DEET Human Health Risk Assessment DP No

. D413872

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WA S HIN G TON, D.C. 2 0460

MEMORANDUM

Date: February 27

, 2014 OFFICE OF
C H E MI C A L S A F ETY A N D
POLL UTION PREV E NTI ON

SUBJECT: DEET {N,N-diethyl

- meta-toluamide). Revised Human Health Risk Assessment

in Support of Registration Review

.

PC Code: 080301

Decision No.: 481725

Petition No

. : NA DP Barcode: D413872 Registration No.: NA Regulatory Action: Registration Review Risk

Assessment

Risk Assessment T y pe: Single Chemical

TXRNo.: NA CaseNo.: NA

CAS No.: 134

- 62

- 3

MRIDNo.: NA

FROM:

THROUGH:

TO: 40 CFR: NA

Ronnie J

. Bever Jr., PhD

,

# DAB**ij/J ico** **gist ~** **~- .**  Alexandra LaMay, Biologist 

# r jv-**~** ldeliz Negron

- Encarnacion, Ph.

., Chemist

## ~ Risk Assessment Branch V Nil /

Health Effects Division (7509P) 

# Lid /

Michael Metzger, Branch Chief

Wade Britton, Industrial Hygienist 

### lt c.**~~ r------.:** **~** Risk Assessment Branch V Nil

Health Effects Division (7509P)

Susan Bartow, Risk Manager Reviewer

Kevin Costello, Branch Chief

Risk Management and Implementation Branch IV (RMIB IV)

Pesticide Re-Evaluation Division (7508P)

Note: This document was revised to indicate that it represents the scoping and preliminary risk

assessment for DEET.

Page 1 of20DEET Human Health Risk Assessment DP No. D413872

Page 2 of 20 1.0 Executive Summary

................................ ................................ ................................ ........... 3

2.0 HED Recommendations

................................ ................................ ................................ .... 3

2.1 Data D eficiencies: .

................................ ................................ ................................ ........ 3

2.2 Tolerance Considerations

................................ ................................ .............................. 3

2.3 Label Recommendations

................................ ................................ ................................ 4

3.0 Intr oduction

................................ ................................ ................................ ........................ 4

3.1 Chemical Identity

................................ ................................ ................................ ........... 4

3.2 Physical/Chemical Characteristics

................................ ................................ ............... 5

3.3 Pesticide Use Pattern

................................ ................................ ................................ ...... 5

3.4 Anticipated Exposure Pathways

................................ ................................ ................... 5

3.5 Consideration of Environmental Justice

................................ ................................ ...... 6

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ............ 6

4.1 Toxicology Studies Available for Analysis

................................ ................................ ... 6

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

............................... 7

4.2.1 Dermal Absorption

................................ ................................ ................................ ..... 8

4.3 Toxicological Effects

................................ ................................ ................................ ...... 8

4.4 Sa fety Factor for Infants and Children (FQPA Safety Factor)

................................ . 9

4.4.1 Completeness of the Toxicology Database

................................ .............................. 10

4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 10

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

........ 10

4.4.4 Residual Uncertainty in the Exposure Database

................................ ................... 11

4.5 Toxicity Endpoint and Point of Departure Selections

................................ .............. 11

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 11

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 11

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 12

8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 12

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 12

10.0.1 Literature References

................................ ................................ ................................ .. 12

10.0.2 Other References

................................ ................................ ................................ .......... 13 Appendix A. Toxicology Profile

................................ ................................ ................................ 14

A.1 Toxicology Data Requirements

................................ ................................ ................... 14

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 15

A.3 Hazard Identification and Endpoint Selection:

................................ ....................... 18

A.4 Executive Summaries:

................................ ................................ ................................ 18 Appendix B. Metabolism Summary Table:

................................ ................................ ........... 18 Appendix C. Physical/Chemical Properties:

................................ ................................ ......... 18 Appendix D. Review of Human Research

................................ ................................ ................ 19 Appendix E. Endocrine Disruptor Screening Program

................................ ....................... 19DEET Human Health Risk Assessment DP No. D413872

Page 3 of 20 1.0 Executive Summary

HED has prepared a qualitative human health risk assessment to support registration review for

the uses o f DE ET ( N,N

- diethyl

- meta

- toluamide)

. When writing this risk assessment, HED primarily considered the following four documents: (i) The HED Chapter of the Reregistration Eligibility Document (RED) for N,N

- diethyl

- meta

- toluamide (DEET) (Kathleen Martin, 4/22/1997, DEETCH.RED.pdf); ( ii) EPA. R.E.D. Facts (1998, http: //www.epa.gov/oppsrrd1/REDs/factsheets/0002fact.pdf ) ; and (iii ) DEET Summary of Toxicology Data and Hazard Characterization, 4/30/1997).

Every year, approximately one

- third of the U.S. population is expected to use DEET (Veltri, et al., 1994) , as a reside ntial personal insect repellent. Individuals are exposed to DEET primarily

via the dermal route ; however, inhalation is possible when sprays are used and ingestion is possible if hands are not washed after application. Residential e xposure is expected to be typically of a short

- and intermediate

- term duration ; however, long

- term exposure s are possible

for some individuals in some climates. Except for a few veterinary labels, all uses of DEET are

residential . T here are no food uses for DEET ; therefore

, dietary exposure is not anticipated.

The toxicity of DEET has been investigated since the 1940's , and the toxicology database is

extensive. Based on the available toxicological data, the Agency believes that us ing DEET according to the label instructions does not present a health concern to the general U.S. population. T he empirical toxicity testing does not demonstrate significant human toxicity to

DEET.

