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Executive Summary 

The Health Effects Division (HED) Amitraz Registration Review Team has evaluated the 

status of the human health assessments for the insecticide/acaricide amitraz to determine the 

scope of work necessary to support Registration Review. Amitraz is an insecticide/acaricide 

with registered uses on cattle, swine, dogs and pups. Amitraz was first registered in 1975. The 

most recent risk assessment for Amitraz was completed in July 2006. There is a pending new 

use under PRIA that may be included later in the registration review process. The tolerances for 

meats, meat by-products, and milk will be maintained to support the animal health uses. The 

toxicology database is incomplete with several major data gaps, specifically related to 

developmental, reproductive and neurotoxic effects, plus new requirements for Part 158. The 

total uncertainty factor is currently 100X (10X FQPA Safety Factor and 10X for intra-species 

variation). 

The 2006 risk assessment identified no deficiencies in the amitraz residue or product 

chemistry database. In the registration review process, the dietary exposure analysis should 

include updated percent crop treated information from BEAD relative to imported cottonseed, 

and the percent of treated cattle and swine in the US. Also during registration review, the 

tolerance expression for amitraz as listed in 40 CFR §180.287 should be revised. 

1.0 Introduction 

Amitraz [N'-(2,4-dimethylphenyl)-N-[[(2,4-dimethylphenyl)imino]methyl]-Nmethylmethanimidamide] is an insecticide/miticide used on cattle, swine, dogs and pups. 

Amitraz has active registrations for the control of pests such as ticks, mites, lice and mange. 

Currently, the U.S. technical registrations for Amitraz are held by Arysta Life Sciences and Ft. 

Dodge/Wyeth. Amitraz formulations include impregnated materials and emulsifiable 

concentrates. There are also dog shampoos and dips which are regulated under the FDA as 

veterinary medicines (21 CFR 524.86). HED has considered the most recent exposure and risk 

assessments for this chemical, updates to its toxicity, exposure and usage databases, and the 

latest Agency science policy and risk assessment methodologies. 

2.0 Hazard Identification/Toxicology 

 Amitraz is an alpha-adrenoceptor agonist, which causes an increase in nerve activity 

within arachnids. It also exerts a toxic effect through the octopamine receptor, which binds to a 

neuromodulator, causing ticks to withdraw their mouth parts and fall off the host animal, as well 

as killing the pest (i.e. tick). The NOAEL is 0.125 mg/kg and the LOAEL is 0.250 mg/kg for all 

exposure scenarios based on oral studies in humans (the most sensitive species), which revealed 

clinical signs of sedation, disorientation and hypothermia from a single dose. (Section 12 

describes the human studies in more detail.) These effects were reversible within 12 hours, so the 

human oral endpoint is appropriate for assessing the exposure to amitraz, regardless of duration. 

The 0.125 mg/kg/day dose will be protective, since it required higher doses for other systemic 

effects, such as body weight change in animals. Amitraz is classified as producing “suggestive 

evidence of carcinogenicity” due to tumor responses in the mouse at the highest dose (but none 

in the rat) and SAR relations to the reported carcinogen chlordimeform. 
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Clinical signs of toxicity seen in animal tests include central nervous system depression, 

ataxia, ptosis, emesis, labored respiration, muscular weakness, tremors, hypothermia, dry mouth, 

hypertension and bradycardia. The Registration Standard (TXR 005633), states that the 

pharmacotoxic profile suggests a depression of hypothalmic function. The endpoint for 

regulation is based upon clinical signs of sedation, disorientation and hypothermia in humans 

observed at the acute exposure of 0.25 mg/kg, the LOAEL. The acute human oral exposure is 

protective for exposure scenarios of longer duration. The CNS (Central Nervous System) effects 

of amitraz do not appear to be cumulative, i.e., do not accumulate with increased duration. In the 

90-day repeat dose dog study, the CNS effects appear early on (within 3 hours of dosing), rapidly 

end, and recur daily after dosing throughout the study. In rodents, dimethylaniline (DMA) is an 

intermediate metabolite at 1.4% or less composition. This DMA metabolite can be much higher 

in swine and bovine, up to 14.0% levels. A meeting of HED’s Residues of Concern Committee 

may be needed to confirm that DMA is of concern. 

The summary of toxicological dose and endpoints are listed in Table 1. The toxicology 

data base is incomplete with several major data gaps, especially in those areas relating to 

developmental, reproductive and neurotoxic effects. A NOAEL of 0.125 mg/kg bw established 

in a study conducted in human subjects was used for overall risk assessment. Since a human 

study was used for the POD, the 10X inter-species uncertainty factor is not needed. However, 

due to the existing data gaps, primarily due to deficiencies within the particular studies, the 

default 10X FQPA Safety Factor is retained in the form of a database uncertainty factor (UFDB) 

for a total UF of 100. Without the inclusion of the human studies, the total UFs would be 1000X. 

The specific study data gaps including the studies required in accordance with the revised Part 

158 are listed in Section 13.0. 

Table 1 Summary of Toxicological Dose and Endpoints for Amitraz Risk Assessment 

Exposure 

Scenario

Dose Used in Risk 

Assessment, UF

Study and Toxicological 

Effects

Acute Dietary 

(General population 

including infants and 

children) 

NOAEL = 0.125 mg/kg 

UF = 1001

Acute RfD = 0.00125 mg/kg 

Acute PAD = 0.00125 mg/kg 

2 combined human studies (a 

single oral dose and a single oral 

dose metabolism) 

LOAEL = 0.25 mg/kg based on 

dry mouth, drowsiness, decreased 

temperature, decreased blood 

pressure and decreased heart rate. 

Incidental Oral * NOAEL= 0.125 mg/kg 

Residential 

MOE = 1001

2 combined human studies (a 

single oral dose and a single oral 

dose metabolism) 

LOAEL = 0.25 mg/kg 

(effects listed above) 
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Table 1 Summary of Toxicological Dose and Endpoints for Amitraz Risk Assessment 

Exposure 

Scenario

Dose Used in Risk 

Assessment, UF

Study and Toxicological 

Effects

Dermal * Oral NOAEL = 0.125 mg/kg 

(dermal absorption rate 8%) 

Residential 

MOE = 1001

2 combined human studies (a 

single oral dose and a single oral 

dose metabolism) 

LOAEL = 0.25 mg/kg 

(effects listed above) 

Inhalation * Oral NOAEL = 0.125 mg/kg 

(inhalation absorption rate = 

100%) 

Residential 

MOE =1001

2 combined human studies (a 

single oral dose and a single oral 

dose metabolism) 

LOAEL = 0.25 mg/kg 

(effects listed above) 

UF = uncertainty factor, LOC = level of concern 

1

 UF of 100 (10x for intra-species variations and 10x database uncertainty factor). The FQPA safety factor is 

subsumed by the 10X database uncertainty factor for both acute dietary assessments, and dermal and inhalation 

assessments involving non-occupational exposures. Since a human study was used for the POD, the 10X interspecies Uncertainty Factor is not needed. * Because of the reversibility of the CNS effects, exposures of all durations can be regarded as repeating one-day 

exposures. Therefore, the single-dose human oral endpoint is appropriate for assessing exposures to amitraz 

regardless of exposure duration. 

