zinc pyrithione failed to induce a
mutagenic response.  

iii. In vivo Micronucleus Assay in  Mice

In this study (MRID # 41906501), intraperitoneal injection of single
doses of 11, 22, or 44 mg/kg zinc pyrithione (48% aqueous dispersion) to
ICR mice did not cause a significant increase in the frequency of
micronucleated  polychromatic erythrocytes (MPEs) in bone marrow cells
harvested 24, 48, or 72 hours post-dose. High dose mice exhibited signs
of toxicity (including mortality, lethargy, piloerection, and diarrhea)
but there was no evidence of a cytotoxic effect on the target organ.
Therefore, zinc pyrithione is concluded to be negative for mutagenicity
in this test system.

VI.  FQPA CONSIDERATIONS

1.  Adequacy of the Data Base

The toxicology data base is not complete with respect to assessing
adequate to assess the increased susceptibility to infants and children
as required by FQPA.   Acceptable developmental toxicity studies in the
rat and rabbit are available as well as reproduction toxicity data in
the rat for sodium pyrithione, however, a datagap exists for acute and
subchronic  neurotoxicity of zinc pyrithione.

2.  Neurotoxicity Data

The existing database shows significant nervous system deficits
following either acute or subchronic oral administration of zinc
pyrithione. For example,  intravenous administration of 5 mg/kg zinc
pyrithione to female Yorkshire pigs produced  cholinergic effects
lasting for 30-60 minutes post- dose (HED document 003933). Increased
salivation was reported immediately after dosing in the rat
developmental toxicity  study at a dose of 3 mg/kg/day (MRID #
42827904).  Subchronic administration of zinc pyrithione at 3.75
mg/kg/day has been shown to produce hindlimb weakness (HED document no.
003933). Peripheral neuropathy in the form of axonal degeneration has
been observed.  Recently submitted and reviewed studies on dermal
developmental toxicity (MRID 46534001) and acute neurotoxicity (MRID
46534002) have provided additional characterization of neurotoxic
potential for zinc pyrithione. 

3.  Developmental & Reproductive Toxicity

(I)  Developmental Toxicity: 

Executive summaries for the prenatal developmental studies are provided
under acute RfD (Rat) and chronic RfD (rabbit).  These studies showed no
quantitative evidence of increased susceptibility (i.e., maternal and
developmental NOAELs/LOAELs were the same).  There was, however,
qualitative evidence of increased susceptibility (i.e., fetal effects
were considered to be severe in the presence of minimal maternal
toxicity).

(ii)  Reproductive Toxicity:

A two-generation reproduction study in rats is  available for sodium
pyrithione to assess the reproductive toxic potential of zinc
pyrithione.  

4.  Determination of Susceptibility

Qualitative evidence of increased susceptibility was demonstrated both
in the rat and rabbit prenatal developmental toxicity studies.  In rats,
fetal effects were manifested as increased incidence of fused ribs at
the same dose that caused only minimal maternal toxicity characterized
as salivation.  In the rabbit study, fetal effects were manifested as
increased post-implantation loss and decreased viable fetuses at the
same dose that caused only minimal maternal toxicity characterized as
resorptions.  A two-generation reproduction study is not available in
the database.  Although no fetal abnormalities were seen in the prenatal
studies, available data indicated neurotoxic effects in adult animals at
doses of approximately 3 mg/kg/day and higher.

5.  Determination of the Need for Developmental Neurotoxicity Study

The HIARC in 1999 initially determined that, based on the observed
effects of zinc pyrithione to the nervous system from available reviewed
data, that a developmental neurotoxicity study will be required for zinc
pyrithione.   However, the ADTC, in revisiting this issue in 2003,
concluded that the requirement for the developmental neurotoxicity study
should be held in reserve pending submission of acute and subchronic
neurotoxicity studies for zinc pyrithione. 



