UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM

DATE: 4/11/2013

SUBJECT: Demiditraz: Human Health Risk Assessment to Support Section 3 New Use for 

Proposed Dog Spot-On Use

PC Code: 577501 DP Barcode: D410552

MRID No.: Not Applicable Registration No.: 1007-OT

Petition No.: Not Applicable Regulatory Action: Section 3 Registration

Assessment Type: Single Chemical,

Non-Aggregate

Reregistration Case No.: Not Applicable

TXR No.: Not Applicable CAS No.: 944263-65-4

FROM: Wade Britton, MPH, Risk Assessor and ORE

Linda Taylor, Ph.D., Toxicologist

Risk Assessment Branch V/VII

Health Effects Division (HED; 7509P)

THROUGH: William H. Donovan, Ph.D., Chemist

And

Michael Metzger, Branch Chief

Risk Assessment Branch V/ VII

Health Effects Division (7509P)

TO: Bewanda Alexander, Risk Manager

Richard Gebken, PM 10

Insecticide Branch

Registration Division (RD; 7505P)
Demiditraz Human Health Risk Assessment D410552

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Table of Contents

1.0 Executive Summary............................................................................................................. 4

2.0 HED Recommendations....................................................................................................... 6

2.1 Data Deficiencies ............................................................................................................. 6

2.2 Tolerance Considerations................................................................................................. 7

2.3 Label Recommendations from Occupational and Residential Assessment ..................... 7

3.0 Introduction.......................................................................................................................... 7

3.1 Chemical Identity ............................................................................................................. 7

3.2 Physical/Chemical Characteristics................................................................................... 7

3.3 Pesticide Use Pattern........................................................................................................ 8

3.4 Anticipated Exposure Pathways....................................................................................... 8

3.5 Consideration of Environmental Justice .......................................................................... 8

4.0 Hazard Characterization and Dose-Response Assessment.................................................. 9

4.1 Summary of Toxicological Effects .................................................................................. 9

4.2 Considerations of Toxicity to Children.......................................................................... 10

4.2.1 Completeness of the Toxicology Database ................................................................ 10

4.2.2 Evidence of Neurotoxicity.......................................................................................... 11

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal............. 11

4.2.4 Residual Uncertainty in the Exposure Database......................................................... 12

4.3 Toxicity Endpoint and Point of Departure Selections.................................................... 12

4.3.1 Dose-Response Assessment ....................................................................................... 12

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........... 13

4.3.3 Cancer Classification and Risk Assessment Recommendation.................................. 13

4.3.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment................................................................................................................................ 13

5.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 15

5.1 Residential Handler Exposure........................................................................................ 15

5.2 Residential Post-Application Exposure.......................................................................... 16

5.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)......................... 18

5.4 Residential Risk Estimates for Use in Aggregate Assessment ...................................... 18

5.5 Residential Bystander Post-Application Inhalation Exposure ....................................... 18

6.0 Aggregate Exposure/Risk Characterization....................................................................... 19

7.0 Cumulative Exposure/Risk Characterization..................................................................... 19
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8.0 Occupational Exposure/Risk Characterization .................................................................. 19

8.1 Occupational Handler Exposure/Risk Estimates............................................................ 19

8.2 Occupational Post-Application Risk................................................................................... 22

Appendix A. Toxicology Profile and Executive Summaries....................................................... 23

A.1 Toxicology Data Requirements...................................................................................... 23

A.2 Toxicity Profiles............................................................................................................. 24

A.3 Hazard Identification and Endpoint Selection .................................................................. 27

A.4 Executive Summaries..................................................................................................... 29

Appendix B. Physical/Chemical Properties................................................................................. 47
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1.0 Executive Summary

Demiditraz, 2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole is an acaricide which acts on 

the octopamine nervous system in invertebrates and acts on neurotransmitter systems, such as the 

alpha 2 adrenergic receptor in mammals. Demiditraz is proposed by the submitter, Pfizer 

Animal Health, as a spot-on liquid product for dogs to control ticks and mites. There are 

currently no active registrations for demiditraz. A human health risk assessment was previously 

conducted for the proposed dog spot-on product1 which identified risks of concern for the use. 

This document updates the prior assessment with incorporation of additional exposure and 

toxicity data submitted since the prior assessment, and uses the 2012 Health Effects Division 

(HED) Residential Standard Operating Procedures (SOPs) to assess residential exposure and 

risk. 

Proposed Use Profile: The proposed dog spot-on product, 1007-OT, contains two active 

ingredients; demiditraz (14%) and fipronil (4.8%). This human health risk assessment only

addresses human health risk from potential exposures to demiditraz. The proposed product is 

labeled for application to four dog weight ranges: small, 11 to 20 pounds (lbs); medium, 21 to 

33 lbs; intermediate, 34 to 50 lbs; and large, 51 to 66 lbs. 

Exposure Profile: Non-occupational (residential) use of the dog spot-on product is anticipated to 

result in dermal exposures for adult handlers. In addition, residential post-application dermal 

exposures are expected for adults and children, and incidental oral exposures for children. 

Occupational dermal exposures are expected from use of the proposed spot-on product by 

veterinarians, veterinary assistants, and groomers. Inhalation exposures are not anticipated from 

either occupational or residential use of the spot-on product. 

Current HED policy requires assessment for occupational handler and residential postapplication exposures of short- (1 to 30 days), intermediate- (1 to 6 months), and long-term 

(greater than 6 months) exposures from pet spot-on products due to the preventative nature of pet 

products and the potential for extended usage in more temperate parts of the country. Residential

handler exposure is assumed to be short-term due to the intermittent nature of homeowner spoton applications (i.e., once monthly treatment). 

Toxicity/Hazard: The nervous system is the primary target organ for demiditraz. Pfizer Animal 

Health maintains that demiditraz affects neurotransmitter systems such as the alpha-2 (α2) 

adrenergic receptor in mammals. There are no chronic studies for demiditraz; however, the

toxicological database is adequate for selecting endpoints for a human health risk assessment and 

is considered complete because all the data requirements for a non-food use have been satisfied. 

A database uncertainty factor (UFDB) of 10X was retained in the previous human health risk 

assessment of the proposed demiditraz dog spot-on product based on the lack of developmental 

neurotoxicity (DNT) and non-rodent (dog) studies. The data requirement has been satisfied with 

submission of rat developmental neurotoxicity and dog subchronic oral toxicity studies, and the 

dog was not found to be more sensitive than the rat to the neurotoxic effects of demiditraz. 

 

1 W. Britton. Demiditraz: Human Health Risk Assessment for Proposed Dog Spot-On Use. D378783. 11/30/2010.
Demiditraz Human Health Risk Assessment D410552

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Accordingly, the additional UFDB has been removed due to satisfaction of the required study

requirements. 

Demiditraz has not been classified for carcinogenic potential. Rat and mouse carcinogenicity 

studies with demiditraz have not been submitted, but are not required for the proposed nonfood/non-feed use. All studies conducted for mutagenicity/genetic toxicity were determined to 

be negative and, therefore, there is no concern for mutagenicity/genetic toxicity for demiditraz. 

There are also no reproductive toxicity concerns. No specific immunotoxicity was identified in a 

guideline immunotoxicity study.

The database for demiditraz is complete, which includes a developmental neurotoxicity

assessment; and there is no evidence of increased susceptibility and no residual uncertainties 

with regard to pre- and/or postnatal toxicity following in utero exposure to rats or rabbits and 

pre- and/or postnatal exposures to rats.

An incidental oral endpoint for risk assessment of all exposure durations was selected from the 

oral subchronic neurotoxicity study in the rat with a no observed adverse effect level (NOAEL) 

of 5 mg/kg/day. At the study lowest observed adverse effect level (LOAEL) of 25 mg/kg/day, 

clinical signs of neurotoxicity, decreased motor activity, and decreased body weights were 

observed in both sexes. The total uncertainty factor applied for assessment of incidental oral 

exposures and risks is 100X. 

Dermal endpoints for all durations of risk assessment were selected from the route-specific 

subchronic dermal toxicity study in the rat with a LOAEL of 100 mg/kg/day. A NOAEL was not 

identified. Alterations in motor activity and grooming behavior were observed at all dose levels. 

An additional uncertainty factor, UFLOAEL, of 3X has been retained due to the lack of a NOAEL 

(i.e., LOAEL to NOAEL extrapolation). The total uncertainty factor applied for assessment of 

dermal exposures and risks is 300X. 

Residential Exposure and Risk Estimates: There is a potential for residential exposures from the 

use of the proposed demiditraz spot-on for dogs. Short-term residential handler dermal exposure 

and risk was assessed and is not of concern (i.e., MOES are > 300). Inhalation exposures for 

residential handler and from post-application exposures to the proposed spot-on product are 

assumed to be negligible. 

Residential post-application dermal and incidental oral exposures (all durations) were combined 

for all children 1 to < 2 years old exposure scenarios assessed. Children’s combined exposures 

were presented using the aggregate risk index (ARI) approach. This approach was required to 

assess combined post-application exposure and risks for children 1 to < 2 years old because the 

LOCs are not the same for dermal and oral routes of exposure (i.e., dermal, 300; and incidental 

oral, 100). For adults, only post-application dermal exposure is anticipated from contact with a 

demiditraz treated dog.

Pfizer Animal Health submitted a pet residue transfer study in support of the proposed 

demiditraz spot-on use. These data were used in conjunction HED’s 2012 Residential SOPs to 

refine the assessment of residential post-application exposures to demiditraz. Day of application 
Demiditraz Human Health Risk Assessment D410552

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(Day 0) residues were used to assess all durations of residential post-application exposure. For 

the purpose of characterizing longer-term exposures and risks (i.e., intermediate and long-term), 

multi-day exposure risk estimates were also quantified by use of the average of percent residue 

using transfer values predicted from Days 0 to 30 (i.e., the proposed product re-treatment 

interval).

Residential post-application adult dermal, and combined children 1 to < 2 years old exposures

are not of concern for all durations of exposure (i.e., adult dermal MOEs are > 300; and children

1 to < 2 years old ARIs are > 1) with use of Day 0 residue data. Exposures estimated for longerterm exposures using 30 day average residue data are approximately 7X below (MOEs 7X 

greater) those estimated for all durations using Day 0 data. 

Occupational exposures to veterinarians, veterinary assistants, and groomers may occur from the 

application of the proposed spot-on product to dogs. Dermal exposure assessments (all 

durations) were conducted to assess occupational handlers applying the demiditraz spot-on to 

dogs. Occupational handlers of the proposed product could potentially treat up to 170 dogs per 

day without resulting in risks of concern for all durations assessed (i.e., MOEs are ≥ 300). 

Occupational handler inhalation exposure is expected to be negligible and was not quantitatively

assessed. Further, a quantitative assessment of occupational post-application exposure from the 

proposed demiditraz spot-on product was not conducted. Occupational post-application 

activities are expected to be significantly less than residential post-application exposures. That 

is, dogs are expected to be treated and returned to their owners such that post-application contact 

will be negligible. 

Residential Aggregate Exposure and Risk Estimates: An aggregate exposure assessment, which 

combines exposures from different sources and routes, is typically conducted for non-food/ nonfeed chemicals when there is potential for human exposure through water and residential 

pathways. Demiditraz currently has no registered food/feed uses and no drinking water residues 

are expected to result from the proposed pet use; therefore, aggregate exposure includes only the 

exposure from the dog spot-on use.

Environmental Justice: Potential areas of environmental justice concerns, to the extent possible, 

were considered in this human health risk assessment. Only non-dietary exposures were 

considered.

2.0 HED Recommendations

HED has evaluated the exposure and toxicology databases, and assessed occupational and 

residential exposure and risk from the proposed demiditraz dog spot-on use and no issues have 

been identified which would preclude granting the Section 3 registration of the proposed use. 

2.1 Data Deficiencies

There are no exposure or toxicology data deficiencies to prohibit product registration. 
Demiditraz Human Health Risk Assessment D410552

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2.2 Tolerance Considerations

The dog spot-on product is the only use proposed for demiditraz and is classified (a nonfood/non-feed use); therefore, there are no tolerances to evaluate.

2.3 Label Recommendations from Occupational and Residential Assessment

As currently proposed, 1007-OT labeling does not include directions regarding the manner in 

which the spot-on should be applied to dogs. Label directions should include the following: 

how the application tube is prepared for treatment (i.e., snap or twist open); whether preparation 

of the application site is required (e.g., parting dog’s hair coat); and where on the dog’s body the 

product should be applied (i.e., single or multiple application points). Such language is 

necessary for appropriate use of the proposed product. 

3.0 Introduction

3.1 Chemical Identity

Table 3.1. Demiditraz Nomenclature

Chemical Structure

Empirical Formula C13H16N2

Common Name Demiditraz

Company Experimental Names PF-3814927

CAS Name 2-[(1S)-1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole

CAS Registry Number 944263-65-4

End Use Product/EP 1007-OT, 14.4% SC

Chemical Class Acaricide

Known Impurities of Concern None

3.2 Physical/Chemical Characteristics

The physicochemical properties of the technical grade of demiditraz are summarized in 

Appendix B, Table B.1. The log of the octanol/water partition coefficient is 2.8, which indicates 

no special concern for bioaccumulation in lipophilic matrices. Technical grade demiditraz is a 

solid at room temperature and, therefore, the volatility of the chemical was not determined as it is 

not anticipated to have significant volatility. 

 
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3.3 Pesticide Use Pattern

The proposed spot-on product (EPA Reg. No. 1007-OT) has been formulated by Pfizer Animal 

Health for the control of fleas and ticks on dogs and puppies ages 8 weeks and older. The liquid 

product contains 14.4% demiditraz and 4.8% fipronil and is available in four dog weight ranges: 

small, 11 to 20 lbs (1.0 ml); medium, 21 to 33 lbs (1.5 ml); intermediate, 34 to 50 lbs (3.0 ml); 

and large, 51 to 66 lbs (4.0 ml). The spot-on product is not proposed for use on cats. Details of 

the proposed use are summarized in Table 3.3. 

Table 3.3. Summary of Proposed Demiditraz Spot-On Use

EPA Reg. 

No. Use Site Application Rate Use Restrictions

1007-OT

(14.4% ai)

Small dogs from 11 

to 20 lbs 

0.00032 lb ai;

150 mg ai A single dose of 1007-OT is 

effective up to 6 weeks in controlling 

fleas and up to 4 weeks for ticks.

Monthly application is recommended 

for effective control of fleas and ticks 

and to prevent infestation. 