3.0 Dietary Exposure 

An acute probabilistic dietary exposure analysis for amitraz was conducted in support of 

the TRED (D300300, J. Morales, 30-APR-2004). Drinking water was not included in the dietary 

assessment as it was determined that amitraz is not expected to enter water-bodies or drinking 

water through currently registered uses. This decision will be re-examined during the 

registration review process. In particular, the previous determination that cattle and swine are 

seldom treated outdoors with amitraz needs to be confirmed and perhaps the implications of this 

situation need to be reconsidered with regard to large, modern feedlots and other animal 

operations. The Biological and Economic Analysis Division (BEAD) provided percent crop 

treated information for the requested import uses on cotton seed and for dermal livestock 

treatments. Based on the percent treated estimate from BEAD together with magnitude of the 

residue studies depicting dermal treatments of cattle and swine, HED had calculated anticipated 

residue levels for the relevant livestock commodities to include in the acute dietary analysis. 

HED had determined that the acute assessment would be protective of any chronic dietary 

exposures to amitraz; therefore, a separate chronic dietary exposure assessment was not 

conducted. This initial assessment showed some population subgroups exceeding 100% of the 

aPAD based upon an acute toxicological endpoint taken from a dog study. 

Subsequently, this risk assessment was revised using an acute endpoint based upon a 

human study (D309794, D320083). In this study, the acute dietary exposures for all population 
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subgroups were determined to be below HED’s level of concern of 100% aPAD (the highest 

exposed population subgroup is Children 1-2 years old at 28% of the aPAD). However, a recent 

update from BEAD (D367939, C. Doucoure, 10/27/09) indicates that the previous estimate of 

0.1% for cattle and swine head treated should be increased to 0.3% for cattle and 1.2% for swine. 

These changes will need to be incorporated into a revised dietary exposure analysis during the 

registration review process, along with any other relevant changes identified. 

The 2006 dietary exposure assessment showed that exposure was acceptable given that 

the percentage of animals treated was estimated by BEAD to be less than 0.1%, nationwide. A 

driver of that exposure for infants and children was milk. Amitraz is allowed to be applied to 

dairy animals with no required withdrawal interval after treatment. The resulting amitraz 

residues used to calculate exposure through the meat and milk of cattle are measured 

experimentally in field trials for individual animals after dosing with known amounts of amitraz. 

These values are then corrected by the estimated national value for percent head of cattle treated. 

For milk, real field practices by which residues may be incurred differ from this 

theoretical scenario in that milk is not collected from a single animal, but is mixed together from 

many animals in a region, so that the residues are directly diluted by the local percent head 

treated. On the other hand, when there is a tick infestation that needs to be controlled locally, it 

is expected that a larger proportion of the dairy herd in that region will be treated than is 

represented by the national average percent head treated estimate provided by BEAD. 

Furthermore, HED generally expects that most fresh milk is mostly regionally produced and 

consumed, so the local percent head treated is more germane to estimating exposure through 

fresh milk than the national percent head treated. 

For the above reasons, the theoretical exposures calculated in the last dietary exposure 

assessment may not be representative of actual residues. As a public health practice, the control 

of ticks in cattle is coordinated by the Animal and Plant Health Inspection Service (APHIS) of 

USDA, and EPA intends to work with APHIS on the amitraz dietary assessment of milk. 

4.0 Residue Chemistry 

 The qualitative nature of the residue in plants and animals is adequately understood 

based on plant metabolism studies with apples, beans, lemons, citrus, cotton, and pears, and 

animal metabolism studies with cattle and swine (dermal application) as well as cattle, goats and 

hens (oral dosing). Tolerances for residues of amitraz in/on plant and animal commodities are 

currently expressed in terms of the combined residues of amitraz (N'-[2,4-dimethylphenyl]-N-

[[(2,4-dimethylphenyl)imino]methyl]]-N-methylmethanimidamide) and its metabolites 

containing the 2,4-dimethylaniline moiety, both calculated as the parent compound [40 CFR 

180.287]. 

 The amitraz risk assessment in 2006 determined that the residue chemistry database 

was complete and that no additional studies are needed. Since the registrant requested 

cancellation of all U.S. registrations on crops used as foods/feeds, the only source of amitraz 

residues in foods arise from dermal uses on livestock, and from imported treated cotton seed. 

There are two adequate methods listed in FDA's Pesticide Analytical Manual (PAM Vol. 

II) for purposes of data collection and enforcement of tolerances for residues of amitraz and its 
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metabolites containing the 2,4-dimethylaniline moiety. Methods I (designed for animal tissues 

and milk) and II (designed for plant commodities) are both GLC methods with electron capture 

detection (ECD), and involve conversion of residues of amitraz and its metabolites containing 

the 2,4-dimethylaniline moiety to 2,4-DMA using acid and base hydrolysis, respectively. The 

FDA PESTDATA database dated 11/01 (PAM Volume I, Appendix I) indicates that amitraz has 

small recovery (<50%) using Multi-residue Method Section 302 (Luke Method; Protocol D) and 

that metabolite BTS-27919 is completely recovered using Section 302. The detection limits of 

the methods are 0.01 ppm for milk and 0.05 ppm for plant commodities and animal tissues. 

HED now recommends revision of the tolerance expression to clarify: 1) that, as provided 

in FFDCA section 408(a)(3), the tolerance covers metabolites and degradates of amitraz not 

specifically mentioned; and 2) that compliance with the specified tolerance levels is to be 

determined by measuring only the specific compounds mentioned in the tolerance expression. 

This change is recommended for the tolerance expression for plant and livestock commodities, 

because it clarifies the existing language. 

Accordingly, in order to ensure that the tolerance expression adequately addresses both 

coverage and measurement issues, HED recommends that paragraph (a) of 40 CFR 180.287 be 

rewritten to read as follows: “Tolerances are established for residues of the insecticide amitraz 

(N'-[2,4-dimethylphenyl]-N-[[(2,4-dimethylphenyl)imino]methyl]]-N-methylmethanimidamide), 

including its metabolites and degradates, in or on the commodities in the table below. 

Compliance with the tolerance levels specified below is to be determined by measuring only 

those amitraz residues convertible to 2,4-dimethylaniline, expressed as the stoichiometric 

equivalent of amitraz, in or on the following raw agricultural commodities:” 

Commodity Parts Per Million 

Cattle, fat 0.1 

Cattle, meat 0.02 

Cattle, meat byproducts 0.2 

Cotton, undelinted seed 1.0 

Hog, fat 0.1 

Hog, kidney 0.1 

Hog, liver 0.1 

Hog, meat 0.05 

Hog, meat byproducts 0.3 

Milk 0.03 

Milk, fat 0.2 

5.0 Residential Exposure 

Residential exposure to amitraz is anticipated for individuals who apply amitrazcontaining products to companion animals via pet collars and spot-on formulations. In addition, 

EPA anticipates residential exposure to individuals from contact with previously treated pets. 