No data deficiencies were identified for the toxicology or resi dential exposure databases

.

A quantitative risk assessment is not required for DEET. No dietary or occupational exposures are anticipated. R esidential and aggregate were not risks of concern for D EET , due to the lack of

hazard.

2.0 HED Recommendations

HED has no objection for continued registration of the current DEET pesticide products.

2.1 Data Deficiencies : None

.

2.2 Tolerance Considerations

DEET is not a food

- use chemical. There are no US tolerances established for DEET.DEET Human Health Risk Assessment DP No. D413872

Page 4 of 20 2.3 Label Recommendations

On September 3, 1991, EPA issued label improvement statements (i.e., PR 91

- 4) to decrease the

likeli hood of adverse health e ffects from possible misuse or overuse of DEET products. Among the required statements are: "do not spray in enclosed areas;" "do not apply to eyes and mouth and do not apply to the hands of young children;" "do not spray directly on face;" and "after returning indoors, wash treated skin with soap and water." HED has no further label

recommendations at this tim e.

3.0 In troduction

DEET is a widely used personal insect repellant that can be applied directly to the skin of adults

and children. The structure, chemical names, and other identifiers are found in the chemical identity table below.

3.1 Chemical Identity

Table 3.1 Test Compound Nomenclature.

Compound Chemical Structure

Common name DEET

IUPAC name N,N

- Diethyl

- 3

- methylbenzamide

CAS name N,N

- Diethyl

- 3

- methylbenzamide

CAS # 134

- 62

- 3

PC Code 080301

End

- use product/(EP) Not applicableDEET Human Health Risk Assessment DP No. D413872

Page 5 of 20 3.2 Physical/Chemical Characteristics

Table 3.2 Physicochemical Properties of DEET 1

Parameter Value Reference
Boiling point 285 °C
pH 6.7 (in 1% distilled water) 45163501 Density 0.998 g/mL Water solubility ( 25°C) 9.04 mg/mL 45163503

Solvent solubility (g/100mL at 25°C) Soluble in acetone, ethanol, isopropanol, heptanes, toluene, mineral spirits, vegetable oil

, and triethyl citrate at 25/75, 50/50/ and 75/25 ratios. 45163501

Octanol/water partition coefficient Log(K OW ) 2. 5 45163503

UV/visible absorption spectrum 200

- 225 nm (10 ppm DEET in methanol) 45163502

1 Product Chemistry Review: TGAI; Paul Homg; D276463, D274018, D270354

, and D262310; 07/26/2001.

3.3 Pesticide Use Pattern

DEET is an insect repellent used in households/domest ic dwellings, on the human body and clothing being worn, on cats, dogs, horses and pet living/sleeping quarters. There are no food

uses. It is used to repel flies, midges, black flies, chiggers, deer flies, fleas, gnats, horse flies, mosquitoes, no

- see

- u ms, sand flies, small flying insects, stable flies, and ticks. In 1998 it was estimated that about 30% of the US population uses DEET annually (K. Martin, DEET RED, 4/22/1997). DEET can be applied on clothing or directly on the skin.

Currently, there are 123 active registrations for DEET: 15 correspond to co

- formulations with MGK 326 and MGK 264, 10 formulations with sunscreen and 1 registration for use on horses. The products are available as aerosol sprays (44), pump sprays (38), impregnated materia ls (15), and ready to use solutions/emulsifiable concentrates (25) with conce ntratio ns of DEET ranging from approximately 4% to 100 %. The products can be used either by adults or children single or multiple times per day.

3.4 Anticipated Exposure Pathways

DEET is only applied directly to the human body/clothing, cats, dogs, pet quarters and household/domestic dwellings. Dermal exposure it is anticipated to be the primary route of exposure; however, inhalation is possible when sprays are used and ingestion is possible if hands are not washed after application. Because of its use pattern, people are not normally exposed to residues of DEET through the diet. Because the majority of DEET products are ready

- to

- use and

based on DEET’s residential use pattern, mixers and loaders are not exposed to DEET; only applicators are exposed.DEET Human Health Risk Assessment DP No. D413872

Page 6 of 20 3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, will be considered in

future human health risk assessm ents for DEET, 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

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to

well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patte rns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, seaso n of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- diet ary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas

post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characteriz ation and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database on DEET is sufficient for the assessment of toxicity and characterizing

the hazard of DEET

. The toxicology studies for DEET are summarized in Appendix A.

Several guideline and open literature toxicity studies are available for DEET; however, endpoints for risk assessment have not been selected for DEET. This decision was supported by the FIFRA Scientific Advisory Panel (Ju ne 4, 1997): “The Panel agrees with the Agency’s hazard characterization and decision not to establish toxicity endpoints to be used for risk assessment, as exposure to DEET does not result in clearly specific toxicological responses; to rationally choose toxicity endpoints that reflect a consistent response to DEET would be impossible.”DEET Human Health Risk Assessment DP No. D413872

Page 7 of 20 Since the last risk assessment was performed in 1997, several acute 6

- pack studies have been submitted. Additionally, the following studies were submitted: Pharmacoki netics and Comparative Dermal Absorption Study of N,N Diethyl

- m

- Toluamide (DEET) in the Rat (MRID 44783301), and Blood Level Study in Rats Following Single and Repeated Dermal Applications of N,N

- Diethyl

- m

- Toluamide (DEET; MRID 45041603). These studies ar e not expected to change the conclusions of the SAP.