Medium dogs from 

21 to 33 lbs

0.00050 lb ai;

230 mg ai

Intermediate dogs 

from 34 to 50 lbs

0.00099 lb ai;

450 mg ai

Large dogs from 51 

to 66 lbs 

0.0013 lb ai;

600 mg ai

3.4 Anticipated Exposure Pathways

The Registration Division (RD) has requested an assessment of human health risk to support the 

proposed new use of demiditraz as a dog spot-on product. Humans may be exposed to 

demiditraz from occupational and/or residential use of the proposed product. Exposures may

occur from occupational and residential adult handlers applying the spot-on product to dogs, as 

well as from adult and child post-application contact with treated dogs. Because there are no 

proposed or existing food uses for demiditraz, no dietary or drinking water exposures are 

anticipated. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and/or the CDC under the National Health and 

Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), and are used in 

pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and 
Demiditraz Human Health Risk Assessment D410552

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categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Summary of Toxicological Effects

The nervous system is the primary target organ for demiditraz. Evidence of neurotoxicity after 

demiditraz exposure was observed in the following toxicity studies: acute neurotoxicity (ACN);

subchronic neurotoxicity (SCN); developmental neurotoxicity (DNT); subchronic dermal in rats;

subchronic oral in dogs; 2-generation reproduction in rats; and rat and rabbit developmental. 

Demiditraz effects on the nervous system were manifested as the following clinical signs which 

were observed within 30 minutes of dosing: altered gait and posture; impaired mobility;

decreased rearing, in-coordination; increased urination; lower body temperature; subdued 

appearance; rocks; lurches and sways when walking; hunched posture; hypoactivity; sitting with 

the head held low; a flattened body; piloerection; tremors/convulsions; prostration; wet and 

yellow urogenital area; shallow and/or decreased respiration; lacrimation; salivation; and dilated 

pupils. Decreased motor activity was noted in both sexes in the ACN and dermal toxicity

studies, whereas increased motor activity was observed in the SCN study. In the DNT, decreases 

and increases in motor activity were observed in the offspring at various ages; reduced grip 

strength, and increased amplitude and reduced latency were observed in the startle response test. 

Although the latter findings may be related to a general delay in offspring development rather 

than to neurotoxicity, they are consistent with the findings in other demiditraz toxicity studies. 

In the developmental toxicity studies, maternal toxicity was observed in the rat and rabbit, as 

evidenced by mortality, clinical signs of toxicity, and decreased body weight. Developmental 

toxicity was observed in the rat and rabbit, as evidenced by decreased fetal body weight and 

associated delayed ossification of the skeleton in rats and slight increases in the incidence of 27th

presacral vertebrae and 13th full ribs in the rabbit. In the rat reproductive toxicity study, 

mortality, clinical signs, and decreased body weight were observed in parental rats, and 

decreased survival, decreased brain weight, and decreased pup body weight were observed in the 

offspring. Reproductive toxicity was not observed. In the developmental neurotoxicity study in 

rats, maternal toxicity was observed, as evidenced by clinical signs of toxicity and effects on 

maternal behavior. The effects observed in the offspring included a delay in preputial separation 

in males and changes in motor activity, startle response, and grip strength, which may be 

attributed to a general delay in development.

The mutagenicity/genetic toxicity database consists of a bacterial reverse mutation test (Ames 

test), a forward mutation test in the V79/HGPRT test, chromosome aberration test in Chinese 
Demiditraz Human Health Risk Assessment D410552

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Hamster Ovary cells, and a mouse bone marrow micro nucleolus test. All studies were 

determined to be negative for mutagenicity and/or genetic toxicity, and there is no concern for 

mutagenicity/genetic toxicity for demiditraz. Demiditraz was assessed in a guideline 

immunotoxicity study, and no specific immunotoxicity was identified. 

In an absorption and distribution study in rats, evidence was obtained that showed a significant 

portion of the administered dose to the maternal rat partitioned into the milk and was available to 

the F1 offspring through nursing. The amount of test material in the stomach of the offspring 

was similar to the concentration in maternal milk. Detectable levels of the test material were 

observed in neonatal plasma demonstrating exposure to the offspring following maternal 

exposure, which negated the need for direct exposure of the offspring in the developmental 

neurotoxicity study. 

Based on limited metabolism data, demiditraz was rapidly absorbed and eliminated via the urine 

(71%) and feces (21%), with 92% being excreted within 48 hours post dose in the rat. The halflife in rats following oral exposure was determined to be approximately 30 minutes. In the dog, 

the half-life was 4.7 hours (oral) and 347 hours (dermal), and bioavailability was 10.1% 

following oral exposure and 18.6% following dermal exposure. 

A dermal absorption study is available for demiditraz, which identified a dermal absorption 

factor of 30%. Since the dermal risk assessments for all durations of exposure are based on a 

route-specific study (subchronic dermal toxicity study in rats), a dermal absorption factor is not 

needed. 

There is no subchronic inhalation toxicity study currently available to determine the potential for 

demiditraz to affect the nervous system by this route of exposure. It should be noted, however,

that an inhalation study is not relevant to the exposure pattern anticipated for the pet use, since 

significant inhalation exposure is not expected. 

4.2 Considerations of Toxicity to Children

Demiditraz does not require food tolerances and is considered to be a non-food/non-feed use chemical; 

therefore, it is not subject to the amendments to the Federal Food, Drug, and Cosmetic Act (FFDCA) 

promulgated under the Food Quality Protection Act (FQPA) of 1996. However, HED has assessed the 

potential for increased susceptibility for infants and children, and determined that no additional 

uncertainty factor is required for the protection of children based on considerations summarized 

in Sections 4.2.1 through 4.2.4, below. 

4.2.1 Completeness of the Toxicology Database

The toxicology database for demiditraz is complete for the pet use being assessed. The 

following studies have been submitted and found to be acceptable: rat and rabbit developmental 

toxicity studies; rat 2-generation reproduction; rat acute and subchronic neurotoxicity; rat 

developmental neurotoxicity; and rat immunotoxicity study. 
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4.2.2 Evidence of Neurotoxicity

There is evidence of neurotoxicity throughout the database, but neuropathology was not 

observed. Altered gait and posture, impaired mobility, decreased rearing, in-coordination, lower 

body temperature, and decreases in motor activity were observed in both sexes in the acute 

neurotoxicity study in rats. Several clinical signs of neurotoxicity, which included subdued 

appearance, rocks/lurches/sways when walking, hunched posture, hypoactivity, wet and yellow 

urogenital area, shallow and/or decreased respiration, lacrimation, and dilated pupils, and 

increased motor activity were observed in both sexes in the subchronic neurotoxicity study in 

rats. Decreased motor activity and altered grooming behavior were observed in both sexes in the 

90-day dermal toxicity study in rats. In the developmental toxicity studies, clinical signs 

suggestive of neurotoxicity were observed in the maternal rats (rocking, lurching, or swaying 

while walking, piloerection, dilated pupils, and subdued appearance) and rabbits (tremors, 

prostration, and/or clonic convulsions). In the 2-generation reproduction study in rats, clinical 

signs (subdued appearance, rocks/lurches/sways while walking, hypoactivity, tremors, clonic 

convulsions) suggestive of neurotoxicity were observed. In the developmental neurotoxicity

study in rats, decreased/increased motor activity and increased startle response amplitude and 

reduced latency were observed at the high dose where a delay in overall development was 

observed, mainly in males, as evidenced by decreased body weights throughout lactation in both 

sexes, and a delay in preputial separation. 

4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased susceptibility following in utero exposure to demiditraz in 

either the rat or rabbit developmental toxicity study, and there is no evidence of increased 

susceptibility following in utero and/or pre-/post-natal exposure in the 2-generation reproduction 

study in rats or in the developmental neurotoxicity study in rats. 

Demiditraz has been evaluated for potential developmental effects in the rat and rabbit (gavage 

administration). Maternal toxicity was observed in the rat and rabbit, as evidenced by mortality 

and clinical signs of toxicity and decreased body weights. Developmental toxicity was observed 

in the rat and rabbit, as evidenced by decreased fetal body weight and associated delayed 

ossification of the skeleton in rats and slight increases in the incidence of 27th presacral vertebrae 

and 13th full ribs in the rabbit. The developmental effects were observed at the same dose where 

maternal effects were observed in the rat and at a higher dose than where maternal effects were 

observed in the rabbit. In the rat reproductive toxicity study, mortality, clinical signs (subdued 

appearance, rocks/lurches/sways while walking, hypoactivity, tremors, clonic convulsions), and 

decreased body weight were observed in parental rats, and decreased survival, decreased brain 

weight, and decreased pup body weight were observed in the offspring at the same dose levels. 

In the developmental neurotoxicity study in rats, maternal toxicity (sitting with head held low, 

hypoactivity, a flattened body, slightly drooping eyelids, decreased respiration, clear material 

around mouth/salivation, lacrimation, and/or dilated pupils) was observed at a dose where no 

effects were observed in the offspring. 
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4.2.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database. Dietary (food and water) exposure 

assessments are not applicable to this assessment. Chemical-specific data are available for 

assessing exposure resulting from spot-on treatments of demiditraz; these data will not 

underestimate residential exposure. 

4.3 Toxicity Endpoint and Point of Departure Selections

4.3.1 Dose-Response Assessment

A detailed description of the toxicity studies used for toxicity endpoints and points of departure 

for various exposure scenarios is presented in Appendix A.

No acute or chronic dietary assessments are required since demiditraz is a non-food use 

pesticide.

The incidental oral endpoint (all durations) for risk assessment was from the oral subchronic 

neurotoxicity study in the rat with a NOAEL of 5 mg/kg/day. At the study LOAEL of 25 

mg/kg/day, clinical signs of neurotoxicity (subdued appearance, rocks, lurches, or sways when 

walking, hunched posture, hypoactivity, shallow/decreased respiration, lacrimation, dilated 

pupil), decreased motor activity, and decreased body weights were observed in both sexes. 

Inhalation hazard is assumed to be equivalent to oral hazard. 

The current risk assessment includes a chronic exposure assessment. The Point of Departure for 

assessing risks resulting from this duration of exposure was also the NOAEL from the 

subchronic neurotoxicity study. This 90-day duration POD is acceptable for quantifying chronic 

risks for the long-term incidental oral and inhalation risk assessments because there is no 

evidence of cumulative toxicity; i.e., rapid onset (within 30 minutes of exposure) and short 

duration (2 hours) of transient clinical signs.

Dermal endpoints (all durations) for risk assessment were from the route-specific subchronic 

(90-day) dermal toxicity study in the rat with a LOAEL of 100 mg/kg/day. A NOAEL was not 

identified. Alterations in motor activity and grooming behavior were observed at all dose levels. 

The same dermal study and endpoints are appropriate for long-term dermal assessment because 

there is no evidence of cumulative toxicity. 

An additional uncertainty factor of 3X is applied for the lack of a NOAEL (UFLOAEL→NOAEL). 

The 3X factor is considered appropriate for dermal exposure assessment (all durations). 

Application of the 3X factor results in an extrapolated dermal NOAEL of 33 mg/kg/day. Based 

on a dermal absorption factor of 31%, the orally equivalent dose is about 10 mg/kg/day. This is 

consistent with the 2-generation reproduction study NOAEL of 7.5 mg/kg/day, which noted 

similar effects as observed in the dermal study at an oral dose of 50 mg/kg/day. 

The UFDB of 10X retained in the previous human health risk assessment was removed since the 

data requirements for a rat developmental neurotoxicity study and a dog subchronic oral toxicity
Demiditraz Human Health Risk Assessment D410552

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study have been satisfied, and the dog was not found to be more sensitive than the rat to the 

neurotoxic effects of demiditraz. The demiditraz database is now considered complete.

4.3.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Since the dermal and oral endpoints are based on the same effects (neurotoxicity) these routes of 

exposure may be combined for purposes of this risk assessment. 

4.3.3 Cancer Classification and Risk Assessment Recommendation

Demiditraz has not been classified for carcinogenic potential. Rat and mouse carcinogenicity 

studies with demiditraz have not been submitted and are not required for the current nonfood/non-feed use. All studies conducted for mutagenicity/genetic toxicity were determined to 

be negative and, therefore, there is no concern for mutagenicity/genetic toxicity for demiditraz. 

There are also no reproductive toxicity concerns. 

4.3.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

Table 4.3.4.1. Summary of Toxicological Doses and Endpoints for Demiditraz for Use in 

Non-Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern 

for Risk 

Assessment

Study and Toxicological Effects

All dietary

Exposures

There are no current registrations for food uses. Therefore, no dietary endpoint has 

been selected for demiditraz at this time. 

Dermal 

(All Durations)

LOAEL = 100

mg/kg/day

UFA= 10X

UFH= 10X

UFLOAEL= 3X

MOE = 300

Subchronic dermal toxicity study 

LOAEL = 100 mg/kg/day, based on 

decreased motor activity in males 

and indications of ungroomed 

appearance. 

A NOAEL was not demonstrated 

since there was toxicity (decreased 

motor activity) and ungroomed 

appearance at the lowest dose tested. 

Incidental Oral 

(All Durations)

NOAEL= 5 

mg/kg/day

UFA= 10X

UFH= 10X MOE = 100

Subchronic neurotoxicity study with 

a LOAEL = 25 mg/kg based on 

clinical signs of neurotoxicity.
Demiditraz Human Health Risk Assessment D410552

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Table 4.3.4.1. Summary of Toxicological Doses and Endpoints for Demiditraz for Use in 

Non-Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern 

for Risk 

Assessment

Study and Toxicological Effects

Inhalation 

(All Durations) NOAEL= 5 

mg/kg/day

UFA= 10X

UFH= 10X MOE = 100

Subchronic neurotoxicity study with 

a LOAEL = 25 mg/kg, based on 

clinical signs of neurotoxicity. 

Cancer (oral, 

dermal, 

inhalation)

There are no carcinogenicity studies with demiditraz. The carcinogenic potential of 

demiditraz has not been evaluated.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFLOAEL = additional factor for extrapolation 

from LOAEL to NOAEL. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.3.4.2. Summary of Toxicological Doses and Endpoints for Demiditraz for Use in 

Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal 

(All Durations)

LOAEL ≤ 100

mg/kg/day

UFA= 10X

UFH= 10X

UFLOAEL= 3X

MOE = 300

Subchronic dermal toxicity study 

LOAEL = 100 mg/kg/day, based 

on decreased motor activity in 

males and indications of 

ungroomed appearance. 

A NOAEL was not demonstrated 

since there was toxicity 

(decreased motor activity) and 

ungroomed appearance at the 

lowest dose tested. 

Inhalation 

(All Durations)

NOAEL = 5 

mg/kg/day

UFA= 10X

UFH= 10X MOE = 100

Subchronic Neurotoxicity study 

LOAEL = 25 mg/kg, based on 

clinical signs of neurotoxicity. 