An assessment of the amitraz-impregnated pet collar residential use was assessed in the June 26, 

2006 memorandum, “Amitraz Revised Human Health Risk Assessment for the Tolerance 

Reassessment Eligibility Decision” and included as a part of the July, 2006 amitraz TRED. 
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Residential handler (applicator) exposure from the pet collar use was not assessed since it was 

assumed that residential post-application exposure estimates were protective for adult handler 

exposure. Residential post-application exposure was assessed for a pet collar containing 3.8 g ai 

and 2.4 g ai. It was assumed that while longer-term durations of exposure could potentially 

occur based upon the use pattern of pet collars (i.e., up to 90 days), that a short-term exposure 

duration of 1 to 30 days best represents a series of repeating one-day exposures based upon the 

reversibility of the CNS effects demonstrated in the toxicity database. The short-term duration 

is, therefore, protective for all exposure durations. Estimated post-application adult dermal 

exposure assessed for the maximum rate pet collar (3.8 g ai) was not of concern to the Agency 

(i.e., an MOE ≥ 100). However, toddler dermal and incidental oral (hand-to-mouth) exposures 

were of concern to the Agency. Because individual toddler routes of exposure were of concern, 

these routes of exposure were not combined. Furthermore, the 3.8 g ai pet collar was not 

accepted for registration. Estimated post-application adult dermal exposure assessed at the lower 

rate collar (2.4 g ai) was not of concern to the Agency. Combined toddler dermal and incidental 

oral (hand-to-mouth) exposure for this lower rate collar resulted in a MOE of 97. 

 It is important to note that the amitraz collar assessment was based upon a carbaryl 

collar study, “Transferable Residues from Dogs Treated with 16% Carbaryl Collar (MRID 

457922-01),” which was later determined to lack appropriate quality assurance and quality 

control (QA/QC) procedures and adequate documentation for all data generated in the laboratory 

and in the field (S. Tadayon, D320047). Upon making this determination, the Agency upheld the 

prior requirement for confirmatory data for the assessment of the carbaryl pet collar use. In 

response to this finding the study, “Determination of Dislodgeable Residues of Carbaryl from the 

Hair of Dogs Wearing Collars Impregnated with Carbaryl (MRID 477394-02),” was submitted 

to the Agency. This study was determined to be acceptable for use in quantifying estimated 

exposure for the carbaryl pet collar use. The most recent carbaryl pet collar study is the only one 

which the Agency has identified that has been conducted for the determination of human 

exposure from pet collars. Since the study which was used in the prior assessment is no longer 

valid, a comparison was drawn between the prior study and the current, acceptable carbaryl pet 

collar study. The prior study (MRID 457922-01) determined that 2.6% of the total active 

ingredient (ai), carbaryl, in the collar was anticipated to transfer from the animal to an exposed 

person on the highest day of exposure (day of application). In comparison, the current study 

(MRID 477394-02) results in 1.6% anticipated transfer of the ai from the treated animal to the 

exposed individual on the highest day of exposure. Based upon this comparison, the Agency is 

satisfied that the post-application exposure assessment conducted previously for the amitraz pet 

collar (2.4 g ai) would result in a higher MOE if updated using data from the new carbaryl pet 

collar study. 

An assessment of the amitraz pet spot-on products was conducted in the July 25, 2007 

memorandum, “Occupational and Residential Exposure Assessment for Proposed Section 3 

Registration of Amitraz on Domestic Pets.” HED determined that exposure to pesticide handlers 

is likely during the residential use of the spot-on product on dogs. However, exposure/risk from 

amitraz application to domestic pets was not assessed because handler contact was expected to 

be negligible. The spot-on product is designed to be self-contained as it is applied directly from 

the tube to the pet with the tip of the applicator used to part the pet’s hair. Residential postapplication exposure from contact with dogs treated with the spot-on product was assessed using 

data from, "Haircoat Distribution of R-28153 and Amitraz after a Single Topical Application to 

Dogs (MRID 468783-01)”. 
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Adult dermal post-application risk was not of concern to the Agency (i.e., an MOE ≥ 100). 

Combined dermal and hand-to-mouth exposures of a toddler to a medium-sized dog (22 -55 lbs) 

treated with the spot-on product (application rate, 500 mg ai / treatment) was also not of concern 

to the Agency. 

Conclusions 

No residential data gaps were identified during the registration review scoping process. 

A residential assessment to assess handler exposure should be conducted based upon the revision 

of HED’s Residential SOPs which was reviewed by the Scientific Advisory Panel (SAP) in 

October 2009. Under the revised pet treatment SOP, residential handling of pet collars and spoton products are assessed. An updated residential assessment may also be required if new data 

are identified which impact exposure estimates, new points of departure or uncertainty factors 

are selected, or revisions to exposure policies and procedures are made. 

6.0 Aggregate Risk Assessment 

Summary of Amitraz Aggregate Risk Assessment from 2004 TRED 

Acute Aggregate (food) 

The acute aggregate assessment generally combines acute dietary exposures with 

drinking water. Because there was no expectation of drinking water exposure, the acute food 

exposure alone was compared to the acute reference dose (i.e., the acute aggregate risk 

assessment is identical to the acute food-only dietary assessment). The acute dietary risk 

estimates are below HED’s level of concern for adults and for the most highly exposed subpopulation (28% of the aPAD for children 1-2 yrs). 

Short-, Intermediate- and Long-term Aggregate (food plus residential) 

In general, short-, intermediate-, and long-term aggregate assessments combine average 

(chronic) dietary exposures with conservative short-, intermediate- and long-term residential 

exposures. However, in the case of amitraz, a chronic dietary assessment was not performed 

since the acute dietary assessment is protective of any chronic exposures. In the 2004 TRED, 

residential post-application exposures from dog collar uses (the residential scenario resulting in 

the highest estimated exposures) were combined with acute (high-end) dietary exposures to 

calculate aggregate risks to cover short-, intermediate- and long-term exposures. Based on this 

approach, the resulting aggregate risk estimates are considered to be protective, and may overestimate risk. 

 

The short-, intermediate- and long-term aggregate risk assessment takes into account the 

dietary exposures to amitraz in food (no exposure through drinking water) along with the postapplication dermal exposure for adults and dermal and incidental oral exposures for toddlers 

resulting from the handling of amitraz-treated pets. An aggregate MOE of 100 or greater does 

not exceed HED’s level of concern. 
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For adults, aggregating the acute dietary exposures with post-application dermal exposure 

from the lower rate (2.4 g ai) dog collars results in aggregate MOEs of 150 for the US population 

and 160 for females 13-49 years old. 

For children (1-2 yrs), the combined dermal and incidental oral exposures from the lower 

rate, 2.4g ai, collar resulted in a MOE of 97. Combining this exposure with acute dietary 

exposure results in an aggregate MOE of 76 based on conservative or worst-case assumptions, 

which exceeds HED’s level of concern. A discussion of this aggregate MOE calculation is 

described below in more detail. 

Aggregate Risk Summary 

Generally aggregate risk assessments combine average (chronic) dietary exposures with 

estimates of residential exposures. For amitraz, the chronic dietary assessment was not 

performed because the acute dietary assessment is protective of any chronic dietary exposures. 

Consequently, this aggregate assessment for amitraz combines acute dietary exposures 

(considered high-end) with residential exposures. HED notes however, that average (chronic) 

dietary exposures would more accurately reflect actual dietary exposures occurring over an 

intermediate-term to long-term timeframe than one-day dietary exposures estimated from the 

acute dietary assessment. To incur high-end dietary exposure, a person must have high-end 

consumption of a food commodity with high-end residues of amitraz. Since it is likely that there 

are significant differences between one day consumption estimates and average consumption 

estimates for many commodities, and since there is considerable variability in pesticide residues 

in/on foods, it is unlikely that an individual receives high-end dietary exposures over a period of 

greater than one day. HED believes the combination of acute (one-day) dietary exposure with 

residential post-application exposures is conservative and will be protective of exposure to 

amitraz regardless of route of exposure and duration of exposure. Residential post-application 

exposures based on standard exposure input values and a non-route-specific toxic endpoint to 

estimate dermal risks combined with high-end acute dietary exposures, while protective, may 

result in an over-estimate of the aggregate (residential plus food) risk 

In the registration review process, the residential exposure estimates from dog collars 

should be updated to conform to revisions in the recently revised residential SOPs. Together 

with any appropriate modifications to the dietary exposure assessment, this may result in changes 

to the aggregate risk assessment results summarized above. 

