Page 2 of 13 Tetramethrin is a pyrethroid insecticide. Pyrethroids are synthetic esters derived from naturally occurring pyrethrins. There are no registered food-use applications for tetramethrin and no tolerances for specific raw agricultural commodities. Tetramethrin is used to control mosquitoes and other insects indoors and outdoo rs in residential and commercial areas. Tetramethrin is also applied directly to pets.

The liver is the principal ta rget organ for exposure to te tramethrin. Tetramethrin is classified as “Suggestive Evidence of Carcinoge nic Potential” based on benign interstitial cell adenomas in rats. In the 2008 risk assessments, no risks of concern were identified for dietary, occupational, residential, and aggregate exposur es, and all risk estimat es were below Agency
levels of concern.

HED’s Registration Review Scopi ng Document conclusions are as follows. 1) A dietary exposure assessment was not conducted and is not required for Registration Review as there are no food uses for tetramethrin and dietary expos ure is not expected. 2) Given the limited potential exposure and the environmental fate pr operties of tetramethri n, a quantitative drinking water assessment will not be conducted. 3) The residential exposure assessment needs to be updated according to current stan dard operating procedures and may need to be revised if incidental oral endpoints change based on newly required toxicity data. 4) The occupational exposure assessment needs to be updated to refl ect current standard operating procedures. 5) The following studies have been requested under a generic data call-in issued in June 2010 based the 2010 Amended RED; a rat developmental toxicity study; acu te, subchronic, and developmental neurotoxicity studies ; and an immununotoxicity study.Page 3 of 13 Introduction

HED has evaluated the existing human health risk assessments for tetramethrin to
determine whether sufficient data are available and whether a new human health risk assessment is needed to support Registration Review. HED has considered the most recent risk assessments for tetramethrin, updates to its toxicity, expos ure and usage databases, and current Agency science policies and risk assessment methods.

Use Profile

Tetramethrin is a Type I pyrethroid insecticid e. Pyrethroids are s ynthetic esters derived from naturally occurring pyrethrins (which are extracts of chrysanthemum flowers). Type I pyrethroids act on axons in the pe ripheral and central nervous syst em by interacting with sodium
channels in mammals and/or ins ects. Tetramethrin and other pyr ethroids are usually combined with synergists that enhance insecticidal ac tivity by preventing enzymatic breakdown of the pyrethroid. Tetramethrin is not registered for direct appli cation to agricultura l crops and there are no tolerances for specific raw agricultural commodities

. Tetramethrin is registered for use in indoor and outdoor residential, institutional, and i ndustrial settings. It is also registered for use on pets. Tetramethrin is applied primarily by aer osol cans, handheld sprayers, and foggers.

Hazard Identification/Toxicology

Acceptable subchronic and chr onic rodent and dog studies in dicate that the liver is the primary target organ for effects following repeated oral exposure to tetram ethrin. Tetramethrin was classified as a “Group C, possible human carcinogen without quantification” by the Cancer Peer Review Committee in 1989 based on the pres ence of benign interstitial cell adenomas in both Sprague-Dawley and Long Evans rats. This cl assification corresponds to a classification of as “Suggestive Evidence of Carcinogenic Potential,” under EPA’s 2005 Guidelines for Carcinogen Risk Assessment. Tetramethrin exhib its low acute toxicity (T oxicity Category III or IV) in rats by oral and dermal routes of exposure.

For the tetramethrin risk assessments (D 292298, 6/18/08), toxicity e ndpoints or points of departure (PODs) were selected for residential an d occupational exposure scenarios. A POD for incidental oral exposures wa s selected from a 2-generation rat reproduction study based on decreased body weight in parental animals and pups and bile duct effect s in parents. The incidental oral endpoint was refined based on a benchmark dose analysis (BMD) submitted by the registrant and reviewed by HED using the en dpoint of body weight on Day 21 in females in the F0 and F1 generations. A POD from two subc hronic inhalation studies in rats was selected for assessment of inhalation exposure pathway fo r workers and resident ial handlers/occupants based on increased clinical signs that were more indicative of re spiratory toxicity/irritation than neurotoxicity (e.g. irregular respiration and br adypnea), changes in hematology and urinalysis, changes in blood chemistry, and gross pathology findings in the liver and kidney. A POD for dermal exposure was not selected based on dermal absorption studies whic h indicate low dermal absorption and a dermal toxicity study in which dermal effects were not observed at the limit dose. An uncertainty factor of 1000 was app lied in 2008 for all exposure routes (10x forPage 4 of 13 interspecies extrapolation, 10x for intraspecies variation, and 10x fo r database uncertainty factor for the inadequate toxicology database i.e., abse nce of acceptable neurotoxicity studies).