Several studies were found in the open literature suggesting that dermal exposure may result in neurotoxicity in rats. These studies are listed in the Reference Section 10.0 below. On June 7, 2012, HE D’s Hazard Science Policy Council (HASPOC) reviewed these published reports (July 31, 2012, TXR # 0056346) in consultation with the Office of Research and Development (ORD).

The HASPOC concluded that these studies do not contribute high quality scientific information

useful for human risk assessment and thus do not suggest that the Agency’s current experimental toxicology database is insufficient for evaluating potential hazard to humans.

The database includes the following toxicity studies (some of whi ch were considered Unacceptable/Guideline) :

 Subchronic: 90

- day dermal toxicity in rats and micropigs, 90

- day feeding in rats, mice,

and hamsters , 8

- week feeding in dogs, 8

- week capsule in dogs

 Developmental toxicity: developmental toxicity in rat s and rabbits

 Reproduction: 2

- generation reproduction study in rat s

 Chronic : combined oral chronic toxicity/carcinogenicity in rat s , carcinogenicity in mice, chronic oral toxicity in dog s

 Neurotoxicity: acute neurotoxicit y in rat s, neurotoxicity screening with in utero exposure until the age of 9 months (in rats)

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The absorption, distribution, metabolism, and eliminatio n (ADME) of DEE T have been examined in rats following both oral and dermal administration with varying dose levels and durations of treatment (MRID s 41994401 and 41994402). I t was demonstrated that DEET is rapidly absorbed, metabolized, and excreted in the urine. Peak blood levels were reached within

0.5 hour in males and 2 hou rs in females following oral administration, while after dermal dosing levels reach a plateau lasting 1.5

- 24 hours post

- dose . Approximately 53

- 62% of the orally administered dose (AD) was absorbed. After 7 days, less than 0.7% AD remained in the body.

T he major route of elimination was the urine. In a human dermal absorption study (MRID 42578501), e ssentially all of the absorbed DEET was metabolized prior to elimination and

excreted in the urine (6

- 8% AD), while <0.1% AD was isolated in the feces. Ther e were two major metabolites found in the urine. One derived from the oxidation of the ring methyl group

of DEE T

, while the other was the product of N

- dealkylation of an ethyl group of the diethylamide moiety and the oxidation of the ring methyl group. F our minor metabolites were

also noted.DEET Human Health Risk Assessment DP No. D413872

Page 8 of 20 4.2.1 Dermal Absorption

In a human dermal absorption study (MRID 42578501), the dermal absorption was conservatively estimated to be 20% of the administered dose (AD) of a 15% DEET solution and

12% of the AD for und iluted DEET.

4.3 Toxicological Effects

DEET may bind to olfactory receptors of insects, interfer ing with their normal feeding response. DEET serves as a true repellent in that some insects intensely dislike the smell of the chemical repellent (Z. Syed, 2008)

.

Reduced body weight was a common finding among species and the various toxicity tests. Liver weight increases were noted in some studies, but there were no accompanying microscopic lesions. Tremors in dogs and reduced activity in rat s were observed. Testis and epididymides degeneration was reported in hamsters. DEET induced α2μ

- globulin kidney lesions that are specific to male rats and are not relevant to human health. There is no mutagenicity concern for

DEET (TXR No. 011831, repo rt dated January 4, 1996) , and it was classified as Category D ("Not Classifiable as to Human Carcinogenicity") for carcinogenicity. Increased sensitivity was not observed in the offspring ; and evidence of neurotoxicity was considered to be of negligible biological significance . Technical grade DEET is of low acute toxicity: Category III for oral and dermal toxicity and eye irritation; Category IV for inhalation toxicity and dermal irritation.

DEET is not a dermal sensitizer.

In subchronic oral toxicity studies in rats (MRIDs 42518101 and 40241703), mice (MRID 40241704), and hamsters (MRID 41344101), notable responses to treatment include decreased body weight, body weight gain, and/or food consumption. Other findings in rodents included

renal l esions in male rats associa ted with α2μ

- globulin, increased incidences of small testes and epididymides with degeneration and cellular debris in hamsters, and increased liver weight without corroborating histological evidence of an adverse effect in mice a nd rats. In dogs (MRIDs 43514201 and 43514202), there was body weight loss and decreased organ weights, due to rejection of the diet in the feeding study. When DEET was administered to dogs in c apsules, pytalism was observed in both sexes and a bnormal he ad movements in males; and decreased body weight in both sexes, cholesterol in males, and food consumption in females. Decreased testes and epididymides weights were noted (without corroborating gross or histological pathology), but were not observed at t he same dose in the chronic study.

In the combined chronic oral toxicity/carcinogenicity study in rats (MRID 43514203) , findings included decreased body weight and food consumption and increased cholesterol in females. The chronic oral toxicity study i n mice (MRID 41351501) demonstrated decreased body weight, body weight gain, and food consumption in both sexes. When DEET was administered to dogs (MRID 43320101) in capsules, the following findings were observed: increased ptyalism, tremors, platelets (females only), and hyperplasia of the uterine epithelium; and decreased body weight in both sexes , food consumption in both sexes (with associated thin appearance), and cholesterol ( males only, rather than the increase seen in rats).DEET Human Health Risk Assessment DP No. D413872

Page 9 of 20 In a 90

- day derm al study in rats (MRID 40241703 and 40241702) , systemic effects included decreased body weight in males and increased liver weight in both sexes ; α2μ

- globulin nephropathy was noted in male rats. Local site of application effects included acanthosis and hyperkeratosis. In a 90

- day dermal study in micropigs (MRID 4 1344101 ), systemic effects were not observed; acanthosis and/or hyperkeratosis were noted at the skin application site.