7.0 Occupational Exposure 

 

Occupational exposure to amitraz is anticipated to occur based on the use pattern of the 

chemical. Occupational handlers can be potentially exposed from applications of the companion 

animal products, pet collar and spot-on, in a professional animal care setting. Handler exposure 

is also likely from the treatment of livestock via spray-dip machine for feeder and dairy cattle 

and enclosed animal premise treatment via low-pressure handwand for swine. Occupational 

post-application exposure from contact with animals treated with pet collar, spot-on product, the 

spray-dip machine and enclosed animal premise treatments are either not expected to occur or 

are expected to be significantly less than residential post-application exposures. 
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An occupational exposure assessment of the amitraz-impregnated pet collar has not been 

previously performed. An occupational assessment of the amitraz spot-on product was 

considered as a part of the July 25, 2007 memorandum, “Occupational and Residential Exposure 

Assessment for Proposed Section 3 Registration of Amitraz on Domestic Pets.” HED 

determined there is a potential for short- and intermediate-term handler exposure in occupational 

settings during the application of products containing amitraz. Proposed domestic pet spot-on 

use of amitraz could be performed by professional animal care workers; however, exposure/risk 

from application to dogs was not assessed because handler contact is expected to be negligible. 

Post-application activities with an animal treated with spot-on product are either not expected to 

occur or are expected to be significantly less than residential post-application exposures. Even if 

the spot-on pet treatment is administered by a professional animal care worker, minimal 

involvement with the animal is assumed to occur after such treatment occurs. 

Occupational assessments of exposure from the treatment of cattle via the spray-dip 

machine and swine via low pressure handwand treatment to enclosed animal premises have not 

been assessed by the Agency. 

Conclusions 

No occupational data gaps were identified during the registration review scoping process. 

An occupational assessment of handler exposure from the application of the pet collar product 

should be conducted. In addition, an occupational handler assessment should also be conducted 

for application to cattle via the spray-dip machine and swine via low pressure hand wand 

treatment to enclosed animal premises should be conducted. The Agency does not anticipate 

post-application occupational exposure from livestock or premise treatments. An updated 

occupational assessment may also be required if new data are identified which impact exposure 

estimates, new PODs or uncertainty factors are selected, or revisions to exposure policies and 

procedures are made. 

8.0 Public Health and Pesticide Epidemiology Data 

 

For IDS, five incidents were identified for amitraz occurring in the United States from 2002 to 

the present for the single chemical only. The evaluation of incident data for amitraz has 

determined that the symptoms appear generic and are not confirmed to be related to exposure, 

there is no clear evidence of a trend or exposure pattern. Therefore, at this time, there are no 

remarkable case reports which suggest a plausible association between a moderate or severe 

health outcome and exposure to the pesticide amitraz, nor can it be discerned any suggestion of a 

trend or pattern regarding the health effects due to the alleged exposure to the pesticide amitraz. 

For NIOSH SENSOR, ten reported cases were identified that involved amitraz. Of these ten 

cases, those that involve only amitraz and where exposure was determined to be definite, 

probable or possible were reviewed in detail, as these cases provide more certain information 

about the potential effect of amitraz exposure. These selection criteria resulted in the exclusion 

of two cases. Of the eight remaining cases, four were professional applicator exposure (three 

treating dogs with dip, fourth unknown), two were unintentional ingestion, one was nonoccupational exposure and one other was unknown exposure. All exposures were of low to 

moderate severity, except one unintentional dose case that involves a six year old male who was 

given flea dip mistakenly by his grandmother who thought it was cough medicine. This case was 
11 of 26 

determined high severity. The health effects most often reported include: dermal (13%), 

respiratory (25%), ocular (25%), cardiovascular (25%), gastrointestinal (50%), and neurological 

(75%). Symptoms are not mutually exclusive; a patient may have many symptoms. 

The applicator symptoms (three dog-dip cases) were mostly neurological with nausea and 

vomiting. Two of these cases were not wearing all the appropriate personal protective 

equipment (PPE), but were wearing gloves. The third case was wearing the appropriate PPE. 

The fourth case exhibited dermal symptoms. Details about this case are unknown. 

Based on the low to moderate severity and low number of incident cases, there does not appear 

to be a risk concern at this time that would warrant further investigation. The Agency will 

continue to monitor the incident information and if a concern is triggered, additional analysis 

will be included in the risk assessment. 

9.0 Tolerance Assessment and International Harmonization 

A summary of US tolerances, Codex Maximum Residue Limits (MRLs), Mexican MRLs, 

and Canadian MRLs for amitraz is provided in Attachment 1. Several MRLs for amitraz have 

been established by Codex in various commodities. The Codex MRL expression differs from the 

U.S. tolerance expression. The Codex expression is the sum of amitraz plus metabolite BTS27271, calculated as BTS-27271. The U.S. expression consists of amitraz residues convertible to 

2,4-dimethylaniline expressed as the stoichiometric equivalent of amitraz. 

The enforcement methods for amitraz tolerances in the U.S. (Methods I and II of PAM 

Vol. II) consist of hydrolysis of all metabolites containing the 2,4-DMA moiety to 2,4-DMA and 

determination using gas chromatography with electron capture detection. The enforcement 

method under the Codex system involves treatment of the RAC with acidic methanol to convert 

the parent compound to metabolite BTS-27271, followed by extraction, cleanup, and 

determination of BTS-27271 using gas liquid chromatography with flame ionization detection. 

Presently, compatibility between the Codex MRL and U.S. tolerance cannot be achieved due to 

the differences between the tolerance definitions and analytical enforcement methods. 

The current U.S. tolerances and Codex MRLs are identical in magnitude for hog, meat 

and cattle, meat byproducts. Although the US and Codex levels are not identical for the other 

commodities, the values are similar in all cases. There are several Codex MRLs for which there 

are no U.S. tolerances. 

10.0 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.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf. The 

Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the 

legal use of a pesticide when conducting human health risk assessments, including, but not 

limited to, people who obtain drinking water from sources near agricultural areas, the variability 

of diets within the U.S. (including different ages, regions, and ethnicities), and people who may 

be exposed when harvesting crops. Should these highest exposures indicate potential risks of 
12 of 26 

concern, OPP further refines the risk assessments to ensure that the risk estimates are based on 

the best available information. 

The Agency acknowledges that milk is distributed in a relatively localized area. 

Therefore, the Agency is looking into whether dairy animals in certain localities where use has 

been reported such as southern Texas and Puerto Rico are treated at a higher frequency than 

dairy animals in other parts of the country. During registration review, EPA is seeking 

information on high dairy treatment areas and milk distribution in order to determine if some 

sub-populations are disproportionately exposed to amitraz residues in milk. 