Cancer 

(oral, dermal, 

inhalation)

There are no carcinogenicity studies with demiditraz. The carcinogenic potential of 

demiditraz has not been evaluated.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 
Demiditraz Human Health Risk Assessment D410552

Page 15 of 47

sensitivity among members of the human population (intraspecies). UFLOAEL = extrapolation from LOAEL to 

NOAEL. MOE = margin of exposure. LOC = level of concern. 

5.0 Residential (Non-Occupational) Exposure/Risk Characterization

Residential exposure is expected from the proposed demiditraz dog spot-on use. Residential 

handler exposures are anticipated from application of the proposed product to dogs, and 

residential post-application exposures are expected to occur from contact with dogs previously 

treated with demiditraz. In assessing these exposures, the Health Effects Division’s (HED) 2012 

Standard Operating Procedures (SOPs) for Residential Pesticide Exposure Assessment: Treated 

Pets2 was used. Some of the data included in the 2012 Treated Pet SOP are proprietary and, 

thus, are subject to the data protection provisions of FIFRA.

5.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct tasks related to applications and that 

exposures can vary depending on the specifics of each task. Residential handlers are addressed 

somewhat differently by HED as homeowners are assumed to complete all elements of an 

application without use of any protective equipment.

Residential handler dermal exposure is expected to occur from application of the proposed 

demiditraz spot-on product to dogs. Inhalation exposure of spot-on products is considered to be 

negligible. A short-term residential handler dermal exposure assessment was performed for 

homeowners applying the proposed demiditraz products to dogs. Intermediate- and long-term 

exposures are not likely because of the intermittent nature (i.e., once monthly) of pet treatment

by homeowners. 

No chemical-specific unit exposure data were provided in support of this submission. Therefore,

HED used exposure values from the 2012 Residential SOPs (Treated Pets) as a surrogate to 

estimate handler exposures. Exposure data for spot-on applications (MRID 44433303) were 

used to estimate handler exposures for the proposed demiditraz spot-on product.

The algorithms and inputs used to estimate exposure and dose for residential handlers can also be 

found in the occupational and residential exposure and risk assessment3document which 

supports this memorandum.

Residential handler short-term dermal risk estimates are not of concern (i.e., MOEs > 300) for all 

dog weight ranges proposed. A summary of residential handler risk estimates is presented in 

Table 5.1.

 

2 http://www.epa.gov/pesticides/science/residential-exposure-sop.html

3 W. Britton. Demiditraz: Occupational and Residential Exposure and Risk Assessment for the Proposed Pet SpotOn Use (1007-OT). D400484,.D409676, D409677. 4/11/13.
Demiditraz Human Health Risk Assessment D410552

Page 16 of 47

Table 5.1. Residential Handler Short-Term Non-cancer Exposure and Risk Estimates from Use of the 

Proposed Demiditraz Spot-On

Exposure

Scenario Reg. No. Level of 

Concern

Dermal 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Unit 

Exposure 

(mg/lb ai)

Maximum 

Application 

Rate1

(lb ai/pet)

Amount 

Handled 

Daily2

Dermal

Dose 

(mg/kg/day)3 MOE4

Applying 

Demiditraz 

Spot-on

1007-OT

(14.4% ai)

Dermal:

300 120 Negligible

0.00032

(small)

2 Dogs

0.00097 100,000

0.00050

(medium) 0.0015 67,000

0.00099

(intermediate) 0.0030 34,000

0.0013

(large) 0.0040 25,000

1 Based on registered or proposed label (EPA Reg. No.1007-OT).

2 Based on HED’s 2012 Residential SOPs (Treated Pets) (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

3 Dermal Dose = Dermal Unit Exposure (120 mg/lb ai) × Application Rate (lb ai/ treatment) × Area Treated or Amount Handled 

(2 Dogs/day) × Dermal Absorption Factor (1.0) ÷ Body Weight (80 kg).

4 Dermal MOE = Dermal NOAEL (100 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

5.2 Residential Post-Application Exposure

There is the potential for post-application exposure for individuals exposed as a result of 

contacting a dog previously treated with the proposed demiditraz spot-on product. The 

quantitative exposure/risk assessment for residential post-application exposures is based on the 

following scenarios: 

1) Post-application dermal (adults and children 1 to < 2 years old) exposure from contacting 

dogs treated with demiditraz; and 

2) Post-application incidental oral exposure (children 1 to < 2 years old only) from contacting 

dogs treated with demiditraz.

The lifestages selected for each post-application scenario are based on an analysis provided as an 

Appendix in the 2012 Residential SOPs4. These lifestages are not the only that could be 

potentially exposed for these post-application scenarios; however, the assessment of these 

lifestages is health protective for the exposures and risk estimates for any other potentially 

exposed lifestages.

Due to the preventative nature of pet products and the potential for extended usage in more 

temperate parts of the country, the potential exists for applications to extend beyond a short-term 

duration. Therefore, residential post-application exposures of short-, intermediate-, and longterm durations were assessed for the proposed demiditraz spot-on product. 

 

4 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Demiditraz Human Health Risk Assessment D410552

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A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessment. Each assumption and factor is detailed in the 2012 Residential 

SOPs. A chemical-specific pet fur residue transfer study (MRID 48766704) was submitted by

Pfizer Animal Health in support of the proposed demiditraz spot-on use. HED has reviewed the 

exposure study5and this data was determined to acceptable for use for assessment of exposure 

and risk from the proposed use. 

The 2012 Residential SOPs (Treated Pets) recommends assessment of post-application exposures 

using day of application (i.e., Day 0) residue transfer -- defined as fraction application rate (FAR)

in the 2012 SOPs. HED used the average of Day 0 percent residue transfer values predicted 

from regression analysis in order to assess exposures and risks for all durations of postapplication exposures from the proposed demiditraz spot-on use. Day 0 FAR was determined to 

be 2.8%. 

A refined approach is also presented for the assessment of longer-term (i.e., intermediate- and 

long-term) post-application exposures. Per the 2012 Treated Pet SOP, the assessment of postapplication exposures to treated pets can be refined to more accurately reflect exposures over 

longer periods of time (e.g., several months). Instead of using the Day 0 percent residue transfer 

value, the average of percent residue transfer values predicted from Days 0 to 30 (i.e., proposed 

product re-treatment interval) was inputted. The FAR for the 30 day interval is 0.38%. 

HED combines risk values resulting from separate routes of exposure when the hazard associated 

with the points of departure is similar across routes. A common toxicological endpoint, 

neurotoxicity, exists for dermal and incidental oral routes of exposure to demiditraz. Residential 

post-application inhalation exposure is expected to be negligible from the proposed spot-on 

product and, thus, a quantitative assessment was not performed. 

Residential post-application adult dermal, and combined child 1 to < 2 years old years old

exposures (all durations) are not of concern (i.e., adult dermal MOEs are > 300; and children 1 to 

< 2 years old year old ARIs are > 1) with use of Day 0 FAR. Exposures estimated for the longerterm exposures using 30 day average residue data are approximately 7X below (MOEs 7X 

greater) those estimated for all durations using Day 0 FAR.

Table 5.2. Residential Post-Application Non-Cancer Exposure and Risk Estimates from the 

Proposed Demiditraz Spot-On Product: All Durations (Day 0 FAR)

Lifestage

Post-application Exposure 

Scenario Application Rate

(mg ai)1

Dose 

(mg/kg/day)2 MOEs3 ARI4

Use Site Route of 

Exposure

Adult Dog Dermal

150 (small) 0.066 1,500

NA 230 (medium) 0.067 1,500

450 (intermediate) 0.096 1,000

600 (large) 0.099 1,000

 

5 W. Britton, Demiditraz: Data Evaluation Record for the Study “Determination of Transferable Residues of 

Demiditraz and Fipronil from the Hair of Dogs Following the Spot-on Treatment Separately with Three Different 

Formulated End-Use Products.” D409400, EPA MRID 48766704, 4/11/13.
Demiditraz Human Health Risk Assessment D410552

Page 18 of 47

Table 5.2. Residential Post-Application Non-Cancer Exposure and Risk Estimates from the 

Proposed Demiditraz Spot-On Product: All Durations (Day 0 FAR)

Lifestage

Post-application Exposure 

Scenario Application Rate

(mg ai)1

Dose 

(mg/kg/day)2 MOEs3 ARI4

Use Site Route of 

Exposure

Children 

1 to < 2 

Years Old

Dermal 150 (small) 0.17 600 1.9 Incidental Oral 0.0017 3,000

Dermal 230 (medium) 0.17 590 1.8 Incidental Oral 0.0017 2,900

Dermal 450 (intermediate) 0.25 410 1.3 Incidental Oral 0.0025 2,000

Dermal 600 (large) 0.25 400 1.3 Incidental Oral 0.0025 2,000

1 Based on proposed label (Reg. No. 1007-OT)

2 Dermal Dose = [(Transfer Coefficient (cm2/hr) * (Application Rate (150, 230, 450, 600 mg ai) * Fraction Application Rate 

(0.028) ÷ Surface Area of Dog (cm2)) * Exposure Time (hours/day) * Absorption Factor (unitless)) / Body Weight (80 kg, 

adult; 11 kg, child 1 to < 2 years old years old)]

Hand-to-Mouth Dose = [(Hand Residue Loading (mg/cm2) × Fraction of Hand Mouthed (0.13) × Surface Area of 1 Hand (150 

cm2) × Exposure Time (1.5 hrs/day) × # of Replenishment Intervals/hr (4 int/hr) × (1-((1-Saliva Extraction Factor 

(0.5))^(Number of Hand-to-Mouth Events per Hour (13.9 events/hr) ) ÷ ( # of Replenishment Intervals/hr))] / Body Weight 

(11 kg child 1 to < 2 years old years old)]

3 MOE = Dermal, Incidental Oral POD (mg/kg/day) / Dose (mg/kg/day)

4. ARI = 1÷ [(1/ (Dermal MOE/Dermal LOC; 300)) + (1/(Incidental Oral MOE÷Incidental Oral LOC; 100))]

5.3 Combined Residential Risk Estimates (Multiple Exposure Scenarios)

Residential handler and post-application scenarios should generally not be combined. There is 

the potential for the same individual (i.e., adult) to apply a pesticide in and around the home and 

be exposed by reentering a treated area in the same day; however, combining both of these 

exposure scenarios would be inappropriate because of the conservative nature of each individual 

assessment.

5.4 Residential Risk Estimates for Use in Aggregate Assessment

An aggregate exposure assessment, which combines exposures from different sources and routes, 

is typically conducted for food/feed chemicals when there is potential for human exposure 

through drinking water and residential pathways. Demiditraz currently has no registered 

food/feed uses and no drinking water residues are expected to result from the proposed use; 

therefore, the aggregate exposure assessment consists only of the proposed use.

5.5 Residential Bystander Post-Application Inhalation Exposure

Occupational and residential inhalation exposures from dog spot-on treatments are considered 

negligible.
Demiditraz Human Health Risk Assessment D410552

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6.0 Aggregate Exposure/Risk Characterization

The demiditraz dog spot-on product is classified as a non-food/non-feed use with no proposed or 

existing food uses. Because demiditraz currently has no registered food uses and no drinking 

water residues are expected to result from the proposed pet use, the aggregate exposure 

assessment consists only of exposures from the proposed use. 

7.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to demiditraz and any other substances and demiditraz does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, 

EPA has not assumed that demiditraz has a common mechanism of toxicity with other 

substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s Office of Pesticide Programs concerning common 

mechanism determinations and procedures for cumulating effects from substances found to have 

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

8.0 Occupational Exposure/Risk Characterization

Occupational handler exposures are anticipated from the application of the proposed demiditraz 

spot-on product. Occupational post-application activities are expected to be significantly less 

than residential post-application exposures.

8.1 Occupational Handler Exposure/Risk Estimates

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure (i.e., veterinarians, veterinary

assistants, and groomers) could be expected from the demiditraz spot-on use. The quantitative 

exposure/risk assessment developed for occupational handlers (adults) is based on dermal 

exposure from the application of the spot-on product to dogs. Inhalation exposures are expected 

to be negligible from application of the spot-on product. 

A series of assumptions and exposure factors served as the basis for completing occupational 

handler risk assessments. A number of these are the same used for assessment of residential 

handler exposures. An assumption unique to the assessment of occupational handler exposures 

for the proposed demiditraz dog use is the number of animals treated daily. There is currently no 

recommendation for the number of animals treated by occupational handlers per application 

event. For the purpose of assessing occupational handler risk, the maximum number of dogs that 

could be treated with the proposed spot-on product without resulting in a risk of concern has 

been presented. 

Similar to residential use of the proposed spot-on product, occupational exposures are also 

expected to extend beyond a short-term duration due to temperate climates in some parts of the 
Demiditraz Human Health Risk Assessment D410552

Page 20 of 47

country and the preventative nature of spot-on pet products. For these reasons, it is expected that 

veterinarians, veterinary assistants, and groomers could treat dogs with the proposed demiditraz 

spot-on product for all durations of exposure (short-, intermediate-, and long-term) for flea and 

tick prevention and/or treatment.

The algorithms and inputs used to estimate exposure and dose for occupational handlers are the 

same as though used for residential handler exposure assessment, except for the number of pets 

treated explained above, and can be found in the 2012 Residential SOPs (Treated Pets) SOP, as 

well as in the occupational and residential exposure and risk assessment6 which supports this 

memorandum.

Only dermal exposures are expected from the proposed demiditraz spot-on use and, therefore, 

exposures were not combined from multiple routes. 

Occupational handlers of the proposed demiditraz spot-on product could treat up to 170 large 

dogs per day (all durations) without resulting dermal risks of concern (i.e., MOEs are ≥ 300). It 

is highly unlikely that this large a number of dogs could be treated daily in an occupational 

setting and, therefore, no risk concerns are anticipated from occupational use of the proposed dog 

spot-on product. A summary of occupational handler dermal risk estimates is presented in Table 

8.1. 