Limited inhalation toxicity data are available from studies conducted by the US Army. These studies do not indicate an inhalation hazard. Further inhalation toxicity information for registration review purposes is not needed at this time.

Several studies were found in the open literature sugg es ting that dermal exposure may result in neurotoxicity in rats. These studies are listed in the Reference Section 10.0 below. On June 7, 2012, HED’s Hazard Science Policy Counc il (HASPOC) reviewed these published reports (July 31, 2012, TXR # 0056346) in consultation with the Office of Research and Development (ORD).

The HASPOC concluded that these studies do not contribute high quality scientific information

and thus do not su ggest that the Agency’s current experimental toxicology database is insufficient for evaluating potential hazard to humans.

In Aggregate IDS (S. Recore, D402939) , from January 1, 2007 to February 22, 2012, there were 2769 reported incidents involving DEE T resulting in low severity outcomes. For the Main IDS, from January 1, 2007 to February 22, 2012, there are 387 exposures reported for single chemical only in the database (382 exposure classified as resulting in a moderate severity, 4 classified as majo r severity and 1 classified as an undetermined severity). DEET is not included in the AHS, and therefore this study does not provide information for this report. Overall, a high absolute number of incidents have been reported involving DEET. Although th e vast majority of these incidents were of low severity, several high severity outcomes are reported in the IDS database. It is important to note, however, that there are a large number of users of DEET ( approximately 104 million, based on the estimated u se rate in 1984

- 1989 provided by Veltri , 1994)

. One possible explanation for the seizures in children is coincidence. Seizure coinciding with DEET is not unexpected, given an estimated 15,000

- 20,000 afebrile seizures in children (ages zero

- 19 years) estim ated annually and an estimated 17 million children using DEET 10 times a year.

W hile incident information can be an important source of feedback to the Agency, reports of adverse health effects allegedly due to a specific pesticide exposure (i.e., an “incident”) are largely self

- reported and therefore, generally speaking, neither expo sure to a pesticide or reported symptom (or the connection between the two) is validated or otherwise confirmed. Typically, causation cannot be determined based on incident data. Since the last incident summary was only recently completed, a revised summ ary is not required at this time. As data warrant, preparation of an updated assessment may be considered in the future.

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

DEET does not require food tolerances and is considered to be a ‘ non

- food use’ chemical; therefore, it is not subject to the amendments to the Federal Food, Drug, and Cosmetic Act (FFDCA) promulgated under the Food Quality Protection Act (FQPA) of 1996.DEET Human Health Risk Assessment DP No. D413872

Page 10 of 20 4.4 .1 Completeness o f the Toxicology Database

The toxicological d atabase on DEET is adequate and will support re

- registration eligibility.

Based on a weight

- of

- evidence ( WOE ) approach and considering all of the available DEET hazard and exposure informatio n, the HASPOC recommended that subchronic dermal toxicity, subchronic inhalation toxicity , and immunotoxicity stud ies are not required (Kristin Rury,

7/31 /2012, 080301.haspoc.docx; Kristin Rury, 9/3 /2013, 080301.haspoc.docx )

.

4.4.2 Evidence of N eurotoxicity

There are both acute and subchronic neurotoxicity studies in rats. The acute study (MRID 41368501) demonstrated transient signs (recovery within 24 hours) that included piloerection, increased vocalization, decreased horizontal and vertical activity, and increased response to heat. The subchronic neurotoxicity study was derived from a rat multi

- generation reproduction study (MRID 41368401) and had both in utero and post

- natal exposure. Transiently increased motor activity was observed in this study.

The Agency's Office of Pesticide Programs (OPP) Health Effects Division Toxicity Endpoint Selection (TES) Committee considered subchronic dermal and neurotoxicity data for the short

and intermediate

- term endpoint on October 18, 1995

. The TES Committee d etermined that the possible neurotoxic effect in the two neurotoxicity screening studies was not robust enough to provide an adequate basis for risk assessment for the following reasons: (1) the increase in horizontal activity seen in the 225 mg/kg/day dos e of the subchronic toxicity was transient with significance only at the first measuring period; (2) the effect was not accompanied by any clinical signs or histopathological changes; and (3) the magnitude of the effect was small.

Although abnormal head movement s were noted in the 400 mg/kg/day males only from the

8

- week oral (capsule) dog study (MRID 43514201), this is a relatively large, bolus dose that does not occur through dermal application.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the De veloping o r Young Animal

DEET did not demonstrate increased sensitivity to offspring in the rat and rabbit developmental toxicity studies. In the rat developmental toxicity study (MRID 41351401), maternal toxicity was noted following gavage doses of 750 mg/kg/day, included clinical signs (hypoactivity, ataxia, decreased muscle tone, foot splay, perinasal encrustation, and perioral wetness), decreased body weight and food consumption, increased mortality, and increased liver weight. On Day 7, 2/25 animals were sacrificed in extremis and gross necropsy revealed stomach ulceration (possibly a localized, irritant effect). Th ese sacrifices occurred following an oral gavage dose of 750 mg/kg/day, which is a bolus dose that is not comparable to the current

derm al dose

. At th is same dose, there was a slight increase in post

- implantation loss and

decrease in fetal body weight. An oral rabbit developmental toxicity study (MRID 42141101) did not indicate either definite maternal or fetal effects at the highest dos e tested. The rat multi

generational reproduction study (MRID 40979001) demonstrated systemic effects in the pups (decreased body weight); a concern for increased susceptibility was not indicated, because kidney effects were seen in all treated males.DEET Human Health Risk Assessment DP No. D413872

Page 11 of 20 4.4.4 Residual Uncertainty in the Exposure Database

No quantitative risk assessment was performed; therefore, there are no residual uncertainties.