6.  Hazard-based FQPA Safety Factor:

The  HIARC in 1999 recommended retention of the 10x safety factor for
the protection of infants and children based on qualitative evidence of
increased susceptibility in the rat and rabbit prenatal developmental
toxicity studies.  Since that time, updated guidance on interpretation
of the FQPA safety factor (
http://www.epa.gov/oppfead1/trac/science/determ.pdf ) has been
published.  Based on this updated guidance and the determination of the
Antimicrobials Division’s Toxicology Endpoint Selection Committee, the
hazard-based FQPA safety factor for zinc pyrithione was reduced to 1x. 
This reduction was based on the following: For zinc pyrithione, the
developmental toxicity database shows effects in offspring at similar
dose levels as effects in adults, while the reproductive toxicity
database for sodium pyrithione (a structurally related chemical) shows
effects in offspring at doses above those occurring in parental animals.
Effects observed in offspring from developmental toxicity studies  have
been selected for use in  dietary risk assessments, thus being
protective of infants and children. Therefore the hazard based FQPA
safety factor can be reduced to 1x since the degree of concern is low
(i.e. a complete developmental and reproductive database is available
with clear NOAELs/LOAELs for parental and offspring toxicity) and there
are no residual uncertainties for prenatal toxicity. 

7. Database Uncertainty Factor

A database uncertainty factor of 3x was applied to to non-occupational
risk assessments for zinc pyrithione, due to the lack of
characterization of neurotoxic dose-response relationships for zinc
pyrithione at the time. Based on the additional toxicology data
submitted, the 3x database uncertainty factor can be removed.  

VII.  Bridging of Toxicology Data for Sodium Pyrithione

Zinc pyrithione is structurally related to sodium pyrithione, the
primary differences being the presence of zinc vs. sodium and the
presence of two pyrithione moieties for zinc vs. one moiety for sodium. 
It is useful to compare the results of toxicity testing of zinc and
sodium pyrithione when considering the bridging issue.  The tables below
provide a comparison of results from both chemicals:



Study Type2

	

ZINC Pyrithione 

Doses (mg/kg/day)	

ZINC Pyrithione NOAEL/LOAEL 	

SODIUM Pyrithione

Doses (mg/kg/day)	

SODIUM Pyrithione

NOAEL/LOAEL

	

	

	

	

81-1 Acute Oral

MRID # 42827901 (Zn)

MRID # 40247801 (Na)	

260, 329, 417, 529, 668 mg/kg	

LD50 = 267 mg/kg (M+F)	

	

LD50 = 1500 mg/kg (M+F)

81-2 Acute Dermal

MRID # 42146701 (Zn)

MRID #40247802 (Na)	

2000 mg/kg (limit dose)	

LD50 > 2000 mg/kg	

	

LD50 = 1800 mg/kg (M+F)

81-3 Acute Inhalation

MRID # 42146703 (Zn)

MRID #40339001 (Na)	

0.24, 0.61 mg/L	

LC50 > 0.61 mg/L	

	

LC50 = 1.08 mg/L

81-4 Primary Eye

MRID # 42154601; 42146702 (Zn)	

0.1ml of a 48% solution	

severe eye irritant	

	

data gap

81-5 Primary Dermal

MRID # 42146704 (Zn)

MRID # 40247803 (Na)	

0.5g as an aqueous paste	

slight erythema and edema, reversible by 48 hr.	

	

slight erythema and edema

81-6 Dermal Sensitization

MRID # 43950201 (Zn)

MRID # 40247804 (Na)	

Buehler method using 0.4ml undiluted 48% solution	

non-sensitizer	

	

non-sensitizer

82-1a 90-day feeding- rat    Doc no. 003933 (Zn)

MRID # 40756901 (Na)	

0.75, 3.75, 9.4, 18.75, 37.5, 46.9, and 93.75 mg/kg	

NOAEL = 0.75 mg/kg

LOAEL = 3.75 mg/kg

(increased liver, kidney, testes weight; decreased survival, hindlimb
weakness	

0, 0.5, 2.0, 8.0 mg/kg/day	

NOAEL = 0.5 mg/kg/day

LOAEL = 2.0 mg/kg/day (evidence of neurotoxicity) 



83-3a Developmental tox-rat

MRID # 42827904 (Zn)	

0, 0.75, 3, and 15 mg/kg/day 	

Mat. NOAEL = 0.75 mg/kg/day; Mat. LOAEL = 3.0 mg/kg/day (excessive
salivation).

Devel. NOAEL = 0.75 mg/kg/day; Devel. LOAEL = 3.0 mg/kg/day (increased
incidence of fused ribs)	

	

no data

83-3b Developmental tox -rabbit

MRID # 42827905 (Zn)

MRID # 40487201 (Na)	

0, 0.5, 1.5, 3.0 mg/kg/day	

Mat./Devel. NOAEL = 0.5 mg/kg/day;

Mat./Devel. LOAEL = 1.5 mg/kg/day (incr. Post-impl. loss and decr.
Viable fetuses).	