 

6 W. Britton. Demiditraz: Occupational and Residential Exposure and Risk Assessment for the Proposed Pet SpotOn Use (1007-OT). D409676.D409677. 4/11/13.
Demiditraz Human Health Risk Assessment D410552

Page 21 of 47

Table 8.1. Occupational Handler Non-Cancer Exposure and Risk Estimates (All Durations) for Demiditraz

Exposure 

Scenario Target

Dermal Unit 

Exposure 

(mg/lb ai)1

Inhalation Unit 

Exposure 

(mg/lb ai)

Maximum

Application 

Rate 

(lb ai)2

Maximum

Amount 

Handled 

Daily3

Dermal Inhalation

Single Layer, No 

Gloves No Respirator Dose (mg/kg/day)4 MOE5 Dose (mg/kg/day) MOE

Applying 

Demiditraz SpotOn ProductDogs 120 Negligible

0.00032

(small)

170 

Dogs 

0.082 1,200

Negligible

0.00050

(medium) 0.13 800

0.00099

(intermediate) 0.25 400

0.0013

(large) 0.34 300

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation: Baseline

2 Based on registered or proposed label (Reg. No. 1007-OT)

3. Maximum number of dogs that could be treated per day and not result in risks of concern (i.e., short-, intermediate and long-term, MOEs = 300) 

4 Dermal Dose = Dermal Unit Exposure (120 mg/lb ai) × Application Rate (lb ai/ treatmentl) × Amount Handled Daily (treatments/day) × DAF (1.0) ÷ BW (80 kg)

5 Dermal MOE = Dermal NOAEL (100 mg/kg/day) ÷ Dermal Dose (mg/kg/day)
Demiditraz Human Health Risk Assessment D410552

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8.2 Occupational Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). For the proposed demiditraz pet collar use, occupational post-application 

activities are expected to be significantly less than residential post-application exposures. That 

is, dogs are expected to be treated and returned to their owners such that post-application contact 

will be negligible. As a result, no quantitative occupational post-application exposure and risk 

assessment has been performed. The residential post-application exposure and risk assessment 

(Section 5.2) is considered protective for any potential occupational post-application exposures 

and risks.

References

W. Britton. Demiditraz: Human Health Risk Assessment for Proposed Dog Spot-On Use. 

D378783. 11/30/2010.

W. Britton. Demiditraz: Occupational and Residential Exposure and Risk Assessment for the 

Proposed Pet Spot-On Use (1007-OT). D409676.D409677. 4/11/13.

W. Britton. Demiditraz: Data Evaluation Record for the Study “Determination of Transferable 

Residues of Demiditraz and Fipronil from the Hair of Dogs Following the Spot-on Treatment 

Separately with Three Different Formulated End-Use Products.” D409400, EPA MRID 

48766704, 4/11/13.
Demiditraz Human Health Risk Assessment D410552

Page 23 of 47

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food and non food uses for demiditraz are in Table A.1. 

Use of the new guideline numbers does not imply that the new (1998) guideline protocols were 

used.

A.1. Summary of Toxicology Data Requirements - Demiditraz 

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes*

yes

yes

yes

yes

yes

no*

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent).........................................

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

CR

CR

no

yes

CR

yes

yes

no

yes

no

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

Yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

CR

no

CR

CR

no

no

no

no

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5xxx Mutagenicity—Structural Chromosomal Aberrations...

Yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Develop. Neurotoxicity .................................................

no

no

yes

yes

CR

no

no

yes

yes

yes

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

CR

CR

yes

no

no

yes

*Refer to review by R. Whiting dated May 21, 2010. There were technical problems in generating a test atmosphere

that precluded completion of the acute inhalation toxicity study. 

CR = conditionally required
Demiditraz Human Health Risk Assessment D410552

Page 24 of 47

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile – Technical Demiditraz

Guideline 

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral - rat 47744106 LD50 = 5000 mg/kg III

870.1200 Acute dermal - rat 47744107 LD50 > 5000 mg/kg IV

870.1300

Acute inhalation - rat None Waived

Technical 

complications in 

conducting the study. 

Test material could 

not be generated as an 

aerosol.

870.2400 Acute eye irritation -

rabbit

47744109 Slight or nonirritatingIV

870.2500 Acute dermal irritation -

rabbit

47744110 Slight irritant IV

870.2600 Skin sensitization -

guinea pig 

47744111 Not a sensitizer N/A

Table A.2.2. Demiditraz Study Details and Neurotoxicity Effects Observed

Guideline 

No. Study Type MRID No. (year)/ Classification Doses Results

870.6200a

Acute neurotoxicity 

(rat, Sprague-Dawley)

MRID 47744113 (2008)

Acceptable/Guideline

0, 15, 100, 600 mkd

NOAEL = 15 mkd.

1 dose

via gavage

FOB/MA assessed ≈15 minutes post dose

LOAEL = 100 mkd, based on altered gait and posture, 

impaired mobility, decreased rearing, in-coordination, 

increased urination, lower body temperature, 

decreased in motor activity in both sexes; at 600 mkd, 

clonic convulsions, hindlimb splay/dragging, ↓rotarod 

performance; low arousal. 

870.6200b

Subchronic 

neurotoxicity

(rat, Sprague-Dawley)

MRID 47744114 (2008)

Acceptable/Guideline

0, 5, 25, 125 mkd

NOAEL = 5 mkd.

90 days

via gavage

FOB/MA assessed prior to dosing (wks 1, 3, 7, 12)

LOAEL = 25 mkd, based on clinical signs (subdued 

appearance, rocks, lurches/sways when walking, 

hunched posture, hypoactivity, etc., both sexes), 

↓BW, increased motor activity; 125 mkd increased 

incidence of same findings. 

870.3150 Subchronic oral 

toxicity (dog, Beagle)

MRID 48459302 (2009)

Acceptable/Guideline

0, 10, 30, 100 mkd

NOAEL = 10 mkd.

90 days

capsule

assessed 30 minutes to 2 hrs post dose

LOAEL = 30 mkd, based on hypoactivity in both 
Demiditraz Human Health Risk Assessment D410552

Page 25 of 47

Table A.2.2. Demiditraz Study Details and Neurotoxicity Effects Observed

Guideline 

No. Study Type MRID No. (year)/ Classification Doses Results

sexes. At 100 mkd, all dogs displayed hypoactivity. 

870.3250

Subchronic dermal 

toxicity

(rat, Sprague-Dawley)

MRID 47752701 (2008)

Acceptable/Guideline

6 hr/day for 90 days

0, 100, 300, 1000 mkd

NOAEL not identified.

6 hr/day for 90 days

FOB/MA assessed prior to dosing during wk 10 and 

20 minutes after removal of test material during wk 

11

Dermal LOAEL = 100 mkd, based on decreased 

motor activity in both sexes at all dose levels. With 

31% DAF, internal dose of 31 mkd (LOAEL)

870.3800

2-generation 

reproduction 

(rat, Sprague-Dawley)

MRID 47744117 (2009)

Acceptable/Guideline

Crl:CD(SD)

10 weeks pre-mating

0, 7.5, 50, 150 mkd

NOAEL = 7.5 mkd.

10 weeks pre-mating

via gavage

assessed ≈30 minutes post dose

LOAEL = 50 mkd based on numerous clinical signs 

(both sexes; both generations); subdued appearance; 

rocks, lurches, or sways as it walks; pupils dilated; 

and hypoactivity; at 150 mkd, increased incidences 

tremors (both sexes), respiratory effects, and clonic 

convulsions (females), gasping (F1 male pups). 

870.3700a

Developmental 

toxicity

(rat, Sprague-Dawley)

MRID 47755402 (2008)

Acceptable/Guideline

GD 6-19

0, 5, 25, 100 mkd

NOAEL = 25 mkd.

GD 6-19 (14 days)

via gavage

assessed ≈30 minutes post dose

LOAEL = 100 mkd, based on mortality (1 on GD 19), 

clinical signs (behavioral findings of subdued 

appearance; rocking, lurching, or swaying while 

ambulating; rocking, piloerection, dilated pupils, 

sitting with head held low and appeared hypoactive 

but exhibiting normal behavior when stimulated), and 

wet clear material around mouth. 

870.3700b

Developmental 

toxicity (rabbit)

MRID 47755401 (2008)

Acceptable/Guideline

GD 6-29

0, 10, 50, 200/150 mkd

Maternal NOAEL = 10 mkd.

Developmental NOAEL = 50 mkd.

GD 6-29 (24 days)

via gavage

assessed ≈30 minutes post dose

LOAEL = 50 mkd, based on mortality (GD 16), 

clinical signs (tremors, prostration, and/or clonic 

convulsions); at 200 mkd, mortality GD 6, 9 @ 200 

mkd, clinical signs (tremors, prostration, and/or clonic 

convulsions). 

LOAEL = 200 mkd (developmental). 

870.5100 Gene Mutation

Ames test

MRID 47752704 (2008)

Acceptable/Guideline

0-5000μg/plate

Negative. No evidence of induced mutant colonies 

over background

870.5300 Forward mutation

V79/HPRT

MRID 47755404 (2008)

Acceptable/Guideline

0-9 μg/mL

Negative. No evidence of induced mutant colonies 

over background in the presence or absence of S9-

activation.

870.5375 Mammalian cell 

cytogenetics assay

MRID 47752705 (2008)

Acceptable/Guideline

0-2000 μg/mL

There was no evidence of chromosome aberrations 

induced over background in the presence or absence 

of S9-activation.

870.5395 Bone marrow 

micronucleus assay

MRID 47755403 (2008)

Acceptable/Guideline

There was no significant increase in the frequency of 

micronucleated polychromatic erythrocytes in bone 
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Table A.2.2. Demiditraz Study Details and Neurotoxicity Effects Observed

Guideline 

No. Study Type MRID No. (year)/ Classification Doses Results

0-1000 mg/kg/day marrow after any treatment time.

870.6300

Developmental 

neurotoxicity 

(rat, Sprague-Dawley)

MRID 48766703 (2012)

Acceptable/Guideline

Crl:CD(SD)

GD 6 to LD 21

0, 5, 15, 100 mkd

Maternal NOAEL = 5 mkd.

From GD 6 to LD 21

(≈40 days) via gavage

Offspring NOAEL = 15 mkd.

Until PND 72 via gavage

(≈50 days)

assessed ≈30 minutes and 2 hrs post dose

Maternal LOAEL = 15 mkd, based on maternal 

clinical signs (sitting with the head held low, 

hypoactivity, a flattened body, slightly drooping 

eyelids, decreased respiration, clear material around 

the mouth/salivation, lacrimation, and/or dilated 

pupils); at 100 mkd, same as above and slightly 

increased post-dosing incidences of findings 

indicative of diminished maternal care (dam away

from the nest, but not eating, drinking, grooming, or 

tending to the litter, and 1-3 pups outside of the nest).

Offspring LOAEL = 100 mkd, based on based on 

decreased postnatal survival, decreased pup 

body weights and body weight gains, increased 

maximum response to the auditory startle 

stimulus and reduction in response time on PND 

60, decreased/increased total and ambulatory 

motor activity counts, decreased grip strength 

(PND 21 and PND 35), decreased brain weight 

in PND 21 males, and delayed attainment of

870.7485 General metabolism

MRID 47744136 (2008)

MRID 47752712 (2008)

MRID 47752713 (2009)

MRID 47752714 (2009)

MRID 47755406 (2009)

92% of administered oral dose recovered in 48 hours; 

71% (urine); 21% (feces). Excretion nearly complete 

(84%) in 24 hours.

i.v., oral, i.p., similar half-life of 0.28 to 0.5 hour.

i.v., oral, dermal half-lives of 1.06, 4.72, 347 hours; 

bioavailability reported to be 10.1% (oral); 18.6% 

(dermal).

870.7800 Immunotoxicity

(rat, Sprague-Dawley)

MRID 47744122 (2009)

Crl:CD(SD)

0, 10, 30, 100 mkd

via gavage (28 days)

NOAEL (systemic toxicity) = 30 mkd.

assessed ≈30 minutes post dose

Negative for immunotoxicity potential. 100 mkd 

(HDT).

LOAEL (systemic toxicity) = 100 mg/kg/day, based 

on clinical signs of toxicity (rocking lurching, or 

swaying while walking; drooping eyelids; subdued 

appearance at cage-side observation; flattened body; 

hunched posture; clear material around mouth; and 

yellow material on various body surfaces). 

870.7600 Dermal absorption 

(rat) MRID 47752709 (2008) 31% based on amount absorbed and remaining on skin after 168 hours.
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute and Chronic Reference Doses (aRfD and cRfD) – All Populations

Study Selected: No studies were selected. These values are calculated for dietary exposures, 

which currently is not a relevant route of exposure for the proposed use. 

A.3.2 Incidental Oral – Short- and Intermediate-Terms

Study Selected: Combined Subchronic Oral Toxicity and Neurotoxicity Study

MRID No.: 47744114

Executive Summary: See Appendix A, Guideline [§ 870.3100 and 870.6200b]

Dose and Endpoint for Establishing aRfD: The NOAEL of 5 mg/kg/day is based on clinical 

signs of neurotoxicity (subdued appearance, rocks, lurches/sways when walking, hunched 

posture, hypoactivity, etc.) in both sexes. 

UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies 

variation (10X). 

Comments on Study/Endpoint/UFs: This study provides the lowest NOAEL in the database 

considered to be valid for this exposure and all durations and is protective for any potential 

adverse effects in humans. The developmental neurotoxicity study in rats provided the same 

NOAEL of 5 mg/kg/day in the maternal animals. The combined subchronic oral toxicity and 

neurotoxicity study in rats was selected in preference to the developmental neurotoxicity study

because of the extensive neurotoxicity evaluations carried out in the adult male and female for up 

to 90 days. Most of the other oral toxicity studies gave similar values for the NOAEL: 15 

mg/kg/day in the acute neurotoxicity study in rats, 10 mg/kg/day in the subchronic oral toxicity

study in dogs, 7.5 mg/kg/day in the 2-generation reproduction study in rats, and 10 mg/kg/day

for maternal toxicity in the developmental toxicity study in rabbits. Demiditraz acts on 

neurotransmitter systems in mammals. Clinical signs of neurotoxicity were the most sensitive 

endpoint and were observed in all the toxicity studies. The UFs included the standard accounting 

for interspecies extrapolation and intraspecies variation; no additional uncertainty factors were 

needed. There was no evidence provided which would indicate that children or more sensitive to 

the effects than adults.

A.3.3 Dermal – All Durations

Study Selected: Subchronic Dermal Toxicity Study

MRID No.: 47752701

Executive Summary: See Appendix A, Guideline [§ 870.3250]

Dose and Endpoint for Establishing aRfD: A NOAEL was not established. The 

LOAEL ≤ 100 mg/kg/day is based on decreased motor activity and ungroomed appearance. 
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UF(s): A UF of 300 was applied to account for interspecies extrapolation (10X), intraspecies 

variation (10X), and the use of a LOAEL instead of a NOAEL (3X). 

Comments on Study/Endpoint/UFs: This study provides the lowest LOAEL in the database 

considered to be valid for this exposure and all durations and is protective for any potential 

adverse effects in humans. Considering that the dermal absorption is 31%, the internal dose is 

expected to be 31 mg/kg/day. An uncertainty factor of 3X was applied for the use of a LOAEL 

instead of a NOAEL. Thus, the expected internal dose for the NOAEL is 10 mg/kg/day, which is 

similar to the results of the oral studies. As this was the case, it was preferable to use the dermal 

study for the estimation of a dermal endpoint rather than an oral study. Demiditraz acts on 

neurotransmitter systems in mammals. Clinical signs of neurotoxicity were the most sensitive 

endpoint and were observed in all the toxicity studies. The UFs included the standard accounting 

for interspecies extrapolation and intraspecies variation, and an additional factor for using a 

LOAEL instead of a NOAEL (3X). There was no evidence provided which would indicate that 

children or more sensitive to the effects than adults.