The Office of Pesticide Programs has re-evaluat ed the need of a 10X FQPA Safety Factor
for human health risk assessments for pyrethroid pestic ides. Based on a review of the available guideline and literature studies, th e Agency is reducing the FQPA Safety Factor to 1X for adults, including women of child-bearing ag e, and children greater than 6 years of age. However, the Agency is retaining a 3X FQPA Sa fety Factor for children from birt h to 6 years of age. The 3X is based on age-dependent-pharmacokinetics and is further supported by physiologically-based pharmacokinetic (PK) model predictions of a 3- fold increase of pyrethr oid concentration in juvenile target tissue compared to adults. In addition, there is sufficient evidence that the pharmacodynamic (PD) responses are similar in a dults and juveniles a nd therefore a full 10X safety factor is not warranted (D381210, 6/27/ 11). The Agency is expecting additional in vitro
and in vivo data . Pesticide registrants and product form ulators (Council for the Advancement of Pyrethroid Human Risk Assessmen t (CAPHRA) are i) conducting in vitro studies demonstrating the interaction of pyrethroids exogenous ly expressed rat and human VGSCs in Xenopus oocytes; ii) conducting in vitro studies demonstrating interaction of pyrethroids in rat neurolemma cells; iii) developing rat and human PBPK models, in cluding additional pharmacokinetic data; and iv) conducting in vivo behavioral testing using a uditory startle testing in rats. As more data for individual pyrethroids become available, the Agency will determine whether re-evaluation of the age-related sensitivity of pyr ethroids is appropriate.

Data Requirements

A generic data call-in (GDCI-069003-28621) wa s issued in June 2010 for the following studies based on the 2010 Amended RED; 870.3 700, a rat developmental toxicity study; 870.6200, acute, subchronic, and 870.6300, developm ental neurotoxicity studies; and 870.7800, an immununotoxicity study. The registrant indica ted their intent to conduc t or cite the required studies within the time frames provided in the DCI. The immunotoxicity study was recently received by the Agency (8/11) and is undergoi ng review by HED. Acute toxicity studies,
identified as data deficienci es in the 2008 HED risk assessmen t, including inhalation, eye and skin irritation, and skin sensit ization data for technical tetram ethrin were required by the product specific data call-in (PDCI-069003-28170) also issued in June 2010.

Conclusions

Based on HED’s re-evaluation of the toxi city analysis conducted for the 2008 tetramethrin risk assessment, rat developmental toxicity; acute, subchronic, and developmental neurotoxicity; and immunotoxicity studies were required. These studies were pr eviously calledin through the RED GDCI. PODs for oral (dietar y, drinking water and in cidental oral) exposure are adequate but may need to be reevaluated to incorporate required toxic ity data and to reflect OPP’s reevaluation of the safety factor for pyr ethroid pesticides. P ODs for inhalation and dermal exposures are adequate.Page 5 of 13 Dietary and Drinking Water Exposure

Tetramethrin currently has no registered food us es and there are no tole rances for specific raw agricultural commodities. Tetramethrin is not registered for direct application to agricultural crops, livestock animals, or livestock pr emises, where livestock are used for food

. Although there are no registered food uses for tetramethri n, there are uses in the home where food may be exposed e.g., kitchens. However, labels for th ese uses have restricti ons to prevent/limit food exposure e.g., “In the home, all food-processing su rfaces and utensils should be covered during treatment, or thoroughly washed before use. Cover exposed food.” HED did not conduct a quantitative assessment of dietary risk for home uses because, based on label prescriptions most (if not all) food will be stored prior to applicat ion, any food not stored will likely be covered, and residuals from surfaces/utensils are expected to be low due to washing and/or insignificant transfer to food. Consequently, fo od residues are likely to be neg ligible, and risks are not likely
to be of concern.