11.0 Cumulative 

 

FQPA requires that EPA consider “available information” concerning the cumulative 

effects of a particular pesticide’s residues and “other substances that have a common mechanism 

of toxicity.” The Agency considers other substances because low-level exposures to multiple 

chemical substances that cause a common toxic effect by a common mechanism could lead to the 

same adverse health effect, as would a higher level of exposure to any of the substances 

individually. Risks summarized in this document are those that result only from the use of 

amitraz. The Food Quality Protection Act (FQPA) requires that the Agency consider “available 

information” concerning the cumulative effects of a particular pesticide’s residues and “other 

substances that have a common mechanism of toxicity.” 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 amitraz and any other substances. In 

addition, amitraz does not appear to produce a toxic metabolite produced by other substances 

which have tolerances in the U.S. Therefore, for the purposes of tolerance reassessment, EPA has 

not assumed that amitraz shares a common mechanism of toxicity with other compounds. 

12.0 Human Studies 

Humans are the most sensitive species tested with clinical signs similar to those observed 

in animals, reported within 160 minutes after ingestion and persisting up to 12 hours (i.e. 

sedation, dry mouth, disorientation, bradycardia, hypertension and hypothermia). 

In a human double-blind randomized crossover study of acute neurotoxicity (Cass, L 

(1992) T-344, Amitraz: Report of A Double Blind Tolerance Study of Amitraz in Six Adult 

Healthy Volunteers: Lab Project. Number RD 197/20170. Unpublished study prepared by 

Simbec Research Ltd. MRID 43283101), 6 male volunteers were given sequential oral doses of 

amitraz by capsule, at 0.0625 or 0.125 mg/kg with a placebo control. There were at least 14 days 

between treatments. Vital signs (pulse, respiration rate, blood pressure, and body temperature), 

urine samples and ECGs were taken. Pupil responsiveness and psychomotor performance were 

evaluated. Minimal and transient changes in blood pressure, temperature, ECG rate, and 

psychomotor performance were observed at 0.125 mg/kg. 

In a human metabolism study (Campbell J (1984). A Comparison of the Metabolism of 

(14c)-Amitraz in Rats, Mice, Baboon and Human. FBC Limited. MRID 00160964), 2 male 

volunteers given 0.250 mg/kg by oral route experienced sedation, disorientation, and 

hypothermia. Based on the combined results of the human oral toxicity and metabolism studies, 

the acute oral NOAEL and LOAEL for humans are 0.125 mg/kg and 0.25 mg/kg, respectively. 
13 of 26 

 The human metabolism study showed neurotoxic effects shortly after dosing, which 

disappeared within 12 hours. Although the metabolism study was limited to 2 subjects, both 

exposed human subjects experienced clear CNS effects that were consistent with the animal data. 

This endpoint from the human oral and metabolism studies (CNS effects at 0.25 mg/kg; NOAEL 

of 0.125 mg/kg) is appropriate for assessing acute exposures to amitraz. Because of the 

reversibility of the CNS effects, exposures of all durations can be regarded as repeating one-day 

(acute) exposures. Therefore, the human oral endpoint is appropriate for assessing exposures to 

amitraz regardless of exposure duration. 

 Both these studies were reviewed by the EPA Human Studies Review Board in April 

2006, and determined to be scientifically acceptable (when considered together) and useable to 

establish a point of departure for assessing acute dietary risk. The HSRB recommended against 

other uses of the data. 

 

 As discussed in section 5.0, the 2006 risk assessment for amitraz pet collars (2.4 g ai) 

relied upon the study, Transferable Residues from Dogs Treated with 16% Carbaryl Collar

(MRID 45792201). EPA recently concluded that MRID 45792201 lacks appropriate quality 

assurance and quality control (QA/QC) procedures and adequate documentation for all data 

generated in the laboratory and in the field. As a result, the Agency is no longer relying on 

MRID 45792201. In future risk assessments for the amitraz pet collar uses, EPA will rely on a 

different carbaryl pet collar study, Determination of Dislodgeable Residues of Carbaryl from the 

Hair of Dogs Wearing Collars Impregnated with Carbaryl (MRID 47739402). 

13.0 Data Requirements 

Toxicology

The following are brief descriptions of the toxicology data requirements. The rationale 

for requiring each study is listed in Appendix 2. Overall, there are multiple data gaps, often due 

to study deficiencies, with some being the result of new requirements for Part 158. 

870.3100 90-Day Oral Toxicity in Rats 

This study may be combined with the sub-chronic neurotoxicity study, 870.6200. 

The previous study had no individual animal data for clinical signs and gross 

necropsy. 

870.3150 90-Day Oral Toxicity in Dogs 

The previous study had too few animals. Oral toxicity in a non-rodent animal is a 

fundamental data need for assessing the risk of a compound. 

870.3200 21/28 Day Dermal Toxicity 

The previous study had too few animals, concurrent infections, lack of 

information on the substance tested and limited histopathology was provided. 

870.3250 90 Day Dermal Toxicity (Conditionally Required) 

 This data need is listed in the Revised Part 158. 
14 of 26 

870.3465 90-Day/28-Day Inhalation Study 

This requirement is based on the potential inhalation exposure to workers from all 

registered spray application uses. The exposure time may be reduced from 90 

days to 28 days pending exposure patterns, plateauing of effects and considering 

the overall toxicity potential of amitraz. The previous study had limited individual 

animal data, analytical exposure concentrations were not measured, the purity of 

test material was not reported, and the study protocol/environmental conditions 

reporting were incomplete. HED cannot waive the inhalation study because 

amitraz does not meet the criteria of low toxicity via the inhalation route, low 

vapor pressure and the sub-chronic toxicity database is incomplete. 

870.3700 Pre-natal Developmental Toxicity (rabbits) 

 This study is a new data requirement for Part 158 

870.3800 Two-Generation Reproduction Study 

This study should be modified to include the following: Due to the concern for the 

lack of stability of the test material in the diet, treatment should be via oral gavage 

administration. Previous study had limited data provided, mating was not 1 male 

to 1 female, no data on reproductive organs provided, litter data only provided for 

a few time points, and histopathology data were not provided. 

870.6200 Neurotoxicity (Adult): Acute and 90-Day 

 This study is a new data requirement for Part 158 

870.6300 Developmental Neurotoxicity (Conditionally Required) 

This study may be combined with the reproduction study, 870.3800. Amitraz has 

shown signs of CNS effects, thus DNT needs to be considered in the evaluation. 

870.7800 Immunotoxicity 

An immunotoxicity study is required as a part of new data requirements in the 40 

CFR Part 158 for conventional pesticide registration. Because the immune 

system is highly complex, studies not specifically conducted to assess 

immunotoxic endpoints are inadequate to characterize a pesticide’s potential 

immunotoxicity. While data from hematology, lymphoid organ weights, and 

histopathology in routine chronic or subchronic toxicity studies may offer useful 

information on potential immunotoxic effects, these endpoints alone are 

insufficient to predict immunotoxicity. In the absence of required studies, EPA 

may use a database uncertainty factor of up to 10X. Once all data have been 

received and reviewed, the Amitraz Registration Review Team recommends that 

the points of departure and uncertainty factors used for risk assessment purposes 

be re-examined and a new risk assessment done, if necessary. 