A.3.5 Inhalation – All Durations

Study Selected: Combined Subchronic Oral Toxicity and Neurotoxicity Study

MRID No.: 47744114

Executive Summary: See Appendix A, Guideline [§ 870.3100 and 870.6200b]

Dose and Endpoint for Establishing aRfD: The NOAEL of 5 mg/kg/day is based on clinical 

signs of neurotoxicity (subdued appearance, rocks, lurches/sways when walking, hunched 

posture, hypoactivity, etc.) in both sexes. 

UF(s): A UF of 100 was applied to account for interspecies extrapolation (10X) and intraspecies 

variation (10X). An additional factor (10X) should be applied when calculating reference doses 

for long-term exposure.

Comments on Study/Endpoint/UFs: This study provides the lowest NOAEL in the database 

considered to be valid for this exposure and all durations and is protective for any potential 

adverse effects in humans. No inhalation study was submitted, but inhalation exposures are not 

anticipated from either occupational or residential use of the spot-on product. Consequently, the 

oral study was selected, and complete absorption through the respiratory system was assumed. 

The developmental neurotoxicity study in rats provided the same NOAEL of 5 mg/kg/day in the 

maternal animals. The combined subchronic oral toxicity and neurotoxicity study in rats was 

selected in preference to the developmental neurotoxicity study because of the extensive 

neurotoxicity evaluations carried out in the adult male and female for up to 90 days. Most of the 

other oral toxicity studies gave similar values for the NOAEL: 15 mg/kg/day in the acute 

neurotoxicity study in rats, 10 mg/kg/day in the subchronic oral toxicity study in dogs, 7.5 

mg/kg/day in the 2-generation reproduction study in rats, and 10 mg/kg/day for maternal toxicity

in the developmental toxicity study in rabbits. Demiditraz acts on neurotransmitter systems in 

mammals. Clinical signs of neurotoxicity were the most sensitive endpoint and were observed in 

all the toxicity studies. The UFs included the standard accounting for interspecies extrapolation 
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and intraspecies variation; no additional uncertainty factors were needed, except when assessing 

long-term durations (10X). There was no evidence provided which would indicate that children 

or more sensitive to the effects than adults.

A.4 Executive Summaries

A.4.1 Sub-chronic Toxicity

870.3100a Combined Subchronic Oral Toxicity and Neurotoxicity – Rat

In a subchronic neurotoxicity study (2008, MRID 47744114), PF-3814927 (Demiditraz, 100% 

a.i.; Batch No. PFXU070002) in 0.5% methylcellulose and 0.1% Tween 80 was administered 

daily via gavage (5 mL/kg) to 22 Sprague-Dawley rats/sex/group at dose levels of 0, 5, 25, or 

125 mg/kg/day for 13 weeks. Ten rats/sex/dose were designated as the Phase I (general toxicity) 

group, and were evaluated for hematology, clinical chemistry, ophthalmology, organ weight, and 

gross and histopathology parameters. Neurobehavioral assessment (functional observational 

battery [FOB] and motor activity testing) was performed on the remaining 12 rats/sex/group 

(Phase II) at pre-dosing and Weeks 1, 3, 7, and 12 (prior to administration of dosing). At study

termination, all Phase II animals were anesthetized and perfused in situ for brain weights and 

morphometry. The tissues from 6 rats/sex/group of the perfused animals in the control and 125 

mg/kg/day groups were subjected to histopathological evaluation of central and peripheral 

nervous system tissues. 

At 25 mg/kg/day, body weights were decreased (p<0.05) by 7-8% in the males during Weeks 

8-13 and by 7% each in the females at Weeks 7 and 10. Body weight gains were decreased 

(p<0.05) by 33% in the males during Weeks 7-8. Overall body weight gains were decreased 

(p<0.05) by 11% in the males. At 30 minutes post-dosing, the following treatment-related 

clinical signs of toxicity were observed (# affected/22 vs. 0/22 controls, unless otherwise stated): 

(i) subdued appearance at cage-side observation only (10 males and 9 females); (ii) rocks, 

lurches, or sways when walking (6 males and 6 females); (iii) hunched posture (6 females); (iv) 

hypoactivity (2 males); (v) wet yellow material urogenital area (3 males and 6 females); (vi) 

lacrimation right/left eye (8 males and 19 females vs. 2 control females); (vii) dilated pupil 

right/left eye (5 males and 6 females); (viii) dried red material around mouth (4 males and 1 

female vs. 1 control male); and (ix) wet red material around mouth (2 males). Cumulative 

ambulatory activity was increased (p<0.05) by 41-45% in the males at Weeks 3 and 7.

At 125 mg/kg/day, body weights were decreased (p<0.01) by 9-14% in the males and by 7-10% 

in the females during Weeks 3-13. Additionally, body weight gains were sporadically decreased 

(p<0.05) by 14-48% in the males and by 17-56% in the females. Overall (Weeks 0-13) body 

weight gains were decreased (p<0.01) by 15-19% in both sexes. At 30 minutes post-dosing, the 

following treatment-related clinical signs of toxicity were observed (# affected/22 vs. 0/22 

controls, unless otherwise stated): (i) subdued appearance at cage-side observation only (all 

males and females); (ii) rocks, lurches, or sways when walking (all males and females); (iii) 

hunched posture (17 males and all females); (iv) hypoactivity (11 males and 3 females); (v) wet 

yellow material urogenital area (20 males and 21 females); (vi) shallow respiration (7 males and 

1 female); (vii) decreased respiration (10 males); (viii) lacrimation right/left eye (20 males and 

all females vs. 2 control females); (ix) dilated pupil right/left eye (20 males and 19 females); (x) 
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dried red material around mouth (9 males and 11 females vs. 1 control male); and (xi) wet red 

material around mouth (8 of each sex). Cumulative (session) total activity was increased by 29-

32% in the males at Weeks 1 and 3 and by 31-32% in the females throughout the study. Also at 

this dose, cumulative ambulatory activity was increased by 43-56% in the males at Weeks 1, 3, 

and 7 and by 49-65% in the females throughout the study.

No compound-related effects were observed in mortality, food consumption, ophthalmoscopic 

examinations, hematology, clinical chemistry, FOB parameters (note: FOB assessments were 

made prior to daily dosing), brain weight and morphology, organ weights, gross lesions, or 

microscopic lesion in either sex.

The LOAEL was 25 mg/kg/day based on multiple clinical signs of toxicity in both sexes, 

decreased body weight gains in males, and increased motor activity in males. The NOAEL is 5 

mg/kg/day.

The study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 

870.6200b; OECD 424) for a subchronic neurotoxicity study in rats.

870.3150 90-Day Oral Toxicity – Dog

In a subchronic 90-day oral toxicity study (2009, MRID 48459302) demidiraz (99.8% a.i., Lot # 

TCK08001K) was administered to 4 beagle dogs/sex orally in gelatin capsules at dose levels of 0 

(control), 10, 30 or 100 mg/kg bw/day. Clinical signs of toxicity, mortality, ophthalmologic,

hematology, clinical chemistry, urinalysis, electrocardiographic measurements, pathology and 

biokinetic data were obtained.

There were no adverse effects on mortality, ophthalmology, hematology, clinical chemistry

urinalysis and electrocardiographic examinations. In the 30 mg/kg/day hypoactivity was 

observed in 1 male and 1 female, and in all 8 dogs in the 100 mg/kg/day group. There was an 

increased incidence of vomitus containing food in 2 males and 2 females in the 30 mg/kg/day

group and in 4 males and 3 females in the 100 mg/kg/day group. Body weight gain was 

statistically significantly decreased in males in the 100 mg/kg/day group from predosing day 17 

to Day 91 by 20% . Females in the 100 mg/kg day group from predosing day 17 to Day

91showed a loss of weight of 0.2 kg. Food consumption was statistically significantly decreased 

in males in the 100 mg/kg/day group from 36-80%. Three of 4 males in the 100 mg/kg/day

group exhibited treatment related minimal cell infiltrates in the adrenal zona fasiculata.

The LOAEL is 30 mg/kg bw/day in males and females, based on behavioral toxicity; i.e., an 

increased incidence of hypoactivity. The NOAEL in males and females is 10 mg/kg bw/day.

Pharmacokinetic data indicated that demiditraz did not bioaccumulate and there were no sex 

differences in the pharmacokinetics. 

This 90-day oral toxicity study in the dog is acceptable/guideline and satisfies the requirement 

for a 90-day oral toxicity study (OPPTS 870.3150; OECD 409) in the dog.
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870.3250 90-Day Dermal Toxicity – Rat 

In a repeated-dose dermal toxicity study (2008, MRID 47752701), PF-3814927 (Demiditraz, 

99.5% a.i., Lot #s PFXA070001 and PFXU070002) in deionized water was applied to the 

shaved intact skin of 10 Sprague-Dawley rats/sex/dose at dose levels of 0, 100, 300, or 1000 

mg/kg/day (limit dose), 6 hours/day for 91/92 consecutive days. Additional groups of 3 

rats/sex/dose were exposed at the same doses for 87 consecutive days. Blood was collected from 

the latter animals on Days 0 and 86 (approximately 6, 12 and 24 hours after application of the 

test material and the plasma was used for toxicokinetic exposure evaluations. Systemic exposure 

(as assessed by Cmax and AUC0-24) “generally increased or remained unchanged with increasing 

dose.” For example, at day 87 the mean plasma concentration (ng/ml) was 479±743, 1150±1540 

and 1270±715 for the 100, 300 and 1000 mg/kg/day dose groups, respectively. There is an 

apparent increase between the lowest dose and middle dose but the two highest doses are closer 

together. 

Clinical signs were consisted of increased incidences of wet and/or dried yellow material on 

various body surfaces and dried red material around one or both eyes and nose in the 300 and 

1000 mg/kg/day males and females. During the handling observations of the FOB at Weeks 10 

(prior to dosing) and 11 (after dose removal), unkempt appearance (slightly soiled to very soiled 

fur) was noted in the 1000 mg/kg/day males and females. During Week 11 (after dose removal), 

total motor activity was decreased (p<0.05) in all treated male groups during the 0-10 and 11-20 

minute intervals and all treated female groups during the 11-20 minute interval. These decreases 

in the males resulted in decreases (not dose-dependent, p<0.05) in cumulative total activity of 26, 

40, and 26% in the 100, 300, and 1000 mg/kg/day groups, respectively. The motor activity

decrease is consistent with the decrease seen in the oral acute neurotoxicity study noted 

following dosing. No compound-related effects were observed in mortality, body weight, body 

weight gain, food consumption, ophthalmoscopic exams, hematology, clinical chemistry, 

absolute or relative organ weights, or gross or microscopic pathology in either sex. Application 

site dermal effects were limited to very slight to slight erythema noted in the 300 and 1000 

mg/kg/day groups and are considered self limiting. 

The NOAEL (systemic) < 100 mg/kg/day. The LOAEL is 100 mg/kg/day based on decreased 

motor activity in both sexes at all dose levels tested. 

The LOAEL (local irritation) = 300 mg/kg/day based on erythema. The NOAEL is 100 

mg/kg/day. 

This study is classified as acceptable/guideline and satisfies the guideline requirement for a 90-

day dermal toxicity study (OPPTS 870.3250; OECD 411) in rats.
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A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (2008, MRID 47755402), Demiditraz technical (PF-3814927; 

100% a.i.; Batch # PFXU070002) in 0.5% methylcellulose and 0.1% TweenTM 80 was 

administered daily via gavage in a dose volume of 10 mL/kg to 25 time-mated presumed 

pregnant Sprague Dawley rats/dose group at dose levels of 0, 5, 25, or 100 mg/kg/day from 

gestation days (GD) 6-19. Blood samples were collected from 4 randomly selected rats per 

group 1 hour after dose administration on GD 19 to determine test substance levels in plasma. 

On GD 29, all maternal rats were euthanized; each dam’s uterus and ovaries were removed via 

cesarean section and the contents examined. The fetuses were examined for external, visceral, 

and skeletal malformations and variations.

Plasma concentrations. Demiditraz concentrations in plasma increased in a dose-dependent 

manner, with measurements of 2.41, 39.9, and 1020 ng/mL in the 5, 25, and 100 mg/kg/day

groups. 

Maternal toxicity. At 100 mg/kg/day, one female (# 83309) was found dead approximately 0.5 

hours following dose administration on GD 19. At the 0.5 hour post-dose observations, this 

female had: behavioral findings of subdued appearance upon cage-side observations; rocking, 

lurching, or swaying while ambulating on 3 to 5 occasions during GD 6-18; and a single 

occurrence of clear material around the mouth on GD 14. Although a cause of death could not 

be determined at necropsy, this death was considered treatment-related because it occurred 

around the time of expected peak exposure (0.5 hours post-dose), and the indications of maternal 

toxicity (post-dosing clinical observations, decreased body weight gain, and decreased food 

consumption) were similar to the findings found in the rest of the animals in this group. All 

other dams survived until scheduled termination.

At 100 mg/kg/day, the dams exhibited numerous clinical signs of toxicity at the 0.5-hour postdosing examinations including rocking, lurching, or swaying while walking, piloerection, dilated 

pupils, subdued appearance upon cage-side observation only (sitting with head held low and 

appeared hypoactive but exhibiting normal behavior when stimulated), and wet clear material 

around mouth. These findings were noted as early as the first day of dose administration (GD 6) 

and generally continued throughout the treatment period. Additionally, salivation immediately

prior to dose administration was noted at this dose but was attributed to a response to the taste or 

irritating properties of the test material and was not considered adverse.

At 100 mg/kg/day, body weights were decreased by 5-6% (p<0.05) on GD 18, 19, and 20. Boy

weight gains were decreased (p<0.01) by 58% during GD 6-10, by 16% for GD 14-20, and by 

20% for the overall (GD 6-20) treatment period. Gravid uterine weights were decreased by 12% 

(p<0.01), and corrected body weight gain for the overall (GD 0-20) study were decreased by 

15% (p<0.05). Absolute and relative food consumption was decreased (p<0.01) by 14-15% for 

GD 6-10 and by 6-11% for GD 6-20. Additionally at this dose, absolute food consumption was 

decreased by 7% for GD 14-20. 
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The maternal LOAEL is 100 mg/kg/day based on mortality, clinical signs of toxicity, and on 

decreased body weights, body weight gains, and food consumption. The maternal NOAEL is 25 

mg/kg/day.