The Environmental Fate and Effects Divisi on (EFED) has not previously conducted a quantitative drinking water assessment for tetram ethrin. Tetramethrin is used by individual homeowners and industrial/commercial property ow ners, and the use pattern is in individual, isolated areas, and in small amounts. These amo unts are equivalent to a spray can that may be purchased in a supermarket or hardware store. Tetr amethrin is not used on a wide scale, such as in agriculture or in mosquito abatement by public authorities. The diffuse nature of the use pattern makes it unlikely that any harmful amount of tetramethrin will be released in any one place and time. Tetramethrin photolyzes rapidly in the air with a half-life of 30 minutes, hydrolyzes in water rapidly with half-lives ra nging from 0.89-1.06 days at pH 7, and it strongly adsorbs to soil and sediment (less tetramet hrin available in water column) with K
oc values ranging from 1289- 2933. Given the limited extent of potential exposure a nd the fate properties of tetramethrin, a quantitative drinking water as sessment is not anticipated during registration
review.

Data Requirements

The data base for the dietary and drin king water assessment is complete.

Conclusions

A dietary and drinking water assessment is not re quired for existing uses of tetramethrin.

Residential Exposure

The residential exposure assessment conducte d in July, 2008 include s handler and postapplication residential ex posure scenarios. Residential handler exposure and risk estimates were conducted using HED standard deterministic mo deling methodology and default assumptions for most exposure scenarios. Reside ntial post-application exposure and risk to tetramethrin was assessed using probabilistic modeling approaches . Residential scenarios were assessed for exposure via inhalation and incidental ingesti on pathways. Dermal exposure was not assessed because PODs for dermal exposure were not sel ected based on absence of adverse effects inPage 6 of 13 dermal toxicity studies. Shor t and intermediate-term exposures were assessed for residential handler and post-application expos ure scenarios based on registered uses and expected exposure patterns. Residential handler exposure scen arios, assessed using HED OPP’ standard deterministic risk assessment methodology showed that estimated risks were not of concern. Based on the deterministic post-application as sessment, estimated risks of concern were identified for inhalation exposur e following outdoor total rele ase fogger applications, indoor aerosol can space spray treatments, and hand-to -mouth exposures following indoor aerosol can treatments, and indoor ready-to-use liquid spray treatments. Exposur es from incidental oral and inhalation pathways were not combined for tetram ethrin because the toxicity endpoints for these exposure routes are not based on common toxicity effects.

Based on comments submitted to the Agen cy, HED conducted a refined probabilistic assessment of risks using the Cumulative a nd Aggregate Risk Evaluation System (CARES ®
Version 3.0; http://cares.ilsi.org/ ) for those residentia l post-application exposure scenarios that presented risks of concern based on the determ inistic assessment. Probabilistic exposure assessment is recognized as a refinement over de terministic assessment because it incorporates the full range of exposures and their associated probabilities. All MOEs derived based on the probabilistic assessment were above 1000 except for the 100 th and 99.9 th percentile MOEs for indoor non-dietary ingestion expos ures. Given the use of conservative assumptions, OPP
concluded that these results do not indicate risks of concern.

Addenda were added to the July 2008 tetram ethrin risk assessment in April 2009 and February 2010. The 2009 assessment was conducted to estimate residential exposures risks from a 0.35% tetramethrin indoor space spray produc t not included in the 2008 assessment. A
standard deterministic assessment indicated that estimated inhalation risk to residential handlers was not a concern for the 0.35% spray product. However, HED’s CARES assessment for this use found potential risks of concern for post-app lication incidental oral exposure to children (MOEs < 1000 above the 98.8 th percentile). Based on additional comments submitted to EPA, a benchmark dose (BMD) analysis of the toxicity endpoint for incidental oral exposure was conducted, and HED revised the CARES assessm ent in February 2010 using the endpoint derived based on the BMD analysis. Based on th at assessment, estimated risks were not of concern for incidental oral exposure to child ren from the 0.35% spray (i.e., MOEs are > 1000 (using the BMDL 5 ) at the 99.9 th percentile). The tetramethr in RED was amended in April 2010 to reflect these updated exposure assessments.

Conclusions

During registration review, the residential exposure assessment needs to be updated to reflect current standard operating procedures. It should be noted that HED does not, as a matter of policy, conduct probabilistic residential expos ure analyses using CARES. However, the registrant may again choose to submit a CARES an alysis if desired, based on the results of the assessment conducted for registration review. As previously, HED will review any submissions for possible inclusion in the registration review assessment. The combined non-food pathway exposure assessment for residential uses will need to be reevaluated if PODs change based on newly required toxicity data.Page 7 of 13 Occupational Exposure

Risk assessments were conducted for occupa tional handler exposure scenarios based on registered uses. Occupational post-application sc enarios were not assessed because there is no dermal endpoint and post-application inhalati on exposures are not expected for non-volatile compounds such as tetramethrin. Occupational and handler exposure and risks were estimated for handheld spray and fogging equipment based on registered labels. Occupational exposure and risk estimates indicated occupational exposure scenarios do not present risks of concern (i.e.,

MOEs > 1000).