14.0 References 

Report of the Food Quality Protection Act (FQPA) Tolerance Reassessment Progress and Risk 

Management Decision (TRED) for Amitraz, July 2006 
15 of 26 

Roberts, TR, Hutson, DH, “Metabolic Pathways of Agrochemicals”, The Royal Society of 

Chemistry Information Services (1999) 

Amitraz. Revised Human Health Risk Assessment for the Tolerance Reassessment Eligibility 

Decision (based on discussions of the Human Studies Review Board), July 26, 2006 

Young, FM, et al, “Effects of the insecticide amitraz, an alpha-adrenergic receptor agonist, on 

human luteinized granulosa cells” (2005) Human Reproduction 20(11): 3018-3025 

W. Britton. Occupational and Residential Exposure Assessment for Proposed Section 3 

Registration of Amitraz on Domestic Pets. D341879. 07/25/2007 

W. Britton. Revisions for “Amendment to “Amitraz: Revised Residential Exposure Assessment 

for the Reregistration Eligibility Decision (11/19/2004, D310631)”: (D318939).” D310229. 

07/27/2006 

Amitraz. Reregistration List A Case No. 0234/Chemical ID No. 106201. Nature of the Residue 

in Pigs Following Dermal Application of 14C-Amitraz. MRID No. 42969301. CBRS No. 12801. 

DP Barcode No. D196559. 

Campbell, J.K. and D. Needham. (l984) A comparison of the metabolism of 14C-amitraz in rat, 

mouse, baboon and human. FBC Limited, Chesterford Park Research Station, Saffron Walden, 

Essex CB10 1XL, January 17, 1984. MRID 00160964. Unpublished

Campbell, J.K. and D. Needham. (l984) Urinary excretion of 14C-amitraz by two male humans 

following a single oral dose of 0.25 mg/kg body weight. FBC Limited, Chesterford Park 

Research Station, Saffron Walden, Essex CB10 1XL, February 4, 1984. MRID 46249601. 

Unpublished

Amitraz Multi-species Metabolism Study, Data Evaluation Record, TXR#: 0052737 

April 4-6, 2006 EPA Human Studies Review Board Meeting Report, June 26, 2006 (EPAHSRB-06-01) 

Updated Review of Amitraz Incident Reports , DP Barcode: D368729 

Determination of Dislodgeable Residues of Carbaryl from the Hair of Dogs Wearing Collars 

Impregnated with Carbaryl (MRID 47739402) 

Transferable Residues from Dogs Treated with 16% Carbaryl Collar (MRID 45792201) 

Cass, L (1992) T-344, Amitraz: Report of A Double Blind Tolerance Study of Amitraz in Six 

Adult Healthy Volunteers: Lab Project. Number RD 197/20170. Unpublished study prepared by 

Simbec Research Ltd. MRID 43283101) 
16 of 26 

15.0 Attachments 

Attachment 1: Maximum Residue Limits (MRL) Table 

Table 2. Summary of Amitraz US and International Tolerances and Maximum Residue Limits 

US Canada Mexico2 Codex 

Residue Definition: 

40 CFR 180.287 

Amitraz (N'-[2,4-

dimethylphenyl]-N-[[(2,4-

dimethylphenyl)imino]methyl]]-

N-methylmethanimidamide) and 

its metabolites containing the 2,4-

dimethylaniline moiety calculated 

as the parent 

N,N-bis(2,4-

xylyliminomethyl)methylamine, 

including the metabolite N-(2,4-

dimethylphenyl)-N'-methyl 

formamidine 

amitraz Sum of amitrax and 

N-(2,4-

dimethylphenyl)-N’-

methylformamidine 

calculated as N-(2,4-

dimethylphenyl)-N’-

methylformamidine. 

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) 

Commodity US Canada Mexico2 Codex 

Cattle, fat 0.1 

Cattle, meat 0.02 0.053 

Cattle, meat byproducts 0.2 0.2 (kidney; liver) 0.23 

Cotton, undelinted seed1 1.0 1 0.5 

Hog, fat 0.1 

Hog, kidney 0.1 0.2 0.2 (edible offal)3 

Hog, liver 0.1 0.2 0.2 (edible offal)3 

Hog, meat 0.05 0.053 

Hog, meat byproducts 0.3 

Milk 0.03 0.01 (*)3 

Milk, fat 0.2 

Pear 0.5 (pome fruit) 

Cherries 0.5 

Cucumber 0.5 

Oranges 0.5 

Peach 0.5 

Sheep meat 0.13 

Tomato 0.5 

Apples 0.5 

1 There are no US registrations on cottonseed as of May 3, 2006. 

2 Available information for Mexico is dated (2004). Mexico adopts US tolerances or 

Codex MRLs for export purposes. 

3 The MRL accommodates external animal treatment. 
17 of 26 

Attachment 2. Data Needs For AMITRAZ Technical 

Guideline Number: 870.3100 

Study Title: Repeated Dose 90-Day Oral Toxicity Study in Rats 

Rationale for Requiring the Data 

This study is a fundamental requirement in Revised Part 158 toxicology. This study may be combined with 

the sub-chronic neurotoxicity study, 870.6200. The previous study had no individual animal data for 

clinical signs and gross necropsy-- the data are insufficient at this point to develop and incorporate 

quantitative determinations of this toxicity potential into our assessment. 

Practical Utility of the Data 

How did the Agency make its re-registration decision without this data? 

The Agency was able to make a decision by adding a database uncertainty factor of 10X, in lieu of having a 

an acceptable toxicity study to conduct the human health risk assessment. The Agency was able to select 

doses and endpoints for conducting a risk assessment from the available studies. 

How will the data be used and how could the data impact the Agency’s future decision-making? 

After review and evaluation of the oral toxicity study, EPA will use the data to determine whether the 10X 

database uncertainty factor continues to be appropriate, or if the data show that the 10X uncertainty factor 

should be reduced or removed. 

Guideline Number: 870.3150 

Study Title: Repeated Dose 90-Day Oral Toxicity Study in Dogs 

Rationale for Requiring the Data 

Oral toxicity in a non-rodent animal is a fundamental requirement in Revised Part 158 toxicology for 

assessing the risk of a compound. The previous study had too few animals-- the data are insufficient at this 

point to develop and incorporate quantitative determinations of this toxicity potential into our assessment. 

Practical Utility of the Data 

How did the Agency make its re-registration decision without this data? 

The Agency was able to make a decision by adding a database uncertainty factor of 10X, in lieu of having a 

an acceptable toxicity study to conduct the human health risk assessment. The Agency was able to select 

doses and endpoints for conducting a risk assessment from the available studies. 

How will the data be used and how could the data impact the Agency’s future decision-making? 

After review and evaluation of the oral toxicity study in dogs, EPA will use the data to determine whether 

the 10X database uncertainty factor continues to be appropriate, or if the data show that the 10X 

uncertainty factor should be reduced or removed. 
18 of 26 

Guideline Number: 870.3200 

Study Title: 21/28-Day Dermal Toxicity 

Rationale for Requiring the Data 

The 21/28-day dermal toxicity study is a new data requirement under 40 CFR Part 158 as a part of the 

data requirements for registration of a pesticide for non-food use. 

The dermal toxicity Test Guidelines (OPPTS.870.3200) is intended to evaluate the toxic effects 

associated with continuous or repeated exposures to a test substance for a period of 21/28-days. 

The Agency needs a 21/28-day dermal toxicity study for non-food use pesticides because the dermal 

route will be the primary route of exposures for chemicals designated with this used pattern (i.e., nonfood). The Agency believes that this study is required because the longer term oral studies (i.e., chronic 

or carcinogenicity studies) which are required for food-use pesticides are usually not required for nonfood use pesticides. 

Practical Utility of the Data 

How will the data be used? 