Developmental toxicity. There were no abortions, premature deliveries, complete litter 

resorptions, or dead fetuses. Furthermore, there were no treatment-related effects on the 

numbers of litters, early resorptions, late resorptions, or live fetuses. Sex ratio and postimplantation loss were unaffected by treatment.

Fetal variations were limited to the incidences of delayed ossification. At 100 mg/kg/day, fetal 

body weights were decreased by 11% (p<0.05) each in the males and females. The incidence of 

sternebra(e) #5 and/or #6 unossified was increased at 100 mg/kg/day (42.3% fetuses; 95.7% 

litters) compared to concurrent controls (26.1% fetuses; 87.0% litters) and historical controls 

(0.2-23.1% fetuses). Similarly, the incidence of reduced ossification of the vertebral arches was 

increased at 100 mg/kg/day (1.9% fetuses; 17.4% litters) compared to concurrent controls (0%) 

and historical controls (0.0-1.1% fetuses). Several other skeletal variations characterized by 

delayed ossification differed from concurrent controls at 100 mg/kg/day and, although the fetal 

incidences of these findings fell within the range of historical controls, they were considered to 

be treatment-related because they corresponded to the statistically significant, treatment-related 

decreases in fetal body weights at this dose. These variations included: (i) increases in 

sternebra(e) #1, 2, 3, and/or 4 unossified at 100 mg/kg/day (1.1% fetuses; 17.4% litters) 

compared to concurrent (0.3% fetuses; 4.3% litters) and historical (0.0-1.3% fetuses) controls; 

(ii) increases in pubis unossified at 100 mg/kg/day (1.6% fetuses; 4.3% litters) compared to 

concurrent (0%) and historical (0.0-2.3% fetuses) controls; (iii) increases in hyoid unossified at 

100 mg/kg/day (2.3% fetuses; 17.4% litters) compared to concurrent (1.4% fetuses; 17.4% 

litters) and historical (0.0-4.2% fetuses) controls; and (iv) decreases in incidence of ossified 

cervical centrum #1 at 100 mg/kg/day (12.0% fetuses; 65.2% litters) compared to concurrent 

(19.7% fetuses; 78.3% litters) and historical (6.6-35.8% fetuses) controls. 

There were no treatment-related external, visceral, or skeletal malformations.

The developmental LOAEL is 100 mg/kg/day based on decreased fetal body weights and 

associated delayed ossification of the skeleton. The developmental NOAEL is 25 mg/kg/day.

This study is classified acceptable/guideline and satisfies the guideline requirement (OPPTS 

870.3700a; OECD 414) for a developmental toxicity study in rats.

870.3700b Prenatal Developmental Toxicity Study – Rabbit 

In a developmental toxicity study (2008, MRID 47755401), Demiditraz technical (PF-3814927; 

100% a.i.; Batch # PFXU070002) in 0.5% methylcellulose and 0.1% TweenTM 80 was 

administered via gavage in a dose volume of 5 mL/kg to 25 time-mated presumed pregnant New 

Zealand White rabbits/dose group daily from gestation days (GD) 6-28. Initial doses were 0, 10, 

50, and 200 mg/kg/day. Due to excess toxicity, the high dose level was lowered to 150 

mg/kg/day on GD 9, 10, or 11 for the remainder of the study. Blood samples were collected 

from 4 rabbits per group 1 hour after dose administration on GD 28 to determine test substance 
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levels in plasma. On GD 29, all maternal rabbits were euthanized; each doe’s uterus and ovaries 

were removed via cesarean section and the contents examined. The fetuses were examined for 

external, visceral, and skeletal malformations and variations.

Plasma concentrations. Demiditraz concentrations increased in a dose-dependent manner, with 

measurements of 411, 1940, and 5390 ng/mL in the 10, 50, and 200/150 mg/kg/day animals. It 

was stated that this time point was the expected maximum plasma concentration (0.5 to 2.2 

hours) based on the previously conducted range-finding study (Bowman, 2007, WIL-344041). 

Maternal toxicity. The morbidity in the three animals at the high dose occurred early in the study

(GD 6 or 9) when the animals were receiving 200 mg/kg/day. The female that was euthanized in 

extremis at 50 mg/kg/day was observed with tremors and rales approximately 30 minutes 

following dose administration on GD 14, two days prior to euthanasia on GD 16. The 

deaths/euthanasia in the 50 and 200/150 mg/kg/day groups occurred along with clinical signs 

indicating neurotoxicity (tremors, prostration, and/or clonic convulsions) approximately 30 

minutes following dose administration. 

At 50 mg/kg/day, body weights were decreased by 6% (p<0.05) on GD 14-16. At 200/150 

mg/kg/day, body weights were decreased by 5-9% beginning on GD 8 and continuing throughout 

the remainder of the study; with the exception on GD 26 and 27, these decreases were 

statistically significant (p<0.05). Statistically significant (p<0.05) body weight losses were noted 

in the 50 mg/kg/day (-11 g) and 200 mg/kg/day (-154 g) groups compared to a body weight gain 

in the control group of 35 g at the beginning of the dose administration period (GD 6-9). For GD 

9-12, body weight gains were decreased by 88% (p<0.01), and a significant (p<0.01) body

weight loss was observed at 200/150 mg/kg/day (-4 g) compared to a body weight gain in 

controls (58 g). For the overall treatment period (GD 6-29), a significant (p<0.01) body weight 

loss was noted at 200/150 mg/kg/day (-51 g) compared to a body weight gain in the controls 

(215 g).

Absolute and relative (to body weight) food consumption was decreased (p<0.01) by 20-27% at 

50 mg/kg/day for GD 6-9 and 9-12 and by 42-65% at 200/150 mg/kg/day for GD 6-9, 9-12, and 

12-21. Additionally at 50 mg/kg/day, absolute food consumption was decreased by 24% 

(p<0.05) for GD 12-21. Absolute and relative food consumption for the overall (GD 6-29) 

treatment period were decreased (p<0.05) by 15-20% at 50 mg/kg/day and by 38-42% at 200/150 

mg/kg/day. No treatment-related findings were found at necropsy. The maternal LOAEL is 50 

mg/kg/day based on incidences of mortality/moribundity, clinical signs of toxicity, and 

decreased body weights, body weight gains, and food consumption. The maternal NOAEL is 10 

mg/kg/day.

Developmental toxicity. There were no complete litter resorptions or dead fetuses. Furthermore, 

there were no treatment-related effects on the numbers of early resorptions, late resorptions, or 

live fetuses per doe. Sex ratio was unaffected by treatment. There were no treatment-related 

external, visceral, or skeletal malformations.

At the high dose, fetal body weights were decreased by 12% (not significant [NS]) in the males 

and by 13% (p<0.05) in the females. Fetal and litter incidences of rabbits with 27 presacral 
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vertebrae were dose-dependently increased at 50 mg/kg/day (15.0% fetuses, 54.5% litters) and 

200/150 mg/kg/day (29.6% fetuses, 64.7% litters) compared to concurrent controls (5.0% 

fetuses, 26.1% litters). The fetal incidences of this variation at 50 mg/kg/day fell within the 

range of historical controls (4.8-15.6% fetuses); however, the incidence at 200/150 mg/kg/day

exceeded the range of historical controls. Therefore, the incidences of 27 presacral vertebrae at 

200/150 mg/kg/day were considered to be due to treatment. Similarly, the fetal incidences of 

rabbits with full 13th rib(s) were dose-dependently increased at 50 mg/kg/day (42.9% fetuses, 

90.9% litters) and 200/150 mg/kg/day (57.2% fetuses, 88.2% litters) compared to concurrent 

controls (33.2% fetuses, 91.3% litters). The fetal incidences of this variation at 50 mg/kg/day

fell within the range of historical controls (16.5-45.7% fetuses); however, the incidence at 

200/150 mg/kg/day exceeded the range of historical controls. Therefore, the incidences of full 

13th rib(s) at 200/150 mg/kg/day were considered to be due to treatment. However, it should be 

noted that these findings (27 presacral vertebrae and 13th full ribs) comprise two of the three 

most commonly observed skeletal variations. The developmental LOAEL is 200/150 mg/kg/day

based on decreased fetal body weights and slight increases in the incidences of 27 presacral 

vertebrae and 13th full rib(s). The developmental NOAEL is 50 mg/kg/day. Note: Apparent 

increases in the skeletal variations at the high dose were also evident in the 50 mg/kg/day dose 

but were within historical control range. 

This study is classified acceptable/guideline and satisfies the guideline requirement (OPPTS 

870.3700b; OECD 414) for a developmental toxicity study in rabbits.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat 

In a two-generation reproduction toxicity study (2009, MRID 47744117), Demiditraz (PF03814927; 100% a.i.; Batch #PFXU070002) in 0.5% methylcellose and 0.1% Tween®

80 (10 

mL/kg) was administered daily by gavage at dose levels of 0, 7.5, 50, or 150 mg/kg/day for two 

consecutive generations. The P generation animals (30/sex/dose group) were dosed for 10 weeks 

prior to mating to produce the F1 litters. F1 offspring (30/sex/dose group) were dosed after 

weaning for at least 10 weeks prior to mating to produce the F2 generation. 

In the P and F1 generations, treatment-related generally transient clinical findings indicative of 

neurotoxicity were noted with increased incidences in the 50 and 150 mg/kg/day group at 

approximately 0.5 hours following dose administration starting as early as study day 0 and

lasting through study day 115. The findings were numerous and included effects such as 

subdued appearance; rocks, lurches, or sways as it walks; pupils dilated; and hypoactivity. 

Additionally at 150 mg/kg/day, increased incidences tremors in both sexes and respiratory

effects (except in F1 females) were noted and clonic convulsions were noted in females. 

Gasping was noted especially in F1 male pups at 150 mg/kg/day.

In the P generation, one 150 mg/kg/day female died, exhibiting clonic convulsions immediately

following dosing. In the F1 generation following weaning and starting gavage of the pups, the 

numbers of decedents were higher in the 150 mg/kg/day group (7/sex) than the controls (2/sex). 

The majority of these deaths occurred during PND 23-26. 
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In the P generation, decreases were observed in body weights and gains on LD 7, 14, and 21 at 

50 mg/kg/day and throughout the lactation period at 50 and 150 mg/kg/day. Decreased food 

consumption was noted at 150 mg/kg/day. Decreased food efficiency was observed at 50 and 

150 mg/kg/day. In the F1 generation at 150 mg/kg/day, decreases were observed in body

weights throughout the lactation period; however, the resulting decrease in body weight gain was 

not significant. Decreased food consumption was noted in the 150 mg/kg/day group.

At 150 mg/kg/day, decreased body weights and gains were noted in the P and F1 generations 

males. Average food efficiency (Days 0-126) was decreased in these males. Average food 

efficiency (PND 28-161) was also decreased. Decreased body weights were noted in the 150 

mg/kg/day females in the F1 generation up to PND 91 resulting in a decreased body weight gain 

for the pre-mating period. 

At 150 mg/kg/day, decreases in body weights throughout the gestation period in the P and F1 

generations, resulting in a decreased overall (GD 0-20) body weight gain. Food efficiency was 

decreased during gestation in both generations. 

No adverse, treatment-related effects were noted on organ weights or gross or histological 

pathology in either generation. 

The LOAEL for parental toxicity is 50 mg/kg/day based on: clinical findings indicating nervous 

system toxicity in both sexes and generations; and decreased body weight, body weight gain, and 

food efficiency during the lactation period in the P generation. The NOAEL is 7.5 mg/kg/day.

At 150 mg/kg/day, decreases were noted in the number of pups born (↓13% and 16%) and born 

alive (both ↓18%) in both the F1 and F2 generations. There was also an increase in the number 

of implantation sites that did not result in the birth of a pup in both the F1 and F2 litters. The 

viability indices were decreased in the F1 (↓19%) and F2 (↓29%) generations. The lactation 

indices in the treated groups of both generations were similar to controls. Decreased postnatal 

survival (% per litter) was observed during PND 0-1 in the F1 and F2 generations and during 

PND 1-4 in the F2 generation. 

At 50 mg/kg/day in the F2 generation, decreased body weights were noted in both sexes (↓8-11% 

in males and 8-12% in females) throughout lactation, and decreased body weight gains (up to 

12%) were observed in the males at PND 4-7, 7-14, and 14-21 and females at PND 4-7 and 7-14. 

At 150 mg/kg/day, decreased pup body weights (up to 31%) were observed during PND 1-21 in 

both sexes and generations. Except for the F1 males and females on PND 1-4, body weight 

gains during PND 1-21 were also decreased in both sexes and generations (up to 45%).

Absolute brain weights were decreased in the F2 generation at 50 mg/kg/day (↓4-6%) in both 

sexes in the F2 generation. At 150 mg/kg/day absolute brain weight was decreased 6-13%. 

No treatment-related macroscopic findings were observed in the F1 and F2 generations. Pup sex 

ratio and time until vaginal opening or balano-preputial separation were unaffected by treatment.

Developmental landmarks were not reported.
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The LOAEL for offspring toxicity is 50 mg/kg/day based on decreased pup body weights and 

body weight gains in both sexes in the F2 generation and slight decrease in brain weight in the 

F2 generation. The NOAEL is 7.5 mg/kg/day.

There were no effects of treatment in either generation on: estrous cycle; sperm parameters; 

mating, conception, fertility, or gestation indices; pre-coital interval; or gestation duration in 

either generation.

The LOAEL for reproductive toxicity was not observed. The NOAEL is 150 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3800; OECD 416) for a two-generation reproduction study in the rat.

A.4.4 Chronic Toxicity – No study available

A.4.5 Carcinogenicity – No study available

A.4.6 Mutagenicity

Demiditraz was negative in the mutagenicity studies. 

Study Dose Levels Result

In vitro studies

870.5100

Bacterial Reverse Mutation

MRID#47752704

Mecchi, M.S. (2008)

0-5000 μg/plate Negative

870.5300

Mammalian cell gene mutation (CHO)

MRID #47755404

Stankowski, L.F. (2008)

0-900 μg/mL Negative

870.5375

Mammalian cytogenetics assay 

(chromosomal aberration assay in 

human peripheral blood lymphocytes)

MRID #47752705

Murli, H. (2008)

0-2000 μg/mL Negative

In vivo studies

870.5395

Mouse Bone Marrow Micronucleus 

Assay

MRID#47755403

Xu, Y (2008)

0-1000 mg/kg bw Negative
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A.4.7 Neurotoxicity

870.6200a Acute Neurotoxicity Screening Battery – Acute Rat 

In an acute neurotoxicity screening study (2008, MRID 47744113), PF-3814927 (Demiditraz, 

99.2% a.i., Batch # PFXU060001) in 0.5% methylcellulose/0.1% polysorbate 80 was 

administered once via gavage (5 mL/kg) to 12 Sprague-Dawley rats/sex/group at dose levels of 

0, 15, 100, or 600 mg/kg. Neurobehavioral assessment (functional observational battery [FOB] 

and motor activity testing) was performed on 12 rats/sex/group at pre-dosing and days 0 

(approximately 15 minutes post-dosing; time of peak effect), 7, and 14. At study termination, 6 

rats/sex/group were perfused in situ for neuropathological examination. The tissues from the 

perfused animals in the control and 600 mg/kg groups were subjected to histopathological 

evaluation of brain and peripheral nervous system tissues. 