Conclusions

The occupational exposure asse ssment is adequate but needs to be updated to reflect current standard operating procedures. Recomm ended unit exposures for occupational handler assessments have generally been derived only from PHED. However, recently both the ORETF and AHETF have produced pesticide handler exposur e monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/s cience/handler-exposure-data.html ). As more reliable data become available (such as that from the AHETF and ORETF), the Agency will continue to replace existing data. Reviewers sh ould incorporate new exposure monitoring data, as necessary, during Registration Review.

Incident Report

An updated incident report was conducted for tetramethrin for Registration Review (K. Oo, D392272, 8/11/11). In general, a relatively large number of incidents have been reported involving tetramethrin. Howeve r, because tetramethrin products are almost always coformulated with other pesticide active ingredie nts, there are no cases reported for products containing tetramethrin present as a single chem ical only. Human incident data may warrant further analysis for the risk assessment and/ or risk management of tetramethrin.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA review s numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute,
subchronic and chronic toxici ty, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or syst emic toxicity. These studies include endpoints which may be susceptible to endocrine influenc e, including effects on endocrine target organ histopathology, organ weights, es trus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard asse ssments, EPA evaluates
acute tests and chronic studies that assess growth, developmen tal and reproductive effects in different taxonomic groups. As part of its reregistration decision

, EPA reviewed these data and selected the most sensitive endpoi nts for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA s ection 408(p), tetramethr in is subject to the endocrine screening part of the Endocrine Disruptor Screenin g Program (EDSP).Page 8 of 13 EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredie nts) may have an effect in hu mans or wildlife similar to an effect produced by a “naturally occurring estr ogen, or other such endocrine effects as the Administrator may designate.” The EDSP em ploys a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact w ith the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Ti er 2 tests are necessary based on the available data. Tier 2 testing is designe d to identify any adverse endocr ine-related effects caused by the substance, and establish a dose-re sponse relationship between the dos e and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pest icide active ingredients and 9 inert ingredients. Tetramethrin is not among the group of 58 pesticide active ingred ients on the initial list to be screened under the EDSP. Accordingly, as part of registrati on review, EPA will issue future EDSP orders/data call-ins, requiring the submissi on of EDSP screening assays for tetramethrin. For further information on the status of the EDSP, the polic ies and procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 screening battery, pl ease visit our website: http://www.epa.gov/endo/

.

Cumulative

The Food Quality Protection Act (FQPA) require s the Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. Tetramethrin is a member of the pyrethroid/pyrethrin co mmon mechanism group ( http://www.regulations.gov ; EPA-HQ-OPP2008-0489-0006). The members of this group share th e ability to interact with voltage-gated sodium channels ultimately leading to neurotox icity. The cumulative risk assessment for the pyrethroids/pyrethrins was published on Nov. 9, 2011 and is available at http://www.regulations.gov ; EPA-HQ-OPP-2011-0746. No cumulative risks of concern were identified allowing the Agency to consider ne w uses for pyrethroid actives. For information regarding EPA’s efforts to evaluate the ri sk of exposure to py rethroids, refer to http://www.epa.gov/oppsrrd1/reevalua tion/pyrethroids-pyrethrins.html

.

Human Studies

The residential exposure assessment for tetr amethrin relied in part on data in the residential exposure SOPs from studies in wh ich adult human subjects were intentionally exposed to a pesticide or other chemical. Many such studies, involving exposure to many different pesticides, comprise generic pestic ide exposure databases such as the Outdoor Residential Exposure Task Force (ORETF) Data base. EPA has reviewed all the studies supporting these multi-pesticide generic expos ure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundame ntally unethical or significantly deficient relative to the ethical st andards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for th e Protection of Hu man Subjects ofPage 9 of 13 Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued
reliance on these studies.