A route specific (i.e., dermal) study will provide critical scientific information needed to characterize 

potential hazard to the human population exposed to the pesticide by the dermal route. This study will 

provide a dose and a toxicological endpoint of concern for quantification of risks for dermal exposures. 

This study would eliminate the uncertainties associated with the use of an oral study with a default (100% 

oral equivalent) dermal absorption factor. 

In many cases, toxicity observed via the dermal route will be different than toxicity observed via oral 

exposure, due to absorption and distribution of the toxic agent after exposure or differences in 

metabolism (i.e., systemic versus local). This means that the route-to-route extrapolation (i.e., use of an 

oral dose/endpoint) in risk assessment could result in under or over estimation of risks from the dermal 

route. 

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

If the dermal toxicity study indicates that the test material poses either a greater or lesser risk than that 

calculated using an oral dose, (as used in the interim decision), the risk assessment would be revised to 

reflect the magnitude of potential risk derived from the new data. Also, the requested data would allow 

the Agency to determine if the risks were over-estimated or under-estimated. If the risks were underestimated, additional risk mitigation measures could be required. If the risks were over-estimated, risk 

mitigation measures could be reduced. 
19 of 26 

Guideline Number: 870.3250 

Study Title: 90-Day Dermal Toxicity 

Rationale for Requiring the Data 

The sub-chronic (90-day) dermal toxicity study is a new data requirement under 40 CFR Part 158 as a 

part of the data requirements for registration of a pesticide for non-food use. 

The dermal toxicity Test Guidelines (OPPTS.870.3250) is intended to evaluate the toxic effects 

associated with continuous or repeated exposures to a test substance for a period of 90-days. 

The Agency needs a 90-day dermal toxicity study for non-food use pesticides because the dermal route 

will be the primary route of exposures for chemicals designated with this used pattern (i.e., non-food). 

The Agency believes that this study is required because the longer term oral studies (i.e., chronic or 

carcinogenicity studies) which are required for food-use pesticides are usually not required for non-food 

use pesticides. A 21/28 day dermal toxicity test is insufficient to identify potential hazards for non-food 

use pesticides because of the concern for the longer duration exposure associated with this use pattern. 

For example, professional applicators may be subjected to repeated exposure during the 3 month period 

of peak summer infestation. For this type of increased exposure, professional applicators may not be 

adequately protected using data from a 21/28-day study. 

Practical Utility of the Data 

How will the data be used? 

A route specific (i.e., dermal) study will provide critical scientific information needed to characterize 

potential hazard to the human population exposed to the pesticide by the dermal route. This study will 

provide a dose and a toxicological endpoint of concern for quantification of risks for dermal exposures. 

This study would eliminate the uncertainties associated with the use of an oral study with a default (100% 

oral equivalent) dermal absorption factor. 

In many cases, toxicity observed via the dermal route will be different than toxicity observed via oral 

exposure, due to absorption and distribution of the toxic agent after exposure or differences in 

metabolism (i.e., systemic versus local). This means that the route-to-route extrapolation (i.e., use of an 

oral dose/endpoint) in risk assessment could result in under or over estimation of risks from the dermal 

route. 

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

If the dermal toxicity study indicates that the test material poses either a greater or lesser risk than that 

calculated using an oral dose, (as used in the interim decision), the risk assessment would be revised to 

reflect the magnitude of potential risk derived from the new data. Also, the requested data would allow 

the Agency to determine if the risks were over-estimated or under-estimated. If the risks were underestimated, additional risk mitigation measures could be required. If the risks were over-estimated, risk 

mitigation measures could be reduced. 
20 of 26 

Guideline Number: 870.3465 

Study Title: 90-Day/28-Day Inhalation Toxicity 

Rationale for Requiring the Data 

Instead of conducting the inhalation study for 90-days, the Agency only needs a 28-day inhalation study 

because only short- and intermediate-term (but not long-term) exposure to workers is expected based on 

amitraz's use pattern. A longer-term inhalation study is required in situations in which a specific concern 

exists for increased hazard related to exposure via the inhalation route. The 28-day inhalation toxicity 

study evaluates the potential hazard of a pesticide chemical following repeated inhalation exposures. This 

study is critical for pesticides with use patterns in which there is potential for repeated human exposures 

(e.g., professional applicators, green house use, etc.). The study design simulates the route of human 

exposure (inhalation). In this study, animals are exposed (nose/whole body) to aerosol concentrations of 

the test material for 6 hours/day, 5 days/week for 28 days. A detailed toxicological examination including 

the histopathology of the respiratory system is conducted. This route-specific study would provide data 

for hazard characterization, dose response assessment, and a dose and endpoint for assessing potential 

risks via the inhalation route. 

Practical Utility of the Data 

How will the data be used? 

This study will identify hazard (i.e., provide a dose and endpoint) following repeated inhalation exposures. 

The results will be used in risk assessments as appropriate. 

How could the data impact the Agency’s decision-making? 

A sub-chronic inhalation study provides critical scientific information needed to characterize potential 

hazard to the human respiratory system from pesticide exposure. In the case of amitraz, there is no 

acceptable inhalation study available. A 28-day repeated exposure study that follows the Test Guidelines 

(870.3465) will characterize hazard and provide data for a more refined inhalation risk assessment. 

Exposure time may be reduced 28 days pending exposure patterns, plateauing of effects and considering 

the overall toxicity potential of amitraz. This requirement is pending resolution of inhalation exposure for 

existing and possible future uses. 
21 of 26 

Guideline Number: 870.3700 

Study Title: Pre-Natal Developmental Toxicities-- Rabbit 

Rationale for Requiring the Data 

The pre-natal developmental toxicity study in a second species (non-rodents) is a new data requirement 

under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide for food and nonfood uses. 

The pre-natal developmental toxicity Test Guidelines (OPPTS.870.3700) is designed to provide general 

information concerning the effects of exposure of the pregnant test animals (non-rodent) on the 

developing organism; this may include death, structural abnormalities, or altered growth and an 

assessment of maternal effects.. 

The Agency needs this study in a second species (non-rodents, preferably in rabbits) for food and nonfood use pesticides because the Agency believes that testing in two species (rodents and non-rodents) 

provides a balance assessment, eliminates uncertainty of assessing of risk only in sensitive (or 

insensitive) species, and would adequately characterize potential hazards to pregnant women and their 

fetuses. 

Practical Utility of the Data 

How will the data be used? 

This study will provide critical scientific information needed to characterize potential hazard to pregnant 

women and their fetuses exposed to the pesticide by the oral route. This study can provide a dose and a 

toxicological endpoint of concern for quantification of risks for the sensitive population (i.e. pregnant 

females). 

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

If the results of this study indicate the non-rodent species to be more sensitive than the rodents, and 

provides data that indicates that the test material poses either a greater or lesser risk than that currently 

used, the risk assessment would be revised to reflect the magnitude of potential risk derived from the new 

data. Also, the requested data would allow the Agency to determine if the risks were over-estimated or 

under-estimated. If the risks were under-estimated, additional risk mitigation measures could be 

required. If the risks were over-estimated, risk mitigation measures could be reduced. 
22 of 26 

Guideline Number: 870.3800 

Study Title: Two Generation Reproduction and Fertility effects

Rationale for Requiring the Data

This guideline for two-generation reproduction testing is designed to provide general information 

concerning the effects of a test substance on the integrity and performance of the male and female 

reproductive systems, including gonadal function, the estrous cycle, mating behavior, conception, 

gestation, parturition, lactation, and weaning, and on the growth and development of the offspring. The 

study may also provide information about the effects of the test substance on neonatal morbidity, 

mortality, target organs in the offspring, and preliminary data on prenatal and postnatal developmental 

toxicity and serve as a guide for subsequent tests. Additionally, since the study design includes in utero 

as well as postnatal exposure, this study provides the opportunity to examine the susceptibility of the 

immature/neonatal animal. 