Motor Activity. Findings at 15 mg/kg were limited to decreased (p<0.05) mean total and 

ambulatory activity counts in the females (decr 17-18%) during the 0-15 minute interval on Day

0. Mean total and ambulatory activity counts were decreased (p<0.001) by 90-96% in males and 

88-96% in females at 100 mg/kg and 600 mg/kg. At the higher doses, these decreases resulted in 

decreases (p<0.001) in cumulative total (decr 68-90%) and ambulatory (decr 74-93%) activity 

counts. No statistically significant differences in motor activity were noted on Days 7 or 14. 

Although these values for the low dose group were lower than the minimum historical control 

values provided, these decreases were not sufficient to affect cumulative total or ambulatory

activity counts, as animals at this dose had higher (not statistically significant) values than the 

concurrent control group for the remainder of the 60-minute test session. 

FOB evaluations on Day 0. At 100 and 600 mg/kg, numerous effects were noted but these 

findings were generally resolved by Day 7. During the home-cage observations, the following 

treatment-related effects (# affected/12 vs. 0/12 controls, unless otherwise noted) were reported: 

(i) flattened posture (9 males and 11 females at 100 mg/kg, and 10 males and 7 females at 600 

mg/kg); (ii) immobility (9 males and 7 females at 100 mg/kg, and 7 males and 4 females at 600 

mg/kg); and (iii) eyelids slightly drooping (6 females at 100 mg/kg, and 6 males and 7 females at 

600 mg/kg vs. 3 control males and 0 control females). Additionally at 600 mg/kg on Day 0, 

slight tremors were observed in one male and 3 females, and moderately coarse tremors were 

observed in 2 males. Clonic convulsions (whole body tremors) were also observed at 600 mg/kg 

in 2 males and 1 female.

During handling observations, eyelids slightly drooping were noted in 7 rats of each sex at 100 

mg/kg and in 10 males and 6 females at 600 mg/kg (vs. 0 controls). Additionally at 600 mg/kg, 

6 males displayed slight resistance to handling (vs. 1 control). During the sensory observations, 

increased numbers of animals displayed no reaction to the following stimuli: (i) approach; (ii) 

touch; (iii) tail pinch; and (iv) startle. Several animals in these groups also exhibited no olfactory

response, were slightly uncoordinated (3-6 males and 2-9 females) or landed on their sides (4 

males and 1 female at 600 mg/kg only) during air-righting reflex assessment. Additional 

findings, occurring in 1 or 2 animals at 600 mg/kg, consisted of no eye blink response, no pupil 

response and no forelimb extension. 
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During the open-field observations, the following treatment-related effects were noted: (i) 

impaired mobility, slight (5 males and 6 females at 100 mg/kg, and 7 males and 11 females at 

600 mg/kg), moderate (3 males at 600 mg/kg), and totally impaired (1 rat of each sex at 600 

mg/kg); (ii) abnormal gait, body drags (5 males and 2 females at 600 mg/kg), hindlimbs splayed 

or dragging (6 males and 5 females at 600 mg/kg), hunched body (4 males and 3 females at 100 

mg/kg, and 2 males and 1 female at 600 mg/kg), and ataxia (8 females at 100 mg/kg, and 7 males 

and 10 females at 600 mg/kg); (iii) gait score, slight impairment (6 rats each sex at 100 mg/kg, 

and 4 rats each sex at 600 mg/kg), considerable impairment (1 rat each sex at 100 mg/kg, and 5 

males and 6 females at 600 mg/kg), severe impairment (1 male), and marked impairment (1 

female) at 600 mg/kg); (iv) tremors, slight (2 males and 3 females at 600 mg/kg), moderately 

coarse (2 males and 1 female at 600 mg/kg), and markedly coarse (one 600 mg/kg female); and 

(v) arousal, low (6 of each sex at 100 mg/kg, and 9 of each sex at 600 mg/kg vs. 1 control 

female), and very low (one 600 mg/kg male). Additionally, one 600 mg/kg male displayed 

circling and retropulsion. Rearing counts were decreased (p<0.01) in the males (0.6 to 1.8 

treated vs. 5.8 controls) and females (1.5 to 2.9 treated vs. 7.6 controls). Rearing counts in these 

males remained decreased on Day 7; however, the differences were not statistically significant. 

Urination counts were increased (p<0.05) in the 100 mg/kg males (1.4 to 1.7 treated vs. 0.2 

controls) and females (1.2 to 1.7 treated vs. 0.2 controls). 

During the neuromuscular observations on Day 0, treatment-related decreases (p<0.01) in 

hindlimb footsplay (decr 31-48%) and rotarod performance (decr. 55-67%) were noted at 600 

mg/kg in both sexes. During physiological observations on Day 0, body temperatures (C) were 

decreased (p<0.01) at 100 and 600 mg/kg in both sexes (35.1 and 34.5 treated, respectively, in 

males vs. 37.2 controls, and 35.2 and 34.6 treated, respectively, in females vs. 37.8 controls). 

No compound-related effects were observed in mortality, body weight (except of initial decrease 

in day 0-7 gain at 600 mg/kg), brain weight and morphology, or gross and neuropathology in 

either sex.

The LOAEL was 100 mg/kg based on FOB findings (predominantly altered gait and posture, 

impaired mobility, decreased rearing, incoordination, increased urination, and lower body 

temperature) and statistically significant decreases in motor activity in both sexes. The NOAEL 

is 15 mg/kg. The slight decrease in interval motor activity at 15 mg/kg is a possible threshold 

effect. 

The study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 

870.6200a) for an acute neurotoxicity study in rats.

870.6200b Subchronic Neurotoxicity Screening Battery – Rat 

In a subchronic neurotoxicity study (2008, MRID 47744114), PF-3814927 (Demiditraz, 100% 

a.i.; Batch No. PFXU070002) in 0.5% methylcellulose and 0.1% Tween 80 was administered 

daily via gavage (5 mL/kg) to 22 Sprague-Dawley rats/sex/group at dose levels of 0, 5, 25, or 

125 mg/kg/day for 13 weeks. Ten rats/sex/dose were designated as the Phase I (general toxicity) 

group, and were evaluated for hematology, clinical chemistry, ophthalmology, organ weight, and 

gross and histopathology parameters. Neurobehavioral assessment (functional observational 
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battery [FOB] and motor activity testing) was performed on the remaining 12 rats/sex/group 

(Phase II) at pre-dosing and Weeks 1, 3, 7, and 12 (prior to administration of dosing). At study

termination, all Phase II animals were anesthetized and perfused in situ for brain weights and 

morphometry. The tissues from 6 rats/sex/group of the perfused animals in the control and 125 

mg/kg/day groups were subjected to histopathological evaluation of central and peripheral 

nervous system tissues. 

At 25 mg/kg/day, body weights were decreased (p<0.05) by 7-8% in the males during Weeks 8-

13 and by 7% each in the females at Weeks 7 and 10. Body weight gains were decreased 

(p<0.05) by 33% in the males during Weeks 7-8. Overall body weight gains were decreased 

(p<0.05) by 11% in the males. At 30 minutes post-dosing, the following treatment-related 

clinical signs of toxicity were observed (# affected/22 vs. 0/22 controls, unless otherwise stated): 

(i) subdued appearance at cage-side observation only (10 males and 9 females); (ii) rocks, 

lurches, or sways when walking (6 males and 6 females); (iii) hunched posture (6 females); (iv) 

hypoactivity (2 males); (v) wet yellow material urogenital area (3 males and 6 females); (vi) 

lacrimation right/left eye (8 males and 19 females vs. 2 control females); (vii) dilated pupil 

right/left eye (5 males and 6 females); (viii) dried red material around mouth (4 males and 1 

female vs. 1 control male); and (ix) wet red material around mouth (2 males). Cumulative 

ambulatory activity was increased (p<0.05) by 41-45% in the males at Weeks 3 and 7.

At 125 mg/kg/day, body weights were decreased (p<0.01) by 9-14% in the males and by 7-10% 

in the females during Weeks 3-13. Additionally, body weight gains were sporadically decreased 

(p<0.05) by 14-48% in the males and by 17-56% in the females. Overall (Weeks 0-13) body 

weight gains were decreased (p<0.01) by 15-19% in both sexes. At 30 minutes post-dosing, the 

following treatment-related clinical signs of toxicity were observed (# affected/22 vs. 0/22 

controls, unless otherwise stated): (i) subdued appearance at cage-side observation only (all 

males and females); (ii) rocks, lurches, or sways when walking (all males and females); (iii) 

hunched posture (17 males and all females); (iv) hypoactivity (11 males and 3 females); (v) wet 

yellow material urogenital area (20 males and 21 females); (vi) shallow respiration (7 males and 

1 female); (vii) decreased respiration (10 males); (viii) lacrimation right/left eye (20 males and 

all females vs. 2 control females); (ix) dilated pupil right/left eye (20 males and 19 females); (x) 

dried red material around mouth (9 males and 11 females vs. 1 control male); and (xi) wet red 

material around mouth (8 of each sex). Cumulative (session) total activity was increased by 29-

32% in the males at Weeks 1 and 3 and by 31-32% in the females throughout the study. Also at 

this dose, cumulative ambulatory activity was increased by 43-56% in the males at Weeks 1, 3, 

and 7 and by 49-65% in the females throughout the study.

No compound-related effects were observed in mortality, food consumption, ophthalmoscopic 

examinations, hematology, clinical chemistry, FOB parameters (note: FOB assessments were 

made prior to daily dosing), brain weight and morphology, organ weights, gross lesions, or 

microscopic lesion in either sex.

The LOAEL was 25 mg/kg/day based on multiple clinical signs of toxicity in both sexes, 

decreased body weight gains in males, and increased motor activity in males. The NOAEL is 5 

mg/kg/day.
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The study is classified as acceptable/guideline and satisfies the guideline requirement (OPPTS 

870.6200b; OECD 424) for a subchronic neurotoxicity study in rats.

870.6300 Developmental Neurotoxicity Study 

In a developmental neurotoxicity study (MRID 48766703), demiditraz (PF-03814927) (100% 

purity; Batch 1 Lot # TCK08005K and Batch 2 Lot # TCK08005K) was administered daily by

oral gavage to 25 mated female Sprague-Dawley [Crl:CD(SD)] rats per dose at dose levels of 0 

(0.5% methylcellulose (400 cps)/0.1% Tween® 80 in deionized water), 5, 15, or 100 mg/kg/day

from gestation day (GD) 6 through lactation day (LD) 20. 

Detailed clinical observations were conducted on all dams (F0 females) on GD 10 and GD 15 and 

on LD 10 and LD 20. All F0 females were allowed to deliver and rear their offspring to LD 21. 

All surviving F0 females were euthanized on LD 21 and subjected to a gross necropsy. Clinical 

observations, body weights, and sexes were recorded for the F1 pups at appropriate intervals. On 

postnatal day (PND) 4, litters were culled to 8 pups/litter, and a subset (Subset A) of 20 

pups/sex/group was assigned to the functional observational battery (FOB; PND 4, 11, 21, 35, 

45, and 60), auditory startle response (PND 20 and 60), locomotor activity (PND 13, 17, 21, and 

61), and learning and memory (PND 62) groups. From this subset, 15 pups/sex/group were 

deeply anesthetized and perfused in situ on PND 72 for brain weight and brain measurement 

evaluations; of these, 10 pups/sex/group were selected for neuropathological and brain 

morphometric evaluations. A second subset (Subset B) of 20 pups/sex/group was selected for 

learning and memory (PND 22). A third subset (Subset C) of 15 pups/sex/group was deeply 

anesthetized and perfused in situ on PND 21 for brain weight and brain measurement 

evaluations; of these, 10 pups/sex/group were selected for neuropathological and brain 

morphometric evaluations. Indicators of physical development (balanopreputial separation and 

vaginal patency) were evaluated for all F1 selected pups in Subsets A and B. All F1 pups not 

selected for neuropathological or behavioral evaluations were euthanized and necropsied on 

PND 21. F1 pups selected for learning and memory assessment on PND 22 were necropsied 

following attainment of sexual developmental landmarks. The litter was used as the experimental 

unit for all F1 data.

One F0 female in the 100 mg/kg/day group was found dead on GD 21, and cause of death could 

not be determined. All other F0 females survived to the scheduled euthanasia. One female each 

in the control and 100 mg/kg/day groups failed to deliver and were determined to be non-gravid. 

Treatment-related clinical findings were observed in a dose-dependent manner in the 15 and 100 

mg/kg/day group F0 females and were observed at approximately 15-30 minutes post-dosing 

throughout the treatment period. In both dose groups, these findings included sitting with the 

head held low, hypoactivity, a flattened body, slightly drooping eyelids, decreased respiration, 

clear material around the mouth/salivation, lacrimation, and dilated pupils. Additional signs seen 

in the 100 mg/kg/day dose group included rocking, lurching, or swaying while ambulating, 

piloerection, tremors/convulsions, and yellow material on various body surfaces. These findings 

generally continued to the 2-hour post-dosing observation period for the 100 mg/kg/day group F0

females, but at decreased incidences. 
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Treatment-related decrements in maternal care were observed mainly in the 100 mg/kg/day 

group F0 females during the same interval post dose when clinical signs were observed. A 

decreased incidence of F0 females on the nest, a higher incidence of females that were away

from the nest (not actively eating, drinking, grooming or tending to the litter), and higher 

incidences of scattered litters with 1-3 pups and more than 3 pups outside of the nest were all 

noted at the 100 mg/kg/day dose level. 

During the detailed clinical observations (FOB) for F0 females, a flattened posture or sitting with 

the head held low, low or very low arousal, slight to moderately coarse tremors, lacrimation, 

salivation, piloerection, slightly drooping eyelids, decreased respiration, soft and flabby muscle 

tone, impaired mobility, ataxia, dragging bodies, and/or higher urination counts were observed 

for the 100 mg/kg/day group at each time points. Additionally, a flattened posture or sitting with 

the head held low, ataxia, impaired mobility, and a higher urination count were observed in a 

smaller number of F0 females at 15 mg/kg/day from GD 15 on. 