The occupational exposure assessment for tetram ethrin relied in part on data from studies in which adult human subjects we re intentionally expos ed to a pesticide to determine their dermal and inhalation exposure. Many such st udies, involving exposure to many different pesticides, comprise generic pe sticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) and the Agricultur al Reentry Task Force (ARTF) Database. However, recently both the ORETF and AHETF have produced pesticide handler exposure monitoring data that the Agency is using in place of PHED ( http://www.epa.gov/pesticides/sci ence/handler-exposure-data.html ). As more reliable data become available, the Agency will continue to replace existing data and new exposure monitoring data will be incorporated into HED’ s Registration Review assessments as necessary. EPA has reviewed all the studies supporting th ese multi-pesticide generic exposure databases,
and has found no clear and convinc ing evidence that the conduct of any of them was either fundamentally unethical or signifi cantly deficient relativ e to the ethical sta ndards prevailing at the time the research was conducted. All appl icable requirements of EPA’s Rule for the Protection of Human Subject s of Research (40 CFR Part 26) ha ve been satisfied, and there is no regulatory barrier to continue d reliance on these studies.

Environmental Justice

Potential areas of environmental justice concer ns, to the extent possi ble, were considered in the human-health risk assessment, in accord ance with U.S. Executive Order 12898, “Federal
Actions to Address Environmental Justice in Minority Populations and Low-Income Populations,” (http://www.hss.energy.gov/nuclearsa fety/env/guidance/jus tice/eo12898.pdf). The OPP typically considers the highest potential expo sures 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 diet s within the U.S., and people who might be exposed when harvesting cr ops. Should these highest exposures indicate potential risks of concern, OPP further refines th e risk assessments to ensure that the risk
estimates are based on the best available information.

Conclusions/Future Actions Needed

The actions needed in the future Registrati on Review for tetramethrin are listed below.

Hazard Identification an d Endpoint Selection The following studies were required based on th e 2008 tetramethrin risk assessment and have been called-in through the RED GDCI; 870.3700, a rat developmental toxicity study; 870.6200, acute, subchronic, and 870.6300, developmen tal neurotoxicity studies; and 870.7800, an immununotoxicity study. The registrant indicated their intent to conduct or cite the required studies within the time frames provided in th e RED DCI. A recently submitted immunotoxicity study is currently under review.Page 10 of 13 Dietary and Drinking Wa ter Exposure and Risk A dietary exposure assessment is not required. A drinking wa ter exposure assessment is not required.

Residential Exposure and Risk
The residential risk assessment needs to be updated to reflect current policies and SOPs.

Aggregate Exposure and Risk The aggregate exposure assessment is adequate but may need to be reevaluated if PODs change
based on submission and review of newly required toxicity data.

Occupational Exposure and Risk The occupational exposure assessmen t needs updated to reflect curr ent policies and SOPs.

Incident Report In general, a relatively large number of incide nts have been reported involving tetramethrin. Although there is no case reported for products c ontaining tetramethrin present as a single chemical only, human incident data may warrant fu rther analysis for the risk assessment and/or risk management of tetramethrin.

References

Tetramethrin: Risk Assessment for Reregistration E ligibility Decision, B. Daiss, D292298,

6/18/08

Tetramethrin: Phase IV Revised Occupationa l and Residential E xposure Assessment and Recommendations for the Reregi stration Eligibility Decision M. Crowley, D292299, 6/13/08

Revised Drinking Water Assessment for tetramet hrin use as a rapid knockdown agent against flying and crawling insects, I. Abdel-Saheb, D292294, 2/5/08

HED Review of “Evaluation of Potential Human H ealth Risks Associated with Residential Uses of Tetramethrin: Supplemental Assessm ent for Indoor Space Spray” M Crowley
4/27/09

HED Review of “Evaluation of Potential Human H ealth Risks Associated with Residential Uses of Tetramethrin: Revised Supplemental – Shor t-Term Oral Benchmark Dose Analysis” M. Crowley, D372749, 2/25/10

Tetramethrin: Benchmark Dose Analysis of Toxi city Endpoint for Incidental Oral Exposure, B. Daiss, 1/6/09

Pyrethroids: Evaluation of Data from Developmen tal Neurotoxicity Studies and Consideration of Comparative Sensitivity, E. Scollon, D37 1723, 1/20/10

Tetramethrin: Review of Human Incidents. K. Oo, D392272, 8/11/11Page 11 of 13 Re-Evaluation of the FQPA Safety Factor for Pyrethroid Pesticides, E. Scollon, A. Lowit, D381210, 6/27/11