4.5 Toxicity Endpoint and Point of D eparture Selections

Toxicity endpoints and point of departure selections were not selected . A qualitative toxicity assessment is appropriate for DEET. This decision was supported by the FIFRA Scientific Advisory Panel (June 4, 1997): “The Panel agrees with the Agency’s ha zard characterization and decision not to establish toxicity endpoints to be used for risk assessment, as exposure to DEET does not result in clearly specific toxicological responses; to rationally choose toxicity endpoints that reflect a consistent respon se to DEET would be impossible.”

Since the last risk assessment was performed in 1997, several acute 6

- pack studies have been submitted. Additionally, the following studies were submitted: Pharmacokinetics and Comparative Dermal Absorption Study of N, N Diethyl

- m

- Toluamide (DEET) in the Rat (MRID 44783301), and Blood Level Study in Rats Following Single and Repeated Dermal Applications of N,N

- Diethyl

- m

- Toluamide (DEET; MRID 45041603). These studies are not expected to change the conclusions of the SAP.

5.0 Dietary Exposure and Risk Assessment

As an active ingredient, there are no food uses for D EET

.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

DEET is registered f

or use as an insect repellent , and for use on clothing or directly on the skin. There are also registered DEET

- impregnated products, such as tablecloths. DEET products are available in multiple formulations, including aerosol sprays, creams, lotions, and in multiple

concentrations. Exposures to DEET may occur from delibe rate application to the sk in and clothing of individuals. Repellent

- use can be on the order of days or weeks or longer, depending on the activity pattern and geographic area. Exposure is expected to be of short

- and

intermediate

- term exposure duration ; however, long

- term exposures are possible for some

individuals in some climates.

Insect repellents are used on people of all ages. Adults are assumed to experience both dermal and inhalation handler exposure s , as well as post

- application dermal and, potentially, inhalation

exposure. Adults are assumed to apply repellents to themselves or to others. Additionally , for aerosol repellents, individuals to whom the products are being applied can experience indirec t inhalation exposure during the application. For children, post

- application exposure consists of dermal, (potentially) inhalation, and hand

- to

- mouth exposure. An exposure assessment was previously prepared to support the Registration Eligibility Decisio n (RED). A new Standard Operating Procedure for Residential Pesticide Exposure Assessment (February 2012, http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html) is now available for the exposure assessment of insect repellents. However, sin ce no endpoints have been identified forDEET Human Health Risk Assessment DP No. D413872

Page 12 of 20 DEET (1997 RED), a quantitative exposure and risk assessment for DEET products is not required at this time.

The residential exposure database is adequate to support the registration review process for

DEET. An updated residential exposure assessment is not required as a quantitative exposure and risk assessment is not required

.

7.0 Aggregate Exposure/Risk Characterization

As quantitative dietary and residential exposure assessments are not required for DEET , a

qua ntitative aggregate assessment is not required either. Based on the low hazard associated

with D EET , HED concludes that aggregate risks are not of concern.

8.0 Cumulative Exposure/Risk Characterization

The Agency has not determined that DEET shares a common mechanism of toxicity with other chemical substances; therefore, a cumulative risk assessment to support registration review is not required at this time

.

9.0 Occupational Exposure/Risk Characterization

T here is no occupational exposure associated with DEET; therefore, a quantitative assessment is not required.

10.0 .1 Literature References

Abdel

- Rahman, AK Shetty and MB About

- Donia (2001) Subchronic dermal applicatio n of
N,N

- diethyl m

- toluamide (DEET) and permethrin to adult rats, alone or in combin ation, causes diffuse neuronal cell death and cytoskeletal abnormalities in the cerebral cortex and the hippocampus, and Purkinje neuron loss in the cerebellum. Experiment al Neurology

172:153

- 171.

Abdel

- Rahman, A, Dechkovskaia AM, Goldstein LB, Bullman S H, Khan W, El

- Masry EM, MB

Abou

- Donia (2004) Neurological deficits induced by malathion, DEET, and permethrin, alone and in combination in adult rats. J. Toxicology and Environ. Health. Part A. 67:331

- 356.

Abou

- Donia MB, Goldstein LB, Dechovskaia A, Bull man S, Jones KH, Herrick EA, Abdel

Rahman AA, Khan WA (2001) Effects of daily dermal application of DEET and permethrin, alone and in combination, on sensorimotor performance, blood brain barrier, and blood

- testis barrier in rats. J. Toxicology and Enviro nmental Health, Part AL Current Issues 62(7):523

- 541.

Abou

- Donia, MB, Goldstein LB, Jones KH, Abdel

- Rahman AA, Damodaran TV, Dechkovskaia AM, Bullman SL, Amir BE, Khan WA (2001) Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigime bromide, DEET, and permethrin, alone and in combination. Toxicological Sciences 60:305

- 314.DEET Human Health Risk Assessment DP No. D413872

Page 13 of 20 Fediuk DJ, Wang T, Raizman, JE, Parkinson FE Gu X (2010) Tissue deposition of the insect repleent DEET and the sunscreen oxybenzone from repeated ski n applications in rats. Int. J. Toxicol 29(6):594

- 603.