The data requirements in 40 CFR Part 158 requires a two-generation reproductive toxicity study for all 

chemicals with food use. The study should be modified due to the concern for the lack of stability 

of the test material in the diet, treatment should be via oral gavage administration.

Practical Utility of the Data

How did the Agency make its re-registration decision without this data? 

The Agency was able to make a decision by adding a database uncertainty factor of 10X, in lieu of 

having a reproductive toxicity study to conduct the human health risk assessment. The Agency was able 

to select doses and endpoints for conducting a risk assessment from the available studies. 

How will the data be used and how could the data impact the Agency’s future decision-making? 

After review and evaluation of the reproductive toxicity study, EPA will use the data to determine 

whether the 10X database uncertainty factor continues to be appropriate, or if the data show that the 10X 

uncertainty factor should be reduced or removed. 
23 of 26 

Guideline Number: 870.6200 

Study Title: Neurotoxicity Battery (Acute and Sub-Chronic Studies)

Rationale for Requiring the Data 

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration 

of a pesticide (food and non-food uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the potential adverse 

effects on the nervous system from exposure to pesticide chemicals. The Agency believes that the 

guideline studies are inadequate in their assessment of behavioral effects and do not use optimal methods 

to evaluate the potential toxicity to the nervous tissue structure and function. To detect and characterize 

these potential effects more fully, a battery of more sensitive testing is required. The objective of this 

neurotoxicity battery testing is to evaluate the incidence and severity of the functional and/or behavioral 

effects, the level of motor activity, and the histopathology of the nervous system. The acute neurotoxicity

study is required to detect possible effects resulting from a single exposure. The sub-chronic 

neurotoxicity study is intended to detect possible effects resulting from repeated or long-term exposures. 

Practical Utility of the Data 

How will the data be used? 

The acute and sub-chronic neurotoxicity studies provide critical scientific information needed to 

characterize potential hazard to the human population on the nervous system from pesticide exposure. 

These studies can provide data on a wide range of functional tests for evaluating neurotoxicity including 

sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system 

For example, animal studies with organophosphorous chemicals have shown neurotoxicity to be the 

primary toxic endpoints (e.g., cholinesterase inhibition) of concern in rodents and non-rodents. These 

animal studies can be used to select endpoints and doses for use in risk assessment of all exposure 

scenarios and are considered a primary data source for reliable reference dose calculation. The Agency 

has established an oral reference dose (RfD) for assessing dietary risks for a number of chemicals (e.g., 

organophoshates and carbamates) where neurotoxicity was the most sensitive endpoint of concern. 

How could the data impact the Agency's future decision-making? 

If the acute or sub-chronic neurotoxicity studies show that amitraz poses either a greater or a diminished 

risk than that given in the interim decision’s conclusion, the risk assessment for amitraz may need to be 

revised to reflect the magnitude of potential risk derived from the new data. 

 

If the Agency does not have this data, a 10X database uncertainty factor may be applied when 

conducting a risk assessment using the currently available studies. 
24 of 26 

Guideline Number: 870.6300 

Study Title: Developmental Neurotoxicity Study 

Rationale for Requiring the Data 

A developmental neurotoxicity (DNT) study is conditionally required for all pesticide chemicals to 

determine if developing mammals are susceptible to the neurotoxic effects of the test material especially 

in relation to effects that may persist into adulthood. The trigger for requiring the study is a weight-ofevidence evaluation that considers the kinds of evidence available, how that evidence fits together in 

drawing conclusions, and significant issues/strengths/limitations. Specific to the weight of evidence for 

requiring a DNT is that the pesticide causes treatment-related neurological effects in adult animal studies. 

The criteria that were developed for determining the need for a DNT were developed through extensive 

peer review including the FIFRA Scientific Advisory Panel. This study may be combined with the 

reproduction study, 870.3800 

Amitraz was found to produce sedation, disorientation and hypothermia following acute oral 

administration to humans. This study was selected as the basis for all the toxicology doses and endpoints 

selected for amitraz. Because amitraz has been shown to cause treatment-related neurological effects in 

human studies, a DNT study is warranted. 

Practical Utility of the Data for Developmental Neurotoxicity Study 

How will the data be used? 

The 10X database uncertainty factor may be removed upon submission of the DNT study, effectively 

reducing human health risk estimates by an order of magnitude. In addition, the point of departure for the 

risk assessment may change based on the results of the study. 

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

The removal of the 10x database uncertainty factor, along with a possible change in the point of 

departure, may change the Agency’s dietary assessment by impacting the dietary risk cup. In addition, 

the occupational and residential risk assessments may be changed, depending on the results of the 

requested study. 
25 of 26 

Guideline Number: 870.7800 

Study Title: Immunotoxicity

Rationale for Requiring the Data 

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration 

of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and 

is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., 

suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system 

to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired 

Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies 

assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential 

immunotoxicity. These data will be used in combination with data from hematology, lymphoid organ 

weights, and histopathology in routine chronic or subchronic toxicity studies to characterize potential 

immunotoxic effects. 

Practical Utility of the Data 

How will the data be used? 

These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure 

scenarios and are considered a primary data source for reliable reference dose calculation. For example, 

animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive 

manifestations of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive, and 

endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for 

tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997). 

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than 

that given in the interim decision’s conclusion, the risk assessments for the test material may need to be 

revised to reflect the magnitude of potential risk derived from the new data. 

 

If the Agency does not have this data, a 10X database uncertainty factor may be applied for conducting a 

risk assessment from the available studies. 

Attachment 3: IDS Report
Page 26 of 26 

IDS Report Chemical: Amitraz 106201 Human Incidents 

Incident Number 

Incident 

Date Product Name 

Registration 

Number City State 

Exposure 

Type* Incident Des

016369 001 01-Jan-05 TAKTIC E.C. 05438200003 TX HC A 2 year old Female in

a 1/4 teaspoon of the pprescribed to treat her reported blueness and purple. 

018212 001 31-Dec-06 TAKTIC 

EMULSIFIABLE CONCENTRATE, 12.5% SOLUTION 

05438200003 REDLANDS CA HC A 20 year old Male rep

Vomiting, and Diarrheproduct. 

019496 001 26-Mar-08 TAKTIC E.C. 05438200003 BROOKLET GA HC Unknown Adult (18-64 

Female's friend used thtreat a dog on 3 consecThe friend did not weareported Nausea, DizzVision, Numbness, SwChest Tightness. 

020351 001 02-Nov-08 TAKTIC 

EMULSIFIABLE CONCENTRATE, 12.5% SOLUTION 

05438200003 IN HB A 49 year old Male rep

Blurred Vision, NumbSeizure two days follothe product. He was trphysician. 

020463 004 23-Mar-08 PREVENTIC 

PREVENTION PACK 2 COLLARS 

00238200104 PA HC Unknown Adult (18-64 

Female applied the profamily dog. She reporIrritation and Rash on was evaluated by a phydiagnosed with a hypereaction.