Re-Evaluation of the FQPA Safety Factor for Pyrethroid Pesticides, E. Scollon, A. Lowit, D381210, 6/27/11Page 12 of 13 Attachments

Chemical Identity

Table 1. Tetramethrin Nomenclature

Chemical structure

N

O O O O

Common name Tetramethrin

IUPAC name cyclohex-1-ene-1,2 dicarboximidomethyl (lRS, 3RS; lRS, 3SR)-2,2-dimethyl-3- (2- methylprop-1-enyl) cyclopropane carboxylate

CAS name
CAS registry number 7696-12-0

Summary of Toxicological Points of Departure

Summary of Toxicological Doses and Endpoints for d-Tetramethrin for Use in Dietary and Non-Occupational
Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD,
LOC for Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) An acute RfD for the general population or any po pulation subgroups was not selected because no effect attributable to a single (or few) day(s) oral exposure was observed in animal studies.

Acute Dietary (Females 13-49 years of age) NOAEL =
30 mg/kg/day UF A = 10x

UF H =10x FQPA SF= 10x

UF DB Acute RfD =
0.030 mg/kg/day

aPAD = 0.030 mg/kg/day Developmental Toxicity Study – rabbit
Developmental LOAEL = 100 mg/kg/day based on spina bifida

Chronic Dietary (All Populations) NOAEL=
7.1 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 10x

UF DB Chronic RfD =

0.007 mg/kg/day
cPAD = 0.007 mg/kg/day Chronic Toxicity study in dogs
Chronic toxicity LOAEL = 26.8 mg/kg/day based on hepatocellular enlargement in the liver and focal degeneration in the adrenal
cortex in both sexes.Page 13 of 13 Summary of Toxicological Doses and Endpoints for d-Tetramethrin for Use in Dietary and Non-Occupational
Human Health Risk Assessments

Exposure/
Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD,
LOC for Risk

Assessment Study and Toxicological Effects

Incidental Oral Short-Term (1-30 days) and
Intermediate-Term (1-6 months) BMDL 10 = 100 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF= 10 x

UF DB Residential
LOC for MOE

= 1000 2-generation rat reproduction study. The NOAEL is 1000 ppm (50 mg/kg/day). The LOAEL is 3000 ppm (150 mg/kg/day) based on decreased body weight (4-6%) and increased liver weight in F0 and F1 parental animals, and an increase in absolute and relative spleen weight, and decreased absolute uterine weight in F1 adults and on decreased body weight gain during lactation of F2b pups, and decreased litter size of F1b litters at day 1, decreased absolute heart and kidney weight in F2b males, increased relative liver weight in male and female F2b pups.

Dermal All
Durations Dermal toxicity systemic LOAEL = not established 21/28 Dermal toxicity study in rats dermal toxicity systemic LOAEL not established up to 1000 mg/kg/day (HDT)

Inhalation ShortTerm (1-30 days)
and
Intermediate-Term (1-6 months) NOAEL= 0.104 mg/L (26.6 mg/kg/day) UF A = 10 x

UF H = 10 x FQPA SF= 10 x

UF DB Residential
LOC for MOE

= 1000 90 Day inhalation toxicity study LOAEL = 0.291 mg/L (74.4 mg/kg/day) based on histopathological changes in the nasal
turbinates.

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

Summary of Toxicological Doses and Endpoints for [Chemical] 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 Dermal toxicity systemic LOAEL = not established 21/28 Dermal toxicity study in rats dermal toxicity systemic LOAEL not established up to 1000 mg/kg/day (HDT)

Inhalation ShortTerm (1-30 days)
and
Intermediate-Term (1-6 months) NOAEL= 0.104 mg/L (26.6 mg/kg/day) UF A = 10 x

UF H = 10 x

UF DB = 10 x Occupational LOC
for MOE = 1000 90 Day inhalation toxicity study LOAEL = 0.291 mg/L (74.4 mg/kg/day) based on histopathological changes in the nasal
turbinates.

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dos e-response data and used to mark the beginning of extrapolation to determine risk associat ed with lower environmentally relevant human exposures. NOAEL
= no observed adverse effect level. L OAEL = lowest observed adverse effect le vel. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF DB = to account for the absence of key date (i.e., l ack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic) . RfD = reference dose. MOE = margin of exposure. LOC =
level of concern. N/A = not applicable.