Mean body weights for F0 females in the 100 mg/kg/day group were slightly (↓4.6%) lower than 

the control group by GD 20. F0 females in the 100 mg/kg/day group had slightly lower mean 

body weight gains throughout the gestation treatment period (initially ↓44%; overall GDs 6-20, 

↓15%), and corresponding reductions in food consumption during GDs 6-12 (↓13-14). Mean 

body weights for F0 females in the 100 mg/kg/day group were slightly (↓4% to 6%) lower than 

the control group during LDs 4-17, but were similar to the control group on LD 21. A lower 

mean body weight gain was noted for F0 females in the 100 mg/kg/day group during LDs 1-4 

(67% less than controls), but mean body weight gains for this group were generally similar to the 

control group for the remainder of the lactation treatment period (LDs 4-21). Mean gestation 

length of F0 females was comparable among the groups, and there were no treatment-related 

effects on the process of parturition or macroscopic findings of the F0 females.

The maternal LOAEL is 15 mg/kg/day, based on clinical signs (sitting with the head held low, 

hypoactivity, a flattened body, slightly drooping eyelids, decreased respiration, clear material 

around the mouth/salivation, lacrimation, and/or dilated pupils). The maternal NOAEL is 5 

mg/kg/day. At 100 mg/kg/day, in addition to clinical signs, decrements in maternal care were 

observed during the same time interval post dose when clinical signs were observed (decreased 

incidence of F0 females on the nest, a higher incidence that were away from the nest (not actively 

eating, drinking, grooming or tending to the litter), and higher incidences of scattered litters with 

1-3 pups and more than 3 pups outside of the nest. 

The mean live litter size in the 100 mg/kg/day group was slightly lower than the control group 

(14.0 vs. 15.1 for controls), and mean postnatal survival for the 100 mg/kg/day group was lower 

than the control group during PND 0-1, 1-4 (pre-culling), and birth to PND 4 (pre-culling) 

(87.7% vs. 96.2% for the latter). At the 100 mg/kg/day dose level, a total of 24 pups were found 

dead and 20 others were missing (presumed cannibalized) compared with 11 found dead and 3 

missing at the control level. 

At 100 mg/kg/day, F1 pups of both sexes had decreased body weights [PND 1 (↓8%-9%); PND 4 

(↓14%); PND 21 ↓16%)] and body weight gains (PND 1-4 (↓21%-29%); PND 4-7 (↓27%); PND 

1-21 (↓16%-18%) generally throughout the pre-weaning period, relative to their respective 
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controls. Mean body weights of the F1 males at 100 mg/kg/day were significantly lower than the 

control (PND 28-72 ↓10%-14%), and lower mean body weight gains were noted for the 100 

mg/kg/day F1 males compared to the control throughout the post-weaning period (overall PND 

28-72, ↓11%). Mean body weights for the 100 mg/kg/day F1 females were lower than the 

control during PND 28-72 (↓5%-13%), and lower mean body weight gain was noted for the 100 

mg/kg/day group F1 females during the first post-weaning week (PND 28-35, ↓8%), but mean 

body weight gains were similar to the control for the remainder of the post-weaning period and 

overall. 

A treatment-related delay (2.7 days) in the mean age of attainment of balanopreputial separation 

was noted for the 100 mg/kg/day group F1 males (47.0 days vs. 44.3 days for controls) but mean 

body weights of the F1 males on the day of attainment were not affected. In contrast the F1

females showed no treatment related effects on the mean age of attainment of vaginal patency, 

but a reduced mean body weight (↓11%) on the day of attainment of vaginal patency was noted 

for the F1 females of the 100 mg/kg/day group.

Mean forelimb grip strength for the 100 mg/kg/day group F1 males and F1 females was 

significantly lower than the control group on PND 21 and PND 35 but was no longer 

significantly affected on PND 45 or PND 60. 

Although no statistically significant effects on locomotor activity or habituation were observed 

among the F1 offspring, there were differences in response between the control and 100 

mg/kg/day groups and between the sexes at 100 mg/kg/day. On PND 13, the concurrent control 

males displayed motor activity (MA) that was not consistent with the testing facility’s historical 

control data, which resulted in a finding of decreased MA at all dose levels (males). However, 

when compared to the historical control (HC) mean, the PND 13 males at 100 mg/kg/day showed 

an increase in MA (ambulatory ↑100%/total ↑45%) and the 5 and 15 mg/kg/day PND 13 males 

were comparable to the HC mean. PND 13 females at 100 mg/kg/day showed a reduction in MA 

(ambulatory ↓41%/total 20%) compared to the concurrent control. On PND 17, the 100 

mg/kg/day males displayed reduced MA and the 100 mg/kg/day females displayed MA that was 

comparable to the control. On PND 21, MA among the male groups was comparable, whereas 

the 100 mg/kg/day females displayed an increase (ambulatory ↑40%/total ↑2%) compared to the 

control females. The male control and 5 and 15 mg/kg/day male dose groups showed the 

expected reduction in MA on PND 21 compared to PND 17 levels, but the 100 mg/kg/day males 

did not display the expected reduction in MA. On PND 61, males at 100 mg/kg/day displayed a 

reduced activity (ambulatory ↓18%/total ↓14%), and females at 100 mg/kg/day were comparable 

to the control. 

Both sexes at 100 mg/kg/day displayed an increase in auditory startle response peak amplitude 

on PND 60 compared to the concurrent controls and the historical controls. The PND 60 males 

at 100 mg/kg/day had a mean peak amplitude value that was outside the HC, whereas the PND 

60 females at 100 mg/kg/day were within the HC range, although at the upper end. Additionally, 

both sexes at 100 mg/kg/day displayed a reduction of 4 msec in latency time on PND 60 

compared to the concurrent control and HC control. 
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At 100 mg/kg/day, mean brain weight was significantly lower in PND 21 males compared to the 

control, and relative brain weights were significantly increased in both sexes at 100 mg/kg/day

on PND 21. Relative brain weight was significantly lower in the PND 60 males at 100 

mg/kg/day. 

No treatment related effects were observed in the detailed clinical observations performed on 

PNDs 4, 11, 21, 35, 45, or 60 during the home cage, handling, open field, or sensory

assessments. There were no treatment-related effects on the numbers of former implantation 

sites or unaccounted-for sites, the pup sex ratio at birth, pup survival following culling, clinical 

findings, swimming ability or learning and memory assessments, macroscopic internal findings, 

gross or microscopic observations of the brain or peripheral nervous systems, brain 

measurements at necropsy, or morphometry taken from brain sections. 

The F1 offspring LOAEL is 100 mg/kg/day, based on decreased postnatal survival, decreased 

pup body weights and body weight gains, increased maximum response to the auditory startle 

stimulus and reduction in response time on PND 60, decreased/increased total and ambulatory

motor activity counts, decreased grip strength (PND 21 and PND 35), decreased brain weight in 

PND 21 males, and delayed attainment of balanopreputial separation. The corresponding F1

offspring NOAEL is 15 mg/kg/day.

This study is classified Acceptable/Guideline and satisfies the guideline requirement for a 

developmental neurotoxicity study in rats [OCSPP 870.6300 (§83-6); OECD 426 (draft)].

A.4.8 Metabolism

870.7485 Metabolism - Rat

No guideline study is available. 

870.7600 Dermal Absorption – Rat 

In a dermal penetration study (2008, MRID 47752709), [

14C] PF-03814927 (Demiditraz; 99.0% 

radiochemical purity; Code No. CFQ15145 Batch 1) formulated in diethylene glycol monobutyl 

ether was applied to the shaved skin (10 cm2) of Sprague Dawley rats. Doses of 0.0099, 0.0937, 

or 1.03 mg/rat were applied to the skin of each rat in volumes of 10 μl/cm2skin. Four 

males/dose/time point were tested using exposure durations and termination times of 0.5, 1, 2, 4, 

10, or 24 hours post-administration. Additional groups of 4 male rats was exposed for 10 hours 

at the same dose levels, the application site was washed, and the rats were terminated at 168 after 

application. 

Analytical recoveries were 76-108% of the applied dose (AD). The amount absorbed included 

residues found in the cage wash, blood, urine, feces, and carcass. After 24 hours exposure, there 

was 17.46%, 12.06% and 10.61% of the AD was determined to be absorbed for the low , mid an 

high dose exposure groups, respectively. The groups terminated at 168 hours post-application 

indicated additional absorption (25.8-28.1% AD) resulting from absorption from the skin depots 
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(skin at the application site and adjacent skin). The absorption rate constants were similar 

(0.055-0.089/hr) for each dose level. Thus, absorption was not saturated. 

Because absorption continued to occur from demiditraz remaining at the site of application after 

washing, the total absorbable dose (AD plus remaining on the skin) should also be considered in 

a conservative estimate of absorption. The mid-dose provided the most conservative estimate of 

total absorbed (28.06%) and absorbable (3.09%) for a total of 31% and should be considered for 

a dermal penetration factor in risk assessment. 

Quantifiable residues were detected in the urine and feces by 2 and 10 hours after application, 

respectively. Only minor amounts were found in the blood and cage wash. The carcass 

accounted for ~1-8% AD with the highest percentages in the low dose group. The majority of 

the residues eliminated in the feces and urine were excreted within 72 hours. Regardless of dose 

level, the elimination rate constants were similar in both the urine and feces (0.0227-0.0291/hr). 

The elimination half life was 28-31 hr in urine and 24-28 hr in feces.

A conservative estimate of dermal absorption is 31% based on total absorbed and remaining on 

the skin after 168 hours. 

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.7600; OECD - none) for a dermal penetration study in rats. The study provides data that can 

be useful to derive a dermal absorption factor. It must be noted that the test material was applied 

in diethylene glycol monobutyl ether and the relationship of this vehicle to practical formulations 

in not known. 

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

In an immunotoxicity study (MRID 47744122), female Sprague Dawley Crl:CD(SD) rats

(20/dose group) was administered daily via oral gavage with demiditraz (PF-3814927; 99.5% 

a.i.; Batch # PFXA070001) in 0.5% methylcellulose and 0.1% TweenTM 80 at dose levels of 0, 

10, 30, or 100 mg/kg/day with a dose volume of 10 mL/kg for 28 days. Splenic antibodyforming cell (AFC) assays were conducted on 10 rats/dose group (AFC Group), and the 

remaining 10 rats/dose group were used for Natural Killer (NK) cell activity assay, immune cell 

phenotyping, and anti-CD3 stimulation assay (non-AFC group). In addition, two positive control 

groups (10 rats/group) were included. For all assays except for NK activity and NK cell 

enumeration, the positive control cyclophosphamide was administered by intraperitoneal 

injection (50 mg/kg) on Days 24-27 at a dose volume of 5 mL/kg. For NK cell activity and NK 

cell enumeration, the positive control, Anti-asialo GM1, was administered by intravenous 

injection (1 mL/animal of a 1:10 dilution) approximately 24 hours prior to scheduled necropsy.

For systemic toxicity, there were no treatment-related effects on body weights, body weight 

gains, food consumption, spleen weight, thymus weight, or gross pathology.
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At 100 mg/kg/day, treatment-related clinical signs were noted in all treated animals 30-minutes 

after dose administration. These findings consisted of rocking, lurching, or swaying while 

walking; drooping eyelids; and subdued appearance upon cage-side observation. Clear material 

around the mouth and yellow material on various body surfaces (anogenital area, urogenital area, 

ventral trunk, hindlimbs, and/or around the mouth) were also observed in the animals at 100 

mg/kg/day. Additionally, flattened body was noted in 8 rats, and 2 rats had hunched posture at 

this dose.

At 30 mg/kg/day, subdued appearance was observed in 5 rats in the AFC group for a total of 6 

occurrences and in 4 rats in the non-AFC group for a total of 18 occurrences. Although 

considered treatment-related, in the absence of other clinical signs of toxicity, this finding was 

not considered adverse at this dose.

The only findings noted at the time of dosing or during the daily examinations that were 

considered treatment-related were oral secretions and urogenital/anogenital staining.

Positive control, cyclophosphamide, treated animals showed a few incidence of yellow material 

on various body surfaces (anogenital area, urogential area, ventral trunk, and hindlimbs).

Significant (p<0.01) mean body weight losses were observed for overall (days 0-28) and days 

24-28 in the cyclophosphamide treated animals compared to the negative controls.

For systemic toxicity, the LOAEL is 100 mg/kg/day based on clinical signs of toxicity (rocking 

lurching, or swaying while walking; drooping eyelids; subdued appearance at cage-side 

observation; flattened body; hunched posture; clear material around mouth; and yellow material 

on various body surfaces). The NOAEL for systemic toxicity is 30 mg/kg/day.

For immunotoxicity, there were no significant differences among treated and control groups in 

thymus and spleen weights and total spleen cell numbers. There were no significant treatmentrelated effects on antibody forming cell response (humoral immune response) to the T-dependent 

antigen (SRBC) and on the NK cell activity (innate immunity). Splenocyte surface marker 

differential analyses indicated that the absolute numbers of B cells, total T cells, T helper cells, T 

cytotoxic cells, natural killer cells, and monocytes/macrophages in the treated groups were 

comparable to negative controls. There were no significant differences among treated and 

control groups in the cell-mediated typed proliferative response in spleen cell cultures with or 

without the anti-CD3 antibody stimulation.

Positive controls, cyclophosphamide for antibody forming cell assay and Anti-asialo GM1 for 

NK cell activity assays, were adequately preformed to demonstrate the sensitivity of the assays. 

Under conditions of this study, no immunotoxicity was observed. The NOAEL is 100 

mg/kg/day (the highest dose tested).

This immunotoxicity study is classified acceptable/guideline and satisfies the guideline 

requirement for an immunotoxicity study (OPPTS 870.7800).
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Appendix B. Physical/Chemical Properties

Table B.1 Physicochemical Properties of Demiditraz 

Parameter Value Reference

Melting point/range 138.36 oC (range 137 – 142 oC)

MRID No.

47744103

B. Kitchens. 

8/31/10

pH (23 °C) Not applicable as technical grade demiditraz is 

not soluble in water.

Density 0.15 g/cc

Water solubility (mg/ml) < 0.1 mg/ml 

Solvent solubility (mg/ml) Acetone: 33 to 100 

Acetonitrile: 33 to 100 

Dichloromethane: 100 to 1,000 

Dimethyl sulfoxide: 100 to 1,000 

Ethanol: 100 to 1,000 

Ethyl acetate: 10 to 33 

Toluene: 1 to 10 

Vapor pressure Not applicable as technical grade demiditraz is 

solid at room temperature

Dissociation constant (pKa) Not applicable as technical grade demiditraz is 

a weak base and insoluble in water

Octanol/water partition coefficient The mean log10P value reported is 2.78 

UV/visible absorption spectrum 

methanol (nm)

Shows maximum absorption at about 264 nm