0, 1, 2.5, and 5 mg/kg/d	

NOAEL = 5 mg/kg/d 

LOAEL = 7.5 mg/kg/d (based on toxicity observed in range-finding study)

82-3 90 Day dermal

MRID # 42827902 (Zn)

MRID # 40936201 (Na)	

0, 20, 100, 1000 mg/kg/day	

NOAEL = 100 mg/kg/day

LOAEL = 1000 mg/kg/day (decr. B.w., food cons., food eff.)	

0, 5, 15, and 50 mg/kg	

NOAEL = 15 mg/kg/d (M); 5 mg/kg/d (F)

LOAEL = 50 mg/kg/d (M); 15 mg/kg/d (F) [atrophy of hindlimb muscles and
panniculus muscles]

82-4 90 Day inhalation

MRID # 42827903 (Zn)

MRID # 41178201 (Na)	

0.0005, 0.0025, 0.01 mg/L	

NOAEL = 0.0005 mg/kg/day

LOAEL = 0.0025 mg/kg/day (clinical toxicity, incr. Abs. And rel. Lung
weights)	

0, 0.00046, 0.0011, and 0.0038 mg/L (0.0038 mg/L changed to 0.0081 mg/L
after 6 weeks)	

NOAEL = 0.0081 mg/L (M); 0.0011 mg/L (F)

LOAEL = 0.0081 mg/L (F, based on hindlimb dysfunction)

 83-4 Reproduction  

MRID # 41097201 (Na)	

 	

no data	

0, 0.5, 1.5, 3.5 mg/kg/day	

Systemic NOAEL = 0.5 mg/kg/d

Systemic LOAEL = 1.5 mg/kg/d (F); 3.5 mg/kg/d (M) [histologic atrophy of
hindlimb skeletal muscles]

Repro NOAEL = 1.5 mg/kg/d;  Repro LOAEL = 3 5 mg/kg/d (decr. no. of
pups/litter, decr. pup b.w. and wt. gain)

83-2 Carcinogenicity

MRID # 42100901 (Na)	

	

no data	

0, 0.5, 1.5, 5.0/3.5 g/day	

  NOAEL = 0.5 mg/kg/day

LOAEL = 1.5 mg/kg/day (degeneration of skeletal muscle in both sexes)

84-2 Mutagenicity 

MRID  # 40411501 (Na)

MRID # 41906502 (Zn)	

	

non-mutagenic to Salmonella in the presence and absence of metabolic
activation	

	

negative for forward gene mutations in CHO cells up to 0.08 µg/ml

84-2 Mutagenicity

MRID # 40343701 (Na)

MRID # 41906503 (Zn)	

	

negative for gene mutation at the HGPRT locus in CHO cells up to
cytotoxic concentrations	

	

negative for micronucleus induction in CD-1 mice up to toxic doses (238
mg/kg)

84-2 Mutagenicity

MRID # 40387501 (Na)

MRID # 41906501 (Zn)	

	

not clastogenic in mouse bone marrow cells	

	

no induction of UDS in rat hepatocytes up to cytotoxic concentrations

85-1 Metabolism

MRID # 41269001 (Na)

	

	

	

	

rapidly absorbed and excreted; S-glucuronide the major metabolite. 

The tables above show that in large part, both zinc and sodium
pyrithione produce similar toxic responses at similar dose levels.  Some
differences are noted with respect to the dermal NOAELs for the two
chemicals (NOAEL of 15 mg/kg/day for sodium pyrithione; NOAEL of 100
mg/kg/day for zinc pyrithione) and the observation that sodium
pyrithione resulted in apparent neurotoxic effects by the dermal route
vs. zinc pyrithione.  The dermal absorption values also differ between
zinc (3.0%) and sodium (0.1%) pyrithione, although the value for sodium
pyrithione was estimated and not measured directly.  Outside of these
issues, however, the oral toxicity data do show a similarity in toxic
response at similar dose levels, so in the case of bridging, as it
involves oral exposure, it is possible to use the reproduction study for
sodium pyrithione as a substitute for zinc pyrithione.  Since a 90-day
dermal toxicity study is available for both zinc and sodium pyrithione,
bridging of dermal toxicity data is not necessary, as a chemical
specific endpoint can be selected in this case as needed. 