Jortner BS (2006) The return of the dark neuron. A histological artifact complicating contemporary neurotoxicological evaluation. NeuroToxicology 27: 628

- 634.

Keil DE, McGuinn WD, Dudley AC, EuDa ly JG, Gilkeson GS, Peden

- Adams MM.
N,N,

- diethyl

- m

- toluamide (DEET) suppresses humoral immunological function in B6C3F1 mice. Toxicol Sci. 2009 Mar;108(1):110

- 23. doi: 10.1093/toxsci/kfp001. Epub 2009 Jan 13. PubMed PMID: 19141786.

Peden

- Adam MM, Eudaly J , Eudaly E, Dudley A, Zeigler J, Lee A, Robbs J, Gilkeson G, Keil DE. Evaluation of immunotoxicity induced by single or concurrent exposure to N,N

- diethyl

- m

- toluamide (DEET), pyridostigmine bromide (PYR), and

JP

- 8 jet fuel. Toxicol Ind Health. 2001 Jun;17(5

- 10):192

- 209. PubMed PMID:

12539864.

Van Haaren FV, Haworth SC, Bennett SM, Cody BA, Hoy JB, Karlix JL, Tebbett IR (2001). The effects of pyridostigmine bromide, permethrin and DEET alone, or in combination, on fixed

ratio and fixed

- interval beha vior in male and female rats. Pharmacology, Biochemistry and

Behavior 69:23

- 33.

10.0.2 Other References

Kathleen Martin; The HED Chapter for the Reregistration Eligibility Decision Document (RED) for N,N

- diethyl

- meta

- toluamide (DEET) (Case 0002; PC Code 080301), 04/22/1997.

Martin, K. 1997. The HED Chapter of the Reregistration Eligibility Document (RED) for N,N

diethyl

- meta

- toluamide (DEET) (Case 0002; PC Code 080301)

Shanna Recore; Revised DEET: Review of Human Incidents; D402939 or D401139, 06/19/2 012.

Steven M. Knott, OREB Exposure Assessment and Recommendations for the Reregistration Eligibility Document (RED) for DEET, 09/22/1995.

Syed Z. and Leal, W.S. 2008. Mosquitoes smell and avoid the insect repellent DEET, Proceedings of the National Aca demy of Sciences of the United States of America, June 12,

2008.

Veltri, J.C., Osimitz, T.G., Bradford, D.C., and Page, B.C. 1994. Retrospective analysis of calls to Poison Control Centers resulting from exposure to the insect repellent N,N

- diethyl

- m

toluamide (DEET) from 1985

- 1989. Clinical Toxicology, 32(1):1

- 16.DEET Human Health Risk Assessment DP No. D413872

Page 14 of 20 Appendix A. Toxicology Profile

A.1 Toxicology Data Requirements
The requirements (40 CFR 158.340) for non

- food use for DEET are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

................................ .................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ .............. 870.3150 Oral Subchronic (non

- rodent)

................................ ....... 870.3200 21/28

- Day Dermal

................................ ........................ 870.3250 90

- Day Dermal

................................ ............................. 870.3465 90

- Day Inhalation

................................ ......................... yes

yes

no

yes

no yes

no c

N/A

yes a

N/A

870.3700a Developmental Toxicity (rodent)

................................ . 870.3700b Developmental Toxicity (non

- rodent)

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

................................ ................................ yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ ............. 870.4100b Chronic Toxicity (non

- rodent)

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

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

................................ .................. 870.4300 Chronic Toxicity / Carcinogenicity

................................ yes

yes

yes

yes

yes yes

yes

yes

yes

no c

870.5100 Mutagenicity

— Gene Mutation

- bacterial

.................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

............... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.. 870.5395 Mutagenicity

— Other Genotoxic Effects

...................... yes

yes

yes

yes yes

no b

yes

yes

870.6100a Acute Delayed Neurotox icity (hen)

.............................. 870.6100b 90

- Day Neurotoxicity (hen)

................................ ......... 870.6200a Acute Neurotox icity Screening Battery (rat)

................ 870.6200b 90 Day Neurotox icity Screening Battery (rat)

.............. 870.6300 Develop mental Neuro toxicity

................................ ...... no

no

yes

yes

no no

no

no c

yes N/A

870.7485 General Metabolism

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

................................ ....................... 870.7800 Immunotoxicity in Rats..................................... yes

yes

yes yes

yes

yes a

a This r equirement was waived by HASPOC

. b There are mutagenicity studies which evaluate both somatic and germinal cells, which is considered sufficient to satisfy CFR requirements.

c The 870.3150 study was not submitted. The 870.4300 study was found to be acceptable/guideline in females only, because an adverse effect was not noted in males. The 870.6200b study was classified as acceptable/nonguideline. Considering the totality of the toxicological database, no additional studies are necessary. HASPOC indicated no further data requirements in July 2012. N/A = Not Applicable NR = Not RequiredDEET Human Health Risk Assessment DP No. D413872

Page 15 of 20 A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile

- DE ET

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [ rat ] 00134359

43763201 LD 50 = 2170 to

3664 mg/kg III

870.1200 Acute dermal [ rabbit ] 00134359 LD 50 = 4280 mg/kg III

870.1300 Acute inhalation [ rat ] 00134359 LC 50 = 5.95 mg/L IV

870.2400 Acute eye irritation [ rabbit ] 00134359 Eye irritation and

corneal opacity cleared by day seven and three, respectively III

870.2500 Acute dermal irritation [ rabbit ] 00134359 Minimal irritation

cleared by day

seven. IV

870.2600 Skin sensitization 00134359 Minimal irritation

cleared by day

seven ---

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ TXR #/

Classification /Doses Results

870.1500 Subchronic oral

–

non

- rodent (dog/dietary) 43514202 (1995)