VII.  HAZARD  CHARACTERIZATION  

Zinc Pyrithione demonstrates developmental toxicity as well as
neurotoxicity. In the developmental toxicity studies in the rat and
rabbit, severity of effects in offspring were significant in comparison
to maternal effects, even though the doses at which developmental and
maternal effects occurred were the same.  Zinc pyrithione also
demonstrates significant neurotoxic effects in a variety of studies as
shown by hindlimb weakness and distal axonopathy.  Acute and subchronic
neurotoxicity testing is necessary to define the dose-response
relationships   for the neurotoxic effects of zinc pyrithione. 
Reproductive toxicity data for zinc pyrithione are not available.  Data
are available for sodium pyrithione and can be used as bridging data for
this aspect of zinc pyrithione hazard as concluded by the ADTC in 2003. 

 

VIII.  DATA GAPS

 

IX.  ACUTE TOXICITY ENDPOINTS: 

Guideline No.	

Study Type	

MRID #	

Results	

Tox. Cat.

§81-1

(OPPTS870.1100)	

Acute Oral	

42827901	

LD50 = 267 mg/kg	

II

§81-2 

(OPPTS 870.1200	

Acute Dermal 	

42146701	

LD50 > 2000 mg/kg	

III

§81-3	

Acute Inhalation 	

42146703	

LC50 >0.61 mg/L	

III

§81-4 

(OPPTS 870.2400)	

Primary Eye Irritation	

42146702	

severe irritant	

I

§81-5

 (OPPTS 870.2500)	

Primary Dermal Irritation	

42146704	

slight erythema and edema	

IV

§81-6 

(OPPTS 870.2600	

Dermal Sensitization	

43950201	

no sensitization observed using Buehler method	

N/A

§81-8 

(OPPTS  870.6200)	

Acute and Subchronic Neurotoxicity	

study not available	

	



X   SUMMARY OF TOXICOLOGY ENDPOINT SELECTION

The doses and toxicological endpoints selected for various exposure
scenarios for zinc pyrithione are summarized below. 

Exposure Scenario	

Dose  Used in Risk Assessment, UF	

  LOC for Risk Assessment	

Study and Toxicological Endpoints

Acute Dietary

(Females 13 - 50)	

NOAEL = 0.5

mg/kg/day

UF = 100

Acute RfD = 0.005 mg/kg/day	

FQPA SF = 1x

aPAD = acute RfD

              FQPA SF

aPADa (females 13+) = 0.005 mg/kg/day

	

Developmental Toxicity Study in Rabbits

LOAEL = 1.5 mg/kg/day, based on increased post-implantation loss and
decreased viable fetuses

Acute Dietary

(General population, including infants/children)	

NOAEL = 0.75 mg/kg/day

UF = 100

Acute RfD = 0.0075 mg/kg/day	

FQPA SF = 1x

aPAD = acute RfD

              FQPA SF

aPAD = 0.0075 mg/kg/day	

 Developmental Toxicity Study in Rats

LOAEL = 3.0 mg/kg/day based on increased salivation in maternal rats. 

Chronic Dietary 

(all populations)	

NOAEL = 0.5

mg/kg/day 

UF = 100

Chronic RfD =0.005 mg/kg/day	

 FQPA SF = 1x

cPAD = acute RfD

              FQPA SF

cPAD = 0.005 mg/kg/day	

Developmental Toxicity Study in Rabbits	

LOAEL = 1.5 mg/kg/day, based on increased post-implantation loss and
decreased viable fetuses 

Incidental Oral, 

Short- and Intermediate-Term 	

Maternal

NOAEL= 0.75

mg/kg/day 	

MOE = 100 (residential)

 	

Developmental Toxicity Study in Rats

LOAEL = 3.0 mg/kg/day, Based on increased salivation in maternal rats. 

Short-, Intermediate-, and Long-Term 

Dermal 

  	

Dermal 

NOAEL = 15 mg/kg/day	

MOE = 100 (residential)

MOE = 100 (occupational)	

 Dermal Developmental Toxicity in Rats (MRID 46534001)

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.  

Short-, Intermediate-, and Long-Term

  Inhalation 	

 

HEC = 0.58 mg/m3   	

MOE = 30 (residential)

MOE = 30 (occupational)	

Subchronic Inhalation Toxicity Study in Rats

LOAEL = 0.0025 mg/L

Based on clinical signs of toxicity, decreased activity, and increased
lung weights.

 PAGE  7 

	 

 PAGE   

 PAGE   13