TXR # 0011625 Unacceptable
0, 300, 1000, 3000, or 6000/4500/3000 ppm (equivalent to 0, 8.4, 28.6, 93.3, or 19.5 mg/kg/day in males or
0, 9.7, 30.6, 91.8, or 11.5 mg/kg/day in females) No effects at 3000 ppm or less. The 6000/4500/3000 ppm dose group demonstrated food rejection with associated body weight and organ weight decreases; thin appearance; fat depletion; and histological alterations in the kidneys (vacuolation of tubules in the cortex), b one marrow, and thymus.

Reliability compromised because only two dogs/sex.

870.1500 Subchronic oral

–

non

- rodent (dog/capsule) 43514201 (1995)

TXR # 0011625 Unacceptable
0, 50, 100, 200, or 400 mg/kg/day NOAEL = 50 mg/kg/day.

LOAEL = 100 mg/kg/day, based on ptyalism. At 400 mg/kg/day, decreased body weight in both sexes

, food consumption in females

, cholesterol in males , and testis/ epididymides weight (no associated gross or histopathology) and abnormal

head movements in males

. 870.3100 Subchronic oral

–

rodent (rat) 40241703 (1987)

TXR # 0006599 NOAEL = 500 mg/kg/day LOAEL = 1000 mg/kg/day, based onDEET Human Health Risk Assessment DP No. D413872

Page 16 of 20 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ TXR #/

Classification /Doses Results
Acceptable/Non

- Guideline
0, 100, 500, 1000, 2000 or 4000 mg/kg/day body weight and food consumption

decreases. (Note: kidney effects at all doses and mortality at 4000 mg/kg/day).

870.3100 Subchronic oral

–

rodent (rat) 42518101 (1992)

TXR # 0010528 and 0012510 Unacceptable but Acceptable/Non

- guideline 0 or 400 mg/kg/day in males of

three different rat strains Kidney lesions in the CD and Fischer

strains. The NBR strains did not develop the kidney lesions. Note: p. 6 of the DER shows that the

Fischer and CDR strains have the hyaline droplets and the regenerative

tubules.

870.3100 Subchronic oral

–

rodent (hamsters) 41344101 (1989)

TXR # 0007833 Acceptable/Guideline
0, 61, 305, 624, or 940 mg/kg/day NOAEL = 61 mg/kg/day. LOAEL = 305 mg/kg/day, based on decreased food consumption and body weight. Gross (small appearance) and histological alterati ons (degeneration or cellular debris) in the testis and epididymides at higher doses. At 940 mg/kg/day, there was mortality. No

indication of renal lesions.

870.3100 Subchronic oral

-

rodent (mouse) 40241704 (1987)

TXR # 0006599

Not classified
0, 3 00, 1000, 3000, 6000, or 10,000 mg/kg/day NOAEL < 300 mg/kg/day, based on slight increase in liver weight. At higher doses, there was decreased body weight and food consumption.

870. 3200 Subchronic dermal

(rat) 40241702 (1987)

TXR # 0006599 Unacceptable 0, 100, 300, or 1000 mg/kg/day Kidney effects at all doses. NOAEL = 100 mg/kg/day LOAEL = 300 mg/kg/day, based on increased liver weight. At higher doses, decreased body weight.

870. 3200 Subchronic dermal

(rat, castrated males) 41199301 (1989)

TXR # 0007740 Unacceptable 0 or 1000 mg/kg/day Castration did not prevent the

formation of renal lesions characteristic of the α2μ

- globulin

model.

870. 3200 Subchronic dermal

(micropigs) 44100309 (1996)

TXR # 0012685 and

0029294 Acceptable/Guideline 0, 100, 300, or 1000 mg/kg/day NOAEL > 1000 mg/kg/day

(Lesions at the site of application noted.)

870.3465 Subchronic

inhalation (dog and rat) 1979 studies (MRID #s

00137973 (with dogs) and 00137975 (with rats) are in the bibliogr aphy no DERs could be

found.

Studies would not meet current guidelines. Available study reports are not easily readable. Reports appear to be for the pathology sections only. Only 2 dogs or rats per sex assessed.

870.3700 Developmental

(rat) 41351401 (1990)

TXR # 0008117 Acceptable 0, 125, 250, or 750 mg/kg/day Maternal: NOAEL = 250 mg/kg/day (slight increase in liver weight). LOAEL = 750 mg/kg/day, based onDEET Human Health Risk Assessment DP No. D413872

Page 17 of 20 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ TXR #/

Classification /Doses Results
clinical signs (hypoactivity, ataxia, foot splay, perinasal encrustation, and perioral wetness), reduced body weight and food consumption, increased mortality, and increased liver weight. Developmental: NOAEL = 250 mg/kg/day. LOAEL = 750 mg/kg/day, based on slight increase in percent post

implantation loss and decrease in fetal body weigh t.

870.3700 Developmental

(rabbit) 42141101 (1991)

TXR# 0009470 and 0012510

Not classified. Upgraded to Acceptable), 30, 100, or 325 mg/kg/day. No maternal or developmental effects

at HDT.

870.3800 Multi

- generation

reproduction (rat) 40979001 (1989)

44100304 (1996)

TXR # 007645 Acceptable/Guideline 0, 500, 2000, or 5000 ppm. Parental systemic: (Kidney effects at all doses) Reproductive: NOAEL > 5000 ppm Offspring: NOAEL = 500 ppm LOAEL = 2000 ppm, based on reduction in body weights for male pups starting on Day 7 for males and Day 14 for females.

870.4100 Chronic oral

(dog/capsule) 43320101 (1994)

TXR # 0011630 Acceptable/Guideline 0, 30, 100, or 400 mg/kg/day NOAEL = 100 mg/kg/day LOAEL = 400 mg/kg/day, based on ptyalism; tremor; decreased food intake, body weight, and cholesterol; thin appearance; increase in platelet levels (females only); and hyperplasia in uterine epithelium.

870.4200 Carcinogenicity

(mouse) 41351 501 (1990)

TXR # 0008117 Acceptable/Guideline 0, 250, 500, or 1000 mg/kg/day NOAEL = 500 mg/kg/day LOAEL = 1000 mg/kg/day, based on decreased body weight, body weight gains, and food consumption.

870.4300 Combined chronic

toxicity/ carcinogenicity (rat) 43514203 (1995)

TXR # 0011625 Acceptable/Guideline for females, but males were dosed

too low. 0, 10, 30, or 100 mg/kg/day NOAEL = 30 mg/kg/day for females, > 100 mg/kg/day for males. LOAEL = 100 mg/kg/day for females, based on decreased body weight and food consumption; and increased

cholesterol levels. Not established for

males.

No evidence of carcinogenicity.

870.5100 Mutagenicity

–

Ames test. 41344801 (1989)

TXR # 0008111 Acceptable/Guideline No evidence of mutagenicity.

870.5375 Chromosome 41344401 (1989) No evidence of induced chromosomeDEET Human Health Risk Assessment DP No. D413872

Page 18 of 20 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No. Study Type MRID No. (year)/ TXR #/

Classification /Doses Results

aberration in CHO

cells TXR # 0008111

Acceptable/Guideline aberrations.

870.5550 Unscheduled DNA

synthesis 41344301 (1989)

TXR # 0008111 Acceptable/Guideline No evidence of unscheduled DNA synthesis.

870.6200a Acute

neurotoxicity (rat) 41368501 (1990)

TXR # 0009829 Acceptable/Guideline 0, 50, 200, or 500 mg/kg/day. NOAEL = 50 mg/kg/day. LOAEL = 200 mg/kg/day, based on decreased vertical activity one hour

a fter dosing. At 500 mg/kg/day, piloerection, increased vocalization,

decreased horizontal and vertical activity, and an increased response

time to heat.

870.6200b Subchronic

neurotoxicity (rat) 44100307 (1996)

TXR # 0009829 Acceptable/Non

- Guideline.

0 , 500, 2000, or 5000 ppm. NOAEL = 2000 ppm. LOAEL = 5000 ppm, based on increased motor activity.

870.6300 Developmental

neurotoxicity No Study [Some aspects of a developmental toxicity study were evaluated in the neurotoxicity subgroup in the rat

multi

- generation reproduction study, but only in adults. The study does not have protocol consistent with the DNT study protocol.]

870.7485 General

metabolism (rat) 41994401 (1990)

41994402 (1991) 41994403 (1991)

TXR # 0009065 Absorption, distribution, elimination,

and metabolite identification/quantification was investigated. These studies satisfy the requirement for a general metabolism

stu dy.

870.7600 Dermal absorption

(humans) 42578501 (1995)

TXR # 0010587

[Selim, S, et al, FAP Toxicology, 25 :95

- 100] Dermal absorption factors of 20% for a fifteen percent formulation and 12%

for undiluted DEET.

A.3 Hazard Identification and Endpoint Selection: Only a qua l itative assessment was performed for DEET.

A.4 Executive Summaries: Please refer to the DEET Summary of Toxicology D ata and Hazard Characterization (April 30, 1997).

A ppendix B. Metabolism Summary Table : This table is not neces sary for DEET, considering its use profile.

Appendix C. Physical/Chemical Properties: These properties were provided in Section 3.2

above.DEET Human Health Risk Assessment DP No. D413872

Page 19 of 20 Appendix D. Review of Human Research

A dermal absorption study with human volunteers (1992, MRID 42578501) involving intentional exposure to DEET was relied on in earlier assessments to provide the dermal absorption factor. This study was reviewed by the OPP Human Research Ethics Reviewer (report dated July 6, 2012) and there is "no barrier in law or regulati on to its being relied upon in actions under FIFRA or §408 of FFDCA". If EPA decides to use any other studies with human volunteers, EPA will ensure that all applicable regulatory requirements are met, including, but not limited to, the requirements for E PA ethics review and Human Studies Review Board review of certain research involving intentional exposure of human subjects.

Appendix E

. Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potentia l adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studie s include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As required by FFDCA section 408(p ), DEET is subject to the endocrine screening pa rt of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “nat urally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the p otential of a chemical substance to interact with 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 systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- re sponse relationship between the dose 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 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some pesticides scheduled for Registration Review and chemicals found in water

. For further information on the status of the EDSP, the policies and procedures, the list s of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website. 2

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

2 http://www.epa.gov/endo/DEET Human Health Risk Assessment DP No. D413872

Page 20 of 20 In the interim, EPA is making no human health or enviro nmental safety findings associated with the EDSP screening of DEET

. Before completing this Registration Review, the Agency will make an EDSP FFDCA section 408(p) determination.